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Background: Vilobelimab, an anti-C5a monoclonal antibody, was shown to be safe in a phase 2 trial of invasively mechanically ventilated patients with COVID-19. Here, we aimed to determine whether vilobelimab in addition to standard of care improves survival outcomes in this patient population., Methods: This randomised, double-blind, placebo-controlled, multicentre phase 3 trial was performed at 46 hospitals in the Netherlands, Germany, France, Belgium, Russia, Brazil, Peru, Mexico, and South Africa. Participants aged 18 years or older who were receiving invasive mechanical ventilation, but not more than 48 h after intubation at time of first infusion, had a PaO 2 /FiO 2 ratio of 60-200 mm Hg, and a confirmed SARS-CoV-2 infection with any variant in the past 14 days were eligible for this study. Eligible patients were randomly assigned (1:1) to receive standard of care and vilobelimab at a dose of 800 mg intravenously for a maximum of six doses (days 1, 2, 4, 8, 15, and 22) or standard of care and a matching placebo using permuted block randomisation. Treatment was not continued after hospital discharge. Participants, caregivers, and assessors were masked to group assignment. The primary outcome was defined as all-cause mortality at 28 days in the full analysis set (defined as all randomly assigned participants regardless of whether a patient started treatment, excluding patients randomly assigned in error) and measured using Kaplan-Meier analysis. Safety analyses included all patients who had received at least one infusion of either vilobelimab or placebo. This study is registered with ClinicalTrials.gov, NCT04333420., Findings: From Oct 1, 2020, to Oct 4, 2021, we included 368 patients in the ITT analysis (full analysis set; 177 in the vilobelimab group and 191 in the placebo group). One patient in the vilobelimab group was excluded from the primary analysis due to random assignment in error without treatment. At least one dose of study treatment was given to 364 (99%) patients (safety analysis set). 54 patients (31%) of 177 in the vilobelimab group and 77 patients (40%) of 191 in the placebo group died in the first 28 days. The all-cause mortality rate at 28 days was 32% (95% CI 25-39) in the vilobelimab group and 42% (35-49) in the placebo group (hazard ratio 0·73, 95% CI 0·50-1·06; p=0·094). In the predefined analysis without site-stratification, vilobelimab significantly reduced all-cause mortality at 28 days (HR 0·67, 95% CI 0·48-0·96; p=0·027). The most common TEAEs were acute kidney injury (35 [20%] of 175 in the vilobelimab group vs 40 [21%] of 189 in the placebo), pneumonia (38 [22%] vs 26 [14%]), and septic shock (24 [14%] vs 31 [16%]). Serious treatment-emergent adverse events were reported in 103 (59%) of 175 patients in the vilobelimab group versus 120 (63%) of 189 in the placebo group., Interpretation: In addition to standard of care, vilobelimab improves survival of invasive mechanically ventilated patients with COVID-19 and leads to a significant decrease in mortality. Vilobelimab could be considered as an additional therapy for patients in this setting and further research is needed on the role of vilobelimab and C5a in other acute respiratory distress syndrome-causing viral infections., Funding: InflaRx and the German Federal Government., Competing Interests: Declaration of interests NCR and RG are founders, active officers, and executive directors of the board, and hold shares and stock options in InflaRx. KP is the chief clinical development officer and holds stock options in InflaRx. RZ is the program director and holds stock options in InflaRx. SR is an employee of Metronomia Clinical Research and a contracted statistical service provider for InflaRx. MW receives grants from the German Research Foundation (SFB-TR84 C6, SFB-TR84 C9, and SFB 1449 B02) and German Ministry of Education and Research (e:Med CAPSyS [01ZX1304B], SYMPATH [01ZX1906A], NUM-NAPKON [01KX2021], and PROVID [01KI20160A]). APJV received consulting fees from InflaRx for advisory work, paid to the institution. GM received honoraria for lecturing and consulting from B Braun, 4TEEN4, Adrenomed, and Philips. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The implementation of immune checkpoint inhibitors to the oncology clinic signified a new era in cancer treatment. After the first indication of melanoma, an increasing list of additional cancer types are now treated with immune system targeting antibodies to PD-1, PD-L1 and CTLA-4, alleviating inhibition signals on T cells. Recently, we published proof-of-concept results on a novel checkpoint inhibitor, NKG2A. This receptor is expressed on cytotoxic lymphocytes, including NK cells and subsets of activated CD8 + T cells. Blocking antibodies to NKG2A unleashed the reactivity of these effector cells resulting in tumor control in multiple mouse models and an early clinical trial. Monalizumab is inhibiting this checkpoint in human beings and future clinical trials will have to reveal its potency in combination with other cancer treatment options.

Checkpoint inhibitors have revolutionized cancer treatment. However, only a minority of patients respond to these immunotherapies. Here, we report that blocking the inhibitory NKG2A receptor enhances tumor immunity by promoting both natural killer (NK) and CD8 + T cell effector functions in mice and humans. Monalizumab, a humanized anti-NKG2A antibody, enhanced NK cell activity against various tumor cells and rescued CD8 + T cell function in combination with PD-x axis blockade. Monalizumab also stimulated NK cell activity against antibody-coated target cells. Interim results of a phase II trial of monalizumab plus cetuximab in previously treated squamous cell carcinoma of the head and neck showed a 31% objective response rate. Most common adverse events were fatigue (17%), pyrexia (13%), and headache (10%). NKG2A targeting with monalizumab is thus a novel checkpoint inhibitory mechanism promoting anti-tumor immunity by enhancing the activity of both T and NK cells, which may complement first-generation immunotherapies against cancer., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Anti-KIR monoclonal antibodies (mAbs) can enhance the antitumor responses of natural killer (NK) cells. We evaluated the safety of the anti-KIR2D mAb lirilumab in patients with various cancers., Experimental Design: Thirty-seven patients with hematological malignancies ( n = 22) or solid tumors ( n = 15) were included in the study. Dose escalation (0.015 to 10 mg/kg) was conducted following a 3 + 3 design. Patients were scheduled to receive four cycles of treatment. In a second (extension) phase 17 patients were treated at 0.015 ( n = 9) or 3 mg/kg ( n = 8)., Results: No dose-limiting toxicity was recorded. The most frequent lirilumab-related adverse events were pruritus (19%), asthenia (16%), fatigue (14%), infusion-related reaction (14%), and headache (11%), mostly mild or moderate. Pharmacokinetics was dose-dependent and linear, with minimal accumulation resulting from the 4-weekly repeated administrations. Full KIR occupancy (>95%) was achieved with all dosages, and the duration of occupancy was dose-related. No significant changes were observed in the number or distribution of lymphocyte subpopulations, nor was any reduction in the distribution of KIR2D-positive NK cells., Conclusions: This phase 1 trial demonstrated the satisfactory safety profile of lirilumab up to doses that enable full and sustained blockade of KIR., Competing Interests: CONFLICTS OF INTEREST DM, PA, CP, RZ are employees of Innate Pharma. The other authors received research funding from Innate Pharma. The authors confirm that neither the submitted manuscript nor any similar manuscript, in whole or in part, is under consideration, in press, or published elsewhere.

Purpose: Natural killer (NK) cells may play an important role in the immune response to multiple myeloma; however, multiple myeloma cells express killer immunoglobulin-like receptor (KIR) ligands to prevent NK cell cytotoxicity. Lenalidomide can expand and activate NK cells in parallel with its direct effects against multiple myeloma; however, dexamethasone may impair these favorable immunomodulatory properties. IPH2101, a first-in-class antiinhibitory KIR antibody, has acceptable safety and tolerability in multiple myeloma as a single agent. The present work sought to characterize lenalidomide and IPH2101 as a novel, steroid-sparing, dual immune therapy for multiple myeloma., Experimental Design: A phase I trial enrolled 15 patients in three cohorts. Lenalidomide was administered per os at 10 mg on cohort 1 and 25 mg on cohorts 2 and 3 days 1 to 21 on a 28-day cycle with IPH2101 given intravenously on day 1 of each cycle at 0.2 mg/kg in cohort 1, 1 mg/kg in cohort 2, and 2 mg/kg in cohort 3. No corticosteroids were utilized. The primary endpoint was safety, and secondary endpoints included clinical activity, pharmacokinetics (PK), and pharmacodynamics (PD)., Results: The biologic endpoint of full KIR occupancy was achieved across the IPH2101 dosing interval. PD and PK of IPH2101 with lenalidomide were similar to data from a prior single-agent IPH2101 trial. Five serious adverse events (SAE) were reported. Five objective responses occurred. No autoimmunity was seen., Conclusions: These findings suggest that lenalidomide in combination with antiinhibitory KIR therapy warrants further investigation in multiple myeloma as a steroid-sparing, dual immune therapy. This trial was registered at www.clinicaltrials.gov (reference: NCT01217203)., (©2015 American Association for Cancer Research.)

Unlabelled: Thalidomide monotherapy has demonstrated consistent results in the treatment of advanced multiple myeloma. We report a 9-year follow-up of a French multicenter nonrandomized phase II study that evaluated the effect of oral thalidomide in 120 patients with advanced multiple myeloma. Independent predictors of survival were response to last therapy, performance status, serum β(2)-microglobulin level, platelet count, and response at day 60 of treatment., Background: Thalidomide monotherapy has demonstrated consistent results in the treatment of advanced multiple myeloma., Patients and Methods: We report the 9-year follow-up of a French multicenter, nonrandomized, phase II study that evaluated the effect of oral thalidomide in advanced multiple myeloma. Thalidomide was started at 200 mg/d and increased to 400 mg/d at day 15., Results: One hundred twenty patients were enrolled in 2 months at 33 centers. The overall response rate was 31.7% (38/120) on day 60. Overall survival rates were 47.5% (95% confidence interval [CI], 38.6-56.4), 25.0% (95% CI, 17.3-32.7), 11.7% (95% CI, 5.9-17.4), and 7.5% (95% CI, 2.8-12.2) at 1, 3, 6, and 9 years, respectively. Independent predictors of short survival at 1, 3, 6, and 9 years were multiple myeloma refractory to last therapy, performance status ≥ 2, serum β(2)-microglobulin level ≥ 3.5 mg/L, platelet count < 152 × 10(9)/L, and nonresponse at day 60 (Cox proportional hazards regression model)., Conclusion: Our study identified 5 independent unfavorable prognostic factors associated with short survival. These prognostic factors were very robust, allowing the prediction of patient survival not only during the first year but also during 3, 6, and even 9 years after the beginning of treatment., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Thalidomide has potent antimyeloma activity, but no prospective, randomized controlled trial has evaluated thalidomide monotherapy in patients with relapsed/refractory multiple myeloma., Design and Methods: We conducted an international, randomized, open-label, four-arm, phase III trial to compare three different doses of thalidomide (100, 200, or 400 mg/day) with standard dexamethasone in patients who had received one to three prior therapies. The primary end-point was time to progression., Results: In the intent-to-treat population (N=499), the median time to progression was 6.1, 7.0, 7.6, and 9.1 months in patients treated with dexamethasone, and thalidomide 100, 200, and 400 mg/day, respectively; the difference between treatment groups was not statistically significant. In the per-protocol population (n=465), the median time to progression was 6.0, 7.0, 8.0, and 9.1 months, respectively. In patients who had received two or three prior therapies, thalidomide significantly prolonged the time to progression at all dose levels compared to the result achieved with dexamethasone. Response rates and median survival were similar in all treatment groups, but the median duration of response was significantly longer in all thalidomide groups than in the dexamethasone group. Adverse events reported in the thalidomide groups, such as fatigue, constipation and neuropathy, confirmed the known safety profile of thalidomide., Conclusions: Although thalidomide was not superior to dexamethasone in this randomized trial, thalidomide monotherapy may be considered an effective salvage therapy option for patients with relapsed/refractory multiple myeloma, particularly those with a good prognosis and those who have received two or three prior therapies. The recommended starting dose of thalidomide monotherapy is 400 mg/day, which can be rapidly reduced for patients who do not tolerate this treatment. (, Clinical Trial Registration Number: NCT00452569).

This multicentre prospective randomised trial compared the efficacy and safety of two doses of thalidomide in patients with relapsed or refractory myeloma. The study was designed to test the non-inferior efficacy and to confirm the better tolerability of low-dose thalidomide as compared to a higher dose. Four hundred patients were randomly assigned to receive either 100 or 400 mg/day of thalidomide. Dexamethasone treatment was added in both arms for patients with stable disease or treatment failure at 12 weeks. The primary endpoint was 1-year overall survival (OS). Thalidomide 100 mg/day was better tolerated than 400 mg/day with less high-grade somnolence, constipation, nausea/vomiting and peripheral neuropathy (P < 0.001, P = 0.007, P = 0.03 and P = 0.007, respectively). In the per-protocol population (PP), the estimated 1-year OS rates were of 74.5% (n = 149) and 67.3% (n = 156) in the 400 and 100 groups, respectively. The upper limit of the difference between these rates was of 15.6% higher than the non-inferiority acceptable limit of 12.75%, and the hypothesis of non-inferiority of 100 could not be established (P = 0.14). On the other hand, when intent-to-treat (ITT) population was analysed, the non-inferiority was demonstrated because the 1-year OS rates were of 72.8% (n = 195) and 68.8% (n = 205) in the same groups, leading to an upper limit of the difference of 11.49% lower than the non-inferiority acceptable limit. In addition, in patients alive 12 weeks postrandomisation and those who received thalidomide plus dexamethasone, there were no significant differences in response rates, time to progression, progression-free survival and OS between the two groups. Collectively, low-dose thalidomide 100 mg/day has significant activity in advanced myeloma with an improved safety profile and can be a good salvage therapy in combination with dexamethasone., (© 2011 John Wiley & Sons A/S.)

Background and Objectives: In non-randomized studies, thalidomide appeared to be effective in myeloid metaplasia with myelofibrosis (MMM). We compared thalidomide to placebo for treatment of anemia in MMM., Design and Methods: A prospective phase II B, randomized double-blind multicenter trial comparing thalidomide 400 mg/d with placebo for 180 days was conducted in 52 anemic patients (hemoglobin pounds Sterling 9 g/dL or transfused). The main outcome measure was a 2 g/L increase in hemoglobin or 20% reduction in transfusions., Results: In the thalidomide group only 10 patients completed 6 months of treatment. At 180 days, in an intention-to-treat analysis, no difference was observed between the thalidomide and placebo groups as regards improvement of hemoglobin levels (one patient in each group) or reduction of red blood cell transfusions (three vs five patients, respectively). The spleen size, determined by ultrasonography, increased significantly less in the thalidomide group than in the placebo group (p < 0.05). Thalidomide had no apparent benefit on the Dupriez score, the severity score, survival, death, or any other clinical or biological parameter. Somnolence, gastro-intestinal signs, weight gain, and edema were significantly more frequent in the thalidomide group. Outpatient discontinuation of thalidomide was significantly correlated with a high severity score > 4 (odds ratio, OR = 16; p < 0.01), and g-glutamyl transferase levels > 40 IU/L (OR = 12; p < 0.05)., Interpretation and Conclusions: Thalidomide (200-400 mg/d) does not demonstrate substantial efficacy in anemic MMM patients. The natural history of disease in the placebo group revealed spontaneous periods of remission of anemia. Tolerance of thalidomide was significantly correlated wih the severity and liver involvement of the disease.

The anxiolytic properties of melatonin are revealed by two behavioral studies. In a free exploratory situation, the holeboard test, melatonin decreased head-dip performance. In an unconditioned conflict test, the light/dark box choice situation, melatonin increased the time spent in the lit box as well as the number of transitions between the two compartments. Melatonin was given in a dose range from 0.5 to 5.0 mg/kg body weight i.p. 30 minutes before testing in daytime. Moreover, the anxiolytic activity of diazepam (2.5 mg/kg i.p.) was evaluated and found to be completely inhibited by the specific benzodiazepine antagonist flumazenil (10 mg/kg i.p. 30 minutes before). In the same manner flumazenil counteracted melatonin activity in the two tests. Involvement of the benzodiazepine/GABAergic system in the anxiolytic activity of melatonin is discussed.

The authors experience on twelve patients in the field of bone grafting prior to implant surgery is presented. The technique employed depends largely on the anatomical location of bone insufficiency, such as: 1) Where there is not enough bone beneath sinus locations, grafting with cancellous iliac bone blended with coral particles is suggested. 2) Where the jaw is not sufficiently thick, such as in the incisor-cuspid regions, the authors employ cancellous and/or cortical bone grafts. 3) Horizontal osteotomy and interposition of cortical-cancellous bone graft is proposed where there is a lack of bone height in the incisor-cuspid regions. The results of the various techniques are analysed from a clinical, radiographic and histologic perspective. Twelve patients have been treated with 2 years follow-up.

Restraint stress for ten days (two times two hours daily) induces a hypersensitivity of the central cholinergic system, reflected by antagonism to amnesia induced by scopolamine at 0.1 mg/kg in a passive avoidance test and by hypersensitivity to the hypothermic effect of oxotremorine at 1 mg/kg. A restraint stress for 30 days, on the other hand, diminishes animal retention in the passive avoidance test and causes a hyposensitivity to oxotremorine-induced hypothermia, reflecting a hypoactivity of the central cholinergic system. An acute 24-hour stress causes no change. The relationship between chronic stress and associated memory deficits is discussed.

The role of various second messengers in the learning and retention of a passive or active avoidance has been investigated in mice. Scopolamine at 3 mg/kg i.p. inhibits muscarinic M1 and M2 receptors and thus acetylcholine activation of the phosphoinositide cycle. This results in amnesia of passive avoidance but has no effect on active avoidance learning. Oxotremorine at 0.05 mg/kg i.p., whose preferential M2 muscarinic action limits acetylcholine release and also inhibits adenylate cyclase activity, causes amnesia of the retention of a passive avoidance and antagonizes the learning of an active avoidance. DL-propranolol at 40 mg/kg i.p., which inhibits cAMP formation, does not affect retention of a passive avoidance but antagonizes that of an active avoidance. Similarly, phorbol myristate acetate a 0.1 mg/kg i.p., which activates protein kinase C, has no effect on the retention of a passive avoidance but antagonizes that of an active avoidance. The results tend to show a distinct role for cAMP-dependent protein kinase, which would participate in memorization processes of an active avoidance, and for protein kinase C, which would participate in that of a passive avoidance. The authors discuss the involvement of different neurophysiological mechanisms as a function of the type of behavior, depending on whether or not it is related to the control of environmental situations.

44 cases of tympanic involvement in the context of chronic otitis are described. 34 occurred during active chronic otitis. This is a rare possibility (approximately 4% of our own cases of chronic otitis). The following may be mentioned amongst them: 21 cases of osteitis, for which the following concepts should be borne in mind: the extreme severity of the chronic otitis responsible, in most instances, ears which had undergone multiple surgery (17/21), lesions exclusively of osteitis, but very extensive in 2/3 of cases (14/21). 7 cases of osteolytic disease, occurring severe or atypical cholesteatomatous chronic otitis and quite often involving associated osteolysis affecting the main VII, the promontory, the bulb of the internal jugular vein, or even the carotid canal. 4 cases of diffuse sub-obstructive osteomatous disease of the walls of the E.A.M., "progressive" development of which over several months was noted in 3 cases. Finally, 2 cases of mixed disease: (osteitis--osteomatoma and osteitis--osteolysis). 8 cases occurred following myringoplasty: this is a rare eventuality (approximately 1%), 1 case only of osteolysis due to iatrogenic cholesteatoma, 7 cases of osteitis, either highly localized and not preventing further myringoplasty (4 cases), or very extensive, finally resulting in a vast evacuation cavity. In 2 cases, a malformation is the origin of involvement of the tympanic at the origin of chronic otitis was felt probable, without it being possible to reach any definite conclusion concerning auriculobranchial fistula or Huschke foramen.

Use of a silicone menton endoprosthesis appears to be a seductive alternative to menton osteotomy for profile reconstructions of a certain type, whether pure or associated with orthognathic treatment. A strict surgical technique is essential, particularly a limited incision and median and low situated positioning. The advantages and inconveniences of this procedure are described and the need for very selective choice of patients emphasized.

Results of treatment of 16 cases of severe pharyngo-esophageal stenosis of caustic origin are reviewed. Emergency treatment is described, the place of otorhinolaryngology in investigation of lesions of upper respiratory and digestive tract discussed, and a description given of a technique of esophagopharyngoplasty by right ileocolic transplant with a suprahyoidal or supraglottic anterior cervical approach with epiglottectomy. Strict selection of patients is essential, taking into account their psychiatric profile. The functional result of this operation, with its long and difficult postoperative course, was inconstant (11 of the 16 cases could be fed liquids and solids by mouth exclusively, ensuring maintenance of body weight, although endoscopic dilatation might be necessary in one or two cases), and appears to depend on the outcome of corrosive lesions and psychologic behavior of patients.