SAMCEP Society consensus on the treatment of upper facial lines with botulinum neurotoxin type A: A tailored approach.

BACKGROUND: The safety and efficacy of botulinum neurotoxin type A (BoNTA) treatments are well established, but injection techniques, target muscles, and toxin doses continue to evolve, with each refinement producing improvements in treatment outcomes. The recommendations in this consensus move away from standard templates and illustrate how to tailor treatments to individual patterns and strengths of muscle activity, and patient preferences. METHODS: Seventeen experts in the fields of plastic surgery, dermatology, ophthalmology, otorhinolaryngology, and neurology convened in 2022 to develop consensus-based recommendations for the use of botulinum toxin A for the treatment of horizontal forehead lines, glabellar frown lines, and crow's feet lines that reflect current clinical practice. The focus was on how to tailor injections to individual patients to optimize treatment outcomes. RESULTS: For each upper face indication, consensus members describe how to perform a dynamic assessment to optimize the dose and injection technique for each patient. A tailored treatment protocol is presented for commonly observed patterns of dynamic lines. Units of Inco are defined and the precise location of injection points, illustrated with the use of anatomical images. CONCLUSION: This consensus provides up-to-date recommendations on the tailored treatment of upper facial lines based on the latest research and collective clinical experience of the expert injectors. Optimal outcomes require thorough patient evaluation, both at rest and during animation, using both visual and tactile cues; detailed understanding of facial muscular anatomy and how opposing muscles interact; and use of a BoNTA with high precision to target identified zones of excess muscle activity.

Weight-bearing MRI with a knee flexion angle of 20°: a study on additional MRI investigation modalities to support a more accurate understanding of patellofemoral instability.

BACKGROUND: Diagnosing patellofemoral instability disorders correctly, weight-bearing MRI (WB-MRI) has become an option. Aiming for a best possible accuracy in displaying potentially underlying causes, the named MRI modalities were sporadically even investigated in different knee flexion angles. However, despite confirmed MRI-outcome-differences between WB-MRI and non-WB-MRI, none of the described MRI modalities have so far established themselves. Mainly this is due to an unfeasibility in daily clinical routine in regard to time and economic aspects. Thus, we intended to evaluate an additional but reduced patellofemoral MR-imaging solely in a relevant 20° of knee flexion under WB- and non-WB-MRI conditions. METHODS: Seventy-three subjects with and without patellofemoral instability were investigated under supine as well as under WB-MRI conditions in a 20° of knee flexion angle. Patellofemoral risk indices in the sagittal plane (Insall-Salvati-Index, Caton-Deschamps-Index, Patellotrochlear Index) and the axial plane (Patella tilt of Fulkerson and Sasaki) were detected and compared between the different MRI conditions. Significance, reliability and Cohen's effect size was calculated. RESULTS: Nearly all assessed indices showed significant differences between patients and controls in the different MRI positions. Comparing pairwise, all measured indices failed to show significant differences between the two MRI positions. However, patella tilt angles of the patient group showed an elevation from supine to WB-MRI (14.00 ± 7.54° to 15.97 ± 9.10° and 16.34 ± 7.84° to 18.54 ± 9.43°). Here, Cohen's d showed small to medium effects between supine and WB-MRI. CONCLUSION: In comparison to standard MRI in supine position, axial risk indices seem to be accentuated under WB-MRI and a knee flexion angle of 20°. In particular, symptomatic cases with inconspicuous conventional MRI imaging, additional MRI imaging only in the axial plane in a 20° of knee flexion could be beneficious and useful in clinical daily routine.

Patient-related outcome measurements after operative and conservative management of traumatic proximal adductor longus avulsion injuries.

PURPOSE: In the rare case of complete proximal adductor longus avulsion injuries, scientific recommendations of surgical or conservative injury management are limited to small case series and reviews of small cohorts about treatment examples. A clear consensus regarding optimal management so far has not been made. Thus, the aim of our study was to investigate patient-related outcome measurements (PROM) after either operatively or conservatively treated patients in order to evaluate and display own decision criteria for one of the two treatment options. METHODS: In this retrospective case control study, two cohorts after MRI-confirmed, isolated, acute proximal adductor longus avulsion injury without concomitant injuries was investigated. Depending on stump retraction (less or more than 2 cm), patients of the particular cohorts had either been treated conservatively or by surgical refixation with suture anchors. All patients were asked to complete different PROM forms (Hip Osteoarthritis Outcome Score (HOS), Modified Harris Hip Score (MHHS)) in order to evaluate the particular procedures outcome. RESULTS: Between July 2015 and July 2018, eighteen avulsion injuries met our inclusion criteria, of which 14 were treated conservatively and operatively in equal parts and could be included into the study. The mean stump retraction of the conservative group was 1.3 cm (SD ± 0.5); patients in the surgical group had a mean stump retraction of 3.0 cm (± 1.5). Irrespective of the treatment option, all patients achieved a maximum score using the MHHS. Also in the HOS subscale respecting all day activities, almost all patients (13/14) achieved a maximum score. Instead, using the HOS subscale respecting sportive activities, one surgically and one conservatively treated patient described little restrictions compared with their pre-injury level. CONCLUSION: Conservative as well as operative treatment leads to very good patient-related outcome measurements if the decision for either of the two treatment options is made upon a stump retraction above or below 2 cm. Smaller restrictions regarding pre-injury level could rather be seen in the conservative instead of the operative group, favouring a more generous perspective for surgical refixation.

Patella alta and patellar subluxation might lead to early failure with inlay patello-femoral joint arthroplasty.

PURPOSE: With the growing interest in resurfacing procedures, several new implants have been recently introduced for isolated patello-femoral joint arthroplasty (PFA). However, not much data are available for these new techniques or about the right indications for each type of implant. METHODS: Out of a retrospective cohort of 20 inlay PFA, 11 PFA with an elevated Insall-Salvati index and an increased patello-femoral congruence angle showed an initial satisfactory result, but presented thereafter with recurrent pain and "clunk" phenomena. They were all revised after a median time of 25 months (range 8-28 months) into an onlay technique PFA and analyzed for their failure mode and revision technique. RESULTS: Clinical symptoms such as clunking, as well as abraded areas craniolateral of the inlay implant found intraoperatively, were the main observations of this study. The modified Insall-Salvati index (mISI) was significantly higher in the revised knees compared to the unrevised (median 1.8 versus 1.6; p = 0.041). VAS and KSS significantly improved after revision (median VAS reduction in pain of 4.0 points, median KSS improvement of 20.0 points; p < 0.05). CONCLUSION: Patients with high-normal patellar height index or patella alta, as well as a craniolateral type of arthritis with additional lateralization, should be considered contra-indicated for an inlay technique PFA. They could be considered for a PFA system reaching further proximal into the distal femur. An onlay PFA can be an option for early revision of failed inlay implants. The clinical relevance of this study is that patella alta and patellar subluxation are more difficult to adjust for with an inlay PFJ component. LEVEL OF EVIDENCE: Level IV.

Influence of tibial hybrid fixation on graft tension and stability in ACL double-bundle reconstruction.

PURPOSE: Initial graft tension in anterior cruciate ligament (ACL) reconstruction affects stability and tension loss at follow-up. This study investigated the influence of hybrid tibial fixation in 3-tunnel double-bundle ACL reconstruction on initial graft tension and tension change and stability under anterior and combined rotatory loads. METHODS: Eleven fresh-frozen cadaveric knees were reconstructed with an ACL double bundle using a 3-tunnel technique. Grafts were tightened to 80 N in 60° (AM bundle) and 15° (PL bundle) of flexion. Anterior tibial translation under 134 N of anterior shear load and translation under combined rotatory and valgus loads (10 Nm valgus stress, 4 Nm internal tibial torque) were determined at 0°, 30°, 60°, and 90° flexion. In addition, graft tension under continuous passive motion was determined. Intact, ACL-resected and ACL-reconstructed joints with either tibial extracortical graft fixation or extracortical plus supplemental aperture graft fixation (hybrid fixation) were tested. RESULTS: Hybrid fixation did not increase graft tension in either bundle during fixation or in motion without additional load. AM-bundle tension increased (p < 0.05) at 0° under combined rotatory and valgus loads and at 30° and 60° under both loading conditions without decreasing the anterior tibial translation. PL-bundle tension increased (p < 0.05) only at 90° under combined rotatory and valgus loads. CONCLUSIONS: Tibial hybrid fixation in 3-tunnel double-bundle ACL reconstruction increases time-zero AM- and PL-bundle tensions under loading conditions, generating greater construct stiffness. This could lead to a longer preservation of ACL-graft stability in clinical follow-up before bony incorporation.

Serial clinical and MRI examinations after arthroscopic rotator cuff reconstruction using double-row technique.

PURPOSE: Rotator cuff reconstruction using arthroscopic double-row technique enables a better repair of the anatomical footprint at the tendon insertion. Objective of this serial study was to illustrate structural and functional results during recovery following double-row reconstruction. METHODS: Forty-five patients with mid-sized ruptures of the supraspinatus tendon were assessed prospectively and underwent arthroscopic surgery using the double-row technique. Rupture localization, size, form, and extent of retraction were recorded intraoperatively. Clinical and MRI follow-up examinations were carried out for all patients after 6, 12, 26, and 52 weeks. A A standard protocol was used during the follow-up examinations to determine tendon integration, signal changes in the tendon, extent of bone marrow edema near the enclosed absorbable suture anchors, muscle changes. The clinical results were correlated with the MRI appearance. RESULTS: After 26 weeks, the Constant score (CS) showed a highly significant increase for the first time with a value of 78 (p < 0.001). Tendon integration according to Sugaya showed a left shift over time, with higher CS-values for lower Sugaya classifications. Significant improvements in strength were first measured between the 26-week and 52-week follow-ups (9->19/p < 0.001). Highly significant improvement (p < 0.001) of the tendon signal and the fatty infiltration was found in the same time interval. The hypotrophy showed slight improvement, while a highly significant reduction of the bone marrow edema was found between weeks 12 and 26 (p < 0.001). There were no re-ruptures after week 26. CONCLUSIONS: The present serial study showed that it took 26 weeks to reach a significant clinical improvement concerning CS. With regard to tendon healing, no further deterioration of the structural results occurred between week 26 and week 52 postoperative. There were slightly but not significant better clinical results according to the the Sugaya classification. However, parameter "strength" was significantly increased between weeks 26 and 52. This was consistent with a significant decrease in the signal intensity at the repaired tendon site, an additional improvement in the fatty infiltration, and the atrophy according to Thomazeau in the same time interval. LEVEL OF EVIDENCE: I.

Periarticular injections with continuous perfusion of local anaesthetics provide better pain relief and better function compared to femoral and sciatic blocks after TKA: a randomized clinical trial.

PURPOSE: Combined femoral and sciatic nerve blocks for post-operative pain management following total knee arthroplasty (TKA) improve patient satisfaction, decrease narcotic consumption and improve pain. However, accompanying motoric weakness can cause falls and related complications. We wonder whether peri-capsular injections in combination with intra-articular perfusion of local anaesthetics would result in equal or less pain without the related complications of nerve blocks. The objective of the study was to verify these aspects in a prospective randomized trial comparing both treatments. METHODS: Fifty TKA patients randomly received either a femoral (continuous) and a sciatic (single-shot) nerve block (CFNB group, 25 knees) or periarticular infiltrations and a continuous post-operative intra-articular infusion (PIAC group, 25 knees). VAS for pain, pain medication consumption, functional assessment, straight leg raising as well as KSS were recorded post-operatively for 6 days. RESULTS: VAS (p < 0.001) and KSS (p = 0.05) were significantly better for PIAC. There was increased pain following CFNB compared to PIAC. Catheters stayed for 4 days, a pain 'rebound' occurred after removing in CFNB but not after PIAC. There was no difference in regard to knee function (n.s.), but straight leg raising was significant better following PIAC. There were two falls in patients with CFNB. CONCLUSION: Peri-capsular injections combined with an intra-articular catheter provide better pain control, no rebound pain with better function and might decrease the risk of complications related to motor weakness. LEVEL OF EVIDENCE: I.

Surface biofunctionalization of ß-TCP blocks using aptamer 74 for bone tissue engineering.

Successful bone regeneration following oral and maxillofacial surgeries depends on efficient functionalization strategies that allow the recruitment of osteogenic progenitor cells at the tissue/implant interface. We have previously identified aptamer 74, which exhibited a binding affinity for osteogenically induced jaw periosteal cells (JPCs). In the present study, this aptamer was used for the surface biofunctionalization of ß-tricalcium phosphate (ß-TCP) blocks. Atomic force microscopy (AFM) measurements showed increased binding activity of aptamer 74 towards osteogenically induced JPCs compared to untreated controls. The immobilization efficiency of aptamer 74 was analyzed using the QuantiFluor ssDNA assay for 2D surfaces and by amino acid analysis for 3D ß-TCP constructs. Following the successful immobilization of aptamer 74 in 2D culture wells and on 3D constructs, in vitro assays showed no significant differences in cell proliferation compared to unmodified surfaces. Interestingly, JPC mineralization was significantly higher on the 2D surfaces and higher cell adhesion was detected on the 3D constructs with immobilized aptamer. Herein, we report an established, biocompatible ß-TCP matrix with surface immobilization of aptamer 74, which enhances properties such as cell adhesion on 3D constructs and mineralization on 2D surfaces. Further studies need to be performed to improve the immobilization efficiency and to develop a suitable approach for JPC mineralization growing within 3D ß-TCP constructs.

MRI-associated classification to evaluate the outcome after autologous reconstruction of the medial patellofemoral ligament: a preliminary study.

PURPOSE: Purpose of this study was to establish and validate an MRI-associated classification to graduate postoperative results of MPFL reconstructions. METHODS: 30 autologous MPFL reconstructions of 28 patients were evaluated by two independent raters using MRI. All grafts were assigned to a novel graduation system respecting the graft's anchoring insertions, its MRI signal appearance, continuity and tension and the differentiation relating to the surrounding soft tissue. RESULTS: All grafts could reliably be assigned to one of the subgroups by both raters. 86.6 % of the grafts could be classified A1 or B1, reflecting a correct positioning and a low to intermediate signal intensity. Only one graft had to be classified C3 (malpositioned, elongated). CONCLUSION: We were able to establish and validate an MRI-associated classification to graduate the postoperative outcome after MPFL reconstructions. Foresighted, the presented classification might support further decision making in case of unsatisfying postoperative results.

Coating of ß-tricalcium phosphate scaffolds-a comparison between graphene oxide and poly-lactic-co-glycolic acid.

Bone regeneration in critical size defects is a major challenge in oral and maxillofacial surgery, and the gold standard for bone reconstruction still requires the use of autologous tissue. To overcome the need for a second intervention and to minimize morbidity, the development of new biomaterials with osteoinductive features is the focus of current research. As a scaffolding material, ß-tricalcium phosphate (ß-TCP) is suitable for bone regeneration purposes, although it does not carry any functional groups for the covalent immobilization of molecules. The aim of the present study was to establish effective coating variants for ß-TCP constructs to enable the biofunctionalization of anorganic blocks with different osteogenic molecules in future studies. We established working protocols for thin surface coatings consisting of polylactic-co-glycolic acid (PLGA) and graphene oxide (GO) by varying parameters. Surface properties such as the angularity and topography of the developed scaffolds were analyzed. To examine biological functionality, the adhesion and proliferation behavior of jaw periosteal cells (JPCs) were tested on the coated constructs. Our results suggest that PLGA is the superior material for surface coating of ß-TCP matrices, leading to higher JPC proliferation rates and providing a more suitable basis for further biofunctionalization in the field of bone tissue engineering.

[Cosmetic radiofrequency]. / La radiofréquence cutanée.

Cosmetic radio frequency uses an electric current of high frequency that generates heat through the subcutaneous tissues enough to break the collagen fibers and allow synthesis of a neo-collagen. It permits cutaneous resurfacing, improving the tone and quality of the skin (wrinkles and enlarged pores), and delicately reshaping facial volumes. The principle of a type Ellman monopolar radiofrequency at a rate of 4 MHz Pellevé, Surgitron Dual RF S 5 is described. Its use inclines more towards anti-aging and natural rejuvenation of the face, neck and neckline. It may be associated with other rejuvenation techniques such as fillers and botulinum toxin within certain time limits.

Contrast-enhanced ultrasound pattern of splenic metastases - a retrospective study in 32 patients.

PURPOSE: To characterize the pattern of contrast-enhanced ultrasonography (CEUS) in splenic metastases compared to standard B-mode ultrasonography. MATERIALS AND METHODS: Between January 2004 and March 2009, about 50,000 abdominal ultrasound examinations were performed, and n = 279 (< 0.6 %) of focal splenic lesions were detected of which n = 32 (11.5 %) were highly suggestive for splenic metastases of various solid tumors. The number of lesions, size, echogenicity, rim appearance, presence of halo sign and necrosis were recorded via B-mode sonography. Contrast enhancement was determined in the arterial phase (5 - 30 sec) and parenchymal phase (3 - 5 min). B-mode sonography and CEUS were compared in terms of the visibility of splenic metastases. All data was evaluated retrospectively. RESULTS: On B-mode sonography lesions were solitary n = 18 (56 %), multiple n = 14 (44 %), < 2 cm n = 11 (34 %), > or = 2 cm n = 21 (66 %), hypoechoic n = 14 (44 %), isoechoic n = 12 (38 %) and hyperechoic n = 6 (19 %), with regular rim appearance n = 27 (84 %), and with irregular rim appearance n = 5 (16 %). During the arterial phase CEUS lesions were hypoechoic n = 21 (66 %), isoechoic n = 2 (6 %), hyperechoic n = 1 (3 %) and complex n = 8 (25 %). During the parenchymal phase lesions were hypoechoic n = 24 (75 %) and complex n = 8 (25 %). CEUS provided improved visualization of splenic metastases in n = 12 (38 %) cases. CONCLUSION: CEUS of splenic metastases is characterized by reduced contrast enhancement in both the arterial and the parenchymal phase in most cases. Moreover, CEUS improved the visualization of splenic metastases in about 40 % of cases in comparison to standard B-mode sonography.

Increased Duodeno-Gastro-Esophageal Reflux (DGER) in symptomatic GERD patients with a history of cholecystectomy.

BACKGROUND: Duodenal-Gastro-Esophageal Reflux (DGER) represents an independent risk factor for the development of complicated Gastro-esophageal-reflux-disease (GERD) and Barrett's esophagus. Clinical and epidemiological data suggest a potential association between cholecystectomy (CCE) and augmented bile reflux. METHODS: 132 patients (67 women, 65 men, median age 55) with typical symptoms of GERD were enrolled in the study and divided in cholecystectomized (CCE-group: n = 107) and non- cholecystectomized (nCCE-group: n = 25) patients. Standardized clinical work-up of patients included combined esophageal 24 h pH-measurement and Bilitec 2000 esophageal manometry and upper endoscopy. RESULTS: In the statistical analysis no differences between the cholecystectomized group (CCE-group, n = 25) and the patients without cholecystectomy (nCCE-group, n = 107) could be observed in quantity or quality of reflux symptoms. Furthermore, neither acid reflux nor severity of inflammation and frequency of Barrett's esophagus significantly differed between the nCCE and CCE-group. However, the percentage of patients with pathological DGER were significantly higher in the CCE-group as compared to the nCCE-group (76 vs. 55 %, p < 0.01). Moreover, the CCE-group revealed significant higher levels of pathological DGER compared to the nCCE-group (15.5 % +/- 14.1 vs. 8.6 % +/- 15.4; p < 0.05). CONCLUSION: To conclude, our data provide first evidence of elevated DGER after CCE in patients with typical clinical symptoms of GERD using the Bilitec device. Both the frequency and the extent of DGER was significantly increased in the CCE-group. Prospective studies are urgently needed to elucidate the impact of CCE on DGER in patients with clinical symptoms of a reflux disease.

Accuracy and reproducibility of axial length measurement in eyes with silicone oil endotamponade.

AIM: To assess the accuracy and signal quality of axial length measurements by partial coherence laser interferometry (PCI) for optical biometry in eyes with conventional silicone oil (SO) or heavy silicone oil (HSO) as endotamponade. METHODS: We included 26 eyes with SO endotamponade (SO, n = 15; HSO, n = 11) using a Zeiss IOLMaster for measurement of axial length the day before and at least 6 weeks after SO removal. We analysed the intra-individual deviation between both measurements and signal-to-noise ratio (SNR) as a marker for signal quality. We included 16 contralateral eyes without history of vitreoretinal surgery to act as the control group. RESULTS: The mean axial length was 24.76 (SD 2.07) mm (SO 24.63 (SD 2.12) mm, HSO 24.93 (SD 2.10) mm, control 24.95 (SD 2.61) mm) before and 24.75 (SD 1.96) mm after oil removal with a mean intra-individual deviation of 0.13 (SD 0.11) mm (SO 0.13 (SD 0.12) mm, HSO 0.13 (SD 0.09) mm, control 0.02 (SD 0.01) mm) while SNR at baseline was 5.7 (SD 3.5) (SO 6.6 (SD 4.0), HSO 4.4 (SD 2.2), control 8.6 (SD 3.9)). CONCLUSION: In our analysis, optical biometry using PCI generated results with acceptable accuracy and signal quality for measurement of axial length in SO-filled eyes.

Echo-rich and echo-poor periportal cuffing: pole position for inflammatory bowel diseases.

PURPOSE: To determine the prevalence of echo-rich and echo-poor periportal cuffing in patients from a German tertiary referral hospital and correlate ultrasonographic findings with clinical data. MATERIALS AND METHODS: From April 2002 till April 2008 about 10 500 abdominal examinations were performed by a single physician in our interdisciplinary ultrasound unit. During this time, n = 100 patients (62 male/ 38 female) with periportal cuffing of the liver were detected qualifying for the retrospective study design. Echomorphology of periportal cuffing was evaluated and clinical diagnoses of the underlying diseases were clustered in four main groups: Liver diseases, haematological diseases, bowel diseases and others. Furthermore, liver function tests and body mass index were determined. RESULTS: The mean age of the patients was 57.06 years (SD +/- 19.47). Mean body-mass-index was 24.76 kg/m (2) (SD +/- 4.28). Periportal cuffing was echo-poor in n = 9 (9 %) and echo-rich in n = 91 (91 %). Echo-poor periportal cuffing was significantly more often associated with malignant diseases as compared to echo-rich periportal cuffing (78 vs. 36 %) (p < 0.025). Liver diseases (n = 33) were malign n = 10 (10 %), autoimmune n = 8 (8 %), infectious n = 8 (8 %) and cholestatic n = 7 (7 %). Bowel diseases (n = 34) originated from the upper gastrointestinal tract n = 7 (7 %), lower gastrointestinal tract n = 21 (21 %) and the pancreas n = 6 (6 %). Haematological disorders (n = 15, 15 %) were chronic myeloproliferative n = 2 (2 %), lymphoma n = 8 (8 %), leukemia n = 4 (4 %) and miscellaneous n = 1 (1 %). Other diseases accounted for 18 (18 %) of cases. Aspartat-aminotrasferase (AST) and alanin-aminotransferase (ALT) were elevated in 39 patients (40 %) and 34 patients (35 %), respectively. Total bilirubin was elevated in 35 patients (36 %). Alkaline phosphatase (AP) was detected above normal range in 49 patients (50 %) whereas g-glutamyl-transferase was elevated in 58 patients (59 %). CONCLUSION: Periportal cuffing of the liver is an extremely rare ultrasonographic phenomenon with a prevalence of approximately 0.95 % in our unit. Echo-rich periportal cuffing occurs more frequently than echo-poor periportal cuffing. The majority of echo-poor periportal cuffing is associated with malignant disorders, in particular haematological diseases, whereas echo-rich periportal cuffing is most frequently seen in inflammatory bowel disease patients.

[Characteristics of the consultation in medicine and/or plastic surgery]. / Particularités de la consultation en médecine et/ou chirurgie esthétique.

Consultation in medicine and/or plastic surgery presents specific elements which must first be organized. These characteristics concern the location of exercise and both the reception and the ancillary medical staff The consultation requires a different listening from a consultation for another reason. The psychological aspect is of primary importance here. The photographs are essential as well as information and enlightened assent. A relation of confidence, the technical skill of the doctor and his team which must discrete, combined with accessible buildings, will be the assets of a successful aesthetic consultation and a treatment which will satisfy the patient.

[Cystic adenoid carcinoma of the larynx: two cases]. / Carcinome adénoïde kystique du larynx. A propos de deux cas.

Adenoid cystic carcinoma is the most common malignant tumor of the minor salivary glands in the head and neck. Laryngeal localization is rare due to the poor distribution of the accessory salivary glands in this area. It arises exceptionally before 20 years and no risk factor is known. Diagnosis is a histological finding because symptoms do not differ greatly from other laryngeal tumors. Histological features, stage, quality of tumor resection and nerve invasion are prognostic factors. These tumors grow slowly and local recurrence or systemic metastasis are exceptional. Surgery is the treatment of choice but outcome is always fatal, after a long clinical course in many patients.

Discovery of novel p-arylthio cinnamides as antagonists of leukocyte function-associated antigen-1/intercellular adhesion molecule-1 interaction. 4. Structure-activity relationship of substituents on the benzene ring of the cinnamide.

We have shown that p-arylthio cinnamides can inhibit the interaction of LFA-1 and ICAM-1, which is involved in cell adhesion and the inflammatory process. We now show that 2,3-disubstitution on the aryl portion of the cinnamide results in enhanced activity over mono substitution on the ring. The best 2,3-substituents were chlorine and trifluoromethyl groups. Compounds 39 and 40 which contain two CF3 groups have IC(50) values of 0.5 and 0.1 nM, respectively, in inhibiting JY8 cells expressing LFA-1 on their surface, from adhering to ICAM-1. The structure-activity relationship (SAR) was examined using an NMR based model of the LFA-1 I domain/compound 31 complex. One of our compounds (38) was able to reduce cell migration in two different in vivo experiments.

Discovery of potent antagonists of leukocyte function-associated antigen-1/intercellular adhesion molecule-1 interaction. 3. Amide (C-ring) structure-activity relationship and improvement of overall properties of arylthio cinnamides.

The interaction of LFA-1 and ICAM-1 plays an important role in the cell adhesion process. On the basis of previously reported SAR and structural information on the binding of our p-arylthiocinnamide series to LFA-1, we have identified the cyclic amide (C-ring) as a site for modification. Improvement in potency and, more importantly, in the physical properties and pharmacokinetic profiles of the leading compounds resulted from this modification. One of the best compounds (11f) is also shown to reduce myocardial infarct size in rat.

Novel p-arylthio cinnamides as antagonists of leukocyte function-associated antigen-1/intracellular adhesion molecule-1 interaction. 2. Mechanism of inhibition and structure-based improvement of pharmaceutical properties.

The interaction between leukocyte function-associated antigen-1 (LFA-1) and intracellular adhesion molecule-1 (ICAM-1) has been implicated in inflammatory and immune diseases. Recently, a novel series of p-arylthio cinnamides has been described as potent antagonists of the LFA-1/ICAM-1 interaction. These compounds were found to bind to the I domain of LFA-1 using two-dimensional NMR spectroscopy of 15N-labeled LFA-1 I domain. On the basis of NOE studies between compound 1 and the I domain of LFA-1, a model of the complex was constructed. This model revealed that compound 1 does not directly inhibit ICAM-1 binding by interacting with the metal ion dependent adhesion site (MIDAS). Instead, it binds to the previously proposed I domain allosteric site (IDAS) of LFA-1 and likely modulates the activation of LFA-1 through its interaction with this regulatory site. A fragment-based NMR screening strategy was applied to identify small, more water-soluble ligands that bind to a specific region of the IDAS. When incorporated into the parent cinnamide template, the resulting analogues exhibited increased aqueous solubility and improved pharmacokinetic profiles in rats, demonstrating the power of this NMR-based screening approach for rapidly modifying high-affinity ligands.