Sequential combination of Sonic Hedgehog inhibitors followed by consolidation radiotherapy in locally advanced basal cell carcinoma.

BACKGROUND: Sonic Hedgehog inhibitors (SHHis) are an effective treatment in locally advanced basal cell carcinoma (laBCC), but the use of these drugs is limited by adverse events and relapse at discontinuation in around half of patients. A few cases of patients treated concomitantly by radiotherapy (RT) and SHHis have been reported in the literature, suggesting that the combination results in an improved overall response. Maintaining complete response after stopping treatment is a concern, especially since resuming treatment in the case of relapse does not guarantee a new therapeutic response. The optimal combination and sequence of treatment to improve local control of laBCCs are not yet defined. OBJECTIVE: We hypothesized that consolidation RT after complete response to SHHis could reduce the risk of relapse at discontinuation. METHODS: We present a case series of patients with laBCCs who achieved complete response (CR) after SHHi treatment and were treated with consolidation RT. Patients were evaluated by a skin cancer board. The closure RT technique and dosage were refined by a radiotherapist. RESULTS: Eleven patients were included. SHHis were prescribed for 5 months (range 4-11). Consolidation RT was performed after CR to SHHis and discontinuation. RT was delivered at a median dose of 45 Gy (range 40.5-66) in 10 fractions (range 9-33). With a median follow-up of 23 months, all patients maintained complete clinical response. This strategy was well tolerated with no grade 3 adverse events. CONCLUSION: SHHi treatment followed by RT consolidation after drug discontinuation seems effective and safe. Further studies are needed to develop a precise strategy for the management of laBCCs.

Radiotherapy and prognostic factors in adnexal carcinomas: A retrospective study of 657 patients from the French CARADERM network.

BACKGROUND: Cutaneous adnexal carcinomas are a heterogeneous group of rare neoplasms. Surgical excision is the first-line treatment in localized stage. The use and effectiveness of radiotherapy have not been thoroughly evaluated in these neoplasms. OBJECTIVES: The present work analyses prognostic factors on outcomes in skin adnexal carcinomas, based on data from the CARADERM (CAncers RAres DERMatologiques) database. METHODS: Data were collected retrospectively including demographic data, tumour types and therapeutic characteristics of all patients included in the CARADERM database, with at least one informative follow-up visit. Analyses were performed on three populations: patients with complete resection of the primary tumour (ADJ/primary population), patients achieving complete remission after complete resection of a recurrent tumour (ADJ/recurrent population) and patients with unresectable locally advanced or metastatic tumours (ADV/MET population). Overall and recurrence/progression-free survivals at 3-year were analysed using Cox regression models. RESULTS: Radiotherapy did not affect overall survival (OS) in the ADJ/primary population. Adjusted recurrence-free survival (RFS) was significantly lower in the radiotherapy group in ADJ/primary group. Older patients had significantly poorer OS and RFS. Tumour size and immunosuppression were significantly associated with poorer RFS only. Radiotherapy had no effect on OS and RFS in the ADJ/recurrent population. Age was the only factor associated with a poorer OS. Radiotherapy was significantly associated with longer progression-free survival (PFS) in age-sex adjusted analysis in the ADV/MET population, without effect on OS. CONCLUSIONS: Our study shows that age, tumour size and immunosuppression are significantly associated with survival in localized adnexal carcinomas. Radiotherapy may improve PFS in the ADV/MET population but not in localized and recurrent carcinomas after complete excision.

Knowledge-based, computerized, patient clinical decision support system for perioperative pain, nausea and constipation management: a clinical feasibility study.

Opioid administration is particularly challenging in the perioperative period. Computerized-based Clinical Decision Support Systems (CDSS) are a promising innovation that might improve perioperative pain control. We report the development and feasibility validation of a knowledge-based CDSS aiming at optimizing the management of perioperative pain, postoperative nausea and vomiting (PONV), and laxative medications. This novel CDSS uses patient adaptive testing through a smartphone display, literature-based rules, and individual medical prescriptions to produce direct medical advice for the patient user. Our objective was to test the feasibility of the clinical use of our CDSS in the perioperative setting. This was a prospective single arm, single center, cohort study conducted in Strasbourg University Hospital. The primary outcome was the agreement between the recommendation provided by the experimental device and the recommendation provided by study personnel who interpreted the same care algorithm (control). Thirty-seven patients were included in the study of which 30 (81%) used the experimental device. Agreement between these two care recommendations (computer driven vs. clinician driven) was observed in 51 out 54 uses of the device (94.2% [95% CI 85.9-98.4%]). The agreement level had a probability of 86.6% to exceed the 90% clinically relevant agreement threshold. The knowledge-based, patient CDSS we developed was feasible at providing recommendations for the treatment of pain, PONV and constipation in a perioperative clinical setting.Trial registration number & date The study protocol was registered in ClinicalTrial.gov before enrollment began (NCT05707247 on January 26th, 2023).

Severe non-atopic asthma: omalizumab can reduce severe asthma exacerbations.

INTRODUCTION: Humanized monoclonal anti-IgE antibody (omalizumab) has demonstrated efficacy in severe atopic asthma. However, few studies have assessed its efficacy in non-atopic and even less in T2-low severe asthma. The objective was to determinate the omalizumab response according to atopic status. METHODS: This retrospective, real-world study was performed in the Chest Diseases Department of Strasbourg University Hospital from January 1, 2006, to June 30, 2017. The response to omalizumab was assessed in 139 patients 4, 6, and 12 months after treatment and compared to data collected prior to omalizumab initiation. RESULTS: Forty-four patients (31.7%) had severe non-atopic asthma and 95 (68.3%) had a severe atopic asthma. In the non-atopic group, omalizumab significantly reduced the severe exacerbation rate by 44% (95% CI 18-64%, p < 0.05), 43% (CI 95% 20-60%, p < 0.05), and 54% (CI 95% 36-67%, p < 0.05), at 4, 6 and 12 months, respectively. A trend toward improvement in FEV1, asthma control and oral corticosteroid use was also observed. These results were not significantly different from those obtained in atopic asthmatics except a more effective oral corticosteroid sparing in atopic group (p < 0.05). Similar reduction of severe exacerbation rates were observed in T2-low asthma subgroup (non-atopic, non-eosinophilic). CONCLUSION: Omalizumab was effective in severe asthma, regardless of atopic status.

Efficacy of imiquimod in the management of lentigo maligna.

BACKGROUND: Lentigo maligna (LM) is a melanocytic proliferation occurring on photo-exposed skin that may progress to LM melanoma. Surgery is recommended as first-line treatment. Excision margins of 5-10 mm remain, without international consensus. Several studies have shown that imiquimod, an immunomodulator, induces LM regression. This study investigated the effect of imiquimod versus placebo in neoadjuvant settings. PATIENTS AND METHODS: We performed a prospective, randomized, multicentre, phase III clinical study. Patients were randomly assigned in 1:1 ratio to receive imiquimod or placebo for 4 weeks, followed by LM excision 4 weeks after the last application of imiquimod or placebo. The primary endpoint was extra-lesional excision, with a 5 mm margin from the residual pigmentation after imiquimod or vehicle. Secondary endpoints included the gain on the surface removed between the two groups; number of revision surgeries to obtain extra-lesional excisions; relapse-free time; and number of complete remissions after treatment. RESULTS: A total of 283 patients participated in this study; 247 patients, 121 patients in the placebo group and 126 in the imiquimod group, accounted for the modified ITT population. The first extralesional extirpation was performed in 116 (92%) imiquimod patients and in 102 (84%) placebo patients; the difference was not significant (p = 0.0743). Regarding the surface of LM, imiquimod reduced the LM surface (4.6-3.1 cm2 ) significantly (p < 0.001) more compared to the placebo (3.9-4.1 cm2 ). CONCLUSION: Imiquimod reduces the lentigo maligna surface after 1 month of treatment, without a higher risk of intralesional excision and with a positive aesthetic outcome.

Metabolic Benefit of Teleconsultation for Diabetes Management During the COVID-19 Pandemic: A French Observational Prospective Study.

Aim: To investigate the impact of teleconsultation on glycemic control in patients with diabetes during the COVID-19 pandemic. Methods: In this observational prospective study, the main outcome was the comparison of glycated hemoglobin (HbA1c) between patients with or without teleconsultation at 6-month follow-up. Results: From March 17 to May 31, 2020, 610 patients were included, 456 were followed-up using Teleconsultation présent (TC+) and 154 not using No Teleconsultation (TC-). Patients of TC+ Group were younger, 57 ± 17 versus 65 ± 15.5 years (p < 0.001), with a lower body mass index, 28 ± 6.2 kg/m2 versus 30 ± 5.8 kg/m2, compared to those of TC- Group (p < 0.001). HbA1c were comparable between the two groups: 7.35 ± 0.27% for TC+ versus 7.48 ± 0.22% for TC- Group. At 6-month follow-up, HbA1c was lower in TC+ versus TC- Group: 7.21 ± 0.15% versus 7.6 ± 0.18% (p = 0.004). Conclusion: Our findings point toward the feasibility and usefulness of teleconsultation for the follow-up of patients with diabetes in such exceptional circumstances.

Cerebral perfusion using ASL in patients with COVID-19 and neurological manifestations: A retrospective multicenter observational study.

BACKGROUND AND PURPOSE: Cerebral hypoperfusion has been reported in patients with COVID-19 and neurological manifestations in small cohorts. We aimed to systematically assess changes in cerebral perfusion in a cohort of 59 of these patients, with or without abnormalities on morphological MRI sequences. METHODS: Patients with biologically-confirmed COVID-19 and neurological manifestations undergoing a brain MRI with technically adequate arterial spin labeling (ASL) perfusion were included in this retrospective multicenter study. ASL maps were jointly reviewed by two readers blinded to clinical data. They assessed abnormal perfusion in four regions of interest in each brain hemisphere: frontal lobe, parietal lobe, posterior temporal lobe, and temporal pole extended to the amygdalo-hippocampal complex. RESULTS: Fifty-nine patients (44 men (75%), mean age 61.2 years) were included. Most patients had a severe COVID-19, 57 (97%) needed oxygen therapy and 43 (73%) were hospitalized in intensive care unit at the time of MRI. Morphological brain MRI was abnormal in 44 (75%) patients. ASL perfusion was abnormal in 53 (90%) patients, and particularly in all patients with normal morphological MRI. Hypoperfusion occurred in 48 (81%) patients, mostly in temporal poles (52 (44%)) and frontal lobes (40 (34%)). Hyperperfusion occurred in 9 (15%) patients and was closely associated with post-contrast FLAIR leptomeningeal enhancement (100% [66.4%-100%] of hyperperfusion with enhancement versus 28.6% [16.6%-43.2%] without, p = 0.002). Studied clinical parameters (especially sedation) and other morphological MRI anomalies had no significant impact on perfusion anomalies. CONCLUSION: Brain ASL perfusion showed hypoperfusion in more than 80% of patients with severe COVID-19, with or without visible lesion on conventional MRI abnormalities.

Increased operative time has a negative impact on clinical outcome in arthroscopic rotator cuff repair.

BACKGROUND: Few data are available about the impact of operative time on outcome of rotator cuff repair. AIM: The aim of this study was to evaluate the impact of operative time on clinical outcome and tendon healing after arthroscopic rotator cuff repair. METHODS: Patients operated on for distal supraspinatus tear in our institution between 2012 and 2018 were included retrospectively. Operative time, from skin incision until skin closure, was extracted from medical files. For statistical analysis, operative time was treated as a quantitative variable. Endpoints were clinical outcome (Constant score, range of motion), tendon healing (on CT or MRI) and complications at 1 year. The significance threshold was set at p = 0.05. RESULTS: A total of 219 Patients, with a mean age of 54.6 years (range 40-70 years), were included. Mean operative time 44.9 min (range 14-140 min). Significant correlations (p < 0.05) were found for Constant score and external rotation at 1 year: increasing operative time by 1 min led to a decrease in Constant score of 0.115 points, or 6.9 points for a 60-min increase (p = 0.0167) and a decrease in external rotation of 0.134°, or 8.04° for a 60-min increase (p = 0.0214). No significant correlations were found for anterior elevation at 1 year (p = 0.2577), tendon healing at 1 year (p = 0.295) or onset of complications during follow-up (p = 0.193). DISCUSSION: The minimal clinically important difference in Constant score in patients undergoing rotator cuff surgery is between 6 and 10 points. An increase of more than 60 min in operative time significantly impacted clinical outcome of arthroscopic distal supraspinatus repair, but not tendon healing. LEVEL OF EVIDENCE: Level III: Retrospective Cohort Design. Therapeutic Study.

Determinants of the evolutions of behaviours, school adjustment and quality of life in autistic children in an adapted school setting: an exploratory study with the International Classification of Functioning, disability and health (ICF).

BACKGROUND: Previous studies about Quality of Life (QoL) in autistic children (ASD) have put forward the negative impact of factors such as Autism Spectrum Disorder (ASD) severity, psychiatric comorbidities and adaptive behaviour impairment. However, little is known about the relation of these factors to school adjustment, measured with the International Classification of Functions disability and health (ICF) framework (World Health Organization, 2001), and QoL evolutions. Thus, this study aimed at investigating the determinants of behaviours, school adjustment and QoL changes in 32 children in an ASD inclusion program over one academic year. METHODS: Using Bayesian methods, we studied the impact of ASD severity, psychiatric comorbidities, adaptive behaviour level and a diagnosis of Pathological Demand Avoidance (PDA) on evolutions of behaviour, school adjustment (measured with the ICF) and QoL. RESULTS: As predicted, adequate adaptive behaviour levels were associated with better progress of behaviours and school adjustment whereas psychiatric comorbidities were related to worse outcome of school adjustment. Contrary to our hypotheses, severe ASD was associated to better evolution of adjustment at school. PDA was not discriminant. We did not find any association between the studied factors and the evolution of QoL over the academic year. CONCLUSION: Our results show that the assessment of adaptive behaviour levels, psychiatric comorbidities and ASD severity level may be useful predictors to discriminate of school adjustment evolution (assessed by teachers within the ICF model) over a one-year period in autistic children. The assessment of this time course of school adjustment was sensitive to change and adapted to differentiate evolutions in an inclusive education framework. The investigation of quality of school life of autistic children as well as its determinants may therefore be relevant to improving academic adaptation. However, further research in larger groups, over longer periods and in different personalized school settings for autistic children is needed.

Sex Differences in the Evolution of Neutralizing Antibodies to Severe Acute Respiratory Syndrome Coronavirus 2.

We measured anti-spike (S), nucleoprotein (N), and neutralizing antibodies in sera from 308 healthcare workers with a positive reverse-transcription quantitative polymerase chain reaction result for severe acute respiratory syndrome coronavirus 2 and with mild disease, collected at 2 timepoints up to 6 months after symptom onset. At month 1, anti-S and -N antibody levels were higher in male participants aged >50 years and participants with a body mass index (BMI) >25 kg/m2. At months 3-6, anti-S and anti-N antibodies were detected in 99% and 59% of individuals, respectively. Anti-S antibodies and neutralizing antibodies declined faster in men than in women, independent of age and BMI, suggesting an association of sex with evolution of the humoral response.

Effectiveness and safety of nivolumab in patients with advanced melanoma: A multicenter, observational study.

This retrospective observational study aimed to determine the effectiveness, safety and patterns of the use of nivolumab in patients with advanced melanoma in real-world clinical practice in France using data from a Temporary Authorization for Use Program (ATU). Data were collected from patients with unresectable or metastatic melanoma enrolled in a French national database (Réseau pour la Recherche et l'Investigation Clinique sur le Mélanome: Ric-Mel) and treated with nivolumab during the ATU program (12 September 2014 to 31 August 2015). The primary objectives of the study were to evaluate the effect of patient characteristics on clinical response and overall survival (OS). Among 400 included patients (median age 66 years), the majority (83%) received nivolumab as second- or subsequent-line therapy. The median durations of progression-free survival and OS were 3.3 and 14.1 months, respectively, and 31.6% of patients achieved an objective response with a median duration of 20.1 months (range: 0-34.7). The safety profile of nivolumab was manageable and consistent with those of previous clinical trials, with an incidence of grade 3-5 adverse events of 13.8%. The safety and effectiveness of nivolumab in patients with advanced melanoma in real-world clinical practice in France were in line with the data reported in the Phase 3 trials CheckMate 066 and 037 of nivolumab in this patient population.

Interleukin 6 receptor inhibition in primary Sjögren syndrome: a multicentre double-blind randomised placebo-controlled trial.

OBJECTIVES: No immunomodulatory drug has been approved for primary Sjögren's syndrome, a systemic autoimmune disease affecting 0.1% of the population. To demonstrate the efficacy of targeting interleukin 6 receptor in patients with Sjögren's syndrome-related systemic complications. METHODS: Multicentre double-blind randomised placebo-controlled trial between 24 July 2013 and 16 July 2018, with a follow-up of 44 weeks, involving 17 referral centres. Inclusion criteria were primary Sjögren's syndrome according to American European Consensus Group criteria and score ≥5 for the EULAR Sjögren's Syndrome Disease activity Index (ESSDAI, score of systemic complications). Patients were randomised to receive either 6 monthly infusions of tocilizumab or placebo. The primary endpoint was response to treatment at week 24. Response to treatment was defined by the combination of (1) a decrease of at least 3 points in the ESSDAI, (2) no occurrence of moderate or severe activity in any new domain of the ESSDAI and (3) lack of worsening in physician's global assessment on a Visual Numeric Scale ≥1/10, all as compared with enrolment. RESULTS: 110 patients were randomised, 55 patients to tocilizumab (mean (SD) age: 50.9 (12.4) years; women: 98.2%) and 55 patients to placebo (54.8 (10.7) years; 90.9%). At 24 weeks, the proportion of patients meeting the primary endpoint was 52.7% (29/55) in the tocilizumab group and 63.6% (35/55) in the placebo group, for a difference of -11.4% (95% credible interval -30.6 to 9.0) (Pr[Toc >Pla]=0.14). CONCLUSION: Among patients with primary Sjögren's syndrome, the use of tocilizumab did not improve systemic involvement and symptoms over 24 weeks of treatment compared with placebo. TRIAL REGISTRATION NUMBER: NCT01782235.

Bayesian predictive probabilities: a good way to monitor clinical trials.

BACKGROUND: Bayesian methods, with the predictive probability (PredP), allow multiple interim analyses with interim posterior probability (PostP) computation, without the need to correct for multiple looks at the data. The objective of this paper was to illustrate the use of PredP by simulating a sequential analysis of a clinical trial. METHODS: We used data from the Laryngobloc trial that planned to include 480 patients to demonstrate the equivalence of success between a laryngoscopy performed with the Laryngobloc® device and a control device. A crossover Bayesian design was used. The success rates of the two laryngoscopy devices were compared. Interim analyses, computed from random numbers of subjects, were simulated. RESULTS: The PostP of equivalence rapidly reached the predefined bound of 0.95. The PredP computed with an equivalence margin of 10% reached the efficacy bound between 352 and 409 of the 480 included patients. If a frequentist analysis had been made on the basis of 217 out of 480 subjects, the study would have been prematurely stopped for equivalence. The PredP indicated that this result was nonetheless unstable and that the equivalence was, thus far, not guaranteed. CONCLUSIONS: Based on these interim analyses, we can conclude with a sufficiently high probability that the equivalence would have been met on the primary outcome before the predetermined end of this particular trial. If a Bayesian approach using PredP had been used, it would have allowed an early termination of the trial by reducing the calculated sample size by 15-20%.

Statin (mis)use in older people: A cross-sectional study using French health insurance databases.

PURPOSE: To describe the occurrence of potential statin misuse, its characteristics and associated factors in older people. METHODS: A retrospective cross-sectional study was conducted in Alsace and Lorraine (France) using French health insurance databases. Study population comprised community-dwelling patients and nursing homes residents aged 80 and over, who received at least one statin prescription between January 1, 2017 to April 30, 2017 (N = 38 268). Potential statin misuse was identified considering off-label uses, high-intensity doses, drug contraindications and statin-drug interactions. RESULTS: At least one potential statin misuse was detected for 19 468 patients (50.9%). Off-label prescription was the most frequent misuse observed (53.6%), followed by high-intensity statin dose (30.5%). Polypharmacy (five to nine drugs) and excessive polypharmacy (10 or more drugs) were the main risk factors associated with potential statin misuse (adjusted OR = 2.6 and 4.7 respectively). Nursing home, multi-morbidity and the presence of multiple prescriptions from different doctors for the same patient were other risk factors significantly associated. Two sensitivity analyzes (reconsiderations of off-label and high statin dose definitions) revealed the same statistical trend. CONCLUSION: Potential statin misuse is frequent in people aged 80 and over. These findings should serve as a warning to health care professionals and hopefully will contribute to ensure an appropriate and safe use of statin in aged population.

Randomized Study Comparing a Reusable Morcellator with a Resectoscope in the Hysteroscopic Treatment of Uterine Polyps: The RESMO Study.

STUDY OBJECTIVE: To compare a reusable hysteroscopic morcellator and standard resectoscopes in the hysteroscopic management of uterine polyps. DESIGN: Single-center randomized prospective single-blind trial (resectoscope-morcellator study). SETTING: Centre Médico-chirurgical Obstétrique teaching hospital, Strasbourg University Hospitals, France. PATIENTS: All patients presenting with a single endometrial polyp of size 1 cm or larger. INTERVENTIONS: After consent, the patients were randomized into 2 groups: hysteroscopic morcellation (HM) group or standard resection (SR) group. Office-based review hysteroscopy was performed 6 weeks to 8 weeks after surgery. Primary end point: time of morcellation or resection. SECONDARY OUTCOMES: total operating time (minutes), volume of fluid used (mL), fluid deficit (mL), number of morcellator or resectoscope insertions, operator comfort (visual analog scale: 0 to 10) and quality of vision (0 to 5), perioperative complications, completeness of resection, need to convert to another technique, pain assessment (visual analog scale), and length of hospitalization. At review hysteroscopy, we noted whether the resection or morcellation had been effective and if synechiae were present or absent. Statistical analyses followed Bayesian methods. MEASUREMENTS AND MAIN RESULTS: Ninety patients were randomized: 45 in the HM group and 45 in the SR group. The average size of polyps at hysteroscopy was 13.3 mm. Morcellation time was lower than resection time (6.1 minutes vs 9 minutes; p [HM < SR] = .996). This also applied to total operating time (12.7 minutes vs 15.6 minutes; p [HM < SR] = .985), number of device insertions (1.50 vs 6; p [HM < SR] > .999), volume of fluid used (766.9 mL vs 1118.9 mL; p [HM < SR] = .994), and fluid deficit (60.2 mL vs 169.8 mL; p [HM < SR] = .989). Operator comfort was better in the HM group (8.4 vs 7.4; p [HM > SR] = .999) as was visualization (4 vs 3.7; p [HM > SR] = .911, highly probable). Operative complications were higher in the SR group (5 vs 0; p [HM < SR] = .989]. One patient in the SR group died after surgery owing to an anesthetic complication (anaphylactic shock complicated by pulmonary embolism). No differences were noted between the groups for pain assessment, length of hospitalization, and outcome on review hysteroscopy. CONCLUSION: The reusable morcellator is quicker, uses less fluid with less deficit and fewer introductory maneuvers, and offers better comfort and visualization than the resectoscope while being as effective for the hysteroscopic treatment of uterine polyps.

Very preterm infants displayed similar imitation skills to full-term infants at term equivalent age.

AIM: Very preterm infants are exposed to an atypical environment that could alter their developmental trajectory. We aimed to examine neonatal imitation, a foundation of social cognition, in very preterm and full-term infants. METHODS: In Strasbourg, France, between 2015 and 2018, we prospectively investigated the development of imitation skills. Very preterm (27 to 33 weeks of gestational age, n = 20) and full-term infants (n = 20) were enrolled using four gestures: tongue protrusion, mouth opening, sequential finger movements and hand movements. All testing were performed in infants at term-equivalent age. Two independent and blinded observers coded the behaviour of each infant on video recording. Facial expressions or hand movements, similar to the one presented, were quantified and classified according to their timing. RESULTS: A total of 37 out of 40 infants imitated at least one gesture. The very preterm and term infants did not differ in the presence of imitation or its timing for the four gestures tested. The very preterm infants displayed more imitation abilities for sequential finger movement. Tongue protrusion and sequential finger movement were the particularly strong imitated gesture in both groups. CONCLUSION: These findings are the first to show similar neonatal imitation in term and very preterm infants. Our results may support early parent-infant social interactions.

Postoperative rotator cuff integrity: can we consider type 3 Sugaya classification as retear?

BACKGROUND: Sugaya classification is a widely accepted classification system that is used to analyze postoperative rotator cuff tendon integrity. However, there are inconsistencies in the literature as to whether type 3 Sugaya should be considered as a retear or healed tendon. PURPOSE: We aimed to show that type 3 Sugaya is not a retear by comparing the long-term supraspinatus and infraspinatus muscle degeneration and the functional outcomes of type 3 with those of type 4 and 5 Sugaya. We hypothesized that the clinical course of type 3 Sugaya would be different from type 4 or 5 Sugaya. METHOD: The study was a retrospective multicenter review of all the rotator cuff repair done in 2003-2004. We included all the patients who had undergone supraspinatus repair with 10-year follow-up (magnetic resonance imaging done with full functional assessment). Data collection included pre- and postoperative supraspinatus and infraspinatus fatty infiltration, supraspinatus muscle atrophy, and Constant score with a separate analysis of its Strength subsection. Supraspinatus tendon integrity at 10-year follow-up was determined according to Sugaya classification. The patients were divided into 2 groups: type 3 Sugaya and type 4 and 5 Sugaya. Statistical comparison was done between the groups. RESULTS: There was no significant difference in the preoperative fatty infiltration of the supraspinatus and infraspinatus, supraspinatus muscle atrophy, and Constant score between the 2 groups. However, type 3 Sugaya patients had significantly better scores in the preoperative Strength subsection. Postoperatively, type 3 Sugaya patients showed significantly lesser fatty infiltration of the supraspinatus and infraspinatus, lesser supraspinatus muscle atrophy, and higher Constant score compared with type 4 and 5 Sugaya (P < .001). CONCLUSION: Patients with type 3 Sugaya supraspinatus tendon exhibited lesser muscle degeneration in the supraspinatus and infraspinatus and performed better in functional assessment compared with type 4 and 5 Sugaya patients. We inferred that type 3 Sugaya should not be considered as a retear.

Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma.

BACKGROUND: Nivolumab and ipilimumab are immune checkpoint inhibitors that have been approved for the treatment of advanced melanoma. In the United States, ipilimumab has also been approved as adjuvant therapy for melanoma on the basis of recurrence-free and overall survival rates that were higher than those with placebo in a phase 3 trial. We wanted to determine the efficacy of nivolumab versus ipilimumab for adjuvant therapy in patients with resected advanced melanoma. METHODS: In this randomized, double-blind, phase 3 trial, we randomly assigned 906 patients (≥15 years of age) who were undergoing complete resection of stage IIIB, IIIC, or IV melanoma to receive an intravenous infusion of either nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks (453 patients) or ipilimumab at a dose of 10 mg per kilogram every 3 weeks for four doses and then every 12 weeks (453 patients). The patients were treated for a period of up to 1 year or until disease recurrence, a report of unacceptable toxic effects, or withdrawal of consent. The primary end point was recurrence-free survival in the intention-to-treat population. RESULTS: At a minimum follow-up of 18 months, the 12-month rate of recurrence-free survival was 70.5% (95% confidence interval [CI], 66.1 to 74.5) in the nivolumab group and 60.8% (95% CI, 56.0 to 65.2) in the ipilimumab group (hazard ratio for disease recurrence or death, 0.65; 97.56% CI, 0.51 to 0.83; P<0.001). Treatment-related grade 3 or 4 adverse events were reported in 14.4% of the patients in the nivolumab group and in 45.9% of those in the ipilimumab group; treatment was discontinued because of any adverse event in 9.7% and 42.6% of the patients, respectively. Two deaths (0.4%) related to toxic effects were reported in the ipilimumab group more than 100 days after treatment. CONCLUSIONS: Among patients undergoing resection of stage IIIB, IIIC, or IV melanoma, adjuvant therapy with nivolumab resulted in significantly longer recurrence-free survival and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with ipilimumab. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 238 ClinicalTrials.gov number, NCT02388906 ; Eudra-CT number, 2014-002351-26 .).

Effect of adding vildagliptin to insulin in haemodialysed patients with type 2 diabetes: The VILDDIAL study, a randomized, multicentre, prospective study.

AIM: To evaluate the effect of adding the dipeptidyl-peptidase-4 inhibitor vildagliptin to insulin on the glycaemic control of patients with type 2 diabetes undergoing haemodialysis. METHODS: Overall, 65 insulin-treated patients with type 2 diabetes undergoing haemodialysis (HbA1c: 7.3% ± 1.1%; age: 70.5 ± 8.5 years) were randomized (1:1) either to receive vildagliptin 50 mg/day in addition to insulin (vildagliptin-insulin group) or to pursue their usual insulin regimen (insulin-only group). Continuous glucose monitoring (CGM) was performed for 48 ± 6 hours at baseline and at week 12. The primary study endpoint was change from baseline in mean interstitial glucose using CGM. The secondary endpoints included other CGM variables and glucose control markers. RESULTS: After 12 weeks, a greater reduction in mean CGM glucose from baseline was observed in the vildagliptin-insulin group compared with the insulin-only group, although the between-treatment difference was not statistically significant (mean difference [CI 95%]: -0.96 mmol/L [-2.09; 0.18] vs. -0.29 mmol/L [-1.29; 0.76], P = 0.32). However, a significant decrease from baseline in HbA1c, glycated albumin and insulin daily doses was observed in the vildagliptin-insulin group versus the insulin-only group (-0.6% [-1.19; -0.1], P < 0.01), in the vildagliptin-insulin group versus no change in the insulin-only group (-130.6 µmol/L [-271; 10.7] vs. +36.2 µmol/L [-164.4; 236.9], P = 0.04 and - 5.9 IU/day [-1.8; 7.1] vs. +1.1 IU/day [-14.5; 16.6], P = 0.01, respectively). There was no significant difference in the percentage of time spent in hypoglycaemia using CGM, occurrence of severe hypoglycaemia or number of adverse events. CONCLUSION: In this study, vildagliptin added to insulin improved glycaemic control with an associated insulin-sparing effect in patients with type 2 diabetes undergoing haemodialysis and was well tolerated.

Determining the number of components in PLS regression on incomplete data set.

Partial least squares regression - or PLS regression - is a multivariate method in which the model parameters are estimated using either the SIMPLS or NIPALS algorithm. PLS regression has been extensively used in applied research because of its effectiveness in analyzing relationships between an outcome and one or several components. Note that the NIPALS algorithm can provide estimates parameters on incomplete data. The selection of the number of components used to build a representative model in PLS regression is a central issue. However, how to deal with missing data when using PLS regression remains a matter of debate. Several approaches have been proposed in the literature, including the Q2 criterion, and the AIC and BIC criteria. Here we study the behavior of the NIPALS algorithm when used to fit a PLS regression for various proportions of missing data and different types of missingness. We compare criteria to select the number of components for a PLS regression on incomplete data set and on imputed data set using three imputation methods: multiple imputation by chained equations, k-nearest neighbour imputation, and singular value decomposition imputation. We tested various criteria with different proportions of missing data (ranging from 5% to 50%) under different missingness assumptions. Q2-leave-one-out component selection methods gave more reliable results than AIC and BIC-based ones.