Tyrosine Kinase Inhibitors in Cancers: treatment optimization - Part I.

A multitude of TKI has been developed and approved targeting various oncogenetic alterations. While these have provided improvements in efficacy compared with conventional chemotherapies, resistance to targeted therapies occurs. Mutations in the kinase domain result in the inability of TKI to inactivate the protein kinase. Also, gene amplification, increased protein expression and downstream activation or bypassing of signalling pathways are commonly reported mechanisms of resistance. Improved understanding of mechanisms involved in TKI resistance has resulted in the development of new generations of targeted agents. In a race against time, the search for new, more potent and efficient drugs, and/or combinations of drugs, remains necessary as new resistance mechanisms to the latest generation of TKI emerge. This review examines the various generations of TKI approved to date and their common mechanisms of resistance, focusing on TKI targeting BCR-ABL, epidermal growth factor receptor, anaplastic lymphoma kinase and BRAF/MEK tyrosine kinases.

Evaluation of a new tool - "Step by step with my baby" - to support parental involvement in the care of preterm infants.

BACKGROUND AND AIMS: Parental guidance is essential for supporting parental involvement, maintaining the quality and safety of infant care, and limiting parental stress. The efficiency of a new tool to support parental empowerment - "Step by step with my baby" - was evaluated. The perception of this tool by parents and nurses was studied. METHODS: This was a prospective, observational study conducted from September 2019 to December 2020 at a level-3 neonatal center. A total of 79 newborns (<33 weeks of gestational age or small for gestational age), 84 parents, and 94 nurses were included. The new tool that was evaluated is in the form of a drawing of flowers to be colored according to the parents' ability to care for their newborn. Six domains were explored and given a score (total of 35 points) according to the parents' ability to care for each item: behavior, skin-to-skin contact, carrying, oral and tube feeding, and routine care. The use and relevance of this tool were evaluated by parents and caregivers. RESULTS: At a mean of 19 days of life, parents required caregiver support regardless of the skill domain (6/35). After 26 days, the mean score increased to 19.4 (p < 0.05). Parents felt autonomous in changing diapers and monitoring temperature but always required help for skin-to-skin contact, carrying, and feeding with or without a tube. The progression was not affected by the presence of siblings, the distance from home, and staying in the parental hospital room. For 67 % of the parents, the tool gave them a better understanding of their newborn and helped them be more confident (69 %) without feeling judged (81 %). These feelings were upheld by nurses. CONCLUSIONS: This tool was efficient for evaluating parents' autonomy and helped them take ownership of the care provided.

Neoadjuvant in Situ and Systemic Immunotherapy with Lymph Node Cryoablation in Resectable Stage III Melanoma Metastasis: a Proof-of-Concept Study.

PURPOSE: Complete lymph node dissection is the recommended treatment for clinically detectable lymph nodes in stage III melanoma. This surgery is associated with substantial morbidity. We hypothesize that combining percutaneous imaging-guided cryoablation of locoregional lymph nodes metastases with neoadjuvant in situ and systemic immunotherapy could allow disease control and evaluate the feasibility of this combination in this proof-of-concept study. METHODS: We enrolled 15 patients with stage IIIB/IIIC melanoma. Patients were treated as follows: a single 240 mg flat dose infusion of nivolumab on day 1, cryoablation under local anesthesia using CT on day 2, and a single intralesional injection of 10-20 mg of ipilimumab into the lymphadenopathy treated by cryotherapy on day 3. Five-eight weeks after this procedure, complete lymph node dissection was performed according to routine care. The primary outcome measure of this study was feasibility, measured as the number of failures (i.e., inability to complete the entire procedure). RESULTS: The procedure was carried out successfully in 15 out of 15 patients with an observed number of failures of 0. The Bayesian analysis showed an estimated failure rate of 4.2% [0.2-20.6]. Eight patients (53%) had adverse events secondary to either immunotherapy or cryotherapy. Grade 3/4 events occurred in three patients, but all resolved quickly and patients could proceed to surgery as scheduled. Eight patients (53%) had a pathological complete or near complete response. CONCLUSION: Combining percutaneous cryotherapy with in situ ipilimumab and systemic nivolumab for stage III resectable melanoma is feasible with tolerable toxicity.

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).

Repurposing the Fibrosis-4 Score in Rheumatoid Arthritis: Data from the ESPOIR Cohort.

Background: We aimed to evaluate the value of the Fibrosis-4 (FIB-4) score as a prognostic factor in RA in the prospective ESPOIR cohort. Methods: We included patients from the ESPOIR cohort with a diagnosis of RA according to ACR/EULAR criteria. The formula for the FIB-4 score is as follows: [age (years) × aspartate transaminase level (U/L)]/[platelet count (109/L) × alanine aminotransferase level (U/L)1/2]. We used a linear mixed-effects model with a random effect of patient to account for repeated measures over time. Results: Overall, 647 of the 813 patients included met the ACR/EULAR criteria for RA, with no differential diagnosis during the first 10 years of follow-up. Of these patients, at baseline, 633 had a calculable FIB-4 score. Median FIB-4 score was 0.75 (interquartile range 0.53-0.99). On multivariate analysis, FIB-4 score was not independently associated with progression of Disease Activity Score in 28 joints over 10 years of follow-up, unlike baseline C-reactive protein level and SJC. Baseline FIB-4 score was not associated with the modified Sharp score at 5-year follow-up, unlike age and ACPAs. FIB-4 score was not associated with mortality (hazard ratio 1.1 [95% CI 0.46; 2.8], p = 0.77) or major adverse cardiovascular events (0.46 [0.13; 1.6], p = 0.22) over the 10-year follow-up. No significant change in FIB-4 score over time was related to treatments. Conclusions: The present prospective cohort study did not find a prognostic role of FIB-4 score in RA. Reassuringly, FIB-4 score was not increased with DMARD treatment after 10 years of follow-up.

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.

History of mood and anxiety disorders affects return to work and return to sports after rotator cuff repair.

INTRODUCTION: After rotator cuff repair (RCR), return to work and return to sports is affected by various psychosocial factors. The role of one of these factors - mood and anxiety disorders (MAD) - is still not clear. The primary objective of this study was to determine the influence of prior MAD on the return to work and return to sports after RCR. Our hypothesis was that patients with a history of MAD would take longer to return to work and to sports after RCR, and the rate of return would be lower, than for patients without MAD. MATERIALS AND METHODS: This was a retrospective single-center study of patients who underwent arthroscopic RCR (distal supraspinatus tear). Patients who were employed and those who participated in sports before the surgery were included in the "working" and "sports" groups, respectively. The primary outcomes were the time to return to work and return to sports after surgery. The secondary outcomes were the ratio of patients returning to work and to sports at 3, 6 and 12 months; rate of return to same level of sports; need to change or stop working or sports. The effects of prior MAD on these various outcomes were determined using Bayesian multivariate analysis. RESULTS: The "working" group consisted of 158 patients (of which 16.5% had MAD) and the "sports" group consisted of 118 patients (of which 17.8% had MAD). In those with a history of MAD, return to work was 21±11 weeks later and the return to sports was 17±8 weeks later than in those without MAD. There was a 98% probability that return to work or return to sports was delayed by at least 4 weeks in patients with history of MAD. The likelihood that patients with prior MAD who undergo RCR will completely abandon their sport was 2.8 times higher (OR=2.8 [1; 7.8]). CONCLUSION: We found a negative influence of prior MAD on the return to work and return to sports after RCR. LEVEL OF EVIDENCE: III; retrospective case-control study.

Prognosis of impulse control disorders in Parkinson's disease: a prospective controlled study.

BACKGROUND: The long-term prognosis of impulsive compulsive disorders (ICD) remains poorly studied in Parkinson's disease (PD). OBJECTIVE: Evaluating the natural history of ICD and its impact on PD symptoms including cognition and treatment adjustments. MATERIALS AND METHODS: We assessed PD patients at baseline (BL) with (BL-ICD+) or without (BL-ICD-) ICD despite dopamine agonist (DA) exposure of > 300 mg levodopa-equivalent daily dose for > 12 months at baseline and after more than two years of follow-up. ICD were assessed using the Ardouin's Scale of Behaviors in PD (ASBPD), cognition using the Mattis scale, and PD symptoms using the UPDRS score. Treatment adjustments, DA withdrawal-associated symptoms, and ICDs social consequences were recorded. RESULTS: 149 patients were included (78 cases and 71 controls), mean duration of follow-up was 4.4 ± 1 years. At baseline, psychiatric disorders were more common among BL-ICD + (42.3 vs 12.3% among BL-ICD-, p < 0.01). At follow-up, 53.8% of BL-ICD + were not ICD-free while 21.1% of BL-ICD- had developed ICD. BL-ICD + more frequently experienced akinesia (21.8 vs 8.5%, p = 0.043) and rigidity worsening (11.5 vs 1.4%, p = 0.019) following therapeutic modifications. Decision to decrease > 50% DA doses (12.8 vs 1.4%, p = 0.019) or to withdraw DA (19.2 vs 5.6%, p = 0.025) was more frequently considered among BL-ICD+ . At follow-up, the prevalence of cognitive decline was lower among BL-ICD + (19.2 vs 37.1%, p = 0.025). CONCLUSION: ICDs were associated with increased psychiatric burden at baseline and better cognitive prognosis. Most patients were still showing ICDs at the follow-up visit, suggesting ICD to be considered as a chronic, neuropsychiatric disorder.

COVID-19 promotes endothelial dysfunction and thrombogenicity: role of proinflammatory cytokines/SGLT2 prooxidant pathway.

BACKGROUND: COVID-19 is associated with an increased risk of cardiovascular complications. Although cytokines have a predominant role in endothelium damage, the precise molecular mechanisms are far from being elucidated. OBJECTIVES: The present study hypothesized that inflammation in patients with COVID-19 contributes to endothelial dysfunction through redox-sensitive SGLT2 overexpression and investigated the protective effect of SGLT2 inhibition by empagliflozin. METHODS: Human plasma samples were collected from patients with acute, subacute, and long COVID-19 (n = 100), patients with non-COVID-19 and cardiovascular risk factors (n = 50), and healthy volunteers (n = 25). Porcine coronary artery endothelial cells (ECs) were incubated with plasma (10%). Protein expression levels were determined using Western blot analyses and immunofluorescence staining, mRNA expression by quantitative reverse transcription-polymerase chain reaction, and the level of oxidative stress by dihydroethidium staining. Platelet adhesion, aggregation, and thrombin generation were determined. RESULTS: Increased plasma levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor-α, monocyte chemoattractant protein-1, and soluble intercellular adhesion molecule-1 were observed in patients with COVID-19. Exposure of ECs to COVID-19 plasma with high cytokines levels induced redox-sensitive upregulation of SGLT2 expression via proinflammatory cytokines IL-1ß, IL-6, and tumor necrosis factor-α which, in turn, fueled endothelial dysfunction, senescence, NF-κB activation, inflammation, platelet adhesion and aggregation, von Willebrand factor secretion, and thrombin generation. The stimulatory effect of COVID-19 plasma was blunted by neutralizing antibodies against proinflammatory cytokines and empagliflozin. CONCLUSION: In patients with COVID-19, proinflammatory cytokines induced a redox-sensitive upregulation of SGLT2 expression in ECs, which in turn promoted endothelial injury, senescence, platelet adhesion, aggregation, and thrombin generation. SGLT2 inhibition with empagliflozin appeared as an attractive strategy to restore vascular homeostasis in COVID-19.

Health-Related Quality of Life with Pembrolizumab in Patients with Locally Advanced or Recurrent or Metastatic Cutaneous Squamous Cell Carcinoma: KEYNOTE-629.

INTRODUCTION: At first interim analysis of KEYNOTE-629, health-related quality of life (HRQoL) with pembrolizumab was stable or improved over 48 weeks in recurrent or metastatic (R/M) cutaneous squamous cell carcinoma (cSCC). HRQoL results from the second interim analysis in R/M or locally advanced (LA) cSCC are presented. METHODS: Patients received pembrolizumab 200 mg every 3 weeks for ≤ 2 years. Change in EORTC Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and EQ-5D-5L scores were exploratory end points. Primary analysis was performed at week 12 to ensure adequate completion/compliance. Descriptive analyses were also conducted through weeks 48 and 75 for the LA and R/M cohorts, respectively. RESULTS: At data cutoff (29 July 2020), mean scores in the LA cohort (n = 47) were stable from baseline to week 12 for EORTC QLQ-C30 global health status (GHS)/quality of life (QoL) (-0.27 points [95% confidence interval (CI) -10.93 to 10.39]), physical functioning (-1.29 points [95% CI -8.77 to 6.19]), and EQ-5D-5L visual analog scale (2.06 [95% CI -7.70 to 11.82]). HRQoL remained stable through week 48 in the LA cohort; 76.6% and 74.5% of patients had improved or stable GHS/QoL and physical functioning scores, respectively. HRQoL continued to show stability or improvement through week 75 in the R/M cohort (n = 99); 71.7% and 64.6% of patients had improved or stable GHS/QoL and physical functioning scores, respectively. CONCLUSIONS: Pembrolizumab has demonstrated antitumor activity and manageable safety. The current analysis shows pembrolizumab treatment preserved HRQoL. Collectively, these results support pembrolizumab as standard of care for LA or R/M cSCC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03284424-September 15, 2017.

Evolutionary design of explainable algorithms for biomedical image segmentation.

An unresolved issue in contemporary biomedicine is the overwhelming number and diversity of complex images that require annotation, analysis and interpretation. Recent advances in Deep Learning have revolutionized the field of computer vision, creating algorithms that compete with human experts in image segmentation tasks. However, these frameworks require large human-annotated datasets for training and the resulting "black box" models are difficult to interpret. In this study, we introduce Kartezio, a modular Cartesian Genetic Programming-based computational strategy that generates fully transparent and easily interpretable image processing pipelines by iteratively assembling and parameterizing computer vision functions. The pipelines thus generated exhibit comparable precision to state-of-the-art Deep Learning approaches on instance segmentation tasks, while requiring drastically smaller training datasets. This Few-Shot Learning method confers tremendous flexibility, speed, and functionality to this approach. We then deploy Kartezio to solve a series of semantic and instance segmentation problems, and demonstrate its utility across diverse images ranging from multiplexed tissue histopathology images to high resolution microscopy images. While the flexibility, robustness and practical utility of Kartezio make this fully explicable evolutionary designer a potential game-changer in the field of biomedical image processing, Kartezio remains complementary and potentially auxiliary to mainstream Deep Learning approaches.

Impact of a reduced iodine load with deep learning reconstruction on abdominal MDCT.

To evaluate the impact of a reduced iodine load using deep learning reconstruction (DLR) on the hepatic parenchyma compared to conventional iterative reconstruction (hybrid IR) and its consequence on the radiation dose and image quality. This retrospective monocentric intraindividual comparison study included 66 patients explored at the portal phase using different multidetector computed tomography parameters: Group A, hybrid IR algorithm (hybrid IR) and a nonionic low-osmolality contrast agent (350 mgI/mL); Group B, DLR algorithm (DLR) and a nonionic iso-osmolality contrast agent (270 mgI/mL). We recorded the attenuation of the liver parenchyma, image quality, and radiation dose parameters. The mean hounsfield units (HU) value of the liver parenchyma was significantly lower in group B, at 105.9 ± 10.9 HU versus 118.5 ± 14.6 HU in group A. However, the 90%IC of mean liver attenuation in the group B (DLR) was between 100.8 HU and 109.3 HU. The signal-to-noise ratio of the liver parenchyma was significantly higher on DLR images, increasing by 56%. However, for both the contrast-to-noise ratio (CNR) and CNR liver/PV no statistical difference was found, even if the CNR liver/PV ratio was slightly higher for group A. The mean dose-length product and computed tomography dose index volume values were significantly lower with DLR, corresponding to a radiation dose reduction of 36% for the DLR. Using a DLR algorithm for abdominal multidetector computed tomography with a low iodine load can provide sufficient enhancement of the liver parenchyma up to 100 HU in addition to the advantages of a higher image quality, a better signal-to-noise ratio and a lower radiation dose.

Early Hospital Discharge Using Remote Monitoring for Patients Hospitalized for COVID-19, Regardless of Need for Home Oxygen Therapy: A Descriptive Study.

AIM: Since beds are unavailable, we prospectively investigated whether early hospital discharge will be safe and useful in patients hospitalized for COVID-19, regardless of their need for home oxygen therapy. POPULATION AND METHODS: Extending the initial inclusion criteria, 62 patients were included and 51 benefited from home telemonitoring, mainly assessing clinical parameters (blood pressure, heart rate, respiratory rate, dyspnea, temperature) and peripheral saturation (SpO2) at follow-up. RESULTS: 47% of the patients were older than 65 years; 63% needed home oxygen therapy and/or presented with more than one comorbidity. At home, the mean time to dyspnea and tachypnea resolutions ranged from 21 to 24 days. The mean oxygen-weaning duration was 13.3 ± 10.4 days, and the mean SpO2 was 95.7 ± 1.6%. The nurses and/or doctors managed 1238 alerts. Two re-hospitalizations were required, related to transient chest pain or pulmonary embolism, but no death occurred. Patient satisfaction was good, and 743 potential days of hospitalization were saved for other patients. CONCLUSION: The remote monitoring of vital parameters and symptoms is safe, allowing for early hospital discharge in patients hospitalized for COVID-19, whether or not home oxygen therapy was required. Oxygen tapering outside the hospital allowed for a greater reduction in hospital stay. Randomized controlled trials are necessary to confirm this beneficial effect.

Cost-effectiveness of encorafenib with binimetinib in unresectable or metastatic BRAF-mutant melanoma.

OBJECTIVE: The objective of this study was to determine the cost-effectiveness of encorafenib with binimetinib (EncoBini) as compared to other targeted double combination therapies, namely dabrafenib with trametinib (DabraTrame) and vemurafenib with cobimetinib (VemuCobi), for the treatment of BRAF V600-mutant unresectable or metastatic melanoma (MM) from the French payer perspective. METHODS: A partitioned survival model was developed considering a lifetime horizon. The model structure simulated the clinical pathway of patients with BRAF V600-mutant MM. Clinical effectiveness and safety inputs were sourced from the COLUMBUS trial, a network meta-analysis and published literature. Costs, resource use, and the quality of life inputs were obtained from the literature and appropriate French sources. RESULTS: Over a lifetime horizon, EncoBini was associated, on average, with reduced costs and increased quality adjusted life years (QALYs), dominating both targeted double combination therapies. For a willingness-to-pay threshold of €90,000 per QALY, the probability of EncoBini being cost-effective against either comparator remained above 80%. The most influential model parameters were the hazard ratios for the overall survival of EncoBini vs DabraTrame and VemuCobi, the pre- and post-progression utility values, as well as treatment dosages and the relative dose intensity of all interventions. CONCLUSION: EncoBini is associated with reduced costs and increased QALYs, dominating other targeted double combination therapies (DabraTrame, VemuCobi) for patients with BRAF V600-mutant MM in France. EncoBini is a highly cost-effective intervention in MM.

First-Line, Fixed-Duration Nivolumab Plus Ipilimumab Followed by Nivolumab in Clinically Diverse Patient Populations With Unresectable Stage III or IV Melanoma: CheckMate 401.

PURPOSE: To address the paucity of data in patients with historically poor outcomes, we conducted the single-arm phase IIIb CheckMate 401 study to evaluate the safety and efficacy of nivolumab plus ipilimumab followed by nivolumab monotherapy in clinically diverse patient populations with advanced melanoma. METHODS: Treatment-naive patients with unresectable stage III-IV melanoma received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg (240 mg following a protocol amendment) once every 2 weeks for ≤24 months. The primary end point was the incidence of grade 3-5 select treatment-related adverse events (TRAEs). Overall survival (OS) was a secondary end point. Outcomes were evaluated in subgroups defined by Eastern Cooperative Oncology Group performance status (ECOG PS), brain metastasis status, and melanoma subtype. RESULTS: In total, 533 patients received at least one dose of study drug. Grade 3-5 select TRAEs affecting the GI (16%), hepatic (15%), endocrine (11%), skin (7%), renal (2%), and pulmonary (1%) systems occurred in the all-treated population; similar incidence rates were observed across all subgroups. At 21.6 months' median follow-up, 24-month OS rates were 63% in the all-treated population, 44% in the ECOG PS 2 subgroup (including patients with cutaneous melanoma only), 71% in the brain metastasis subgroup, 36% in the ocular/uveal melanoma subgroup, and 38% in the mucosal melanoma subgroup. CONCLUSION: Nivolumab plus ipilimumab followed by nivolumab monotherapy was tolerable in patients with advanced melanoma and poor prognostic characteristics. Efficacy was similar between the all-treated population and patients with brain metastases. Reduced efficacy was observed in patients with ECOG PS 2, ocular/uveal melanoma, and/or mucosal melanoma, highlighting the continued need for novel treatment options for these difficult-to-treat patients.

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.

Association Between Bruton's Tyrosine Kinase Gene Overexpression and Risk of Lymphoma in Primary Sjögren's Syndrome.

OBJECTIVE: We undertook this study to analyze whole blood gene expression and to investigate the role of B cell genes in primary Sjögren's syndrome-related non-Hodgkin lymphoma (primary SS-NHL). METHODS: Peripheral whole blood samples were collected from 345 well-phenotyped patients with primary SS enrolled in the prospective Assessment of Systemic Signs and Evolution in Sjögren's Syndrome (ASSESS) cohort. Transcriptomic analysis was performed using human Clariom S Arrays (Affymetrix). In our primary analysis, we considered patients with incident lymphoma (i-primary SS-NHL) as the case group and all patients without lymphoma as the comparison group. In our sensitivity analyses, we considered all patients with primary SS-NHL, including those with a history of lymphoma (h-primary SS-NHL), as the case group and primary SS patients without lymphoma, stratified on their risk factors of lymphoma, as the comparison group. RESULTS: Twenty-one patients with primary SS-NHL (including 8 with i-primary SS-NHL and 13 h-primary SS-NHL) were eligible for transcriptomic analysis; we compared these patients to 324 primary SS controls without lymphoma, including 110 with moderate to severe disease activity and 61 with no risk factor of lymphoma. Functional clustering analyses revealed an enrichment of genes related to innate and adaptive immunity, including B cell-related genes. Bruton's tyrosine kinase (BTK) and a proliferation-inducing ligand (APRIL) genes were overexpressed before the occurrence of lymphoma in patients with incident lymphoma compared with patients without lymphoma. In sensitivity analyses, BTK was consistently up-regulated across all comparisons performed. BTK expression was associated with risk of lymphoma on multivariate analyses, which considered 9 validated predictors of lymphoma in primary SS. CONCLUSION: BTK and APRIL were overexpressed in the peripheral blood of primary SS patients prior to lymphoma. The association between BTK, APRIL, and primary SS-NHL requires confirmation in other prospective cohorts.

Implementation of an enhanced recovery program for complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in a referral center: a case control prospective study.

Objectives: Current recommendations regarding enhanced recovery programs (ERPs) after complete cytoreductive surgery (CCRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are based on a low level of evidence. The aim of this study is to evaluate the effect of implementing an adapted ERP for CCRS and HIPEC in a referral center. Methods: We conducted a study with a prospective group of 44 patients (post-ERP group) who underwent CCRS with HIPEC between July 2016 and June 2018, the period during which ERP was implemented. This group was compared to a second retrospective group of 21 patients who underwent CCRS with HIPEC between June 2015 and June 2016, during which ERP was not yet implemented (pre-ERP group). Results: The ERP compliance rate was 65% in the post-ERP group. The hospital length of stay (HLS) was shorter in the post-ERP group: 24.9 days (IQR 11-68, pre-ERP group) vs. 16.1 days (IQR 6-45, post-ERP group), as was the major morbidity rate (pre-ERP group=33.3% vs. post-ERP group=20.5%). The nasogastric tube, urinary catheter and abdominal drains were all retrieved faster in the post-ERP group. Conclusions: The implementation of an adapted ERP after CCRS with HIPEC procedures reduces morbidity and shortens the HLS.

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.

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.