Safety and efficacy of salvage endoscopic submucosal dissection for Barrett's neoplasia recurrence after radiofrequency ablation.

BACKGROUND AND STUDY AIMS: This study evaluated the safety and efficacy of salvage endoscopic submucosal dissection for Barrett's neoplasia recurrence after radiofrequency ablation. PATIENTS AND METHODS: Data from patients at sixteen centers were collected for a multicentric retrospective study. Patients who underwent at least one RFA treatment for Barrett's esophagus and thereafter underwent further esophageal ESD for neoplasia recurrence were included. RESULTS: Data from 56 patients treated by salvage ESD performed between April 2014 and November 2022 were collected. Immediate complications included one muscular tear (1.8%) treated with stent (Agree classification: grade IIIa), two patients had transmural perforations (4%) and five patients had muscular tears (9%) treated with clips and without clinical impact and not considered as adverse event. Seven patients (12.5%) developed strictures, treated by balloon dilation (grade IIIa). Histological analysis showed 36 adenocarcinomas, 17 high-grade dysplasia, and 3 low-grade dysplasia. En-bloc and R0 resection rates were 89% and 66%, respectively. Resections were curative in thirty-three patients (59%), non-curative in 22 patients (39%), including 11 "local risk" (19.5%) and 11 "high risk" resections (19.5%). At the end of follow-up with a median time of 14 [0-75] months after salvage ESD eventually associated with further endoscopic treatment (RFA, argon plasma coagulation, endoscopic mucosal resection, ESD), neoplasia remission ratio was 37/53 (70%) and the median remission time was 13 [1-75] months. CONCLUSION: In expert hands, salvage ESD is a safe and effective treatment for recurrence of Barrett's neoplasia after RFA treatment.

Chronic spontaneous urticaria: Evidence of systemic microcirculatory changes.

BACKGROUND: Chronic spontaneous urticaria (CSU) is a chronic inflammatory skin disease where activation of endothelial cells (ECs) at sites of skin lesions leads to increased blood flow, leakage of fluid into the skin, cellular infiltration, and vascular remodeling. To understand the disease duration and the sometimes vague systemic symptoms accompanying flares, the objective of this study was to examine if CSU comes with systemic vascular changes at the microcirculatory level. METHODS: We investigated CSU patients (n = 49) and healthy controls (HCs, n = 44) for microcirculatory differences by nailfold videocapillaroscopy (NVC) and for blood levels of the soluble EC biomarkers serum vascular endothelial growth factor (VEGF), soluble E-selectin, and stem cell factor (SCF). Patients were also assessed for clinical characteristics, disease activity, and markers of autoimmune CSU (aiCSU). RESULTS: CSU patients had significantly lower capillary density, more capillary malformations, and more irregular capillary dilations than HCs on NVC. Serum levels of VEGF, soluble E selectin and SCF were similar in CSU patients and HCs. CSU patients with higher VEGF levels had significantly more abnormal capillaries. Patients with markers of aiCSU, that is, low IgE levels or increased anti-TPO levels, had significantly more capillaries and less capillary dilations than those without. CONCLUSION: Our results suggest that CSU comes with systemic microcirculatory changes, which may be driven, in part, by VEGF.

Myopic (Peri)papillary Changes and Visual Field Defects.

Purpose: Myopic eyes combining gamma peripapillary atrophy and peripapillary staphyloma were sorted according to the presence of intrachoroidal cavitation (PICCs) or its absence (combinations). Visual field defects (VFDs) and factors discriminating these groups were analyzed. Methods: These groups were sorted by optical coherence tomography. VFDs were assessed using the Humphrey® Field Analyzer 3, SITA standard. Ovality index (OI) was the ratio between the shortest and longest diameters of the disc. The proportions of PICCs, lamina cribrosa defects (LCDs) and clusters in each Garway-Heath's sector (A-F) were analyzed. All variables were compared between PICCs and combinations. A multivariate logistic regression analysis was performed ultimately. Results: Of the 93 eyes, we obtained, 20 PICCs and 73 combinations. The prevalence of VFDs and LCDs in PICCs were 65% (13/20) and 30% (6/20), respectively. PICCs 85% (17/20) and LCDs 12% (11/93) predominated in sector B (inferotemporal) and clusters 9.7% (9/93) in the corresponding sector. The proportion of VFDs was significantly higher in PICCs than combinations (p < 0.001). In sector B, the proportion of LCDs was significantly higher in PICCs than combinations (p = 0.011). The mean OI was significantly lower (p < 0.001) in PICCs than combinations. Multivariate logistic regression analysis concluded that mean OI (p < 0.001) was the only statistically significant factor discriminating PICCs and combinations. Conclusion: Mean OI discriminating PICCs from combinations is further evidence of a gradation of structural changes between them. It could be related to the higher proportion of VFDs in PICCs. The predominant distribution of PICCs infero-temporally supports PICC as a cause of uncertainty in glaucoma diagnosis in high myopia. Furthermore, the highest proportion of PICCs and LCDs in this sector highlights its vulnerability to damage in myopic eyes and deserves further investigation as it is also primarily involved in glaucoma.

Chronic Spontaneous Urticaria in Belgium: Deciphering the Clinical Profile and Treatment of Patients Visiting an Urban City Immunology Department.

BACKGROUND: Chronic urticaria (CSU) is a chronic inflammatory mast cell-driven disorder of which reliable clinical data in Belgium are lacking. This study focusses on clinical characteristics of CSU patients presenting at an urban Immunology-Allergology department. METHODS: Outpatients with CSU were included from 2018 to 2021. Clinical characteristics, Dermatology Life Quality Index (DLQI) and Urticaria activity score (UAS7) were collected by thorough anamnesis and questionnaires. Furthermore, patients underwent provocational testing, an autologous serum skin test (ASST) and a blood analysis. RESULTS: The study included 49 CSU patients and 20 non-CSU subjects. CSU was distributed differently with age and sex, showing higher numbers in female patients below the age of 46 years. 67% of CSU patients had accompanying angioedema of which 9% were reported genital. CSU patients scored a mean 8/30 on their DLQI questionnaire. There was no significant difference in immunoglobulin E (IgE), C-reactive protein, and tryptase levels between CSU patients and controls. Oral glucocorticosteroids were prescribed in 23% of CSU patients during their disease course though only half of these patients had a severity grade 4 CSU. In 82% of the included CSU patients, Urticaria Control Test (UCT) scores were below 12. When we hypothetically considered low IgE levels and high IgG anti-thyroid peroxidase levels as differentiation marker for autoimmune (ai)CSU and non-aiCSU, we found that 4% of all included CSU patients could be considered aiCSU. CONCLUSION: Generally, the inner-city population displayed the same clinical characteristics, as previous cohorts from Northern Europe. The relatively high rate of CSU patients receiving oral glucocorticosteroid treatment for their disease though not always classified as severe, underlines the need to train doctors of various specialties in the treatment algorithms of CSU. Furthermore, by looking at potential autoimmune characteristics, our findings open perspectives on the identification of new routinely used clinical parameters for the detection of aiCSU, a relatively small immunological subtype of CSU.

The Association Between Meningioma and Breast Cancer: A Systematic Review and Meta-analysis.

Importance: A potential relationship between meningioma and breast cancer was suggested 70 years ago. However, to date, no conclusive evidence is available on this topic. Objective: To provide a comprehensive review of the literature on the association of meningioma with breast cancer, supported by a meta-analysis. Data Sources: A systematic PubMed search was performed up to April 2023 to identify articles on the association of meningioma with breast cancer. The following key words were used strategically: meningioma, breast cancer, breast carcinoma, association, relation. Study Selection: All studies reporting women diagnosed with meningioma and breast cancer were identified. The search strategy was not limited by study design or publication date but only included articles in English. Additional articles were identified via citation searching. Studies reporting a complete population of meningiomas or breast cancer patients throughout a specific study period and a proportion of patients with a second pathology could be used for the meta-analysis. Data Extraction and Synthesis: Data extraction was performed by 2 authors in accordance with the Preferred Reporting Items for Systematic Reviews (PRISMA) statement. Meta-analyses regarding both populations were performed using a random-effects model. Risk of bias was assessed. Main Outcomes and Measures: The main measures were whether there was an increased prevalence of breast cancer in female patients with meningioma and whether there was an increased prevalence of meningioma in female patients with breast cancer. Results: A total of 51 retrospective studies (case reports, case series, and cancer registry reports) describing 2238 patients with both diseases were identified; 18 studies qualified for prevalence analyses and meta-analysis. The random-effects meta-analysis (13 studies) revealed a significantly greater prevalence of breast cancer in female patients with meningioma than in the overall population (odds ratio [OR], 9.87; 95% CI, 7.31-13.32). Meningioma incidence in patients with breast cancer (11 studies) was greater than that in the baseline population; however, the difference according to the random-effects model was not statistically significant (OR, 1.41; 95% CI, 0.99-2.02). Conclusions and Relevance: This large systematic review and the meta-analysis on the association between meningioma and breast cancer found nearly 10-fold higher odds of breast cancer in female patients with meningioma compared with the general female population. These findings suggest that female patients with meningioma should be screened more intensively for breast cancer. Further research is required to identify the factors causing this association.

RHOJ controls EMT-associated resistance to chemotherapy.

The resistance of cancer cells to therapy is responsible for the death of most patients with cancer1. Epithelial-to-mesenchymal transition (EMT) has been associated with resistance to therapy in different cancer cells2,3. However, the mechanisms by which EMT mediates resistance to therapy remain poorly understood. Here, using a mouse model of skin squamous cell carcinoma undergoing spontaneous EMT during tumorigenesis, we found that EMT tumour cells are highly resistant to a wide range of anti-cancer therapies both in vivo and in vitro. Using gain and loss of function studies in vitro and in vivo, we found that RHOJ-a small GTPase that is preferentially expressed in EMT cancer cells-controls resistance to therapy. Using genome-wide transcriptomic and proteomic profiling, we found that RHOJ regulates EMT-associated resistance to chemotherapy by enhancing the response to replicative stress and activating the DNA-damage response, enabling tumour cells to rapidly repair DNA lesions induced by chemotherapy. RHOJ interacts with proteins that regulate nuclear actin, and inhibition of actin polymerization sensitizes EMT tumour cells to chemotherapy-induced cell death in a RHOJ-dependent manner. Together, our study uncovers the role and the mechanisms through which RHOJ acts as a key regulator of EMT-associated resistance to chemotherapy.

Embolization before Gamma Knife radiosurgery for cerebral arteriovenous malformations does not negatively impact its obliteration rate: a series of 190 patients.

PURPOSE: Embolization of arteriovenous malformations (AVMs) before radiosurgery has been reported to negatively impact the obliteration rate. This study aims to assess treatment outcomes in a series of 190 patients treated by Gamma Knife radiosurgery (GKRS) for previously embolized AVMs. METHODS: The institutional database of AVMs was retrospectively reviewed between January 2004 and March 2018. The clinical and radiological data of patients treated with GKRS for previously embolized AVMs were analyzed. Predicting factors of obliteration and hemorrhage following GKRS were assessed with univariate and multivariate regression analyses. RESULTS: The mean AVM size was significantly reduced after embolization (p < 0.001). The obliteration rate was 78.4%. Multivariate analyses showed that a lower Spetzler-Martin grade (p = 0.035) and a higher marginal dose (p = 0.007) were associated with obliteration. Post-GKRS hemorrhages occurred in 14 patients (7.4%). A longer time between diagnosis and GKRS was the only factor associated with post-GKRS hemorrhages in multivariate analysis (p = 0.022). Complications related to the combined treatment were responsible for a new permanent neurological disability in 20 patients (10.5%), and a case of death (0.5%). CONCLUSIONS: This study shows that the embolization of AVMs does not have a negative impact on the obliteration rate after radiosurgery. Embolization reduces the AVM size to a treatable volume by GKRS. However, the combined treatment results in an increased complication rate related to the addition of the risks of each treatment modality.

Fibrin-coated collagen fleece versus absorbable dural sealant for sellar closure after transsphenoidal pituitary surgery: a comparative study.

Various surgical methods to prevent postoperative cerebrospinal fluid (CSF) leaks during transsphenoidal surgery have been reported. However, comparative studies are scarce. We aimed to compare the efficacy of a fibrin-coated collagen fleece (TachoSil) versus a dural sealant (DuraSeal) to prevent postoperative CSF leakage. We perform a retrospective study comparing two methods of sellar closure during endoscopic endonasal transsphenoidal surgery (EETS) for pituitary adenoma resection: TachoSil patching versus DuraSeal packing. Data concerning diagnosis, reconstruction technique, and surgical outcomes were analyzed. The primary endpoint was postoperative CSF leak rate. We reviewed 198 consecutive patients who underwent 219 EETS for pituitary adenoma from February 2007 and July 2018. Intraoperative CSF leak occurred in 47 cases (21.5%). A total of 33 postoperative CSF leaks were observed (15.1%). A reduction of postoperative CSF leaks in the TachoSil application group compared to the conventional technique using Duraseal was observed (7.7% and 18.2%, respectively; p = 0.062; Pearson exact test) although non-statistically significant. Two patients required lumbar drainage, and no revision repair was necessary to treat postoperative CSF rhinorrhea in Tachosil group. Fibrin-coated collagen fleece patching may be a valuable method to prevent postoperative cerebrospinal fluid (CSF) leaks during EETS for pituitary adenoma resection.

Worldwide Evolution of Vaccinable and Nonvaccinable Viral Skin Infections: Google Trends Analysis.

BACKGROUND: Most common viral skin infections are not reportable conditions. Studying the population dynamics of these viral epidemics using traditional field methods is costly and time-consuming, especially over wide geographical areas. OBJECTIVE: This study aimed to explore the evolution, seasonality, and distribution of vaccinable and nonvaccinable viral skin infections through an analysis of Google Trends. METHODS: Worldwide search trends from January 2004 through May 2021 for viral skin infections were extracted from Google Trends, quantified, and analyzed. RESULTS: Time series decomposition showed that the total search term volume for warts; zoster; roseola; measles; hand, foot, and mouth disease (HFMD); varicella; and rubella increased worldwide over the study period, whereas the interest for Pityriasis rosea and herpes simplex decreased. Internet searches for HFMD, varicella, and measles exhibited the highest seasonal patterns. The interest for measles and rubella was more pronounced in African countries, whereas the interest for HFMD and roseola was more pronounced in East Asia. CONCLUSIONS: Harnessing data generated by web searches may increase the efficacy of traditional surveillance systems and strengthens the suspicion that the incidence of some vaccinable viral skin infections such as varicella, measles, and rubella may be globally increasing, whereas the incidence of common nonvaccinable skin infections remains stable.

Effectiveness of benzyl benzoate treatment on clinical symptoms and Demodex density over time in patients with rosacea and demodicosis: a real life retrospective follow-up study comparing low- and high-dose regimens.

BACKGROUND: Patients with rosacea and demodicosis have high facial skin Demodex densities (Dds), which decrease with benzyl benzoate (BB) treatment. OBJECTIVES: To evaluate the impact of topical BB (+crotamiton) treatment on Dds and clinical symptoms during prolonged follow-up and to compare low (12% once daily) and high (12% twice daily or 20-24% once daily) BB dose regimens. METHODS: This retrospective study included 344 patients (103 rosacea, 241 demodicosis) observed for 7.1 ± 0.5 months. Dds were measured on two consecutive standardized skin surface biopsies and symptoms evaluated using investigator global assessment. Compliance was considered good if patients correctly followed treatment instructions. RESULTS: At final follow-up, in the 248 patients with good compliance, Dd had normalized in 217 (88%) and symptoms cleared in 204 (82%). The high dose was associated with better compliance and faster results than the low-dose. The higher the initial Dd, the longer it took to normalize. In the 96 poorly compliant patients, treatment was less effective and slower. CONCLUSIONS: These findings indirectly support a key role of the mite in rosacea and suggest that topical treatment with BB (+crotamiton), especially the higher dose, may be a useful alternative treatment for rosacea as well as for demodicosis.[Formula: see text].

Epidemiologic evolution of common cutaneous infestations and arthropod bites: A Google Trends analysis.

BACKGROUND: Common cutaneous infestations and arthropod bites are not reportable conditions in most countries. Their worldwide epidemiologic evolution and distribution are mostly unknown. OBJECTIVE: To explore the evolution and geographic distribution of common cutaneous infestations and arthropod bites through an analysis of Google Trends. METHODS: Search trends from 2004 through March 2021 for common cutaneous infestations and arthropod bites were extracted from Google Trends, quantified, and analyzed. RESULTS: Time series decomposition showed that total search term volume for pubic lice decreased worldwide over the study period, while the interest for ticks, pediculosis, insect bites, scabies, lice, and bed bugs increased (in increasing order). The interest for bed bugs was more pronounced in the former Union of Soviet Socialist Republics countries, interest for lice in Near East and Middle East countries, and interest for pubic lice in South American countries. Internet searches for bed bugs, insect bites, and ticks exhibited the highest seasonal patterns. LIMITATIONS: Retrospective analysis limits interpretation. CONCLUSION: Surveillance systems based on Google Trends may enhance the timeliness of traditional surveillance systems and suggest that, while most cutaneous infestations increase worldwide, pubic lice may be globally declining.

Real-world adherence to topical therapies in patients with moderate acne.

BACKGROUND: Real-life data on topical treatments in daily practice in patients with moderate acne are poorly characterized. OBJECTIVE: To investigate the drug survival of topical treatments administered to patients with moderate acne in a daily practice. METHODS: Survival analysis was performed on subjects (Belgian university hospital and private practice outpatient dermatology patients) with moderate acne who received topical therapies according to the current published guidelines. RESULTS: A total of 1160 treatment series (1029 patients) were included, including benzoyl peroxide (BPO, n = 93), azelaic acid (n = 246), adapalene (n = 254), a fixed combination of adapalene 0.1% and BPO 2.5% (A/BPO, n = 264), and a fixed combination of clindamycin 1.2% and tretinoin 0.025% gel (Clin-RA, n = 303). The calculated overall median treatment duration of all drugs was 2 months. The probability of treatment discontinuation after only 3 months was 50%. Overall, the drugs were discontinued for the following reasons: controlled acne (9%), side effects (9%), ineffectiveness (52%), combination of side effects and ineffectiveness (3%), and other reasons (1%). Overall, 27% patients were lost to follow-up. LIMITATIONS: The post hoc study design and generalizability limit interpretation of the data. CONCLUSION: Overall, the median treatment duration of topical anti-acne therapies was short (2 months). The main reason for discontinuation was ineffectiveness.

Which factors influence Demodex proliferation? A retrospective pilot study highlighting a possible role of subtle immune variations and sebaceous gland status.

Demodex folliculorum and brevis are commensal mites that live in low densities in human pilosebaceous follicles as part of the normal adult microbiota, but that give rise to demodicosis and, possibly, rosacea, when they proliferate excessively. This proliferation is favored by various factors, including age, marked immunosuppression, sebaceous gland hyperplasia, and hypervascularization-related factors. To study possible factors influencing mite proliferation, we explored the effects of different variables on Demodex densities (Dd) in a retrospective study of two groups of subjects selected on the basis of their clinical diagnosis: Demodex+, consisting of subjects with demodicosis or with centro-facial papulopustules suggesting rosacea (n = 844, mean Dd 263.5 ± 8.9 D/cm2 ), and Demodex-, consisting of subjects with other facial dermatoses or healthy facial skin (n = 200, mean Dd 2.3 ± 0.4 D/cm2 ). Demodex densities were measured using two consecutive standardized skin surface biopsies (SSSB1 [superficial] and SSSB2 [deep]) taken from the same facial site on each subject. In the Demodex+ group: the SSSB1 decreased with age in women (p = 0.004), and the SSSB2 increased with age in men (p = 0.001) (the pattern was similar for SSSB1 + 2, but not statistically significant); Dds were lower in those who had received cortisone (either topically or systemically); 13 subjects (1.5%) had known immunosuppression, 62 (7.3%) had hypothyroidism, and in 20 (3.6% of the women) there was a reported link with pregnancy; 78 of the subjects (9.2%) were part of a pair from the same family or household; when associated bacterial infection was suspected, Staphylococcus epidermidis was often isolated. Our results suggest close interactions between the mite, sebaceous gland size and function, and subtle variations of immune status. Potential factors influencing Demodex proliferation should be further investigated, including hypothyroidism, pregnancy, corticosteroid administration, Staphylococcus epidermidis, contagiousity, and genetic background.

Prevalence of scratching during examination among patients with scabies and among patients with other pruritic dermatoses.

BACKGROUND: Scabies is a parasitic skin disease. Its clinical diagnosis may be challenging. METHODS: In a prospective observational study, we enrolled all consecutive patients ≥16 years of age with a presumptive diagnosis of scabies and all patients ≥16 years of age with a diffuse itchy dermatosis lasting for more than 1 week. We investigated whether patients with scabies were more prone to scratch themselves during the consultation than patients with other pruritic dermatoses. RESULTS: We observed that a significant proportion of patients (25/62, 40%) with scabies had to scratch while talking or being examined. This clinical sign was less frequently noticed in patients with pruritic dermatoses of other origins (26/196, 13%) (P < 0.001). CONCLUSIONS: The observation of a patient scratching himself during the consultation should prompt serious consideration of scabies. This easily observable clinical sign may be especially useful in low-resource settings, where scabies is known to be very prevalent.

Heterotypic cell-cell communication regulates glandular stem cell multipotency.

Glandular epithelia, including the mammary and prostate glands, are composed of basal cells (BCs) and luminal cells (LCs)1,2. Many glandular epithelia develop from multipotent basal stem cells (BSCs) that are replaced in adult life by distinct pools of unipotent stem cells1,3-8. However, adult unipotent BSCs can reactivate multipotency under regenerative conditions and upon oncogene expression3,9-13. This suggests that an active mechanism restricts BSC multipotency under normal physiological conditions, although the nature of this mechanism is unknown. Here we show that the ablation of LCs reactivates the multipotency of BSCs from multiple epithelia both in vivo in mice and in vitro in organoids. Bulk and single-cell RNA sequencing revealed that, after LC ablation, BSCs activate a hybrid basal and luminal cell differentiation program before giving rise to LCs-reminiscent of the genetic program that regulates multipotency during embryonic development7. By predicting ligand-receptor pairs from single-cell data14, we find that TNF-which is secreted by LCs-restricts BC multipotency under normal physiological conditions. By contrast, the Notch, Wnt and EGFR pathways were activated in BSCs and their progeny after LC ablation; blocking these pathways, or stimulating the TNF pathway, inhibited regeneration-induced BC multipotency. Our study demonstrates that heterotypic communication between LCs and BCs is essential to maintain lineage fidelity in glandular epithelial stem cells.

Did Osteoblastic Cell Therapy Improve the Prognosis of Pre-fracture Osteonecrosis of the Femoral Head? A Randomized, Controlled Trial.

BACKGROUND: In patients with nontraumatic osteonecrosis of the femoral head (ONFH), implantation of bone marrow aspirate concentrate (BMAC) could delay the progression of osteonecrosis and improve symptoms in pre-fracture ONFH. However, the BMAC content, especially in osteoblastic stem cells, could have an important individual variability. An autologous osteoblastic cell product could improve the effect of such cell-based therapy. QUESTIONS/PURPOSES: (1) Does autologous osteoblastic cell therapy decrease the likelihood of progression to subchondral fracture with or without early collapse corresponding to Association Research Circulation Osseous (ARCO) classification Stage III or higher, and provide a clinically important pain improvement compared with BMAC treatment alone? (2) Were patients treated with osteoblastic cell therapy less likely to undergo subsequent THA? (3) What proportion of patients in the treatment and control groups experienced adverse events after surgery? METHODS: Between 2004 and 2011, we treated 279 patients for Stage I to II hip osteonecrosis (ON) with surgery. During that time, our general indications for surgery in this setting included non-fracture ON lesions. To be eligible for this randomized, single-blind trial, patients needed to have an ONFH Stage I or II; we excluded those with traumatic ONFH, hemoglobinopathies and positive serology for hepatitis B, C or HIV. Of those treated surgically for this diagnosis during the study period, 24% (67) agreed to participate in this randomized trial. Hips with pre-fracture ONFH were randomly treated with a core decompression procedure associated with either implantation of a BMAC (BMAC group; n = 26) or osteoblastic cell (osteoblastic cell group; n = 30). The groups were not different in terms of clinical and imaging characteristics. The primary study outcome was treatment response, defined as the absence of progression to subchondral fracture stage (ARCO stage III or higher) plus a clinically important pain improvement defined as 1 cm on a 10-cm VAS. The secondary endpoint of interest was the frequency in each group of subsequent THA and the frequency of adverse events. The follow-up duration was 36 months. We used an as-treated analysis (rather than intention-to-treat) for our efficacy endpoint, and an intention-to-treat analysis for adverse events. Overall, 26 of 26 patients in the BMAC group and 27 of 30 in the osteoblastic cell group completed the trial. RESULTS: At 36 months, no clinically important differences were found in any study endpoint. There was no difference in the proportion of patients who had progressed to fracture (ARCO stage III or higher; 46% of the BMAC hips [12 of 26] versus 22% in the hips with osteoblastic cells [six of 27], hazard ratio, 0.47 [95% CI 0.17 to 1.31]; p = 0.15). There was no clinically important difference in VAS pain scores. No differences were found for either the WOMAC or the Lequesne indexes. With the numbers available, there was no difference in the proportion of patients in the groups who underwent THA at 36 months 15% (four of 27) with osteoblastic cells versus 35% (nine of 26) with BMAC; p = 0.09 With the numbers available, we found no differences between the treatment and control groups in terms of the frequencies of major adverse events. CONCLUSIONS: We found no benefit to osteoblastic cells over BMAC in patients with pre-collapse ONFH; side effects were uncommon and generally mild in both groups. This study could be used as pilot data to help determine sample sizes for larger (presumably multicenter) randomized controlled trials. However, this novel treatment cannot be recommended in routine practice until future, larger studies demonstrate efficacy. LEVEL OF EVIDENCE: Level II, therapeutic study.

Digenic inheritance of human primary microcephaly delineates centrosomal and non-centrosomal pathways.

Primary microcephaly (PM) is characterized by a small head since birth and is vastly heterogeneous both genetically and phenotypically. While most cases are monogenic, genetic interactions between Aspm and Wdr62 have recently been described in a mouse model of PM. Here, we used two complementary, holistic in vivo approaches: high throughput DNA sequencing of multiple PM genes in human patients with PM, and genome-edited zebrafish modeling for the digenic inheritance of PM. Exomes of patients with PM showed a significant burden of variants in 75 PM genes, that persisted after removing monogenic causes of PM (e.g., biallelic pathogenic variants in CEP152). This observation was replicated in an independent cohort of patients with PM, where a PM gene panel showed in addition that the burden was carried by six centrosomal genes. Allelic frequencies were consistent with digenic inheritance. In zebrafish, non-centrosomal gene casc5 -/- produced a severe PM phenotype, that was not modified by centrosomal genes aspm or wdr62 invalidation. A digenic, quadriallelic PM phenotype was produced by aspm and wdr62. Our observations provide strong evidence for digenic inheritance of human PM, involving centrosomal genes. Absence of genetic interaction between casc5 and aspm or wdr62 further delineates centrosomal and non-centrosomal pathways in PM.

Context Dependency of Epithelial-to-Mesenchymal Transition for Metastasis.

Epithelial-to-mesenchymal transition (EMT) has been proposed to be important for metastatic dissemination. However, recent studies have challenged the requirement of EMT for metastasis. Here, we assessed in different models of primary skin squamous cell carcinomas (SCCs) whether EMT is associated with metastasis. The incidence of metastasis was much higher in SCCs presenting EMT compared to SCCs without EMT, supporting the notion that a certain degree of EMT is required to initiate the metastatic cascade in primary skin SCCs. Most circulating tumor cells presented EMT, whereas most lung metastasis did not present EMT, showing that mesenchymal-to-epithelial transition is important for metastatic colonization. In contrast, immunodeficient mice transplanted with SCCs, whether displaying EMT or not, presented metastasis. Altogether, our data demonstrate that the association of EMT and metastasis is model dependent, and metastasis of primary skin SCCs is associated with EMT.

The Number of X Chromosomes Influences Inflammatory Cytokine Production Following Toll-Like Receptor Stimulation.

Sex differences are observed in the evolution of numerous inflammatory conditions. Women exhibit better clinical courses compared to men in acute inflammatory processes, yet worse prognosis in several chronic inflammatory diseases. Inflammatory markers are significantly different between prepubertal boys and girls, whose sex steroid levels are very low, suggesting genetics play a role. To evaluate the potential influence of the X chromosome, we studied cytokine production and protein phosphorylation following Toll-like receptor (TLR) activation in whole blood and purified neutrophils and monocytes of healthy adults of both sexes as well as subjects with Klinefelter syndrome. We recorded higher levels of inflammatory cytokines in men compared to both women and patients with Klinefelter syndrome following whole blood stimulation. In purified monocytes, production of inflammatory cytokines was also higher in men compared to women, while Klinefelter subjects expressed the same pattern of cytokine production as males, in contrast with whole blood analyses. These differences remained after adjusting for sex steroid levels. Our study revealed higher cytokine inflammatory responses in men than women, yet also compared to subjects with Klinefelter syndrome, who carry two copies of the X chromosome, like women, and thus potentially benefit from the cellular mosaicism of X-linked genes.