Clinical networking results in continuous improvement of the outcome of patients with acute promyelocytic leukemia.

The introduction of all-trans retinoic acid (ATRA) combined with anthracyclines has significantly improved the outcomes for patients with acute promyelocytic leukemia (APL), and this strategy remains the standard of care in countries where arsenic trioxide is not affordable. However, data from national registries and real-world databases indicate that low- and middle-income countries (LMIC) still face disappointing results, mainly due to high induction mortality and suboptimal management of complications. The American Society of Hematology established the International Consortium on Acute Leukemias (ICAL) to address this challenge through international clinical networking. Here, we present the findings from the ICAPL study involving 806 patients with APL recruited in Brazil, Chile, Paraguay, Peru, and Uruguay. The induction mortality rate has decreased to 14.6% compared to the pre-ICAL rate of 32%. Multivariable logistic regression analysis revealed as factors associated with induction death: age ≥ 40 years, ECOG = 3, high-risk status based on the PETHEMA/GIMEMA classification, albumin level ≤ 3.5 g/dL, bcr3 PML/RARA isoform, the interval between presenting symptoms to diagnosis exceeding 48 hours, and the occurrence of central nervous system and pulmonary bleeding. With a median follow-up of 53 months, the estimated 4-year overall survival (OS) rate is 81%, the 4-year disease-free survival (DFS) rate is 80%, and the 4-year cumulative incidence of relapse (CIR) rate is 15%. These results parallel those observed in studies conducted in high-income countries, highlighting the long-term effectiveness of developing clinical networks to improve clinical care and infrastructure in LMIC.

Lateral pharyngoplasty: polysomnographic results and phenotype-based analysis of OSA.

PURPOSE: There are several surgical treatments for obstructive sleep apnea (OSA) including lateral pharyngoplasty (LP) have yielded promising results, clearly improving symptoms of the disease. However, there are few publications in relation to polysomnographic (PSG) results, and patient selection remains a challenge. There are currently four pathophysiological phenotypes for OSA: anatomical, low arousal threshold, ventilatory instability, and poor muscle response. This study sought to evaluate the PSG results of LP and to verify whether the phenotypic profile is predictive of surgical success. METHODS: This was an observational, retrospective, cross-sectional study that analyzed the PSG results (pre-surgical and at least 6 months after surgery) of patients treated with Cahali's LP. To assess phenotypes, the following variables of interest (obtained from the pre-operative PSG) were used: apnea-hypopnea index (AHI) during REM sleep (AHIrem), percentage of hypopneas in the AHI, number of central or mixed apneas, and AHIrem and non-REM AHI ratio. RESULTS: Of 46 patients, it was possible to evaluate the phenotype in 28 patients. There were significant differences in the AHI values, ranging from 37.5 (20.8-49.7) to 10.3 (2.3-33.0) (p < 0.001). The minimum oxyhemoglobin saturation ranged from 78 ± 11 to 83 ± 8 p = 0.008. The time with oxyhemoglobin saturation < 90% ranged from 3.6 min (0.5-9.1) to 0.0 (0.0-1.5) p = 0.031. An AHIrem of < 20 events/h showed a positive correlation with surgical success. CONCLUSION: LP is efficient for the treatment of OSA, yielding significant improvement in all respiratory parameters evaluated by PSG. A pre-operative AHIrem of < 20 events/h was associated with surgical success. Other variables of interest for determining the phenotypes were not predictors of surgical success.

Impaired repair properties of endothelial colony-forming cells in patients with granulomatosis with polyangiitis.

In patients with ANCA-associated vasculitis, interactions between neutrophils and endothelial cells cause endothelial damage and imbalance. Endothelial colony-forming cells (ECFCs) represent a cellular population of the endothelial lineage with proliferative capacity and vasoreparative properties. This study aimed to evaluate the angiogenic capacity of ECFCs of patients with granulomatosis with polyangiitis (GPA). The ECFCs of 13 patients with PR3-positive GPA and 14 healthy controls were isolated and characterized using fluorescence-activated cell sorting, capillary tube formation measurement, scratching assays and migration assays with and without plasma stimulation. Furthermore, three patients with active disease underwent post-treatment recollection of ECFCs for longitudinal evaluation. The ECFCs from the patients and controls showed similar capillary structure formation. However, the ECFCs from the patients with inactive GPA exhibited early losses of angiogenic capacity. Impairments in the migration capacities of the ECFCs were also observed in patients with GPA and controls (12th h, p = 0.05). Incubation of ECFCs from patients with GPA in remission with plasma from healthy controls significantly decreased migration capacity (p = 0.0001). Longitudinal analysis revealed that treatment significantly lowered ECFC migration rates. This study revealed that ECFCs from the patients with PR3-positive GPA in remission demonstrated early losses of tube formation and reduced migration capacity compared to those of the healthy controls, suggesting impairment of endothelial function.

Updates on DNA methylation modifiers in acute myeloid leukemia.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Chemotherapy with cytotoxic agents is the standard of care, but is associated with a high rate of adverse events. Elderly patients are frequently intolerant to such treatment, presenting a very poor prognosis. The hypomethylating agents (HMA) azacitidine or decitabine represent one of the main therapeutic alternatives for these patients. Isocitrate dehydrogenase inhibitors (IDH) constitute another therapeutic class with DNA methylation effects in AML. In this article, we review the use of first- and second-generation HMA and IDH inhibitors in AML. The data collected demonstrated that HMA are generally considered effective and safe for AML patients who are not eligible for standard chemotherapy. The combination of azacitidine or decitabine with venetoclax was recently approved by the US Food and Drug Administration (FDA) for older AML patients and those unfit for intense chemotherapy. IDH inhibitors also showed encouraging results for relapsed/refractory AML patients harboring an IDH mutation and received FDA approval. Therefore, recent studies have led to the emergence of new therapeutic options using HMA and IDH inhibitors for specific groups of AML patients, representing an important step in the treatment of this aggressive malignancy. New options should emerge from the ongoing studies in the coming years.

Dakin's solution in the treatment of severe diabetic foot infections.

Acute necrotising diabetic foot (DF) infections are common, costly, and do not infrequently result in debilitating major lower-extremity amputations. Dakin's solution is a long-standing topical antiseptic that has shown benefit in this clinical setting, but its use is undermined by a presumed risk of cytotoxicity. In this single-centre case series, we retrospectively evaluated 24 patients with severe necrotising DF infections treated with a cyclical instillation of Dakin's solution at a referral multidisciplinary DF unit. Most patients achieved favourable outcomes in infection control and limb salvage, with only one patient (4.2%) requiring a major (at or above-the-ankle) amputation. The mean time to complete or near-complete wound granulation was 5.4 weeks. Of the 12 patients who completed 12 or more months of longitudinal follow up, only 2 (12.2%) had a wound recurrence. In this severe DF infection patient cohort, Dakin's solution led to a clinically meaningful improvement. No remarkable impairment in the wound-healing process was observed.

Multidrug-resistant bacteria in diabetic foot infections: Experience from a portuguese tertiary centre.

In recent years, the emergence of antibiotic resistant pathogens made increasingly difficult to establish appropriate empiric antimicrobial therapy protocols for acute diabetic foot infection (DFI) treatment. Early recognition of the population at-risk for multidrug-resistant (MDR) bacterial infection is of paramount importance in order to decrease large-spectrum antibiotic overuse. This study used retrospective cohort study in a multidisciplinary tertiary diabetic foot unit. Patients with severe DFI were included and divided according to their infection resistance profile (susceptible vs MDR bacteria). Data regarding their comorbidities and length of hospital stay were collected. The primary endpoint was to determine the risk factors for MDR infections and to evaluate if these were associated with an increased length of stay (LOS). A total of 112 microbial isolates were included. Predominance of Gram-positive bacteria was observed and 22.3% of isolated bacteria were MDR. Previous hospitalisation was associated with a higher likelihood of MDR infection. MDR bacterial infection was also associated with an increased LOS (P = .0296). Our study showed a high incidence of MDR bacteria in patients with a DFI, especially in those who had a recent hospitalisation. MDR infections were associated with a prolonged LOS and represent a global public health issue for which emergent measures are needed.

Longitudinal sequencing of RUNX1 familial platelet disorder: new insights into genetic mechanisms of transformation to myeloid malignancies.

The mechanisms by which patients with RUNX1 familial platelet disorder with propensity to myeloid malignancies (FPDMM) develop myeloid malignancies (MM) are not fully understood. We report the results of targeted next-generation sequencing on three patients with RUNX1 FPDMM who developed acute myeloid leukaemia or myelodysplastic syndromes (AML/MDS). DNA samples were collected from bone marrow, peripheral blood and buccal swabs at different time points. One patient had clonal haematopoiesis, represented by an SRSF2 p.P95R variant, prior to his AML diagnosis, when he developed an additional NRAS p.G12D variant. His sister presented to us with MDS, with a TET2 p.S471fs and identical NRAS p.G12D variant. The third patient, from another family, had an additional RUNX1 p.R204X and an NFE2 p.Q139fs variant at AML diagnosis. This constitutes the first report of NFE2 variants in AML without extramedullary disease and NRAS variants in AML/MDS in the setting of FPDMM. A systematic review of the literature including our findings distinguishes two genetic landscapes at AML transformation from FPDMM characterized by either the presence or absence of somatic abnormalities in RUNX1 with or without variants in genes usually associated with MM. Whether clonal haematopoiesis precedes transformation only in patients without somatic abnormalities in RUNX1 needs further confirmation.

Adult tinea capitis and tinea barbae in a tertiary Portuguese hospital: A 11-year audit.

Adult tinea capitis and tinea barbae are nowadays considered uncommon in developed countries. Despite their potential for morbidity and healthcare costs, few series have attempted to characterise these infectious disorders. We conducted a cross-sectional study to analyse the epidemiological, clinical and mycological characteristics of adult tinea capitis and tinea barbae of a large tertiary centre in Southern Europe. All adult patients with a mycological-confirmed tinea capitis or barbae over a 11-year period (January 2008 to December 2018) were considered for the analysis. Concerning tinea capitis, 860 culture-confirmed diagnoses were made during this 11-year period, of which only 15 (1.5%) occurred in adults (15 patients). A disproportionately high number of patients were female and immunocompromised. Microsporum audouinii (20%) and Trichophyton rubrum (20%) were the most common isolates. Half of the cases were initially misdiagnosed. Regarding tinea barbae, 7 cases were diagnosed over this time period. Overuse of topical steroids was widespread in this population. Trichophyton rubrum was the infectious agent in all cases. Initial misdiagnosis was very common (43%). Adult tinea capitis and tinea barbae can still be observed in contemporary practice and remain a public health concern, with the immunosuppressed patient being particularly affected. Initial misdiagnosis is a common occurrence. Anthropophilic fungi are now the most common aetiologic agents of these infections, and they will probably continue to do so as the large urban centres expand peripherally. Awareness for this diagnosis is necessary to prevent unwarranted morbidity and costs.

Trichloroacetic acid (80%) as a chemical debridement method for chronic venous leg ulcers-A pilot study.

Debridement is essential for the optimal care of venous leg ulcers. Several debridement methods with different limitations may be deployed. Trichloroacetic acid (TCA) is used for several dermatological purposes. Its application as a chemical debridement method for leg ulcers has never been explored. We designed a prospective study to determine the role of 80% TCA solution as a chemical debridement method for leg ulcers, regarding efficacy and procedure-associated pain. Chronic venous leg ulcers were treated with 3 cycles of 80% TCA solution or curettage over 1 week. Pain and the mean percentage of fibrin and devitalized tissue covering wound bed were evaluated. At the end of the study, a trend towards larger fibrin mean reduction among the TCA treated ulcers was observed, although this difference was not statistically significant (P = .35). The mean pain score after TCA application was significantly reduced compared to pain after curettage alone (P < 0.001). TCA presented several advantages over mechanical debridement: it is a more selective debridement method, has haemostatic properties, and a simpler and faster application. The 80% TCA solution may be a cheap, simple, and considerably less-painful chemical debridement method for venous leg ulcers compared to classical mechanical debridement.

Intermittent low platelet counts hampering diagnosis of X-linked thrombocytopenia in children: report of two unrelated cases and a novel mutation in the gene coding for the Wiskott-Aldrich syndrome protein.

BACKGROUND: Thrombocytopenia can occur in different circumstances during childhood and although immune thrombocytopenia is its most frequent cause, it is important to consider other conditions, especially when there is a persistent or recurrent low platelet count. We report two cases of intermittent thrombocytopenia, previously misdiagnosed as immune thrombocytopenia. CASES PRESENTATION: Both cases described were boys who presented with an intermittent pattern of thrombocytopenia, with a persistently low mean platelet volume. In both patients, peripheral blood smear revealed small platelets and flow cytometry showed low expression of Wiskott-Aldrich syndrome protein (WASP) in leucocytes. Molecular analysis of the first case identified a mutation in exon 2 of the gene coding for WASP, leading to a p.Thr45Met amino acid change and confirming the diagnosis of X-linked thrombocytopenia. In the second case, a novel missense mutation in exon 2 of the gene coding for WASP was detected, which resulted in a p.Pro58Leu amino acid change. CONCLUSION: These two rare presentations of thrombocytopenia highlight the importance of evaluating the peripheral blood smear in the presence of recurrent or persistent thrombocytopenia and show that failing to do so can lead to misdiagnoses. Since thrombocytopenia may be found in pediatric outpatient clinic, increased awareness among general pediatricians will help to improve the differential diagnosis of this condition.

Dakin's solution: is there a place for it in the 21st century?

Dakin's solution (DS) is a time-honoured antiseptic that still remains part of the wound care armamentarium. In spite of its cytotoxicity, some question its use in the current era. We report the case of a 52-year-old diabetic woman who was admitted for sepsis because of a severely infected diabetic foot. Urgent surgical drainage and debridement left a 9 × 9-cm deep, complex, infected wound with both bone and tendon involvement. Treatment with local negative pressure was unsuccessful. DS was regularly instilled through a tube left in the wound dressing. A marked improvement was observed with this strategy as the wound bed was much cleaner and fully granulated after 6 weeks. No adverse effects were noted. This case debunks the myth that topical antiseptics necessarily impair wound healing. DS can still be considered an option for difficult-to-treat, complex and heavily infected wounds.

Relationship between OSA pathophysiological phenotypes and treatment response to mandibular advancement devices: a pilot study.

STUDY OBJECTIVES: We assessed whether critical pathophysiological phenotypes predict treatment response in patients with obstructive sleep apnea using a mandibular advancement device (MAD). METHODS: Thirty-one patients with obstructive sleep apnea were treated with a MAD. Individuals were categorized and graded into 4 pathophysiological phenotypes based on polysomnographic features (anatomical, ventilatory control, arousal threshold, and muscle responsiveness). Morpho-anthropometric data were additionally assessed. Patients were classified as responders or nonresponders. Associations between polysomnographic phenotypes and treatment response were documented, as were morpho-anthropometric data and their impact on therapeutic success. RESULTS: There was a male predominance (64.5%), with a median age of 49 years (25th percentile: 40; 75th percentile: 55), body mass index = 27.4 kg/m2 (25th percentile: 26; 75th percentile: 28.8), and apnea-hypopnea index of 18.2 events/h (25th percentile: 11.7; 75th percentile: 27.6). The majority of patients treated with a MAD (58%) were good responders (68.0% mild and moderate vs 16.7% severe). Treatment response was associated with shorter intermolar and interpremolar distances in the lower arch (P = .0092 and .0129). Rapid eye movement sleep apnea-hypopnea index and MAD-related treatment response were inversely correlated (P = .0013). Favorable anatomical (P = .0339) and low muscle response (P = .0447) phenotypes were correlated with outcomes. CONCLUSIONS: According to our results, a favorable response occurred in a better "anatomical phenotype" and in the worse "muscular responsiveness phenotype" according to polysomnographic data. Furthermore, other favorable predictors, such as a rapid eye movement sleep apnea-hypopnea index < 16 events/h and a smaller distance between lower molars and premolars, were found. These findings indicate that clinical and polysomnographic aspects can discriminate phenotypes that may guide decisions on MAD treatment for obstructive sleep apnea. CITATION: Manetta IP, Duarte BB, Nucci LB, Enes CC. Relationship between OSA pathophysiological phenotypes and treatment response to mandibular advancement devices: a pilot study. J Clin Sleep Med. 2024;20(8):1321-1330.

Cephalometric Evaluation in Patients with Obstructive Sleep Apnea undergoing Lateral Pharyngoplasty.

Introduction Lateral pharyngoplasty (LP) has shown promising results. Craniofacial deformity reduces the pharyngeal space, contributing to the etiopathogenesis. The analysis of craniofacial features can be performed using cephalometry. Objective To verify if craniofacial deformity is associated with worse polysomnographic data in patients with obstructive sleep apnea (OSA), and to verify if the preoperative cephalometric parameters can interfere with the surgical success of the LP. Methods The study included 21 patients with OSA aged between 18 and 65 years who underwent LP in a university hospital from 2015 to 2019. Polysomnography was performed postoperatively, after a minimum period of 6 months from the surgical procedure. In addition, a cephalometric evaluation was performed to assess craniofacial deformity, and to correlate it with the polysomnographic results. Results The mean and median of all polysomnographic respiratory parameters improved postoperatively, especially the apnea-hypopnea index (AHI), which went from 40.15 to 16.60 events per hour ( p = 0.001). Of the 21 patients, 15 showed improvements in the AHI postoperatively. As for the cephalometric evaluations, we found that the longer the distance between the hyoid bone and the mandibular plane, the greater the patient's preoperative AHI ( p = 0.011). When assessing whether cephalometric changes related to craniofacial deformities influence the surgical outcome of LP, no correlation was found for any cephalometric measurement. Conclusion The longer the distance between the hyoid bone and the mandibular plane, the greater the preoperative AHI, and LP was an effective OSA treatment. Cephalometric variables are not able to modify or determine the success of LP in apneic patients in the population assessed.

Use of ultrasonography in the evaluation of patients with sleep apnea: a systematic review.

OBJECTIVES: This study aims to review the current role of various ultrasonographic methods in the evaluation of the upper airway in patients with obstructive sleep apnea. METHODS: A literature review was performed on the medical databases: Pubmed, Web of Science, Scopus and Embase. After analyzing the available studies, six of them were selected for data extraction. RESULTS: All selected studies demonstrated that it is possible to use ultrasonography as a method of evaluating the upper airway. Studies with gray-scale ultrasound concluded that the lateral pharyngeal wall and tongue are thicker in patients with obstructive sleep apnea compared to non-apneic patients. Moreover, studies with tissue characterization ultrasound, nowadays called quantitative ultrasound, have identified unique features in obstructive sleep apnea patients: standardized backscatter ultrasonography demonstrated that this particular sound wave analysis is associated with the severity of obstructive sleep apnea. Ultrasonography with elastography shows that the electrical stimulus generated in the hypoglossal nerve results in greater stiffness on the side of the tongue that is stimulated; whereas studies show conflicting results regarding the evaluation of baseline tongue stiffness in obstructive sleep apnea patients compared to non-apneic subjects. CONCLUSION: There is feasibility of different methods of ultrasonographic evaluation of the upper airway, with emphasis on ultrasonographic methods of tissue characterization, such as elastography, which proved to be a promising method of evaluating the mechanical properties of the muscles involved in the pathogenesis of obstructive sleep apnea and which require further studies for a better elucidation of its applicability.

Lenalidomide or Thalidomide for Transplant-Ineligible Patients With Newly Diagnosed Multiple Myeloma? An Overview of Systematic Reviews.

OBJECTIVES: To present an overview of evidence of efficacy, safety, and health-related quality of life of lenalidomide or thalidomide for transplant-ineligible multiple myeloma. METHODS: A literature search was performed in 5 databases until July 2022. We included systematic reviews with network meta-analyses of randomized controlled trials on the use of lenalidomide compared with thalidomide for transplant-ineligible multiple myeloma. The A Measurement Tool to Assess Systematic Reviews 2 was used to appraise the quality of included reviews. The results were focused on the lenalidomide + dexamethasone until disease progression (RDc) versus thalidomide + dexamethasone until disease progression (TDc) and induction with melphalan + prednisone + lenalidomide, followed by maintenance with lenalidomide (MPR-R) versus induction with melphalan + prednisone + thalidomide, followed by maintenance with thalidomide (MPT-T) regimens. RESULTS: Nine studies were included. Only 1 study did not show any weakness in critical domains of A Measurement Tool to Assess Systematic Reviews 2. For overall survival, RDc proved to be superior to TDc; however, no study showed significant difference between MPR-R and MPT-T. For progression-free survival, 2 of 3 studies showed that RDc is better than TDc; however, no difference between MPR-R and MPT-T was found. Regarding safety, these lenalidomide-based regimens had a lower risk for neurologic adverse events, with an increased risk of hematologic adverse events. No health-related quality of life meta-analyses were found. CONCLUSIONS: These findings suggest that, in terms of efficacy and safety, lenalidomide-based regimen is a good option for treatment of transplant-ineligible multiple myeloma in the public health system of Brazil, especially for those patients who develop severe neuropathy with thalidomide.

Dupilumab in Patients with Atopic Dermatitis: A Multicentric, Long-Term, Real-World Portuguese Study.

INTRODUCTION: Several clinical trials have established the efficacy and safety of dupilumab for treating atopic dermatitis (AD). However, literature remains scarce in reporting the long-term effectiveness, safety, and drug survival of dupilumab in real-world settings. This study aimed to describe the latter outcomes of dupilumab in patients with AD. METHODS: This Portuguese, multicentric, observational, retrospective study included consecutive adult patients with AD who initiated dupilumab between January 2019 and September 2023, with a follow-up period up to 30 months. Drug discontinuation and adverse effects data were used to estimate drug survival. Clinical assessments included the Eczema Area and Severity Index (EASI), pruritus numerical rating scale (NRS), and Dermatology Life Quality Index (DLQI). RESULTS: A total of 312 patients were included in the study, with 56.4% being male (median age of 30 years, range 18-83). The 30-month drug survival rate was 82.0%. During the study period, 12.5% of the sample (n = 39 patients) discontinued treatment: 7.3% due to treatment failure, 2.9% due to safety concerns, 1.3% due to complete disease control, 0.6% due to pregnancy, and 0.3% due to lack of compliance. Adverse events not leading to drug discontinuation were noted in 25.6% of the sample (n = 80). Conjunctivitis was the most frequently reported adverse event (17%), followed by facial erythema (9%). At 30 months, the mean EASI decreased significantly from 27.30 ± 11.89 at baseline to 2.92 ± 3.96 (p < 0.001), reflecting an overall improvement of 89.3%. Similarly, pruritus NRS decreased from 7.36 ± 1.90 at baseline to 1.74 ± 2.16 at month 30 (p < 0.001), improving by 76.4%, and mean DLQI changed from 18.0 ± 7.09 at baseline to 2.67 ± 3.95 at month 30 (p < 0.001), decreasing by 85.2%. CONCLUSIONS: This study increases our current understanding of dupilumab in real-world settings, demonstrating its long-term effectiveness and safety in treating AD.