Real-world efficacy of single-agent belantamab mafodotin in relapsed systemic AL amyloidosis.

Systemic light chain (AL) amyloidosis is a relapsing plasma cell disorder. Therapy is limited, particularly for triple-class refractory disease. We report the use of belantamab mafodotin, a BCMA-directed drug-antibody conjugate, for relapsed AL amyloidosis, including patients traditionally excluded from clinical trials. Thirty-one patients were reviewed, with a median of three prior lines of therapy. The median follow-up was 12 months (95% CI 4-19), and a median of five doses were delivered. The best haematological overall response rate was 71%, and the complete/very good partial response was 58%. Sixty-eight percent had keratopathy and improved in all. Belantamab mafodotin has high efficacy and good tolerability in patients with relapsed AL amyloidosis.

Non-crystalline light chain proximal tubulopathy, a morphologically protean entity.

BACKGROUND: Light chain proximal tubulopathy (LCPT) is a rare form of paraprotein-related disease, occurring in two main histopathological forms: crystalline and non-crystalline. The clinicopathological features, treatment strategies and outcomes, especially of the non-crystalline form, are not well described. METHODS: We conducted a single-centre retrospective case series of 12 LCPT patients, 5 crystalline and 7 non-crystalline, between 2005 and 2021. RESULTS: The median age was 69.5 years (range 47-80). Ten patients presented with CKD and significant proteinuria (median estimated glomerular filtration rate of 43.5 ml/min/1.73 m2; urine protein:creatinine ratio 328 mg/mmol). Only six patients had known haematological disease at the time of renal biopsy. Multiple myeloma (MM) was diagnosed in seven patients cases and monoclonal gammopathy of renal significance (MGRS) in five patients. A clone was detected in all cases combining serum/urine electrophoresis and free light chain (LC) assays. Crystalline and non-crystalline variants had similar clinical presentations. For the non-crystalline variant, a diagnosis was reached based on a combination of CKD without another cause, haematological workup, LC restriction on immunofluorescence and abnormalities on electron microscopy (EM). Nine of 12 patients received clone-directed treatment. Patients who achieved haematological response (including all non-crystalline LCPT) had improved renal outcomes over a median follow-up of 79 months. CONCLUSIONS: The non-crystalline variant may go unrecognised because of its subtle histopathological features and requires EM to distinguish it from 'excessive LC resorption without tubular injury'. Clone-directed treatment with good haematological response improves renal outcomes in both variants but limited data exist in MGRS. Multicentre prospective studies are needed to better define the clinicopathological characteristics associated with poor outcomes and optimize treatment strategies in patients with MGRS.

High patient satisfaction and increased physical activity following a remote multidisciplinary team multiple myeloma clinic.

PURPOSE: Patients with multiple myeloma suffer from disease-related complications such as bone destruction, toxicities from repeated therapies and age-related co-morbidities. With improved treatment options, patients are living longer and have specific survivorship needs such as low exercise levels that need to be addressed. In this study, we designed, implemented and evaluated a multidisciplinary team (MDT) myeloma clinic that provided participants with tailored exercise and lifestyle advice. METHODS: The Promoting Individualised Self-Management and Survivorship (PrISMS) clinic was set up in two UK myeloma centres. This remote MDT clinic comprised of a doctor, a nurse specialist and a physiotherapist. Patients were required to complete blood tests and a questionnaire about their symptoms and concerns before each consultation. Patient-reported outcome measures were captured using validated questionnaires. Patient feedback was collected using a specially designed survey and structured telephone interviews. RESULTS: Sixty-one patients were enrolled in the pilot clinic with 210 consultations held during the study period. Nine patients had disease progression and were referred safely back to face-to-face clinics. There was a significant improvement in patients' exercise score (p = 0.02) after PrISMS clinic. Patient satisfaction was high, with 83% feeling more confident in self-managing myeloma after PrISMS clinic. CONCLUSION: PrISMS clinic is safe and feasible, with high patient compliant and acceptability. It empowers patients to self-manage their condition and encourages physical activity, which is associated with improved quality of life and fatigue level. Future randomised controlled trials will help to confirm its benefits on patient clinical outcomes and cost-effectiveness.

Identification of occult cerebral microbleeds in adults with immune thrombocytopenia.

Management of symptoms and prevention of life-threatening hemorrhage in immune thrombocytopenia (ITP) must be balanced against adverse effects of therapies. Because current treatment guidelines based on platelet count are confounded by variable bleeding phenotypes, there is a need to identify new objective markers of disease severity for treatment stratification. In this cross-sectional prospective study of 49 patients with ITP and nadir platelet counts <30 × 109/L and 18 aged-matched healthy controls, we used susceptibility-weighted magnetic resonance imaging to detect cerebral microbleeds (CMBs) as a marker of occult hemorrhage. CMBs were detected using a semiautomated method and correlated with clinical metadata using multivariate regression analysis. No CMBs were detected in health controls. In contrast, lobar CMBs were identified in 43% (21 of 49) of patients with ITP; prevalence increased with decreasing nadir platelet count (0/4, ≥15 × 109/L; 2/9, 10-14 × 109/L; 4/11, 5-9 × 109/L; 15/25 <5 × 109/L) and was associated with longer disease duration (P = 7 × 10-6), lower nadir platelet count (P = .005), lower platelet count at time of neuroimaging (P = .029), and higher organ bleeding scores (P = .028). Mucosal and skin bleeding scores, number of previous treatments, age, and sex were not associated with CMBs. Occult cerebral microhemorrhage is common in patients with moderate to severe ITP. Strong associations with ITP duration may reflect CMB accrual over time or more refractory disease. Further longitudinal studies in children and adults will allow greater understanding of the natural history and clinical and prognostic significance of CMBs.

Atherogenic cytokines and chemokines in chronic hepatitis C are not associated with the presence of cardiovascular diseases.

There appears to be an associative link between chronic hepatitis C (CHC) and cardiovascular diseases (CVDs). However, the exact nature of the relationship between CHC and CVDs has not been elucidated. We investigated the presence of CVDs and the clinical and laboratory alterations associated with these diseases in CHC patients. Twenty-six CHC patients, 35 individuals with atherosclerosis (Athero) and 27 healthy individuals were examined for risk factors for CVD, lipid profile, atherogenic risk indexes, and insulin resistance (IR). Cardiac biomarkers and the chemokines and cytokines involved in atherosclerosis were also evaluated. A higher prevalence of prior acute myocardial infarction was found in the Athero group. Most CHC patients were infected with the hepatitis C virus genotype 1 and exhibited either no hepatic fibrosis or a mild to moderate liver fibrosis. The apolipoprotein B/apolipoprotein A-I and triglyceride/high-density lipoprotein cholesterol ratios and C-reactive protein levels were lower in CHC patients than in the Athero group. Further, IR was elevated in the CHC group and associated with the waist circumference. High GDF-15 levels were observed in the CHC group, which were inversely correlated with APOB levels. Peripheral blood mononuclear cells from CHC patients produced more IFN-γ, TNF-α and IL-6 than CAD PBMC but the production of IL-10 and IL-1ß was similar. CHC and CAD groups presented similar levels of IL-8, MCP-1 and LAP-TGF-ß1. Increased IR, elevated levels of GDF-15, and high production of atherogenic cytokines can be observed in Brazilian CHC patients without association with diabetes and clinical manifestation of cardiovascular diseases.

Influence of depth of mesio-occlusodistal preparation and mechanical cycling on fracture resistance of restored premolars.

The purpose of this in vitro study was to evaluate the influence of depth (3.0 vs 5.0 mm) of mesio-occlusodistal (MOD) cavity preparation and mechanical cycling on fracture resistance of maxillary premolars restored with resin-based composite (RBC). Seventy premolars were randomly divided into 7 groups (n = 10): NP, no cavity preparation (control); MOD3, 3.0-mm-deep MOD preparation, not restored; MOD3R, 3.0-mm-deep MOD preparation restored with RBC; MOD5, 5.0-mm-deep MOD preparation, not restored; MOD5R, 5.0-mm-deep MOD preparation restored with RBC; MOD3RC, 3.0-mm-deep MOD preparation restored with RBC and subjected to mechanical cycling; and MOD5RC, 5.0-mm-deep MOD preparation restored with RBC and subjected to mechanical cycling under the same conditions as MOD3RC. All specimens were tested using a universal testing machine, resulting in the following mean (SD) values: NP, 224.65 (35.66) kgf; MOD3, 58.92 (15.48) kgf; MOD3R, 95.58 (13.88) kgf; MOD5, 68.06 (10.12) kgf; MOD5R, 98.49 (13.16) kgf; MOD3RC, 83.68 (14.39) kgf; and MOD5RC, 54.25 (11.56) kgf. Analysis of variance and Tukey test showed no statistically significant difference among MOD3, MOD5, and MOD5RC; between MOD5 and MOD3RC; or among MOD3R, MOD5R, and MOD3RC (P > 0.05). MOD3RC had significantly greater fracture resistance than MOD5RC (P < 0.05). NP had the highest fracture resistance of all groups (P < 0.05). The results showed that the depth of the cavity preparation only influenced fracture resistance after mechanical cycling of the specimens.

Management of dental caries guided by the ICDAS-LAA: a 28-month follow-up.

Dental caries is a significant oral health issue and public health concern. Currently conceptualized as a dynamic and multifactorial process, caries is a continuum of disease stages, during which tooth damage may be reversed or controlled, depending on lesion progression. The International Caries Detection and Assessment System, when used in conjunction with the Lesion Activity Assessment (ICDAS-LAA), reflects the dynamic caries process and allows the classification of cavitated lesions according to their severity and progression, which is essential to selecting the appropriate treatment. This case report describes the diagnosis and treatment of a patient who had caries in the past and in whom old lesions remained untreated. The ICDAS-LAA was used to assess caries accurately and guide treatment decisions. The patient maintained a dietary journal for 2 weeks to help establish her risk of developing caries. Treatment involved a minimally invasive dentistry approach, which consisted of remineralization via fluoride applications, placement of a composite resin restoration, microabrasion, and periodic maintenance. During the 28-month follow-up period, rigorous control of caries risk factors was achieved, and the results were satisfactory, demonstrating the effectiveness of the ICDAS-LAA in diagnosing and managing carious lesions.

Immune response of Th17-associated cytokines by peripheral blood mononuclear cells from patients with chronic hepatitis C virus infection.

Hepatitis C virus (HCV) chronic infection causes severe cellular immune dysfunction. Here, we investigated the production of Th17-associated cytokines by peripheral blood mononuclear cells (PBMCs) of untreated patients with HCV, patients presenting an early virologic response (EVR) after 12weeks of treatment with interferon-α plus ribavirin with or without HCV protease inhibitors, and patients who were nonresponders to HCV therapy. PBMCs were stimulated with HCV core and nonstructural antigens, and the production of Th17-associated cytokines was measured with a Milliplex MAP immunoassay. Core-stimulated PBMCs from both untreated and nonresponder patients produced interleukin (IL)-17A, and vigorous production of IL-17A in response to NS3 antigen was only verified in the untreated group. Nonresponder patients also produced IL-17F after core antigen stimulation. IL-21 production was unaltered in the three groups of patients, whereas IL-17E and IL-22 were not detected. The production of Th17 cytokines by cells from patients showing an EVR was insignificant. IL-17A and IL-17F levels were not correlated with alanine aminotransferase levels or viremia. However, advanced fibrosis was associated with higher IL-17A production in T0 cells stimulated with core antigen. Untreated patients with HCV and patients who were nonresponders to antiviral treatment differed in their PBMC immune responses of Th17-associated cytokines. The early virological response to antiviral treatment dramatically decreased Th17 immune responses to HCV antigens.

Determining Optimal Fluorescent Agent Concentrations in Dental Adhesive Resins for Imaging the Tooth/Restoration Interface.

Fluorescent dyes like Rhodamine B (RB) have been used to identify the spatial distribution of adhesive restorative materials in the tooth/restoration interface. Potential effects of the addition of RB to dental adhesives were addressed in the past, but no further information is available on how to determine suitable concentrations of RB in these bonding agents for imaging in the confocal laser scanning microscope. This study provides systematical strategies for adding RB to viscous dental adhesive resins, focusing on the determination of the lowest range of dye concentrations necessary to achieve an acceptable image of the dentin/adhesive interface. It was demonstrated that optimized images of the resin distribution in dentin can be produced with 0.1-0.02 mg/mL of RB in the (tested) adhesives. Our approaches took into account aspects related to the dye concentration, photophysical parameters in different host media, specimen composition and morphology to develop a rational use of the fluorescent agent with the resin-based materials. Information gained from this work can help optimize labeling methods using dispersions of low-molecular-weight dyes in different monomer blend systems.

Peripheral lymphocyte subsets in chronic hepatitis C: Effects of 12 weeks of antiviral treatment with interferon-alpha plus ribavirin.

Chronic infection with hepatitis C virus (HCV) causes a quantitative and functional alteration in innate and adaptative immunity. In the present work, we determined by flow-cytometry the profile of blood lymphocyte of untreated HCV patients and in subjects of this group that achieved or not an early virologic response at 12-weeks of treatment with interferon-α plus ribavirin. Twenty-six untreated HCV patients and 20 control healthy individuals were enrolled in the study. Untreated HCV patients had a higher proportion of B cell and a lower proportion of CD8(+) T cell and NK cells than healthy individuals did, but the proportions of CD4(+) T cells and Treg cells (CD4(+)CD25(+)Foxp3(+)) were similar in these patients and controls. Untreated HCV patients presenting cryoglobulinemia had a lower proportion of Treg cells and a lower Treg/NK cell ratio when compared with those without cryoglobulins. Nineteen out of 26 untreated HCV patients remained in the study and were treated with Interferon-α plus ribavirin. At 12-weeks of treatment, 10 of them achieved early virologic response (EVR), whereas 9 were non-responders (NR). EVR patients differed from NR patients in the increase of their proportion of NK cells at 12 weeks of treatment. In conclusion, untreated HCV patients exhibit an altered profile of blood lymphocyte subsets, including a reduction in the proportion of CD4(+)CD25(+)FoxP3(+)T regulatory cells in patients that present cryoglobulinemia. An early virological response at 12-weeks of treatment with IFN-α plus ribavirin seems to be associated a significant improvement in the proportion of NK cells of HCV treated patients.

Higher level of IL-6 in Jaccoud's arthropathy secondary to systemic lupus erythematosus: a perspective for its treatment?

Jaccoud's arthropathy (JA) is a condition characterized clinically by 'reversible' joint deformities along with an absence of articular erosions on a plain radiograph. The main clinical entity associated with JA is systemic lupus erythematosus (SLE) with a prevalence of around 5 %. The aim of the present study was to compare the inflammatory markers including cytokine levels in blood of SLE patients with and without JA. Patients with diagnosis of SLE as defined by ACR criteria were screened and divided in two groups, one with JA and one control group without JA. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), complement C3 and C4 levels antinuclear antibodies (ANA), anti-dsDNA antibodies and serum levels of IL-2, IL-6, IL-10, IL-21, IL-22 and TNF-α were determined in all patients. Eighty female patients with SLE, 18 (22.5 %) with JA and 62 (77.5 %) without JA, were included in this study. JA patients had higher disease duration (p = 0.008), ESR (p < 0.001), CRP level (p = 0.002), ANA titer (p < 0.001) and dsDNA antibody level (p = 0.009). The serum levels of IL-2, IL-10, IL-21, IL-22 and TNF-α were not significantly different between the two groups (p > 0.05), but the level of IL-6 was higher in JA group (p < 0.001). The serum level of IL-6 might have a correlation with JA secondary to SLE.

Bleaching technique effect on dentin permeability.

PURPOSE: To evaluate the effect of bleaching techniques on dentin permeability. The hypothesis was that the bleaching agent associated or not to etching and/or energy source would be able to increase dentin permeability (conductance). METHODS: Fifty 1 mm-thick disks of mid-coronal dentin were obtained from human third molars, which were mounted in a filtration chamber, allowing exposure of a standardized area of 0.282 mm2. All specimens were treated with 35% liquid phosphoric acid for 15 seconds to maximize dentin permeability. Then they were randomly allocated to five different conditions: C: placebo gel (negative control); HP: Whiteness HP Maxx (WM)-35% hydrogen peroxide; PA-HP: WM preceded by phosphoric acid etching for 15 seconds. HP-E: WM associated to a light source and PA-HP-E: WM preceded by phosphoric acid etching for 15 seconds and associated to a light source. The bleaching agent was applied for 10 minutes with intermediate agitation at 5 minutes. In the groups associated with a light source, it was activated for 30 seconds every 5 minutes. Afterwards, the permeability (Lp) was measured using the Flodec device. The data were collected and analyzed with one-way ANOVA and Tukey's test (P< 0.05). RESULTS: Mean and standard deviation of Lp were: C = 1.92 (1.04); HP = 1.14 (0.29); PA-HP = 14.40 (8.62); HP-E = 4.18 (5.14); PA-HP-E = 27.32 (13.24). Data revealed that phosphoric acid etching could increase the dentin permeability, while the bleaching agent or light curing alone did not.

Prevalence of enamel defects in permanent teeth of patients with complete cleft lip and palate.

Objective : To evaluate the prevalence, types, location, and characteristics of enamel defects in anterior permanent teeth of patients with complete unilateral and bilateral cleft lip and palate, as well as the relation with the cleft. Setting : Hospital for Rehabilitation of Craniofacial Anomalies, Bauru, São Paulo, Brazil. Participants : Eighty patients of both genders, 12 years and older, with unilateral or bilateral cleft lip and palate. Methods : A single examiner carried out clinical examination under artificial light with a dental probe and mirror after drying teeth according to the modified DDE index. Results : Seventy-four of 80 patients presented with at least one tooth affected by enamel defects: 165 of 325 evaluated teeth (50.8%) presented enamel defects, with hypoplasia being the most prevalent (50.7%), followed by diffuse opacity (23.1%) and demarcated opacity (18.4%). The most affected tooth was 21 (36.5%), followed by 11 (34%), located at the middle (40%) and incisal (33%) thirds. Most defects occur at the buccal surface (47.7%), followed by the distal (22.7%), the mesial (19%), and the palatal (10.6%) surfaces. A significant relationship was found between the cleft side and enamel defects. Conclusion : Upper anterior teeth of patients with complete cleft lip and palate present a high prevalence of enamel defects; the highest percentage on the cleft side suggests that the cleft does influence the occurrence of enamel defects in permanent teeth.

Serum levels of Th17 associated cytokines in chronic hepatitis C virus infection.

The Th17-mediated immune response was investigated in patients chronically infected with hepatitis C virus (HCV) by determining the serum levels of the cytokines involved in the induction of the Th17 response (TGF-ß and IL-6), the cytokines produced by Th17 cells (IL-17A, IL-17F and IL-22) and the cytokines whose production is stimulated by Th17 lymphocytes (IL-8 and GM-CSF). We investigated the relationships among the levels of these cytokines by assessing clinical findings, liver histology and viremia. Sixty untreated patients and 28 healthy individuals were included in the study. Cytokine levels were determined using ELISA. Differences between HCV and control groups were identified in the median levels of IL-17F (controls=172.4 pg/mL; HCV=96.8 pg/mL, p<0.001) and IL-8 (controls=30.1 pg/mL; HCV=18.1 pg/mL, p<0.05). IL-6 levels were higher in patients presenting moderate liver necroinflammation than in patients with mild or no liver necroinflammation (p<0.05). IL-17F levels were increased in patients that had increased ALT levels. Additionally, a strong positive correlation was observed between IL-17F and IL-22 levels in the two groups investigated, and the IL-17F/IL-22 ratio was lower in the patients infected with HCV (p<0.0001). Patients with low HCV viral loads had higher median levels of IL-8 (32.5 pg/mL) than did patients with high HCV loads (16.7 pg/mL, p<0.05). These results suggest that in chronic hepatitis C infection, IL-17F and IL-8 could be associated with the control of liver injury and infection, respectively.

Inflammation biomarkers in chronic hepatitis C: association with liver histopathology, HCV genotype and cryoglobulinemia.

OBJECTIVE: This work investigated the profile of inflammation biomarkers in patients with chronic hepatitis C and its association with liver fibrosis, hepatic necroinflammatory activity, viral genotypes and cryoglobulinemia. SUBJECTS AND METHODS: Seventy-eight untreated patients were studied. Biomarker levels were determined by immunoassays, cryoglobulinemia by cryoprecipitation and liver histopathology investigated using METAVIR scores. RESULTS: Decreased levels of α(1)-acid glycoprotein (AGP), C3 and haptoglobin (Hp) were observed in the patients (P < 0.0001). Increased α(1)-antitrypsin (P < 0.01) and ferritin (P < 0.0001) levels were found in this group, but C-reactive protein (CRP) and C4 levels were unaltered. Alanine aminotransferase inversely correlated with Hp (P < 0.01) and AGP (P = 0.01), whereas it was directly correlated with ferritin (P < 0.05) and AGP (P < 0.0001). The levels of CRP, C3 and C4 were lower in the patients with hepatic necroinflammatory activity (P < 0.05). Patients with advanced fibrosis had low levels of Hp and AGP (P < 0.05 and P < 0.01, respectively). Neither infection with different viral genotypes nor cryoglobulinemia caused an alteration in biomarker levels. CONCLUSION: Chronic hepatitis C virus infection alters the levels of some biomarkers, which are mainly observed in patients with liver fibrosis and hepatic necroinflammatory activity.

The role of extracorporeal photopheresis in the treatment of cutaneous T-cell lymphomas.

Extracorporeal photochemotherapy (ECP) is an effective treatment modality for patients with erythrodermic myocosis fungoides (MF) and Sezary syndrome (SS). During ECP, a fraction of peripheral blood mononuclear cells is collected, incubated ex-vivo with methoxypsoralen, UVA irradiated, and finally reinfused to the patient. Although the mechanism of action of ECP is not well established, clinical and laboratory observations support the hypothesis of a vaccination-like effect. ECP induces apoptosis of normal and neoplastic lymphocytes, while enhancing differentiation of monocytes towards immature dendritic cells (imDCs), followed by engulfment of apoptotic bodies. After reinfusion, imDCs undergo maturation and antigenic peptides from the neoplastic cells are expressed on the surface of DCs. Mature DCs travel to lymph nodes and activate cytotoxic T-cell clones with specificity against tumor antigens. Disease control is mediated through cytotoxic T-lymphocytes with tumor specificity. The efficacy and excellent safety profile of ECP has been shown in a large number of retrospective trials. Previous studies showed that monotherapy with ECP produces an overall response rate of approximately 60%, while clinical data support that ECP is much more effective when combined with other immune modulating agents such as interferons or retinoids, or when used as consolidation treatment after total skin electron beam irradiation. However, only a proportion of patients actually respond to ECP and parameters predictive of response need to be discovered. A patient with a high probability of response to ECP must fulfill all of the following criteria: (1) SS or erythrodermic MF, (2) presence of neoplastic cells in peripheral blood, and (3) early disease onset. Despite the fact that ECP has been established as a standard treatment modality, no prospective randomized study has been conducted so far, to the authors' knowledge. Considering the high cost of the procedure, the role of ECP in the treatment of SS/MF needs to be clarified via well designed multicenter prospective randomized trials.