Ixazomib plus daratumumab and dexamethasone: Final analysis of a phase 2 study among patients with relapsed/refractory multiple myeloma.

Novel therapies have improved outcomes for multiple myeloma (MM) patients, but most ultimately relapse, making treatment decisions for relapsed/refractory MM (RRMM) patients increasingly challenging. We report the final analysis of a single-arm, phase 2 study evaluating the oral proteasome inhibitor (PI) ixazomib combined with daratumumab and dexamethasone (IDd; NCT03439293). Sixty-one RRMM patients (ixazomib/daratumumab-naïve; 1-3 prior therapies) were enrolled to receive IDd (28-day cycles) until disease progression/unacceptable toxicity. Median age was 69 years; 14.8% of patients had International Staging System stage III disease; 14.8% had received three prior therapies. Patients received a median of 16 cycles of IDd. In 59 response-evaluable patients, the overall response rate was 64.4%; the confirmed ≥very good partial response (VGPR) rate (primary endpoint) was 30.5%. Rates of ≥VGPR in patient subgroups were: high-risk cytogenetics (n = 15, 26.7%), expanded high-risk cytogenetics (n = 24, 29.2%), aged ≥75 years (n = 12, 16.7%), lenalidomide-refractory (n = 21, 28.6%), and prior PI/IMiD therapy (n = 58, 31.0%). With a median follow-up of 31.6 months, median progression-free survival was 16.8 months (95% confidence interval: 10.1-23.7). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 54.1% of patients; 44.3% had serious TEAEs; TEAEs led to dose modifications/reductions/discontinuations in 62.3%/36.1%/16.4%. There were five on-study deaths. Any-grade and grade ≥3 peripheral neuropathy occurred in 18.0% and 1.6% of patients. Quality of life was generally maintained throughout treatment. IDd showed a positive risk-benefit profile in RRMM patients and was active in clinically relevant subgroups with no new safety signals.

Late versus early response and depth of response are associated with improved outcomes in patients with newly diagnosed multiple myeloma enrolled in the TOURMALINE-MM2 trial.

Deeper responses are associated with longer survival in multiple myeloma (MM); however, limited data exist on the impact of response kinetics on outcomes. We investigated progression-free survival (PFS) and duration of response (DOR) by response depth and in early (best confirmed response 0-4 months; n = 424) versus late responders (best confirmed response >4 months; n = 281). Newly diagnosed patients enrolled in TOURMALINE-MM2 receiving ixazomib-lenalidomide-dexamethasone (IRd) (n = 351) or placebo-Rd (n = 354) were evaluated post hoc. Deeper responses were associated with longer PFS (complete response [CR] not reached [NR], very good partial response [VGPR] 37.2 months, partial response [PR] 16.4 months) and DOR (CR NR, VGPR 42.6 months, PR 15.4 months). Among patients with a PFS (n = 511) or DOR (n = 484) of ≥6 months who achieved ≥PR, median PFS was prolonged among late versus early responders receiving IRd (59.7 vs. 17.9 months) or placebo-Rd (56.6 vs. 12.4 months), as was median DOR (IRd, NR vs. 20.9 months; placebo-Rd, 58.2 vs. 11.7 months). While the treatment paradigm for newly diagnosed MM is treatment to progression, our findings suggest slowness of response to a proteasome inhibitor-immunomodulatory drug-steroid combination is not a negative predictor of outcome.

Phenotypic and Endotypic Determinants of Atopic Dermatitis Severity From the Atopic Dermatitis Research Network (ADRN) Registry.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin condition with a highly variable clinical phenotype. OBJECTIVE: This study aimed to identify historical and clinical features and biomarkers associated with AD severity. METHODS: A US registry of extensively phenotyped AD participants (aged 0.73-80 years) were enrolled at 9 academic centers. Information on family and personal medical history, examination, skin swabs (culture), and serum biomarkers was collected to evaluate their association with AD severity. RESULTS: Participants with AD (N = 2862) whose disease was categorized as mild (11.6%), moderate (58.0%), or severe (30.4%) based on Rajka-Langeland scoring were enrolled. The trend test, when adjusting for gender, race, and age, demonstrated that severity was strongly (P ≤ .04) associated with a personal/family history of allergic disorders, history of alopecia, exposure to passive smoke, ocular herpes infection, skin bacterial and viral infections, and history of arrhythmia. Features observed more frequently (P ≤ .002), as a function of severity, included skin infections (impetigo, human papillomavirus, and molluscum contagiosum virus), Staphylococcus aureus colonization, excoriations, hyperlinear palms, ichthyosis, blepharitis, conjunctivitis, ectropion, and wheezing. Serum IgE, allergen and food (≤6 years) Phadiatop, and eosinophilia were strongly linked to severity (P < .001). CONCLUSIONS: In a diverse US AD population, severity was associated with a history of atopic disorders, skin and extracutaneous bacterial and viral infections (by history and physical examination), higher IgE, eosinophilia and allergen sensitization, atopic skin manifestations (ie, excoriation, hyperlinear palms, and ichthyosis), and atopic ocular features (ie, blepharitis, conjunctivitis, and ectropion) as well as asthma findings (ie, wheezing). Data from our prospective registry significantly advance our understanding of AD phenotypes and endotypes, which is critical to achieve optimal management.

A pooled analysis of outcomes according to cytogenetic abnormalities in patients receiving ixazomib- vs placebo-based therapy for multiple myeloma.

Some cytogenetic abnormalities (CAs) are associated with poorer prognosis in multiple myeloma (MM); proteasome inhibitors appear to benefit patients with high-risk CAs. We evaluated 2247 MM patients from the TOURMALINE-MM1/-MM2/-MM3/-MM4 trials to assess the PFS benefit of ixazomib plus lenalidomide-dexamethasone (Rd) vs placebo-Rd (TOURMALINE-MM1/-MM2) or ixazomib vs placebo (TOURMALINE-MM3/-MM4) in specific high-risk CAs. After a pooled median follow-up of 25.6 months, the hazard ratio (HR) for PFS with ixazomib- vs placebo-based therapy for high-risk patients was 0.74 (95% confidence interval [CI]: 0.59-0.93; median PFS [mPFS] 17.8 vs 13.2 months), and 0.70 (95% CI: 0.62-0.80; mPFS 26.3 vs 17.6 months) for complementary standard-risk patients. The HR for expanded high-risk patients was 0.75 (95% CI: 0.64-0.87; mPFS 18.1 vs 14.1 months), and 0.71 (95% CI: 0.59-0.85; mPFS 36.1 vs 21.4 months) for complementary standard-risk patients. The HR for PFS with ixazomib- vs placebo-based therapy was 0.68 in patients with t(4;14) (95% CI: 0.48-0.96; mPFS 22.4 vs 13.2 months), and 0.77 for patients with amp1q21 (95% CI: 0.63-0.93; mPFS 18.8 vs 14.5 months). A PFS benefit was demonstrated with ixazomib- vs placebo-based therapy regardless of cytogenetic status, with greatest benefit observed in patients with t(4;14) and amp1q21.

Staphylococcal TSST-1 Association with Eczema Herpeticum in Humans.

Atopic dermatitis (AD) is a condition affecting 30 million persons in the United States. AD patients are heavily infected with Staphylococcus aureus on the skin. A particularly severe form of AD is eczema herpeticum (ADEH), where the patients' AD is complicated by S. aureus and herpes simplex virus (HSV) infection. This study examined the S. aureus strains from 15 ADEH patients, provided blinded, and showed a high association of ADEH with strains that produce toxic shock syndrome toxin-1 (TSST-1; 73%) compared to 10% production by typical AD isolates from patients without EH and those from another unrelated condition, cystic fibrosis. The ADEH isolates produced the superantigens associated with TSS (TSST-1 and staphylococcal enterotoxins A, B, and C). This association may in part explain the potential severity of ADEH. We also examined the effect of TSST-1 and HSV-1 on human epithelial cells and keratinocytes. TSST-1 used CD40 as its receptor on epithelial cells, and HSV-1 either directly or indirectly interacted with CD40. The consequence of these interactions was chemokine production, which is capable of causing harmful inflammation, with epidermal/keratinocyte barrier disruption. Human epithelial cells treated first with TSST-1 and then HSV-1 resulted in enhanced chemokine production. Finally, we showed that TSST-1 modestly increased HSV-1 replication but did not increase viral plaque size. Our data suggest that ADEH is associated with production of the major TSS-associated superantigens, together with HSV reactivation. The superantigens plus HSV may damage the skin barrier by causing harmful inflammation, thereby leading to increased symptoms. IMPORTANCE Atopic dermatitis (eczema, AD) with concurrent herpes simplex virus infection (eczema herpeticum, ADEH) is a severe form of AD. We show that ADEH patients are colonized with Staphylococcus aureus that primarily produces the superantigen toxic shock syndrome toxin-1 (TSST-1); however, significantly but to a lesser extent the superantigens staphylococcal enterotoxins A, B, and C are also represented in ADEH. Our studies showed that TSST-1 uses the immune costimulatory molecule CD40 as its epithelial cell receptor. Herpes simplex virus (HSV) also interacted directly or indirectly with CD40 on epithelial cells. Treatment of epithelial cells with TSST-1 and then HSV-1 resulted in enhanced chemokine production. We propose that this combination of exposures (TSST-1 and then HSV) leads to opening of epithelial and skin barriers to facilitate potentially serious ADEH.

Clinical outcomes of treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis based on ANCA type.

OBJECTIVE: To evaluate whether the classification of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) according to ANCA type (anti-proteinase 3 (PR3) or anti-myeloperoxidase (MPO) antibodies) predicts treatment response. METHODS: Treatment responses were assessed among patients enrolled in the Rituximab in ANCA-associated Vasculitis trial according to both AAV diagnosis (granulomatosis with polyangiitis (GPA)/microscopic polyangiitis (MPA)) and ANCA type (PR3-AAV/MPO-AAV). Complete remission (CR) was defined as disease activity score of 0 and successful completion of the prednisone taper. RESULTS: PR3-AAV patients treated with rituximab (RTX) achieved CR at 6 months more frequently than did those randomised to cyclophosphamide (CYC)/azathioprine (AZA) (65% vs 48%; p=0.04). The OR for CR at 6 months among PR3-AAV patients treated with RTX as opposed to CYC/AZA was 2.11 (95% CI 1.04 to 4.30) in analyses adjusted for age, sex and new-onset versus relapsing disease at baseline. PR3-AAV patients with relapsing disease achieved CR more often following RTX treatment at 6 months (OR 3.57; 95% CI 1.43 to 8.93), 12 months (OR 4.32; 95% CI 1.53 to 12.15) and 18 months (OR 3.06; 95% CI 1.05 to 8.97). No association between treatment and CR was observed in the MPO-AAV patient subset or in groups divided according to AAV diagnosis. CONCLUSIONS: Patients with PR3-AAV respond better to RTX than to CYC/AZA. An ANCA type-based classification may guide immunosuppression in AAV. TRIAL REGISTRATION NUMBER: NCT00104299; post-results.

[Urinary protein detection by iTRAQ® associated with renal transplant complications and its modification with therapy]. / Detección de proteínas urinarias por iTRAQ® asociadas a complicaciones del trasplante renal y su modificación con la terapia.

BACKGROUND: After renal transplant, surgical, infection complications, as well as graft rejection may occur; early detection through non-invasive markers is the key to change therapy and avoid biopsy. OBJECTIVE: The aime of the study is to determine urine protein profiles in patients undergoing renal transplant with complications and detect its variation when therapy is modified. MATERIAL AND METHODS: Urine samples were collected from patients prior the transplant and various postoperative stages. Urinary protein profiles were obtained by peptide labeling using isobaric isotopes for relative quantification (iTRAQ(®)). RESULTS: A total of 22 patients were included, of whom 12 developed post-transplant complication: 2 with graft rejection (one male and one female) and 10 (6 males and 4 females) in the group of post-transplant infections. Using iTRAQ(®) 15/345 and 28/113 proteins were identified and fulfilled the acceptance criteria, in graft rejection and post-transplant infections group, respectively. CONCLUSIONS: Albumin was the only protein found in both groups, the remaining proteins were different. The 5 proteins with higher scores in graft rejection were: alpha-1-microglobulin, 5'-nucleotidase cytosolic III, retinol-binding protein 4, membrane protein palmitoylated 4, and serine carboxypeptidase, while post-transplant infections were: mitochondrial acetyl-coenzyme A synthetase, putative adenosyl homocysteinase 2, zinc finger protein GLIS1, putative protein FAM157B, and zinc finger protein 615. It remains to elucidate the involvement of each of these in patients with renal transplantation.

Is Ischemic Preconditioning a Useful Therapeutic Strategy in Liver Transplantation? Results from the First Pilot Study in Mexico.

BACKGROUND AND AIMS: The protective effect of ischemic preconditioning (IP) in liver transplantation (LT) has been studied with controversial results. We undertook this study to investigate whether IP of cadaveric donor livers is protective to allografts. METHODS: IP (LT + IP, n = 6) was induced by 10-min hilar clamping. These were compared to cadaver donors with no IP (LT, n = 7). Clinical data and blood were obtained in donors and recipients for biochemical and inflammatory mediator (IM) measurements (P-selectin, leukotriene B4, myeloperoxidase, ICAM-1, IL-1, IL-6, and TNF-α). Liver tissue samples were obtained from donors and recipients (90 min after reperfusion). RESULTS: No significant differences were found in demographic characteristics between donors and recipients. When comparing both groups (LT + IP vs. LT only), ICU stay was longer in LT + IP group. For biochemical parameters, a significant difference was found only with a higher total bilirubin at postoperative day 3 in LT + IP group. There was no statistical difference in IM between LT and LT + IP groups at different stages of the study. Histological analysis of donor grafts indicated the presence of steatosis (50%) in one graft from the LT + IP group. However, in post-reperfusion biopsies neither neutrophil infiltration nor grade of necrosis showed significant difference between groups. No incidence of primary graft nonfunction (PGNF) was observed and graft and patient survival was similar in the two groups at 24 months. CONCLUSION: IP does not seem to protect against I/R injury in cadaveric LT, and no PGNF was seen.

Recidiva postrasplante de hepatopatías no virales / Posttransplant relapse in non viral hepatopathies

Objetivo: El objetivo del presente trabajo fue analizar la frecuencia y presentación de recidiva de hepatopatías postrasplante no virales. Métodos y Resultados: Los pacientes con hepatopatías no virales que recibieron un trasplante hepático fueron 39 y de éstos, seis presentaron recidiva de la enfermedad (15.3%): uno con recaída del alcoholismo, tres con enfermedad autoinmune (dos trasplantados por cirrosis biliar primaria recurrieron con hepatitis autoinmune y uno con diagnóstico original de cirrosis hepática criptogénica presentó recurrencia de hepatitis autoinmune), uno con diagnóstico de esteatohepatitis no alcohólica tuvo recurrencia con la misma enfermedad; por último, un paciente se trasplantó por cirrosis hepática secundaria a metotrexate y postrasplante manifestó cirrosis biliar secundaria a estenosis del colédoco en el sitio de la anastomosis. Conclusiones: Todos los pacientes aquí analizados presentaron recidiva en el largo plazo (después de 11 meses postrasplante). La recidiva del alcoholismo se identificó en 8.3%, de las hepatopatías autoinmunes en 30%, y de la esteatohepatitis no alcohólica en 20% de los casos. Las tres pacientes con recidiva de hepatopatía autoinmune presentaron en el postras-plante una enfermedad diferente a la que dio origen al trasplante.

OBJECTIVE: We describe the recurrence of non-viral liver disease after orthotopic liver transplantation (OLT). METHODS AND RESULTS: We studied 39 patients who received an OLT for non-viral chronic liver disease. Six (15.3%) of these patients presented disease recurrence after OLT, one following alcohol abuse, 3 presented autoimmune liver disease [2 received an OLT for primary biliary cirrhosis and recurred as autoimmune hepatitis (AIH) one patient had cryptogenic cirrhosis before OLT and recurred as AIH]. One patient showed recurrence of a non-alcoholic steatohepatitis (NASH). One patient received an OLT for cirrhosis secondary to the use of metothrexate and post OLT developed secondary biliary cirrhosis due to a choledocal stenosis in the anastomotic site. CONCLUSIONS: All patients described here displayed long term recurrence (after 11 months post OLT). The recurrence of alcoholism was 8.3% among patients transplanted for this condition. AIH was observed in 30% of cases and NASH in 20%. All three patients with autoimmune liver disease recurred with a different autoimmune disease post OLT.

Lesiones traumáticas del diafragma / Traumatic lesions of the diaphragm

Objetivo: Analizar la experiencia de un hospital universitario en el manejo terapéutico de la lesión diafragmática de origen traumático. Sede: Hospital Universitario "Dr. Eleuterio González", Nuevo León, México. Diseño: Estudio clínico de casos, retrospectivo y observacional, sin diseño estadístico. Pacientes y métodos: Se revisaron los expedientes clínicos de 8721 pacientes hospitalizados de enero de 1988 a diciembre de 1992; (5 años). Se analizaron las siguientes variables: sexo, edad, mecanismo de lesión, síntoma más frecuente, hallazgos radiológicos, lavado peritoneal, tipo de cirugía, lesiones asociadas, características de la lesión del diafragma, colocación de sonda en tórax y su duración, antimicrobianos empleados, complicaciones, días de estancia hospitalaria y mortalidad. Resultados: Se encontraron 54 pacientes con lesión diafragmatica, 53 varones y una mujer. Edad promedio 22 años, 25 por ciento tenían entre 17 y 20 años. Los mecanismos de lesión fueron de tres tipos: herida por arma punzo cortante, herida por proyectil de arma de fuego y traumatismo cerrado múltiple. Al 40 por ciento (22 pacientes) se les tomó telerradiografía de tórax, en 10 se observó hemoneumotórax, 8 del lado izquierdo y 2 del derecho. Se practicó lavado peritoneal a 32 pacientes (59 por ciento), todos resultaron positivos. El abordaje quirúrgico más empleado fue la laparotomía media en 44 sujetos (81 por ciento); el hígado fue el órgano más frecuentemente lesionado en 46 por ciento, le siguió el bazo con un 27 por ciento, todos requirieron esplenectomía. El hemidiafragma más lesionado resultó el izquierdo en 33 pacientes (61 por ciento). En el 74 por ciento (40 enfermos) el material de sutura con que se reparó la herida diafragmática fue la seda. Se colocó sonda de tórax a 30 pacientes con duración promedio de la misma de 5 días, el antimicrobiano más empleado fue la cefaxelina seguido de una combinación de cefalotina con metronidazol. Los días de estancia hospitalaria fueron en promedio de 7. La mortalidad fue del 3.7 por ciento. Conclusión: Las lesiones diafragmáticas son de difícil diagnóstico, se debe sospechar en todo paciente con trauma cerrado de tórax o abdomen superior, la telerradiografía de tórax es un buen método de diagnóstico y el lavado peritoneal lo complementa. La mortalidad es baja