Mezigdomide plus Dexamethasone in Relapsed and Refractory Multiple Myeloma.

BACKGROUND: Despite recent progress, multiple myeloma remains incurable. Mezigdomide is a novel cereblon E3 ubiquitin ligase modulator with potent antiproliferative and tumoricidal activity in preclinical models of multiple myeloma, including those resistant to lenalidomide and pomalidomide. METHODS: In this phase 1-2 study, we administered oral mezigdomide in combination with dexamethasone to patients with relapsed and refractory myeloma. The primary objectives of phase 1 (dose-escalation cohort) were to assess safety and pharmacokinetics and to identify the dose and schedule for phase 2. In phase 2 (dose-expansion cohort), objectives included the assessment of the overall response (partial response or better), safety, and efficacy of mezigdomide plus dexamethasone at the dose and schedule determined in phase 1. RESULTS: In phase 1, a total of 77 patients were enrolled in the study. The most common dose-limiting toxic effects were neutropenia and febrile neutropenia. On the basis of the phase 1 findings, investigators determined the recommended phase 2 dose of mezigdomide to be 1.0 mg, given once daily in combination with dexamethasone for 21 days, followed by 7 days off, in each 28-day cycle. In phase 2, a total of 101 patients received the dose identified in phase 1 in the same schedule. All patients in the dose-expansion cohort had triple-class-refractory multiple myeloma, 30 patients (30%) had received previous anti-B-cell maturation antigen (anti-BCMA) therapy, and 40 (40%) had plasmacytomas. The most common adverse events, almost all of which proved to be reversible, included neutropenia (in 77% of the patients) and infection (in 65%; grade 3, 29%; grade 4, 6%). No unexpected toxic effects were encountered. An overall response occurred in 41% of the patients (95% confidence interval [CI], 31 to 51), the median duration of response was 7.6 months (95% CI, 5.4 to 9.5; data not mature), and the median progression-free survival was 4.4 months (95% CI, 3.0 to 5.5), with a median follow-up of 7.5 months (range, 0.5 to 21.9). CONCLUSIONS: The all-oral combination of mezigdomide plus dexamethasone showed promising efficacy in patients with heavily pretreated multiple myeloma, with treatment-related adverse events consisting mainly of myelotoxic effects. (Funded by Celgene, a Bristol-Myers Squibb Company; CC-92480-MM-001 ClinicalTrials.gov number, NCT03374085; EudraCT number, 2017-001236-19.).

Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma.

BACKGROUND: Elotuzumab, an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7), showed activity in combination with lenalidomide and dexamethasone in a phase 1b-2 study in patients with relapsed or refractory multiple myeloma. METHODS: In this phase 3 study, we randomly assigned patients to receive either elotuzumab plus lenalidomide and dexamethasone (elotuzumab group) or lenalidomide and dexamethasone alone (control group). Coprimary end points were progression-free survival and the overall response rate. Final results for the coprimary end points are reported on the basis of a planned interim analysis of progression-free survival. RESULTS: Overall, 321 patients were assigned to the elotuzumab group and 325 to the control group. After a median follow-up of 24.5 months, the rate of progression-free survival at 1 year in the elotuzumab group was 68%, as compared with 57% in the control group; at 2 years, the rates were 41% and 27%, respectively. Median progression-free survival in the elotuzumab group was 19.4 months, versus 14.9 months in the control group (hazard ratio for progression or death in the elotuzumab group, 0.70; 95% confidence interval, 0.57 to 0.85; P<0.001). The overall response rate in the elotuzumab group was 79%, versus 66% in the control group (P<0.001). Common grade 3 or 4 adverse events in the two groups were lymphocytopenia, neutropenia, fatigue, and pneumonia. Infusion reactions occurred in 33 patients (10%) in the elotuzumab group and were grade 1 or 2 in 29 patients. CONCLUSIONS: Patients with relapsed or refractory multiple myeloma who received a combination of elotuzumab, lenalidomide, and dexamethasone had a significant relative reduction of 30% in the risk of disease progression or death. (Funded by Bristol-Myers Squibb and AbbVie Biotherapeutics; ELOQUENT-2 ClinicalTrials.gov number, NCT01239797.).

Elotuzumab plus lenalidomide/dexamethasone for relapsed or refractory multiple myeloma: ELOQUENT-2 follow-up and post-hoc analyses on progression-free survival and tumour growth.

The randomized phase III ELOQUENT-2 study (NCT01239797) evaluated the efficacy and safety of elotuzumab + lenalidomide/dexamethasone (ELd) versus lenalidomide/dexamethasone (Ld) in relapsed/refractory multiple myeloma. ELd reduced the risk of disease progression/death by 30% versus Ld (hazard ratio [HR] 0·70). Median time from diagnosis was 3·5 years. We present extended 3-year follow-up data. Endpoints included progression-free survival (PFS), overall response rate (ORR) and interim overall survival (OS). Exploratory post-hoc analyses included impact of time from diagnosis and prior lines of therapy on PFS, and serum M-protein dynamic modelling. ORR was 79% (ELd) and 66% (Ld) (P = 0·0002). ELd reduced the risk of disease progression/death by 27% versus Ld (HR 0·73; P = 0·0014). Interim OS demonstrated a trend in favour of ELd (P = 0·0257); 1-, 2- and 3-year rates with ELd versus Ld were: 91% versus 83%, 73% versus 69% and 60% versus 53%. In patients with ≥ median time from diagnosis and one prior therapy, ELd resulted in a 53% reduction in the risk of progression/death versus Ld (HR 0·47). Serum M-protein dynamic modelling showed slower tumour regrowth with ELd. Adverse events were comparable between arms. ELd provided a durable and clinically relevant improvement in efficacy, with minimal incremental toxicity.

Indoleamine 2,3-dioxygenase in T-cell tolerance and tumoral immune escape.

Indoleamine 2, 3-dioxygenase (IDO) degrades the essential amino acid tryptophan in mammals, catalyzing the initial and rate-limiting step in the de novo biosynthesis nicotinamide adenine dinucleotide (NAD). Broad evidence implicates IDO and the tryptophan catabolic pathway in generation of immune tolerance to foreign antigens in tissue microenvironments. In particular, recent findings have established that IDO is overexpressed in both tumor cells and antigen-presenting cells in tumor-draining lymph nodes, where it promotes the establishment of peripheral immune tolerance to tumor antigens. In the normal physiologic state, IDO is important in creating an environment that limits damage to tissues due to an overactive immune system. However, by fostering immune suppression, IDO can facilitate the survival and growth of tumor cells expressing unique antigens that would be recognized normally as foreign. In preclinical studies, small-molecule inhibitors of IDO can reverse this mechanism of immunosuppression, complementing classical cytotoxic cancer chemotherapeutic agents' ability to trigger regression of treatment-resistant tumors. These results have encouraged the clinical translation of IDO inhibitors, the first of which entered phase I clinical trials in the fall of 2007. In this article, we survey the work defining IDO as an important mediator of peripheral tolerance, review evidence of IDO dysregulation in cancer cells, and provide an overview of the development of IDO inhibitors as a new immunoregulatory treatment modality for clinical trials.

Message and talker identification in older adults: effects of task, distinctiveness of the talkers' voices, and meaningfulness of the competing message.

PURPOSE: In this study, the authors investigated (a) the effects of task, vocal distinctiveness of the competing talkers, and meaningfulness of the competitor on older listeners' identification of a target in the presence of competition and (b) the factors that are most predictive of the variability in target identification observed among older listeners. METHOD: Seventeen older and 5 younger adults identified a target in the presence of a competing message. Identification was measured for 2 target types (message; talker), 3 vocal-distinctiveness levels (same talker; different talkers-same sex; different talkers-different sex), and 2 competitors (meaningful speech; nonmeaningful time-reversed speech). Multiple regression analyses were used to identify variables that were predictive of intersubject variability. RESULTS: Significant age-related differences were found in the benefit obtained from increasing vocal distinctiveness. Older listeners showed reduced target identification when (a) the competitor was normal speech compared with time-reversed speech and (b) the target was message identification compared with talker identification. Variability among listeners in the older group was partially explained by auditory and cognitive factors. CONCLUSION: Age-related declines in multitalker environments are not solely due to lower-level deficits in perceptual organization but are also a consequence of an interaction between lower-level and higher-level processes.

Bin1 ablation increases susceptibility to cancer during aging, particularly lung cancer.

Age is the major risk factor for cancer, but few genetic pathways that modify cancer incidence during aging have been described. Bin1 is a prototypic member of the BAR adapter gene family that functions in vesicle dynamics and nuclear processes. Bin1 limits oncogenesis and is often attenuated in human cancers, but its role in cancer suppression has yet to be evaluated fully in vivo. In the mouse, homozygous deletion of Bin1 causes developmental lethality, so to assess this role, we examined cancer incidence in mosaic null mice generated by a modified Cre-lox technology. During study of these animals, one notable phenotype was an extended period of female fecundity during aging, with mosaic null animals retaining reproductive capability until the age of 17.3 +/- 1.1 months. Through 1 year of age, cancer incidence was unaffected by Bin1 ablation; however, by 18 to 20 months of age, approximately 50% of mosaic mice presented with lung adenocarcinoma and approximately 10% with hepatocarcinoma. Aging mosaic mice also displayed a higher incidence of inflammation and/or premalignant lesions, especially in the heart and prostate. In mice where colon tumors were initiated by a ras-activating carcinogen, Bin1 ablation facilitated progression to more aggressive invasive status. In cases of human lung and colon cancers, immunohistochemical analyses evidenced frequent attenuation of Bin1 expression, paralleling observations in other solid tumors. Taken together, our findings highlight an important role for Bin1 as a negative modifier of inflammation and cancer susceptibility during aging.

Double-vowel perception in listeners with cochlear hearing loss: differences in fundamental frequency, ear of presentation, and relative amplitude.

This study presents 2 experiments investigating whether listeners with cochlear hearing loss (hearing impaired; HI) and listeners with normal hearing (NH) show differential susceptibility to masking in double-vowel identification. Experiment 1 addressed how double-vowel perception changes as a function of differences in fundamental frequency (deltaF0) of 0 and 2 semitones and the relative amplitudes of the constituent vowels (target-to-masker ratios: -10, -5, 0, 5, 10 dB). When deltaF0 is 0 semitones, listeners in the HI group often perceive the presence of only 1 vowel, whereas listeners in the NH group generally perceive the presence of 2 vowels. In both groups, deltaF0 benefits target-vowel identification, with the greatest benefit occurring when the target-to-masker ratio is -10 dB. When identification rates of specific vowels (in d') were rank ordered, different patterns of vowel dominance were found between the NH and HI groups. In Experiment 2, the effects of deltaF0 (0 to 4 semitones) were compared for monaural and dichotic presentation of double vowels. Both groups show significant dichotic benefit. In addition, individual listeners in the HI group showed trends toward greater dichotic benefit. In both experiments, identification of competing vowels was significantly worse in HI listeners. The results of this study support the idea that increased susceptibility to masking is a primary factor underlying the degraded double-vowel perception in listeners with hearing loss.

Paradoxical activation of T cells via augmented ERK signaling mediated by a RAF inhibitor.

RAF inhibitors selectively block ERK signaling in BRAF-mutant melanomas and have defined a genotype-guided approach to care for this disease. RAF inhibitors have the opposite effect in BRAF wild-type tumor cells, where they cause hyperactivation of ERK signaling. Here, we predict that RAF inhibitors can enhance T cell activation, based upon the observation that these agents paradoxically activate ERK signaling in BRAF wild-type cells. To test this hypothesis, we have evaluated the effects of the RAF inhibitor BMS908662 on T cell activation and signaling in vitro and in vivo. We observe that T cell activation is enhanced in a concentration-dependent manner and that this effect corresponds with increased ERK signaling, consistent with paradoxical activation of the pathway. Furthermore, we find that the combination of BMS908662 with CTLA-4 blockade in vivo potentiates T cell expansion, corresponding with hyperactivation of ERK signaling in T cells detectable ex vivo. Lastly, this combination demonstrates superior anti-tumor activity, compared to either agent alone, in two transplantable tumor models. This study provides clear evidence that RAF inhibitors can modulate T cell function by potentiating T cell activation in vitro and in vivo. Paradoxical activation of ERK signaling in T cells offers one mechanism to explain the enhanced antitumor activity seen when RAF inhibitors are combined with CTLA-4 blockade in preclinical models.

Brentuximab Vedotin (SGN-35).

Brentuximab vedotin (SGN-35) is an antibody-drug conjugate (ADC) directed against the CD30 antigen expressed on Hodgkin lymphoma and anaplastic large cell lymphoma. SGN-35 consists of the cAC10 chimerized IgG1 monoclonal antibody SGN30, modified by the addition of a valine-citrulline dipeptide linker to permit attachment of the potent inhibitor of microtubule polymerization monomethylauristatin E (MMAE). In phase II trials, SGN-35 produced response rates of 75% in patients with Hodgkin lymphoma (n = 102) and 87% in patients with anaplastic large cell lymphoma (n = 30). Responses to SGN-35 might be related not only to the cytotoxic effect due to release of MMAE within the malignant cell but also to other effects. First, SGN-35 may signal malignant cells through CD30 ligation to deliver an apoptotic or proliferative response. The former would amplify the cytotoxicity of MMAE. A proliferative signal delivered in the context of MMAE intoxication could enhance cell death. Second, the efficacy of SGN-35, particularly in Hodgkin lymphoma, might be attributed to its effect on the tumor microenvironment. Diffusion of free MMAE from the targeted tumor cells could result in a bystander effect that kills the normal supporting cells in close proximity to the malignant cells. The elimination of T regulatory cells that inhibit cytotoxic effector cells and elimination of cells that provide growth factor support for Hodgkin/Reed-Sternberg cells could further enhance the cytotoxic activity of SGN-35. Here we review the biology of SGN-35 and the clinical effects of SGN-35 administration.

Survey of audiologic service provision to older adults with cochlear implants.

PURPOSE: This study examined whether audiologists modify practice patterns in their provision of cochlear implant (CI) services to older adults and, if so, whether the nature of such modifications is consistent across clinical sites. METHOD: An online survey was sent to audiologists at CI centers across the United States. Questions addressed demographics, candidacy, programming, outcomes assessment, rehabilitation, and professional development. RESULTS: Responses were obtained from 47 audiologists who provided CI services to older adults. The majority of these audiologists did not report modifying CI practice patterns on the basis of age. Counseling appeared to be an exception: Audiologists reported that both the content and delivery of information were modified for older adults. Specific to CI candidacy with older adults, under half of the respondents indicated that assessing an older adult's cognitive status was part of their clinical protocol. CONCLUSION: The audiologists who responded to the survey acknowledged issues related to aging when providing CI services to older adults. Despite this acknowledgment, the results of the survey suggest a gap in how age-related issues are incorporated into CI service provision. Continued discussion as to how CI services can be optimized for older adults is needed.

Effects of cochlear hearing loss on perceptual grouping cues in competing-vowel perception.

This study compared how normal-hearing listeners (NH) and listeners with moderate to moderately severe cochlear hearing loss (HI) use and combine information within and across frequency regions in the perceptual separation of competing vowels with fundamental frequency differences (deltaF0) ranging from 0 to 9 semitones. Following the procedure of Culling and Darwin [J. Acoust. Soc. Am. 93, 3454-3467 (1993)], eight NH listeners and eight HI listeners identified competing vowels with either a consistent or inconsistent harmonic structure. Vowels were amplified to assure audibility for HI listeners. The contribution of frequency region depended on the value of deltaF0 between the competing vowels. When deltaF0 was small, both groups of listeners effectively utilized deltaF0 cues in the low-frequency region. In contrast, HI listeners derived significantly less benefit than NH listeners from deltaF0 cues conveyed by the high-frequency region at small deltaF0's. At larger deltaF0's, both groups combined deltaF0 cues from the low and high formant-frequency regions. Cochlear impairment appears to negatively impact the ability to use F0 cues for within-formant grouping in the high-frequency region. However, cochlear loss does not appear to disrupt the ability to use within-formant F0 cues in the low-frequency region or to group F0 cues across formant regions.

Evaluación química y sensorial del chorizo tipo pamplona, elaborado a partir de carne de Cerdo Pelón Mexicano y de Cerdo Mejorado / Chemical and sensory y evaluation of \"chorizo\" Pamplona type from Mexican hairless pigs and commercial pigs

El objetivo fue comprobar las ventajas de la utilización de la carne del Cerdo Pelón Mexicano (CPM) en un embutido procesado y maduro de alta calidad, tal como el chorizo tipo Pamplona. Las diferencias principales, a lo largo del proceso de maduración, entre los chorizos del CPM y de cerdos mejorados (CM) se encontraron en los porcentajes de proteínas solubles, cenizas y humedad (P< 0.05). Los productos del CPM tienden a retener mayor humedad durante todo el proceso de maduración, con excepción de la última etapa, en la que ambos productos finales tienen la misma humedad. El contenido de proteínas solubles en el chorizo a lo largo de la maduración, fue consistentemente mayor en el CPM que en el CM. Por otra parte, los chorizos del CPM obtuvieron mejores calificaciones en apariencia y textura que los del CM (P< 0.05). Se concluye que la carne de CPM ofrece ventajas específicas en la preparación de productos procesados y maduros de alta calidad. Los factores determinantes fueron la mayor retención de humedad y la mayor solubilización de proteínas a lo largo del proceso, pues ayudaron a obtener un poducto final de mejor apariencia y textura. Por otra parte, el sabor y el aroma de los productos no se vieron afectados, pues la elaboración del chorizo tipo Pamplona requiere del picado y la consecuente destrucción de la integridad de la unidad muscular, con lo que la grasa intramuscular que le confiere las características especiales a la carne del CPM pierde parte de su función al mezclarse con la grasa añadida

Evaluación química y sensorial del morcón de Cerdo Pelón mexicano y Cerdo Mejorado / Chemical and sensory evaluation of \"Morcon\" of Mexican Hairless and commercial pigs

El objetivo de este proyecto fue evaluar las características químicas y sensoriales del morcón (producto cárnico tipo español de alta calidad, elaborado con las puntas de lomo del cerdo) a partir de la utilización de carne de Cerdo Pelón Mexicano (CPM), y compararlo con el elaborado con carne de Cerdo Mejorado (CM). Los productos elaborados de los dos tipos de cerdos fueron madurados durante 4 semanas. Los muestreos de las piezas de morcón se tomaron cada 7 días. Los análisis químicos que se realizaron fueron: Actividad de agua (Aw), cenizas, porcentaje de humedad, pH, proteínas solubles, nitratos, nitritos y fosfatos. Las diferencias encontradas entre el CPM y el CM fueron el porcentaje de humedad y la Aw (P< 0.01). El morcón elaborado con carne de CPM retiene mayor agua, obteniéndose una mejor textura. Los resultados en la evaluación sensorial mostraron una diferencia significativa entre los dos productos en el aroma, apariencia y textura (P < 0.05), teniendo una mejor aceptación el de CPM. Este estudio provee de información para la posibilidad de introducir al CPM en el mercado mexicano

Efecto del tipo de grasa y el pirofosfato de sodio en la calidad química y sensorial de productos elaborados con carne de oveja / Effect of type of fat and sodium pirophosphate on the chemical and sensory characteristicas of lamb sausages

Se elaboraron y evaluaron embutidos con carne ovina utilizando grasa vegetal, lardo de Cerdo Pelón Mexicano y pirofosfato de sodio (PF). Se utilizaron 32 kg de carne de borrego: 12 kg para elaborar jamón cocido, realizando 2 tratamientos: El primero con PF y segundo sin PF; 20 kg para elaborar chorizo tipo español realizando 4 tratamientos: El primero con lardo de cerdo, el segundo con grasa vegetal, el tercero con lardo de cerdo con PF y el cuarto con grasa vegetal con PF. Se hicieron análisis químicos: pH, humedad, cenizas, proteína, fosfatos, grasa, nitritos. Entre los tratamientos con y sin pirofosfato no hubo diferencias significativas (P> 0.05) en el porcentaje de humedad, siendo mayor en los productos con lardo de cerdo. La evaluación sensorial de los productos con un panel de consumidores no mostró diferencias significativas (P> 0.05) entre los tratamientos