Bortezomib, thalidomide, and dexamethasone with or without daratumumab and followed by daratumumab maintenance or observation in transplant-eligible newly diagnosed multiple myeloma: long-term follow-up of the CASSIOPEIA randomised controlled phase 3 trial.

BACKGROUND: CASSIOPEIA part 1 demonstrated superior depth of response and prolonged progression-free survival with daratumumab in combination with bortezomib, thalidomide, and dexamethasone (D-VTd) versus bortezomib, thalidomide, and dexamethasone (VTd) alone as an induction and consolidation regimen in transplant-eligible patients newly diagnosed with myeloma. In CASSIOPEIA part 2, daratumumab maintenance significantly improved progression-free survival and increased minimal residual disease (MRD)-negativity rates versus observation. Here, we report long-term study outcomes of CASSIOPEIA. METHODS: CASSIOPEIA was a two-part, open-label, phase 3 trial of patients done at 111 European academic and community-based centres. Eligible patients were aged 18-65 years with transplant-eligible newly diagnosed myeloma and an Eastern Cooperative Oncology Group performance status of 0-2. In part 1, patients were randomly assigned (1:1) to pre-transplant induction and post-transplant consolidation with D-VTd or VTd. Patients who completed consolidation and had a partial response or better were re-randomised (1:1) to intravenous daratumumab maintenance (16 mg/kg every 8 weeks) or observation for 2 years or less. An interactive web-based system was used for both randomisations, and randomisation was balanced using permuted blocks of four. Stratification factors for the first randomisation (induction and consolidation phase) were site affiliation, International Staging System disease stage, and cytogenetic risk status. Stratification factors for the second randomisation (maintenance phase) were induction treatment and depth of response in the induction and consolidation phase. The primary endpoint for the induction and consolidation phase was the proportion of patients who achieved a stringent complete response after consolidation; results for this endpoint remain unchanged from those reported previously. The primary endpoint for the maintenance phase was progression-free survival from second randomisation. Efficacy evaluations in the induction and consolidation phase were done on the intention-to-treat population, which included all patients who underwent first randomisation, and efficacy analyses in the maintenance phase were done in the maintenance-specific intention-to-treat population, which included all patients who were randomly assigned at the second randomisation. This analysis represents the final data cutoff at the end of the study. The trial is registered with ClinicalTrials.gov, NCT02541383. FINDINGS: Between Sept 22, 2015 and Aug 1, 2017, 1085 patients were randomly assigned to D-VTd (n=543) or VTd (n=542); between May 30, 2016 and June 18, 2018, 886 were re-randomised to daratumumab maintenance (n=442) or observation (n=444). At the clinical cutoff date, Sept 1, 2023, median follow-up was 80·1 months (IQR 75·7-85·6) from first randomisation and 70·6 months (66·4-76·1) from second randomisation. Progression-free survival from second randomisation was significantly longer in the daratumumab maintenance group than the observation-alone group (median not reached [95% CI 79·9-not estimable (NE)] vs 45·8 months [41·8-49·6]; HR 0·49 [95% CI 0·40-0·59]; p<0·0001); benefit was observed with D-VTd with daratumumab maintenance versus D-VTd with observation (median not reached [74·6-NE] vs 72·1 months [52·8-NE]; 0·76 [0·58-1·00]; p=0·048) and VTd with daratumumab maintenance versus VTd with observation (median not reached [66·9-NE] vs 32·7 months [27·2-38·7]; 0·34 [0·26-0·44]; p<0·0001). INTERPRETATION: The long-term follow-up results of CASSIOPEIA show that including daratumumab in both the induction and consolidation phase and the maintenance phase led to superior progression-free survival outcomes. Our results confirm D-VTd induction and consolidation as a standard of care, and support the option of subsequent daratumumab monotherapy maintenance, for transplant-eligible patients with newly diagnosed multiple myeloma. FUNDING: Intergroupe Francophone du Myélome, Dutch-Belgian Cooperative Trial Group for Hematology Oncology, and Janssen Research & Development.

Telomouse-a mouse model with human-length telomeres generated by a single amino acid change in RTEL1.

Telomeres, the ends of eukaryotic chromosomes, protect genome integrity and enable cell proliferation. Maintaining optimal telomere length in the germline and throughout life limits the risk of cancer and enables healthy aging. Telomeres in the house mouse, Mus musculus, are about five times longer than human telomeres, limiting the use of this common laboratory animal for studying the contribution of telomere biology to aging and cancer. We identified a key amino acid variation in the helicase RTEL1, naturally occurring in the short-telomere mouse species M. spretus. Introducing this variation into M. musculus is sufficient to reduce the telomere length set point in the germline and generate mice with human-length telomeres. While these mice are fertile and appear healthy, the regenerative capacity of their colonic epithelium is compromised. The engineered Telomouse reported here demonstrates a dominant role of RTEL1 in telomere length regulation and provides a unique model for aging and cancer.

Phase 3 SELENE study: ibrutinib plus BR/R-CHOP in previously treated patients with follicular or marginal zone lymphoma.

The phase 3 SELENE study evaluated ibrutinib + chemoimmunotherapy (CIT; bendamustine and rituximab [BR]; or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]) for patients with relapsed/refractory (R/R) follicular lymphoma (FL) or marginal zone lymphoma (MZL). Adult patients who had received ≥1 prior line of CIT were randomized 1:1 to oral ibrutinib (560 mg) or placebo daily, plus 6 cycles of BR/R-CHOP. The primary end point was investigator-assessed progression-free survival (PFS). Overall, 403 patients were randomized to ibrutinib + CIT (n = 202) or placebo + CIT (n = 201). Most patients received BR (90.3%) and had FL (86.1%). With a median follow-up of 84 months, median PFS was 40.5 months in the ibrutinib + CIT arm and 23.8 months in the placebo + CIT arm (hazard ratio [HR], 0.806; 95% confidence interval [CI], 0.626-1.037; P = .0922). Median overall survival was not reached in either arm (HR, 0.980; 95% CI, 0.686-1.400). Grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 85.6% and 75.4% of patients in the ibrutinib + CIT and placebo + CIT arms, respectively. In each arm, 13 patients had TEAEs leading to death. The addition of ibrutinib to CIT did not significantly improve PFS compared with placebo + CIT. The safety profile was consistent with known profiles of ibrutinib and CIT. This trial was registered at www.clinicaltrials.gov as #NCT01974440.

The Role of Non-Coding RNAs in Liver Disease, Injury, and Regeneration.

Non-coding RNAs (ncRNAs) have diverse functions in health and pathology in many tissues, including the liver. This review highlights important microRNAs (miRs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) in liver disease and regeneration. Greater attention is given to more prevalent and well characterized RNAs, including: miR-122, miR-21, the let-7 family of miRs, miR-451a, miR-144, and MALAT1.

Blocking olfactory input alters aggression in male and female California mice (Peromyscus californicus).

Olfactory input into the brain can be disrupted by a variety of environmental factors, including exposure to pathogens or environmental contaminants. Olfactory cues are often eliminated in laboratory rats and mice through highly invasive procedures like olfactory bulbectomy, which may also disrupt accessory olfactory pathways and detection of non-volatile odors. In the present study, we tested whether inducing anosmia through intranasal infusion of zinc gluconate alters aggression in a monogamous, biparental rodent species, the California mouse (Peromyscus californicus). This less invasive method of manipulating olfaction selectively targets the olfactory epithelium and reduces the detection of volatile odors. Treatment with zinc gluconate extended the time required for male and female California mice to find hidden pieces of apple and reduced the amount of time spent investigating bedding that was soiled by unfamiliar males. Moreover, inhibition of olfaction with zinc gluconate reduced aggressiveness in both sexes as demonstrated by an increased attack latency in the resident-intruder test among same-sex dyads from the same treatment group. These results suggest that volatile olfactory cues are necessary for agonistic responses in both male and female California mice. Therefore, even in species with complex social systems that include territorial aggression and monogamy, volatile olfactory cues modulate agonistic behavior.

Indoximod: An Immunometabolic Adjuvant That Empowers T Cell Activity in Cancer.

Exploding interest in immunometabolism as a source of new cancer therapeutics has been driven in large part by studies of tryptophan catabolism mediated by IDO/TDO enzymes. A chief focus in the field is IDO1, a pro-inflammatory modifier that is widely overexpressed in cancers where it blunts immunosurveillance and enables neovascularization and metastasis. The simple racemic compound 1-methyl-D,L-tryptophan (1MT) is an extensively used probe of IDO/TDO pathways that exerts a variety of complex inhibitory effects. The L isomer of 1MT is a weak substrate for IDO1 and is ascribed the weak inhibitory activity of the racemate on the enzyme. In contrast, the D isomer neither binds nor inhibits the purified IDO1 enzyme. However, clinical development focused on D-1MT (now termed indoximod) due to preclinical cues of its greater anticancer activity and its distinct mechanisms of action. In contrast to direct enzymatic inhibitors of IDO1, indoximod acts downstream of IDO1 to stimulate mTORC1, a convergent effector signaling molecule for all IDO/TDO enzymes, thus possibly lowering risks of drug resistance by IDO1 bypass. In this review, we survey the unique biological and mechanistic features of indoximod as an IDO/TDO pathway inhibitor, including recent clinical findings of its ability to safely enhance various types of cancer therapy, including chemotherapy, chemo-radiotherapy, vaccines, and immune checkpoint therapy. We also review the potential advantages indoximod offers compared to selective IDO1-specific blockade, which preclinical studies and the clinical study ECHO-301 suggest may be bypassed readily by tumors. Indoximod lies at a leading edge of broad-spectrum immunometabolic agents that may act to improve responses to many anticancer modalities, in a manner analogous to vaccine adjuvants that act to boost immunity in settings of infectious disease.

Referential communication skills of children with Williams syndrome: understanding when messages are not adequate.

Although children with Williams syndrome have relatively good structural language and concrete vocabulary abilities, they have difficulty with pragmatic aspects of language. To investigate the impact of pragmatic difficulties on listener-role referential communication, we administered a picture placement task designed to measure ability to verbalize message inadequacy to a speaker separated by a barrier. Participants were 57 children with Williams syndrome 6 to 12 years of age. When messages were inadequate, children verbalized that a problem was encountered less than half the time. The likelihood that children would indicate a message was insufficient and that children who verbalized message inadequacy also would effectively communicate the problem varied as a function of type of problem encountered, theory of mind knowledge, receptive vocabulary, and CA.

The effect of adherence to practice guidelines on depression outcomes.

BACKGROUND: Few studies have assessed clinician adherence to depression practice guidelines and the relationship between clinician adherence and depression outcomes. OBJECTIVE: To estimate how frequently specific guideline recommendations are followed and to assess whether following guideline recommendations is linked to improved depression outcomes. DESIGN: Observational analysis of data collected from 1996 to 1998 in 3 randomized clinical trials. SETTING: 45 primary care practices in 13 U.S. states. PATIENTS: 1131 primary care patients with depression. MEASUREMENTS: Expert panel methods were used to develop a patient survey-based index that measured adherence to clinical practice guidelines on depression. Rates of adherence to the 20 indicators that form the index were evaluated. Multivariable regression that controlled for case mix was used to assess how index scores predicted continuous and dichotomous depression measures at 12, 18, and 24 months. RESULTS: Quality of care was high (clinician adherence > or =79%) for 6 indicators, including primary care clinician detection of depression. Quality of care was low (adherence, 20% to 38%) for 8 indicators, including management of suicide risk (3 indicators), alcohol abuse (2 indicators), and elderly patients; assessment of symptoms and history of depression; and treatment adjustment for patients who did not respond to initial treatment. Greater adherence to practice guidelines significantly predicted fewer depressive symptoms on continuous measures (P < 0.001 for 12 months, P < 0.01 for 18 months, and P < 0.001 for 24 months) and dichotomous measures (P < 0.05 for 18 and 24 months). LIMITATIONS: Data are based on patient self-report. Possible changes in practice since 1998 may limit the generalizability of the findings. CONCLUSIONS: Adherence to guidelines was high for one third of the recommendations that were measured but was very low for nearly half of the measures, pointing to specific needs for quality improvement. Guideline-concordant depression care appears to be linked to improved outcomes in primary care patients with depression.

Use of a consumer-led intervention to improve provider competencies.

OBJECTIVE: Client-centered care is a major aim of health care. In mental health, new client-centered treatment approaches that emphasize recovery, rehabilitation, and empowerment can improve outcomes for people with severe and persistent mental illness. However, these approaches are not widely used, in part because many clinicians lack the necessary competencies. The objective of this study was to evaluate the effectiveness of an innovative, consumer-led intervention, Staff Supporting Skills for Self-Help, which was designed to improve provider quality, empower mental health consumers, and promote mutual support. METHODS: The study was conducted at five large community mental health provider organizations in two western states. One organization in each state received the intervention. The intervention included education, clinician-client dialogues, ongoing technical assistance, and support of self-help. It focused on client-centered care, rehabilitation, and recovery. A one-year controlled trial evaluated the effect of the intervention on clinicians' competencies, care processes, and the formation of mutual support groups. Outcomes were assessed by using competency assessment survey instruments and semistructured interviews with clinicians and managers. RESULTS: A total of 269 clinicians participated in the study: 151 in the intervention group and 118 in the control group. Compared with clinicians at the control organizations, clinicians at intervention organizations showed significantly greater improvement in education about care, rehabilitation methods, natural supports, holistic approaches, teamwork, overall competency, and recovery orientation. CONCLUSIONS: A feasible, consumer-led intervention improves provider competencies in domains that are necessary for the provision of high-quality care.

Intellectual abilities and adaptive behavior of children and adolescents with Kabuki syndrome: a preliminary study.

Very little is known about the intellectual abilities and adaptive behavior of individuals who have Kabuki syndrome, beyond the fact that most individuals with this syndrome have mental retardation. To fill this gap, we have completed psychological assessments of 11 children and adolescents with Kabuki syndrome. Results indicated that most of the participants functioned in the range of mild mental retardation, with both intellectual and adaptive behavior in the mildly deficient range and problem behaviors, if any, limited to mild difficulties with inattention and/or hyperactivity-impulsivity and mild problems with obsession/anxiety. At the lower extreme, one child evidenced severe mental retardation and profound adaptive behavior impairment accompanied by serious externalizing and internalizing problem behaviors. At the upper extreme, one adolescent had average intelligence and adaptive behavior, with problem behaviors well within the normal range for his chronological age. Most participants evidenced relative intellectual strengths in verbal and reasoning abilities and a relative weakness in visuospatial construction abilities. This pattern affected adaptive behavior as well, yielding a relative strength in Social Interaction and Communicative Skills and considerable weakness in Motor Skills and Personal Living Skills.

An instrument to assess competencies of providers treating severe mental illness.

One approach to improving the quality of care for severe mental illnesses (SMI) such as schizophrenia is through the improvement of provider competencies; the attitudes, knowledge, and skills needed to deliver high-quality care. This paper describes a new instrument designed to measure such a set of competencies. A total of 341 providers of services to clients with SMI at 38 clinics within 5 publicly financed treatment organizations in 2 western states were asked to complete a paper-and-pencil survey including the new Competency Assessment Instrument (CAI: 15 scales, each assessing a particular provider competency), and additional measures used to establish validity (Recovery Attitude Questionnaire--7, Client Optimism Scale). Seventy-nine percent (N = 269) responded at baseline, 83% (N = 282) responded at 2 weeks. Ninety-seven percent of baseline respondents completed the survey at 2 weeks. Most CAI scales have good internal consistency (Cronbach's alphas = .52-.93), test-retest reliability (scales ranged from .42 to .78), and validity, and should be useful in efforts to improve care.

Presleep attributions about arousal during sleep: nocturnal panic.

This study examined the role of presleep attributions about physiological events during sleep in nocturnal panic attacks. Patients who regularly experienced nocturnal panic were physiologically monitored as audio signals were presented during sleep. They were randomly assigned to 1 of 3 conditions: expected, in which signals of intense physiological changes were expected; unexpected, in which signals of intense physiological changes were not expected; or control, involving distinctly different signals unrelated to physiological responses. The unexpected condition led to substantially more self-reported distress and panic attacks. The experimental conditions did not elicit different autonomic reactions, but those who panicked showed stronger physiological responses than those who did not panic. The findings are consistent with a cognitive model of nocturnal panic attacks.