A phase I first-in-human study of ABBV-383, a B-cell maturation antigen × CD3 bispecific T-cell redirecting antibody, in patients with relapsed/refractory multiple myeloma

PURPOSE: ABBV-383, a B-cell maturation antigen × CD3 T-cell engaging bispecific antibody, has demonstrated promising results in an ongoing first-in-human phase I study (ClinicalTrials.gov identifier: NCT03933735) in patients with relapsed/refractory multiple myeloma (RRMM). Herein, we report safety and efficacy outcomes of this phase I dose escalation/expansion study. METHODS: Patients with RRMM (≥ three prior lines including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody) were eligible. ABBV-383 was administered intravenously over 1-2 hours once every 3 weeks, without any step dosing. A 3 + 3 design with backfilling for dose escalation was used (intrapatient escalation to highest safe dose permitted) followed by initiation of dose expansion. RESULTS: As of January 8, 2022, 124 patients (dose escalation [0.025-120 mg], n = 73; dose expansion [60 mg], n = 51) have received ABBV-383; median age was 68 years (range, 35-92 years). The most common hematologic treatment-emergent adverse events (TEAEs) were neutropenia (all grades: 37%) and anemia (29%). The most common nonhematologic TEAEs were cytokine release syndrome (57%) and fatigue (30%). Seven deaths from TEAEs were reported with all considered unrelated to study drug by the investigator. For all efficacy-evaluable patients (n = 122; all doses), the objective response rate (ORR) was 57% and very good partial response (VGPR) or better (≥ VGPR) rate was 43%. In the 60 mg dose expansion cohort (n = 49), the ORR and ≥ VGPR rates were 59% and 39%, respectively; and in the ≥ 40 mg dose escalation plus dose expansion cohorts (n = 79) were 68% and 54%, respectively. CONCLUSION: ABBV-383 in patients with RRMM was well tolerated with an ORR of 68% at doses ≥ 40 mg. This novel therapy\u27s promising preliminary antitumor activity in heavily pretreated patients warrants further clinical evaluation

Nematic twist-bend phase with nanoscale modulation of molecular orientation

A state of matter in which molecules show a long-range orientational order and no positional order is called a nematic liquid crystal. The best known and most widely used (for example, in modern displays) is the uniaxial nematic, with the rod-like molecules aligned along a single axis, called the director. When the molecules are chiral, the director twists in space, drawing a right-angle helicoid and remaining perpendicular to the helix axis; the structure is called a chiral nematic. Here using transmission electron and optical microscopy, we experimentally demonstrate a new nematic order, formed by achiral molecules, in which the director follows an oblique helicoid, maintaining a constant oblique angle with the helix axis and experiencing twist and bend. The oblique helicoids have a nanoscale pitch. The new twist-bend nematic represents a structural link between the uniaxial nematic (no tilt) and a chiral nematic (helicoids with right-angle tilt)

Nematic Twist-Bend Phase with Nanoscale Modulation of Molecular Orientation

Peer reviewedPublisher PD

Analysis of waiting time for elective surgical procedures in neurosurgery department at a tertiary care teaching hospital in NCT, India

Background: Reported increases in waiting times for publicly-funded elective surgeries have intensified the need to decrease wait by healthcare providers and hence the study.Methods: Descriptive study done in neurosurgery department, to ascertain waiting times for its elective surgeries, included a retrospective analysis of admitted post-surgical patients and a prospective study using interviews with relevant stakeholders to do a process mapping.Results: Median time from decision of surgery to actual date of surgery was found to be 110.5 days. It was calculated that for optimum utilization of present available OTs, 19 extra beds are required and to address the existing load of patients waiting for their respective surgeries there is a need of 63 additional beds with 2 additional OTs functioning per day.Conclusions: The most common cause of waiting time was unavailability of vacant beds due to mismatch in demand-supply. The reason for postponement of surgery after admission was found to be lack of availability of theatre time followed by patient not being fit for surgery. Shortage of operating time was due to delayed start of operation theatre time. The study recommends improving admission process, restricting OPD time, standardized patient prioritization depending on relevant clinical criteria

Management of Colonic Trauma: Six-Year Experience at Henry Ford Hospital

Surgical management of 114 patients with colonic injuries related to trauma who were treated over a six-year period is reviewed. Eighty-three (73%) injuries were secondary to gunshot wounds. Twenty-six patients (24%) had isolated colonic injuries. The majority of patients (60%)) were treated with colostomies: exteriorization of the injury, repair with proximal colostomy, or resection with colostomy and mucous fistula. Exteriorization of repaired colon, primary repair, and resection with primary anastomosis were performed in 40% of the patients. Six patients (5.3%) in our series died, and 24% had complications directly related to the colon injury. Based on this study, no standard method for treatment of colonic trauma is advised. Colostomy is recommended for patients with massive multiple intra-abdominal injuries and gross fecal contamination. In selected patients, primary repair may be performed

Critical Role of VCP/p97 in the Pathogenesis and Progression of Non-Small Cell Lung Carcinoma

Valosin-containing protein (VCP)/p97 is an AAA ATPase molecular chaperone that regulates vital cellular functions and protein-processing. A recent study indicated that VCP expression levels are correlated with prognosis and progression of non-small cell lung carcinoma (NSCLC). We not only verified these findings but also identified the specific role of VCP in NSCLC pathogenesis and progression.Our results show that VCP is significantly overexpressed in non-small cell lung carcinoma (NSCLC) as compared to normal tissues and cell lines (p<0.001). Moreover, we observed the corresponding accumulation of ubiquitinated-proteins in NSCLC cell lines and tissues as compared to the normal controls. VCP inhibition by si/shRNA or small-molecule (Eeyarestatin I, EerI) significantly (p<0.05, p<0.00007) suppressed H1299 proliferation and migration but induced (p<0.00001) apoptosis. Cell cycle analysis by flow cytometry verified this data and shows that VCP inhibition significantly (p<0.001, p<0.003) induced cell cycle arrest in the G0/G1 phases. We also found that VCP directly regulates p53 and NFκB protein levels as a potential mechanism to control tumor cell proliferation and progression. Finally, we evaluated the therapeutic potential of VCP inhibition and observed significantly reduced NSCLC tumor growth in both in vitro and xenograft murine (athymic-nude) models after EerI treatment (p<0.05).Thus, targeting VCP in NSCLC may provide a novel strategy to restore p53 and NFκB levels and ameliorate the growth and tumorigenicity, leading to improved clinical outcomes

A tumor growth inhibition model based on M-protein levels in subjects with relapsed/refractory multiple myeloma following single-agent carfilzomib use

Change in tumor size estimated using longitudinal tumor growth inhibition (TGI) modeling is an early predictive biomarker of clinical outcomes for multiple cancer types. We present the application of TGI modeling for subjects with multiple myeloma (MM). Longitudinal time course changes in M‐protein data from relapsed and/or refractory MM subjects who received single‐agent carfilzomib in phase II studies (n = 456) were fit to a TGI model. The tumor growth rate estimate was similar to that of other anti‐myeloma agents, indicating that the model is robust and treatment‐independent. An overall survival model was subsequently developed, which showed that early change in tumor size (ECTS) at week 4, Eastern Cooperative Oncology Group performance status (ECOG PS), hemoglobin, sex, percent bone marrow cell involvement, and number of prior regimens were significant independent predictors for overall survival (P < 0.001). ECTS based on M‐protein modeling could be an early biomarker for survival in MM following exposure to single‐agent carfilzomib

Design and Investigation of de Vries Liquid Crystals Based on 5-Phenyl-Pyrimidine and (R,R)-2,3-Epoxyhexoxy backbone.

Calamitic liquid crystals based on 5-phenyl-pyrimidine derivatives have been designed, synthesized, and characterized. The 5-phenyl pyrimidine core was functionalized with a chiral (R,R)-2,3-epoxyhexoxy chain on one side and either siloxane or perfluoro terminated chains on the opposite side. The one involving a perfluorinated chain shows SmA^{*} phase over a wide temperature range of 82 °C, whereas the siloxane analog exhibits both SmA^{*} and SmC^{*} phases over a broad range of temperatures, and a weak first-order SmA^{*}-SmC^{*} transition is observed. For the siloxane analog, the reduction factor for the layer shrinkage R (relative to its thickness at the SmA^{*}-SmC^{*} transition temperature, T_{AC}) is ∼0.373, and layer shrinkage is 1.7% at a temperature of 13 °C below the T_{AC}. This compound is considered to have de Vries smectic characteristics with the de Vries coefficient C_{deVries} of ∼0.86 on the scale of zero (maximum-layer shrinkage) to 1 (zero-layer shrinkage). A three-parameter mean-field model is introduced for the orientational distribution function (ODF) to reproduce the electro-optic properties. This model explains the experimental results and leads to the ODF, which exhibits a crossover from the sugar-loaf to diffuse-cone ODF some 3 °C above T_{AC}