Desmoid tumors (DT) are rare, soft-tissue tumors associated with a potentially debilitating burden. Niro—a targeted gamma secretase inhibitor—is the first systemic treatment for DT approved in the US. In the phase 3 DeFi study, niro demonstrated statistically significant and clinically meaningful improvement vs placebo (pbo) in progression-free survival (PFS), objective response rate (ORR), and PROs of pain, DT-specific symptom burden, physical and role functioning, and overall quality of life (QoL). As DT can have an unpredictable disease course, an improvement in PROs during SD is important to assess, especially during systemic therapy. DeFi was a global, multicenter, double-blind study to determine the efficacy, safety, and tolerability of niro in adults with progressing DT. Patients were randomized to receive niro (150 mg) or pbo twice-daily taken in continuous 28-day cycles. Primary endpoint was PFS; key secondary endpoints were ORR by RECIST 1.1 and change from baseline in PROs (BPI-SF, GODDESS, and EORTC QLQ-C30) at treatment Cycle 10. Post hoc analyses of PROs were conducted in patients with a BOR of SD (07Apr2022 datacut). ORR was significantly greater with niro (29/70 [41%]) than pbo (6/72 [8%]; P<0.001). A total of 35/70 (50%) niro-group patients had a BOR of SD vs 55/72 (76%) pbo-group patients. Niro-treated patients with a BOR of SD had significantly greater improvement from baseline in all PROs at Cycle 10 than pbo (Table). Table: 57MOBOR of SD: Change from BL at Cycle 10, least-squares meanNiro (n=35)Pbo (n=55)P-valueBPI-SF: Brief Pain Inventory-Short FormaWorst pain−1.480.13c<.001GODDESS: Gounder/Desmoid Tumor Research Foundation Desmoid Symptom/Impact ScaleaTotal symptom score (DT Symptom Scale [DTSS])−1.130.68c<.001Physical functioning domain (DT Impact Scale [DTIS])−0.530.16c<.001EORTC QLQ-C30: European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30bPhysical functioning7.93−5.32c<.001Role functioning5.05−13.29c=.006Overall QoL4.05−9.02d=.014aNegative = improve; bPositive = improve; cBL n=54; dBL n=53. BL, baseline. Open table in a new tab aNegative = improve; bPositive = improve; cBL n=54; dBL n=53. BL, baseline. In this post hoc analysis of the DeFi study, patients that achieved RECIST SD as BOR had significantly greater improvement with niro than pbo in pain and DT-specific symptom burden, physical and role functioning, and overall QoL. These results suggest that niro can provide clinically meaningful benefits for patients with DT, including those with RECIST SD as best response.

PDF file - 644KB, Characterizing KPC tumor initiating cells.

PDF file - 1384KB, CD133+ population from human tumor xenografts in SCID mice showed tumor formation.

Tinostamustine, a novel alkylating deacetylase inhibitor, improves drug access to cancer cell DNA strands, breaks them and counteracts damage repair. Here we report safety and efficacy of tinostamustine in a subset of pts with STS from an open-label Ph I/II trial. Pts ≥18 years with advanced solid tumours, life expectancy >3 mo, Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2 were enrolled. Ph I dose escalation (standard 3+3 design 60–100mg/m2) defined the maximum tolerated dose and recommended Ph II dose (RP2D). In Ph II, the objective response rate (complete response + partial response [PR]), together with pts with stable disease (SD) ≥4 mo duration, following the RP2D (80mg/m2 over 60 min on D1 & 15 of each 4-wk treatment cycle) were determined, and are summarised here using descriptive statistics. Two substudies characterised the effects of tinostamustine (60–80mg/m2) on cardiac repolarisation. Forty-nine pts with advanced solid tumours (13 with STS) were enrolled (Table). In Ph II, tinostamustine-related treatment-emergent adverse events (TEAEs) included thrombocytopenia, anaemia, nausea and fatigue. Serious tinostamustine-related AEs were mainly haematological; 1 tinostamustine-related fatal AE (intra-abdominal haemorrhage; ovarian cancer pt) occurred. In the STS subset, a greater proportion of patients experienced tinostamustine-related and serious tinostamustine-related TEAEs compared with the overall Ph II pt population; there were no tinostamustine-related fatal TEAEs. One pt with STS achieved PR as best response, and 3 had SD ≥4 mo duration; 5 pts with STS discontinued treatment due to progressive disease. Table: 1957PDemographic & safety data: Pts with advanced solid tumours receiving tinostamustine & the STS pt subsetPh II pt populationSTS pt subsetN4913*Age (mean ± std dev), yrs57.0 ± 12.551.9 ± 12.1Female, n (%)39 (79.6)9 (69.2)ECOG PS 0 120 (40.8) 29 (59.2)3 (23.1) 10 (76.9)# prior therapies, median (range)3 (1,9)5 (2, 8)N4912†≥1 drug-related TEAE, n (%)44 (89.8)9 (75.0)Serious drug-related AEs, n (%)12 (24.5)3 (25.0)Study discontinuation due to drug-related TEAEs, n (%)3 (6.1)0*Ph I, II & substudies safety analysis set. †Ph II & substudies safety analysis set. AE, adverse event; ECOG-PS, Eastern Cooperative Oncology Group performance status; Ph, Phase; STS, soft tissue sarcoma; TEAE, treatment-emergent adverse event Open table in a new tab *Ph I, II & substudies safety analysis set. †Ph II & substudies safety analysis set. AE, adverse event; ECOG-PS, Eastern Cooperative Oncology Group performance status; Ph, Phase; STS, soft tissue sarcoma; TEAE, treatment-emergent adverse event Tinostamustine demonstrated modest signals of efficacy with manageable tolerability in pts with STS.

PDF file - 184KB, CD133+ population formed serially transplantable tumors.

PDF file - 998KB, Immunohistochemistry of tumors.

PDF file - 614KB, Illumina microarray for CD133+ and CD133- cells.

PDF file - 1784KB, Representative slides from tumors treated (B) and untreated (A) with Minnelide.

PDF file - 124KB, Supplementary Table 1. Tumorigenicity of CD133+ population, CD133 - population and unsorted KPC cells. Supplementary Table 2. Recent therapeutic compounds tested against pancreatic tumor initialing cells.

We present a new four-step feedback procedure to study the full dynamics of a nonlinear dynamical system, namely, the logistic map. We show that by using this procedure, the chaotic behavior of the logistic map can be controlled easily and rapidly or the system can be made stable for higher values of the population growth parameter. We utilize various dynamical techniques (orbit evolution, time series analysis, bifurcation diagrams, and Lyapunov exponents) to analyze the dynamics of the logistic map. Additionally, we adopt the switching strategy to control chaos or to increase the stability performance of the logistic map. Finally, we propose a modified traffic control model to enable rapid control of unexpected traffic on the road. The results of this model are supported by a physical interpretation. The model is found to be more efficient than existing models of Lo and Cho [J. Franklin Inst. 342, 839-851 (2005)] and Ashish et al. [Nonlinear Dyn. 94, 959-975 (2018)]. This work provides a novel feedback procedure that facilitates rapid control of chaotic behavior and increases the range of stability of dynamical systems.

The purpose of this paper is to establish a new iterative process which is hybrid of Picard and SP iterative processes. In this paper, we show that our Picard-SP hybrid iterative process gives faster convergence results than existing Picard, Mann, Krasnoselski, Ishikawa and Picard-Krasnoselski hybrid iterative processes. In support of our claim, a numerical example with graph is presented using the MATLAB software. Moreover, we also show that Picard-SP hybrid iterative process is T-stable. AMS Subject Classification:46A80,47H10

Pancreatic cancer, the fourth most prevalent cancer-related cause of death in the United States, is a disease with a dismal survival rate of 5% 5 years after diagnosis. One of the survival proteins responsible for its extraordinary ability to evade cell death is HSP70. A naturally derived compound, triptolide, and its water-soluble prodrug, Minnelide, down-regulate the expression of this protein in pancreatic cancer cells, thereby causing cell death. However, the mechanism of action of triptolide has not been elucidated. Our study shows that triptolide-induced down-regulation of HSP70 expression is associated with a decrease in glycosylation of the transcription factor Sp1. We further show that triptolide inhibits glycosylation of Sp1, inhibiting the hexosamine biosynthesis pathway, particularly the enzyme O-GlcNAc transferase. Inhibition of O-GlcNAc transferase prevents nuclear localization of Sp1 and affects its DNA binding activity. This in turn down-regulates prosurvival pathways like NF-κB, leading to inhibition of HSF1 and HSP70 and eventually to cell death. In this study, we evaluated the mechanism by which triptolide affects glycosylation of Sp1, which in turn affects downstream pathways controlling survival of pancreatic cancer cells.