Clinical trial of NPI-0052 in advanced malignancies including lymphoma and leukemia (advanced malignancies arm)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3582-3582
Author(s):  
A. R. Townsend ◽  
M. Millward ◽  
T. Price ◽  
P. Mainwaring ◽  
A. Spencer ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Solid Tumor ◽  
Treatment Options ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Hematologic Malignancies ◽  
Volume Of Distribution ◽  
Preclinical Research ◽  
Eyes Closed ◽  
Advanced Malignancies

3582 Background: The novel structure (non-peptide based) of NPI-0052 (NPI) appears to lead to unique proteasome inhibition (PI), toxicology and signal transduction profiles. Preclinical research suggests improvements in therapeutic ratio and activity in hematologic and solid tumor models, leading to clinical trials in patients with myeloma, lymphomas, leukemias, and solid tumors. Methods: Patients with solid tumor, lymphoma or leukemia diagnoses without standard treatment options were treated with IV NPI on Days 1, 8 and 15 of 28-day cycles in a 3+3 design dose escalation to a Recommended Phase 2 Dose (RP2D). Enrollment then began in 10 patient lymphoma and CLL RP2D cohorts. PI (D1 and D15) and PK (D1 and D15) were assayed. Results: 30 patients were treated at doses ranging from 0.1 mg/m2 to 0.9 mg/m2. 0.7 mg/m2 was selected as the RP2D secondary to DLT of transient “hallucinations” (visual imprints when eyes closed) and dizziness/unsteady gait at 0.9 mg/m2. At the RP2D fatigue, parosmia/dysgeusia, transient peri-infusion site pain and lymphopenia were commonly ascribed to NPI. At the RP2D PK data showed: half-life = 31 ± 28 min; AUCtotal = 270 ± 219 ng/mL*min; Cmax = 33.4 ± 34.2 ng/mL; clearance = 7.17 ± 0.40 L/min; volume of distribution (Vz) = 223.3 ± 229.7 L. PI was assayed in blood, indicating a dose:response relationship with mean inhibition of chymotrypsin-like activity up to of 88% Day 1 and 100% Day 15, and inhibition of caspase-like and trypsin-like activity of up to 51% and 72%. PI remained between doses in whole blood (RBC), but recovered between doses in PBMC. Stable disease was induced in 31% of patients, including one each with mantle cell, Hodgkin's lymphoma, follicular lymphoma, sarcoma, prostate carcinoma, and two with melanoma. Conclusions: NPI-0052 produces dose-dependent pharmacologic effects through the predicted efficacious range to an MTD, while producing a toxicity profile that is tolerable and dissimilar to bortezomib in spite of reaching higher PI levels. These data indicate potential for a greater range of uses than other proteasome inhibitors and lead to additional studies being initiated in hematologic malignancies and solid tumors alone and in combination. [Table: see text]

Clinical Trial of NPI-0052 (2nd generation proteasome inhibitor) in Patients Having Advanced Malignancies with Expanded RP2D Cohorts in Lymphoma and CLL

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4934-4934 ◽  
Author(s):  
Timothy Price ◽  
Peeter Padrik ◽  
Amanda Townsend ◽  
Paul Mainwaring ◽  
Lawrence Catley ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Solid Tumor ◽  
Proteasome Inhibitor ◽  
Standard Of Care ◽  
Proteasome Inhibition ◽  
Hematologic Malignancies ◽  
Preclinical Research ◽  
Novel Structure ◽  
Advanced Malignancies ◽  
Mantle Cell

Abstract Background: NPI-0052 is a novel proteasome inhibitor that produces prolonged inhibition of the 20S proteasome. NPI-0052 has a novel structure leading to a unique proteasome inhibition, toxicology and effect profile. Preclinical research suggests an improved therapeutic ratio and activity in hematologic and solid tumor malignancy models. Secondary to these findings, clinical trials are being conducted in patients with myeloma, lymphomas, leukemias and solid tumors. Materials and Methods: In this study patients with solid tumor, lymphoma or leukemia diagnoses were treated with NPI-0052 administered weekly, for 3 weeks in 4-week cycles in a 3+3 design dose escalation. The dose of NPI-0052 was escalated in 50–100% increments dependent on observed adverse events (AE). In addition to regular safety monitoring, proteasome inhibition (PI) (baseline, D1 & D15) and pharmacokinetics PK (D1 & D15) were assayed in blood. Once a Recommended Phase 2 Dose (RP2D) is identified, RP2D cohorts of 10 patients in each lymphoma and CLL are enrolled. Results: 25 patients have been treated at doses ranging from 0.1 mg/m2 to 0.7 mg/m2. The AE profile has been very tolerable with fatigue, transient peri-infusion site discomfort and lymphopenia being commonly ascribed to NPI-0052. Whole blood pharmacokinetics were calculated for all patients on study. At the highest dose assessed PK parameters were (mean ± SD) AUCtot =215±129 ng/mL*min; Cmax =22.8 ±14 ng/mL; t1/2 =13.5 ± 9.2 mins; clearance= 7.8 ± 8.2 L/min and Vss = 132 ± 192 L. AUC and Cmax increased linearly with dose and the kinetics are apparently not dose dependant. PI has been assayed in blood, indicating a dose:response relationship with inhibition of chymotrypsin-like activity up to 100% observed and mean Day 1 inhibition of 78%. This level of proteasome inhibition is higher than that reported with standard doses of bortezomib, yet the profile of adverse drug reactions associated with bortezomib has not been observed. A total of 7 patients (33%) have had stable disease for at least 2 cycles (8 weeks; 2months), including one each with mantle cell lymphoma (4 cycles), Hodgkin’s lymphoma (4 cycles), follicular lymphoma (4 cycles) and sarcoma (5 cycles) and prostate adenocarcinoma, and two with melanoma (4 cycles). Conclusions: NPI-0052 produces dose-dependent pharmacologic effects through the predicted efficacious range while producing a toxicity profile that is tolerable and dissimilar to that of the standard of care proteasome inhibitor bortezomib. These data have supported additional studies being initiated in hematologic malignancies and solid tumors.

scholarly journals Flow Cytometry Immunophenotyping for Diagnostic Orientation and Classification of Pediatric Cancer Based on the EuroFlow Solid Tumor Orientation Tube (STOT)

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4945
Author(s):  
Cristiane de Sá de Sá Ferreira-Facio ◽  
Vitor Botafogo ◽  
Patrícia Mello Ferrão ◽  
Maria Clara Canellas ◽  
Cristiane B. Milito ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Solid Tumors ◽  
Solid Tumor ◽  
Pediatric Cancer ◽  
Diagnostic Procedures ◽  
Hematologic Malignancies ◽  
Multiparameter Flow Cytometry ◽  
Diagnostic Screening ◽  
Pediatric Solid Tumors

Early diagnosis of pediatric cancer is key for adequate patient management and improved outcome. Although multiparameter flow cytometry (MFC) has proven of great utility in the diagnosis and classification of hematologic malignancies, its application to non-hematopoietic pediatric tumors remains limited. Here we designed and prospectively validated a new single eight-color antibody combination—solid tumor orientation tube, STOT—for diagnostic screening of pediatric cancer by MFC. A total of 476 samples (139 tumor mass, 138 bone marrow, 86 lymph node, 58 peripheral blood, and 55 other body fluid samples) from 296 patients with diagnostic suspicion of pediatric cancer were analyzed by MFC vs. conventional diagnostic procedures. STOT was designed after several design–test–evaluate–redesign cycles based on a large panel of monoclonal antibody combinations tested on 301 samples. In its final version, STOT consists of a single 8-color/12-marker antibody combination (CD99-CD8/numyogenin/CD4-EpCAM/CD56/GD2/smCD3-CD19/cyCD3-CD271/CD45). Prospective validation of STOT in 149 samples showed concordant results with the patient WHO/ICCC-3 diagnosis in 138/149 cases (92.6%). These included: 63/63 (100%) reactive/disease-free samples, 43/44 (98%) malignant and 4/4 (100%) benign non-hematopoietic tumors together with 28/38 (74%) leukemia/lymphoma cases; the only exception was Hodgkin lymphoma that required additional markers to be stained. In addition, STOT allowed accurate discrimination among the four most common subtypes of malignant CD45− CD56++ non-hematopoietic solid tumors: 13/13 (GD2++ numyogenin− CD271−/+ nuMyoD1− CD99− EpCAM−) neuroblastoma samples, 5/5 (GD2− numyogenin++ CD271++ nuMyoD1++ CD99−/+ EpCAM−) rhabdomyosarcomas, 2/2 (GD2−/+ numyogenin− CD271+ nuMyoD1− CD99+ EpCAM−) Ewing sarcoma family of tumors, and 7/7 (GD2− numyogenin− CD271+ nuMyoD1− CD99− EpCAM+) Wilms tumors. In summary, here we designed and validated a new standardized antibody combination and MFC assay for diagnostic screening of pediatric solid tumors that might contribute to fast and accurate diagnostic orientation and classification of pediatric cancer in routine clinical practice.

Immunotherapy in Gynecologic Cancers: What We Know Now and Where We Are Headed

2019 ◽  
pp. e126-e140 ◽  
Author(s):  
Kimberly Levinson ◽  
Oliver Dorigo ◽  
Krista Rubin ◽  
Kathleen Moore
Keyword(s):  
Solid Tumors ◽  
Solid Tumor ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Gynecologic Cancer ◽  
Hematologic Malignancies ◽  
Next Generation ◽  
Gynecologic Cancers ◽  
Clinical Benefits

Immunotherapy, mainly in the form of immune checkpoint inhibitors (ICIs), has been transformative in both solid tumor and hematologic malignancies. Patients with previously terminal illnesses have experienced profound responses of great durability with these agents, fueling excitement among patients and providers regarding their use. Unfortunately, the gains seen in some solid tumors have not been replicated in a large percentage of patients with gynecologic cancer. This review focuses on the clinical benefits seen to date, toxicities and management when using ICIs, ways to improve prediction of who should receive immunotherapy, and a discussion of next-generation immunotherapy with cellular therapeutics and how these might relate to gynecologic cancers.

Phase 1 Clinical Trial of the Novel Structure Proteasome Inhibitor NPI-0052.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2693-2693 ◽  
Author(s):  
Andrew Spencer ◽  
Michael Millward ◽  
Paul Mainwaring ◽  
Simon Harrison ◽  
Laurence Catley ◽  
...  
Keyword(s):  
Solid Tumor ◽  
Whole Blood ◽  
Proteasome Inhibitor ◽  
Mononuclear Cells ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Pharmacokinetic Data ◽  
Employment Equity ◽  
Cognitive Changes ◽  
Equity Ownership

Abstract Abstract 2693 Poster Board II-669 Background: NPI-0052 is a proteasome inhibitor with a novel bicyclic structure (other proteasome inhibitors in clinical use are peptide based). Preclinical studies indicate rapid, broad and prolonged inhibition of all 3 catalytic sites of the proteasome, and subsequently unique proteasome inhibition, signal transduction, toxicology and efficacy profiles. Taken together these suggest the potential for improvements in therapeutic ratio and activity in hematologic and solid tumor malignancies. Materials and Methods: Patients with solid tumor, lymphoma, leukemia or myeloma diagnoses without standard treatment options have been treated with IV NPI-0052 on one of two arms (weekly or twice weekly) in this 3+3 design dose escalation study. This is followed by 10 patient Recommended Phase 2 dose Cohorts of patients with lymphomas, CLL and myeloma respectively. Proteasome inhibition (pharmacodynamics) and pharmacokinetics are also assayed in whole blood, and proteasome inhibition in peripheral blood mononuclear cells (PBMC). Results: 44 patients have been treated with NPI-0052 at doses ranging from 0.075 mg/m2 to 0.9 mg/m2. Common adverse events include fatigue, parosmia/dysgeusia, transient peri-infusion site pain, lymphopenia, headaches, dizziness / unsteady gait, closed-eye visuals, cognitive changes. Incidence and grade of these events correlate with dose, being quite tolerable at the MTD of 0.7 mg/m2 on the weekly dosing arm. An MTD has not yet been determined for the twice weekly dosing arm. Pharmacokinetic data has demonstrated a rapid elimination half-life (<20 minutes) and relatively large volume of distribution. Assessment of proteasome inhibition has demonstrated increasing inhibition of chymotrypsin-like activity of up to 88% Day 1 and 100% Day 15. Inhibition of caspase-like and trypsin-like activity of up to 52% and 71% respectively has also been seen. Inhibition remains between doses in whole blood (principally RBC), but recovers between doses in PBMC. Clinical benefit, including stable disease, regression or response, was reported in patients with mantle cell lymphoma, myeloma, Hodgkin's lymphoma, cutaneous marginal zone lymphoma, follicular lymphoma, sarcoma, prostate carcinoma and melanoma. Conclusions: NPI-0052 produces dose-dependent pharmacologic effects through the predicted efficacious range, while producing a toxicity profile that is dissimilar to what is reported with other proteasome inhibitors (notably deficient in peripheral neuropathy, neutropenia and thrombocytopenia) in spite of producing equal or greater proteasome inhibition. These data indicate a broad range of potential uses, and led to additional studies in hematologic malignancies and solid tumors alone and in combination. Disclosures: Longenecker: Nereus Pharmaceuticals: Employment. Palladino:Nereus Pharmaceuticals: Employment, Equity Ownership. Lloyd:Nereus Pharmaceuticals: Employment, Equity Ownership. Neuteboom:Nereus Pharmaceuticals: Employment, Equity Ownership. Spear:Nereus Pharmaceuticals: Employment, Equity Ownership.

scholarly journals Development of noninvasive biomarkers of response to proteasome inhibitor therapy (ixazomib) by imaging disrupted protein homeostasis in mouse models of solid tumors

2017 ◽  
Author(s):  
Yanan Zhu ◽  
Rajiv Ramasawmy ◽  
Sean Peter Johnson ◽  
Valerie Taylor ◽  
Alasdair Gibb ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Solid Tumors ◽  
Proteasome Inhibitor ◽  
Chemical Exchange ◽  
Proteasome Inhibitors ◽  
Surrogate Marker ◽  
Standard Of Care ◽  
Proteasome Inhibition ◽  
Protein Homeostasis

AbstractWith clinically-approved proteasome inhibitors now a standard of care for multiple myeloma, and increasing interest in their use in solid tumors, methods for monitoring therapeutic response in vivo are critically required. Here, we show that tumor protein homeostasis can be noninvasively monitored, using chemical exchange (CEST) magnetic resonance imaging (MRI) as a surrogate marker for proteasome inhibition, alongside diffusion MRI and relaxometry. We show that the in vivo CEST signal associated with amides and amines increases in proportion to proteasome inhibitor dose (ixazomib) and the magnitude of therapeutic effect in colorectal cancer xenografts. Moreover, we show that SW1222 and LS174T human colorectal cancer cell lines demonstrate differing sensitivities to ixazomib, which was reflected in our MRI measurements. We also found evidence of a mild stimulation in tumor growth at low ixazomib doses. Our results therefore identify CEST MRI as a promising method for safely and noninvasively monitoring changes in tumor protein homeostasis.

The efficacy and mechanism of proteasome inhibitors in solid tumor treatment

2021 ◽  
Vol 16 ◽  
Author(s):  
Lei Zhang ◽  
Mengyang Wu ◽  
Ruicong Su ◽  
Di Zhang ◽  
Guilian Yang
Keyword(s):  
Signaling Pathways ◽  
Solid Tumors ◽  
Combination Chemotherapy ◽  
Solid Tumor ◽  
Epithelial Mesenchymal Transition ◽  
Proteasome Inhibitors ◽  
Ubiquitin Proteasome System ◽  
Cellular Protein ◽  
Anticancer Efficacy ◽  
Mesenchymal Transition

Background: The ubiquitin-proteasome system (UPS) is critical in cellular protein degradation and widely involved in the regulations of cancer hallmarks. Targeting the UPS pathway has emerged as a promising novel treatment in hematological malignancies and solid tumors. Objective: This review mainly focuses on the preclinical results of proteasome inhibitors in solid tumors. Methods: We analyzed the published articles associated with the anticancer results of proteasome inhibitors alone or combination chemotherapy in solid tumors. Important data presented in abstract form were also discussed in this review. Results/Conclusion: Proteasome inhibitors, such as bortezomib and carfilzomib, are highly effective in treating solid tumors. The anticancer efficacy is not limited to affect the proteasomal inhibition-associated signaling pathways but also widely involves the signaling pathways related to cell cycle, apoptosis, and epithelial-mesenchymal transition (EMT). In addition, proteasome inhibitors overcome the conventional chemo-resistance of standard chemotherapeutics by inhibiting signaling pathways, such as NF-κB or PI3K/Akt. Combination chemotherapy of proteasome inhibitors and standard chemotherapeutics are widely investigated in multiple relapsed or chemo-resistant solid tumor types, such as breast cancer and pancreatic cancer. The proteasome inhibitors re-sensitize the standard chemotherapeutic regimens and induce synergistic anticancer effects. The development of novel proteasome inhibitors and delivery systems also improves the proteasome inhibitors’ anticancer efficacy in solid tumors. This review summarizes the current preclinical results of proteasome inhibitors in solid tumors and reveals the potential anticancer mechanisms.

First-in-Human Phase 1 Dose Escalation Study of NPI-0052, a Novel Proteasome Inhibitor, in Patients with Lymphoma and Solid Tumor

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4939-4939 ◽  
Author(s):  
Paul A. Hamlin ◽  
Carol Aghajanian ◽  
David Hong ◽  
Anas Younes ◽  
Michael A. Palladino ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Whole Blood ◽  
Proteasome Inhibitor ◽  
Phase 1 ◽  
Proteasome Inhibition ◽  
Hematologic Malignancies ◽  
Dose Escalation Study ◽  
Elimination Half

Abstract Background: NPI-0052 is a novel proteasome inhibitor that produces prolonged inhibition of all three catalytic activities (C-L, T-L, CT-L) of the 20S proteasome. Preclinical data demonstrated activity in hematologic malignancies (myeloma, lymphoma, leukemia) and solid tumors. This Phase 1 study in patients with refractory lymphomas or solid tumors was the first-in-human study of NPI-0052. Materials and Methods: Patients were treated with NPI-0052 administered as a weekly IV injection for 3 weeks in 4-week cycles in a 3+3 design dose escalation study. The dose of NPI-0052 was escalated in 50–100% increments dependent on observed adverse events. Proteasome inhibition was assayed in whole blood and in peripheral blood mononuclear cells (PBMCs). All patients underwent plasma PK sampling. Once a Recommended Phase 2 Dose (RP2D) is identified, two groups of up to 10 patients each (lymphoma and solid tumors) will be treated at that dose. Results: 35 patients (including 5 patients with lymphoma) have been treated between 0.0125 mg/m2 to 0.55 mg/m2 for up to 12 cycles without reaching an MTD. Drug related adverse events at the highest dose level assessable (n=4) include Grade 1: diarrhea (n- 2), fatigue, muscle stiffness, hypotension and hypomagnesemia. At doses tested to date, thrombocytopenia or neuropathy have been unremarkable. SAE reported as potentially related included MRSA sepsis and post-infectious glomerulonephritis/renal failure recovering after antibiotic treatment in one patient treated at 0.1 mg/m2 and Grade 4 neutropenia recovering after 3 days in one patient treated at 0.112 mg/m2. Preliminary PK data indicate an elimination half life of approximately 3–13 minutes, with clearance at 11.7 ± 7.4 mL/min and Vz of 44–99L. Proteasome inhibition in whole blood demonstrate dose dependency for CT-L inhibition (at 0.55 mg/m2), mean D1 and D15 inhibition in whole blood equaled 65 and 90%, respectively. Using PBMCs (cells that can regenerate proteasomes), similar CT-L inhibition was also observed on D1 and D15. Inhibition returned to baseline within one week of each dose in PBMC, whereas significant inhibition remained throughout the cycle in whole blood. No responses have been confirmed; stable disease (&gt;3 months) was observed in patients with cervical carcinoma (11 months; time to progression on the prior treatment regimen was 3 months), colorectal, hepatocellular (6 months), adenoid cystic (4 and 5 months), melanoma (4 months), granulosis cell and ovarian (3+ months). The patient with cervical carcinoma, underwent four dose escalations (from 0.025 to 0.168 mg/m2) with increased proteasome inhibition observed at each higher dose assessed (from 24% to 64%). Preliminary PK data indicate an elimination half life of approximately 3–13 minutes, with clearance at 11.7 ± 7.4 mL/min and Vz of 44–99L. Conclusions: NPI-0052 produces dose-dependent pharmacologic effects through the range of proteasome inhibition produced by therapeutic doses of the approved proteasome inhibitor bortezomib without resulting in the toxicity profile seen with bortezomib treatment. These data have supported additional studies being initiated in hematologic malignancies and solid tumors, including combination studies with other targeted agents.

Identification of a Novel and Efficacious Oral Proteasome Inhibitor As a Potential Clinical Development Candidate

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4808-4808
Author(s):  
Kwang-Ai Won ◽  
Byung Gyu Kim ◽  
Cheol-Kyu Jung ◽  
Eok Park ◽  
Eunbok Baek ◽  
...  
Keyword(s):  
Oral Administration ◽  
Solid Tumor ◽  
Lung Tumor ◽  
Life Sciences ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Clinical Development ◽  
Tumor Xenograft ◽  
Orally Bioavailable ◽  
New Generation

Abstract The proteasome is a validated anti-cancer target and various small-molecule inhibitors are currently in clinical development or on the market. However, adverse events and resistance associated with those proteasome inhibitors call for a new generation of drugs. LC53-0110 and its analogues were identified as novel, reversible, selective, potent, and orally bioavailable proteasome inhibitors which have physicochemical profiles that are distinct from bortezomib, carfilzomib or ixazomib. As compared to those inhibitors, LC53-0110 is far more selective for the chymotrypsin-like proteolytic (β5) site of the 20S proteasome, with an IC50 value of less than 10 nM over the trypsin-like site and the caspase-like site. LC53-0110 treatment showed accumulation of ubiquitinated proteins and inhibited cell viability with a low nM range potency in various hematologic and solid tumor cell lines including multiple myeloma (MM), lymphoma, colon tumor, breast tumor, and lung tumor. When a single dose was administered orally to tumor-bearing mice, LC53-0110 showed both greater maximum and sustained tumor proteasome inhibition as compared with ixazomib in MM and solid tumor xenograft models. The robust pharmacodynamic responses in tumor translated to the efficacy studies. In the RPMI8226 (MM) efficacy model, oral administration twice a week at 50 mg/kg inhibited tumor growth 68% by three weeks. In the MM.1S (MM) efficacy model, oral administration twice a week at 100 mg/kg completely abolished measurable tumor mass by one week and prevented any tumor re-growth during the three-week study period. In the initial studies, LC53-0110 also showed potent activity on freshly isolated CD138+ cells from MM patients (pts) who are resistant/refractory (r/r) to current FDA-approved drug treatment. Further studies, including comparison of the naïve pts vs. thalidomide r/r pts and bortezomib r/r pts as well as their potential clinical implications will be discussed. Disclosures Won: LG Life Sciences: Employment. Kim:LG Life Sciences: Employment. Jung:LG Life Sciences: Employment. Park:LG Life Sciences: Employment. Baek:LG Life Sciences: Employment. Park:LG Life Sciences: Employment. Kang:LG Life Sciences: Employment. Kim:LG Life Sciences: Employment. Jung:LG Life Sciences: Employment.

In-hospital mortality of patients admitted through the emergency department of a comprehensive cancer center.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6125-6125 ◽  
Author(s):  
Ahmed F. Elsayem ◽  
Carmen E. Gonzalez ◽  
S. J. Yeung ◽  
Kelly W. Merriman ◽  
Knox H. Todd
Keyword(s):  
Mortality Rate ◽  
Hospital Mortality ◽  
Cancer Patients ◽  
Solid Tumors ◽  
Solid Tumor ◽  
Hematologic Malignancies ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
Intractable Pain ◽  
Tumor Patients

6125 Background: Cancer is a common presenting condition for emergency departments (EDs); however, there is limited information on outcomes of ED cancer patients subsequently admitted to the hospital. The purpose of this study is to describe outcomes of patients with hematologic malignancies versus those with solid tumors admitted through the ED of a comprehensive cancer center. Methods: We queried the ED database of The University of Texas MD Anderson Cancer Center for calendar year 2010 and linked it to our institutional data warehouse, including tumor registry data. We classified all leukemia and related disorders, lymphoma, multiple myeloma, and bone marrow transplant patients as hematologic malignancies, and remaining cancers as solid tumors. Descriptive statistics, including chi-square, and t-tests were used in two-sided comparisons. All statistical analyses were performed using SPSS version 15. Results: 20,732 total ED visits were made by 9,320 unique cancer patients. Of these, 5,364 (58%) were admitted to the hospital at least once (range 1-13 admits). ED admissions constituted 39% of total unique patients admitted (N=13,753). The main admission indications for solid tumor patients were infectious complications (particularly pneumonia), intractable pain, or dehydration. For hematologic malignancies, the main indication was neutropenic fever. 211/1656 (13%) of liquid tumor patients were admitted to the Intensive Care Unit (ICU) compared to 484/3708 (13%) of solid tumor patients (P=NS). Of all patients admitted through the ED, 587/5364 (10.9%) died during hospitalization. The hematologic hospital mortality rate was 225/1653 (13.6%) versus 362/3708 (9.8%) for solid tumors (P<0.001). Only 242/8389 (3%) of patients admitted directly from outpatient clinics died during the hospitalization (p<0.001). Conclusions: Patients admitted through the ED, particularly those with hematologic malignancies, have a high hospital mortality rate. ED-based palliative care interventions may be justified to improve quality of life and prevent unnecessary costly interventions and ICU admission. Further research should define predictors of poor outcomes in cancer patients admitted through the ED.

PTEN status determines chemosensitivity to proteasome inhibition in cholangiocarcinoma

2020 ◽  
Vol 12 (562) ◽  
pp. eaay0152
Author(s):  
Tian-Yi Jiang ◽  
Yu-Fei Pan ◽  
Zheng-Hua Wan ◽  
Yun-Kai Lin ◽  
Bin Zhu ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Antioxidant Response ◽  
Preclinical Research ◽  
Screening Assay ◽  
Cancer Cell Growth ◽  
Growth And Survival ◽  
Genes Encoding ◽  
Proteasome Subunits

Patient-derived xenografts (PDXs) and PDX-derived cells (PDCs) are useful in preclinical research. We performed a drug screening assay using PDCs and identified proteasome inhibitors as promising drugs for cholangiocarcinoma (CCA) treatment. Furthermore, we determined that phosphate and tensin homology deleted on chromosome ten (PTEN) deficiency promotes protein synthesis and proteasome subunit expression and proteolytic activity, creating a dependency on the proteasome for cancer cell growth and survival. Thus, targeting the proteasome machinery with the inhibitor bortezomib inhibited the proliferation and survival of CCA cells lacking functional PTEN. Therapeutic evaluation of PDXs, autochthonous mouse models, and patients confirmed this dependency on the proteasome. Mechanistically, we found that PTEN promoted the nuclear translocation of FOXO1, resulting in the increased expression of BACH1 and MAFF. BACH1 and MAFF are transcriptional regulators that recognize the antioxidant response element, which is present in genes encoding proteasome subunits. PTEN induced the accumulation and nuclear translocation of these proteins, which directly repressed the transcription of genes encoding proteasome subunits. We revealed that the PTEN-proteasome axis is a potential target for therapy in PTEN-deficient CCA and other PTEN-deficient cancers.

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