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1.
Gastroenterology ; 166(5): 872-885.e2, 2024 05.
Article in English | MEDLINE | ID: mdl-38320723

ABSTRACT

BACKGROUND & AIMS: Genetic testing uptake for cancer susceptibility in family members of patients with cancer is suboptimal. Among relatives of patients with pancreatic ductal adenocarcinoma (PDAC), The GENetic Education, Risk Assessment, and TEsting (GENERATE) study evaluated 2 online genetic education/testing delivery models and their impact on patient-reported psychological outcomes. METHODS: Eligible participants had ≥1 first-degree relative with PDAC, or ≥1 first-/second-degree relative with PDAC with a known pathogenic germline variant in 1 of 13 PDAC predisposition genes. Participants were randomized by family, between May 8, 2019, and June 1, 2021. Arm 1 participants underwent a remote interactive telemedicine session and online genetic education. Arm 2 participants were offered online genetic education only. All participants were offered germline testing. The primary outcome was genetic testing uptake, compared by permutation tests and mixed-effects logistic regression models. We hypothesized that Arm 1 participants would have a higher genetic testing uptake than Arm 2. Validated surveys were administered to assess patient-reported anxiety, depression, and cancer worry at baseline and 3 months postintervention. RESULTS: A total of 424 families were randomized, including 601 participants (n = 296 Arm 1; n = 305 Arm 2), 90% of whom completed genetic testing (Arm 1 [87%]; Arm 2 [93%], P = .014). Arm 1 participants were significantly less likely to complete genetic testing compared with Arm 2 participants (adjusted ratio [Arm1/Arm2] 0.90, 95% confidence interval 0.78-0.98). Among participants who completed patient-reported psychological outcomes questionnaires (Arm 1 [n = 194]; Arm 2 [n = 206]), the intervention did not affect mean anxiety, depression, or cancer worry scores. CONCLUSIONS: Remote genetic education and testing can be a successful and complementary option for delivering genetics care. (Clinicaltrials.gov, number NCT03762590).


Subject(s)
Carcinoma, Pancreatic Ductal , Genetic Predisposition to Disease , Genetic Testing , Pancreatic Neoplasms , Patient Reported Outcome Measures , Telemedicine , Humans , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/psychology , Pancreatic Neoplasms/diagnosis , Male , Female , Middle Aged , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/psychology , Carcinoma, Pancreatic Ductal/diagnosis , Carcinoma, Pancreatic Ductal/therapy , Genetic Predisposition to Disease/psychology , Risk Assessment , Aged , Anxiety/psychology , Anxiety/diagnosis , Anxiety/etiology , Adult , Depression/diagnosis , Depression/genetics , Depression/psychology , Genetic Counseling/psychology , Germ-Line Mutation , Family/psychology
2.
Ann Neurol ; 96(3): 565-581, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38874304

ABSTRACT

OBJECTIVE: Approximately half of ischemic strokes (IS) in cancer patients are cryptogenic, with many presumed cardioembolic. We evaluated whether there were specific miRNA and mRNA transcriptome architectures in peripheral blood of IS patients with and without comorbid cancer, and between cardioembolic versus noncardioembolic IS etiologies in comorbid cancer. METHODS: We studied patients with cancer and IS (CS; n = 42), stroke only (SO; n = 41), and cancer only (n = 28), and vascular risk factor-matched controls (n = 30). mRNA-Seq and miRNA-Seq data, analyzed with linear regression models, identified differentially expressed genes in CS versus SO and in cardioembolic versus noncardioembolic CS, and miRNA-mRNA regulatory pairs. Network-level analyses identified stroke etiology-specific responses in CS. RESULTS: A total of 2,085 mRNAs and 31 miRNAs were differentially expressed between CS and SO. In CS, 122 and 35 miRNA-mRNA regulatory pairs, and 5 and 3 coexpressed gene modules, were associated with cardioembolic and noncardioembolic CS, respectively. Complement, growth factor, and immune/inflammatory pathways showed differences between IS etiologies in CS. A 15-gene biomarker panel assembled from a derivation cohort (n = 50) correctly classified 81% of CS and 71% of SO participants in a validation cohort (n = 33). Another 15-gene panel correctly identified etiologies for 13 of 13 CS-cardioembolic and 11 of 11 CS-noncardioembolic participants upon cross-validation; 11 of 16 CS-cryptogenic participants were predicted cardioembolic. INTERPRETATION: We discovered unique mRNA and miRNA transcriptome architecture in CS and SO, and in CS with different IS etiologies. Cardioembolic and noncardioembolic etiologies in CS showed unique coexpression networks and potential master regulators. These may help distinguish CS from SO and identify IS etiology in cryptogenic CS patients. ANN NEUROL 2024;96:565-581.


Subject(s)
Gene Regulatory Networks , Ischemic Stroke , MicroRNAs , Neoplasms , RNA, Messenger , Humans , Male , Female , RNA, Messenger/blood , MicroRNAs/blood , MicroRNAs/genetics , Middle Aged , Ischemic Stroke/genetics , Ischemic Stroke/blood , Ischemic Stroke/epidemiology , Aged , Neoplasms/genetics , Neoplasms/blood , Neoplasms/complications , Comorbidity , Transcriptome
3.
Ann Neurol ; 90(1): 159-169, 2021 07.
Article in English | MEDLINE | ID: mdl-34029423

ABSTRACT

OBJECTIVE: The objective of this study was to examine the pathophysiology of ischemic stroke with cancer. METHODS: We conducted a prospective cross-sectional study from 2016 to 2020 at 2 hospitals. We enrolled 3 groups of 50 adult participants each. The main group included patients with active solid tumor cancer and acute ischemic stroke. The control groups included patients with acute ischemic stroke only or active cancer only. The patients with stroke-only and patients with cancer-only were matched to the patients with cancer-plus-stroke by age, sex, and cancer type, if applicable. The outcomes were prespecified hematological biomarkers and transcranial Doppler microemboli detection. Hematological biomarkers included markers of coagulation (D-dimer and thrombin-antithrombin), platelet function (P-selectin), and endothelial integrity (thrombomodulin, soluble intercellular adhesion molecule-1 [sICAM-1], and soluble vascular cell adhesion molecule-1 [sVCAM-1]). Hematological biomarkers were compared between groups using the Kruskal-Wallis and Wilcoxon Rank-Sum tests. In multivariable linear regression models, we adjusted for race, number of stroke risk factors, smoking, stroke severity, and antithrombotic use. Transcranial Doppler microemboli presence was compared between groups using chi-square tests. RESULTS: Levels of all study biomarkers were different between groups. In univariate between-group comparisons, patients with cancer-plus-stroke had higher levels of D-dimer, sICAM-1, sVCAM-1, and thrombomodulin than both control groups; higher levels of thrombin-antithrombin than patients with cancer-only; and higher levels of P-selectin than patients with stroke-only. Findings were similar in multivariable analyses. Transcranial Doppler microemboli were detected in 32% of patients with cancer-plus-stroke, 16% of patients with stroke-only, and 6% of patients with cancer-only (p = 0.005). INTERPRETATION: Patients with cancer-related stroke have higher markers of coagulation, platelet, and endothelial dysfunction, and more circulating microemboli, than matched controls. ANN NEUROL 2021;90:159-169.


Subject(s)
Brain/diagnostic imaging , Ischemic Stroke/complications , Neoplasms/complications , Aged , Biomarkers/blood , Cross-Sectional Studies , Female , Fibrin Fibrinogen Degradation Products , Humans , Intercellular Adhesion Molecule-1/blood , Ischemic Stroke/blood , Ischemic Stroke/diagnostic imaging , Male , Middle Aged , Neoplasms/blood , Neoplasms/diagnostic imaging , Prospective Studies , Thrombomodulin/blood , Ultrasonography, Doppler, Transcranial , Vascular Cell Adhesion Molecule-1/blood
4.
Invest New Drugs ; 40(1): 81-90, 2022 02.
Article in English | MEDLINE | ID: mdl-34417914

ABSTRACT

Background RX-3117 is an oral small molecule antimetabolite, cyclopentyl pyrimidyl nucleoside that is activated by cancer cells over-expressing uridine cytidine kinase 2 (UCK2). Single agent RX-3117 demonstrated efficacy in a phase I trial in patients with metastatic (met) pancreatic adenocarcinoma (PC). RX-3117 plus nab-paclitaxel (nab-Pac) was evaluated as a first line treatment in met-PC cancer. Methods This was a multicenter open label phase I/II 2-stage study investigating the combination of RX3117 plus nab-Pac in the frontline treatment of patients with met-PC. The phase I portion comprised a dose de-escalation design with primary objectives of determining the safety, tolerability and recommended phase 2 dose (RP2D) of RX-3117 (orally 700, 600, or 500 mg/day for 5 consecutive days with 2 days off/week) plus nab-Pac (intravenous (IV) 125 mg/m2 once weekly) for 3 weeks with 1 week off per a 4-week cycle. The primary objective was to determine the antitumor efficacy. Results 46 patients were enrolled (22 male/24 female; median age 67; 91% Caucasian). The RP2D of RX-3117 plus nab-Pac was 700 mg/day. No dose-limiting toxicities were observed (DLTs). The overall response rate (ORR) was 23.1% and disease control rate (DCR) 74.4%. RX-3117 pharmacokinetics (PK) results were similar to previously reported monotherapy phase 1 trial. All patients experienced a treatment emergent adverse event (TEAE) with the most common diarrhea, nausea, and fatigue.10.9% of patients experienced a serious adverse event (SAE) related to the combination. Conclusion RX-3117 plus nab-Pac in newly diagnosed met-PC patients demonstrated tolerability, safety, and early treatment efficacy.


Subject(s)
Adenocarcinoma/drug therapy , Albumins/pharmacokinetics , Albumins/therapeutic use , Paclitaxel/pharmacokinetics , Paclitaxel/therapeutic use , Pancreatic Neoplasms/drug therapy , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Area Under Curve , Cytidine/analogs & derivatives , Cytidine/pharmacokinetics , Cytidine/pharmacology , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Half-Life , Humans , Male , Maximum Tolerated Dose , Metabolic Clearance Rate , Middle Aged
5.
Stroke ; 50(11): 3259-3264, 2019 11.
Article in English | MEDLINE | ID: mdl-31510897

ABSTRACT

Background and Purpose- Comorbid cancer is common in patients with acute ischemic stroke (AIS). As blood mRNA profiles can distinguish AIS mechanisms, we hypothesized that cancer-related AIS would have a distinctive gene expression profile. Methods- We evaluated 4 groups of 10 subjects prospectively enrolled at 3 centers from 2009 to 2018. This included the group of interest with active solid tumor cancer and AIS and 3 control groups with active cancer only, AIS only, or vascular risk factors only. Subjects in the AIS-only and cancer-only groups were matched to subjects in the cancer-stroke group by age, sex, and cancer type (if applicable). Subjects in the vascular risk factor group were matched to subjects in the cancer-stroke and stroke-only groups by age, sex, and vascular risk factors. Blood was drawn 72 to 120 hours after stroke. Total RNA was processed using 3' mRNA sequencing. ANOVA and Fisher least significant difference contrast methods were used to estimate differential gene expression between groups. Results- In the cancer-stroke group, 50% of strokes were cryptogenic. All groups had differentially expressed genes that could distinguish among them. Comparing the cancer-stroke group to the stroke-only group and after accounting for cancer-only genes, 438 genes were differentially expressed, including upregulation of multiple genes/pathways implicated in autophagy signaling, immunity/inflammation, and gene regulation, including IL (interleukin)-1, interferon, relaxin, mammalian target of rapamycin signaling, SQSTMI1 (sequestosome-1), and CREB1 (cAMP response element binding protein-1). Conclusions- This study provides evidence for a distinctive molecular signature in blood mRNA expression profiles of patients with cancer-related AIS. Future studies should evaluate whether blood mRNA can predict detection of occult cancer in patients with AIS. Clinical Trial Registration- URL: https://clinicaltrials.gov. Unique identifier: NCT02604667.


Subject(s)
Brain Ischemia , Gene Expression Regulation, Neoplastic , Neoplasms , RNA, Messenger/blood , RNA, Neoplasm/blood , Stroke , Transcriptome , Aged , Aged, 80 and over , Brain Ischemia/blood , Brain Ischemia/etiology , Female , Humans , Male , Middle Aged , Neoplasm Proteins/blood , Neoplasms/blood , Neoplasms/complications , Prospective Studies , Stroke/blood , Stroke/etiology
6.
Chin J Cancer Res ; 30(1): 72-83, 2018 Feb.
Article in English | MEDLINE | ID: mdl-29545721

ABSTRACT

OBJECTIVE: The complexity, heterogeneity and capacity of malignant neoplastic cells and tumors for rapid change and evolution suggest that living-cell-based biological-systems approaches to cancer treatment are merited. Testing this hypothesis, the tumor marker, metabolic activity, and overall survival (OS) responses, to the use of one such system, implantable macrobeads [RENCA macrobeads (RMBs)], in phase I and IIa clinical trials in advanced, treatment-resistant metastatic colorectal cancer (mCRC) are described here. METHODS: Forty-eight mCRC patients (30 females; 18 males), who had failed all available, approved treatments, underwent RMB implantation (8 RMB/kg body weight) up to 4 times in phase I and phase IIa open-label trials. Physicals, labs [tumor and inflammation markers, lactate dehydrogenase (LDH)] and positron emission tomography-computed tomography (PET-CT) imaging to measure number/volume and metabolic activity of the tumors were performed pre- and 3-month-post-implantation to evaluate safety and initial efficacy (as defined by biological responses). PET-CT maximum standard uptake value (SUVmax) (baseline and d 90; SUVmax ≥2.5), LDH, and carcinoembryonic antigen (CEA) and/or cancer antigen 19-9 (CA 19-9) response (baseline, d 30 and/or d 60) were assessed and compared to OS. RESULTS: Responses after implantation were characterized by an at least 20% decrease in CEA and/or CA 19-9 in 75% of patients. Fluorodeoxyglucose (FDG)-positive lesions (phase I, 39; 2a, 82) were detected in 37/48 evaluable patients, with 35% stable volume and stable or decreased SUV (10) plus four with necrosis; 10, increased tumor volume, SUV. LDH levels remained stable and low in Responders (R) (d 0-60, 290.4-333.9), but increased steadily in Non-responders (NR) (d 0-60, 382.8-1,278.5) (d 60, P=0.050). Responders to RMBs, indicated by the changes in the above markers, correlated with OS (R mean OS=10.76 months; NR mean OS=4.9 months; P=0.0006). CONCLUSIONS: The correlations of the tumor marker, tumor volume and SUV changes on PET-CT, and LDH levels themselves, and with OS, support the concept of a biological response to RMB implantation and the validity of the biological-systems approach to mCRC. A phase III clinical trial is planned.

7.
Cancer ; 123(19): 3843-3854, 2017 Oct 01.
Article in English | MEDLINE | ID: mdl-28558150

ABSTRACT

BACKGROUND: Sacituzumab govitecan (IMMU-132), an antitrophoblastic cell-surface antigen (anti-Trop-2) humanized antibody-SN-38 conjugate, had encouraging efficacy in the phase 1 clinical trial. This report further examines the pharmacokinetics and safety of multiple cycles of IMMU-132 at doses of 8 or 10 mg/kg in patients with diverse advanced epithelial cancers. METHODS: Patients who had multiple prior therapies received IMMU-132 on days 1 and 8 of 21-day treatment cycles. Trop-2 staining of archived tumor specimens, clearance of IMMU-132 and its constituents (ie, immunoglobulin G [IgG], SN-38 [a camptothecin, the active component of irinotecan], and glucuronidated SN-38 [SN-38G]), antibody responses, and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) levels were determined. Safety was assessed according to Common Terminology Criteria for Adverse Events version 4.0, and responses were assessed using Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: Patients with diverse metastatic cancers who received IMMU-132 at 8 mg/kg (n = 81) and 10 mg/kg (n = 97) were examined. Trop-2 was positive in 93% of the available specimens. IMMU-132 cleared with a half-life of approximately 11 to 14 hours, reflecting the release of SN-38 from the conjugate; IgG cleared more slowly (half-life, approximately 103-114 hours). Most SN-38 in the serum (>95%) was bound to IgG. SN-38G concentrations were lower than SN-38 concentrations. Dose-limiting neutropenia after the first cycle was not correlated with SN-38 in serum or with UGT1A1 genotype. No antibody responses were detected. Objective responses were observed in several indications, including metastatic triple-negative breast cancer, confirming that 10 mg/kg produced an encouraging overall response. CONCLUSIONS: Sacituzumab govitecan has a predictable pharmacokinetic profile and manageable toxicity at doses of 8 and 10 mg/kg. With objective responses and a good therapeutic index at 10 mg/kg, this dose was chosen for future development. Cancer 2017;123:3843-3854. © 2017 American Cancer Society.


Subject(s)
Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/pharmacokinetics , Antineoplastic Agents, Phytogenic/adverse effects , Antineoplastic Agents, Phytogenic/pharmacokinetics , Camptothecin/analogs & derivatives , Immunoconjugates/adverse effects , Immunoconjugates/pharmacokinetics , Neoplasms/metabolism , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/administration & dosage , Antigens, Neoplasm/metabolism , Antineoplastic Agents, Phytogenic/administration & dosage , Camptothecin/administration & dosage , Camptothecin/adverse effects , Camptothecin/blood , Camptothecin/pharmacokinetics , Cell Adhesion Molecules/metabolism , Female , Glucuronosyltransferase/genetics , Half-Life , Humans , Immunoconjugates/administration & dosage , Immunoglobulin G/metabolism , Irinotecan , Male , Middle Aged , Neoplasms/drug therapy , Neutropenia/chemically induced , Response Evaluation Criteria in Solid Tumors , Time Factors
8.
Invest New Drugs ; 32(3): 542-8, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24526575

ABSTRACT

PURPOSE: To determine the effectiveness of bortezomib plus irinotecan and bortezomib alone in patients with advanced gastroesophageal junction (GEJ) and gastric adenocarcinoma. We also sought to explore the effect of these therapeutics on tumor and normal gene expression in vivo. METHODS: Forty-one patients with advanced GEJ (89 %) or gastric (11 %) adenocarcinoma received bortezomib (1.3 mg/m(2) days 1, 4, 8, 11) plus irinotecan (125 mg/m(2) days 1, 8) every 21 days as first line therapy (N = 29), or bortezomib alone as second line therapy (N = 12). The trial was designed to detect a 40 % response rate for the combination, and 20 % response rate for bortezomib alone. Affymetrix HU133A gene chip arrays were used for gene expression studies. RESULTS: Objective response occurred in 3 of 29 patients (10 %, 95 % confidence intervals [CI] 2 %, 27 %) treated with bortezomib plus irinotecan, and in 1 of 12 patients (8 %, 95 % CI 0 %, 39 %) with bortezomib alone. Due to the limited number of responders, there were no significant correlations with response found in the gene expression profiles of 12 patients whose tumors were sampled before and 24 h after therapy with bortezomib alone (N = 2) or the combination (N = 10). CONCLUSIONS: We conclude that bortezomib is not effective for the treatment of advanced adenocarcinoma of the GEJ or stomach, whether used alone or in combination with irinotecan, in an unselected patient population.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Esophageal Neoplasms/drug therapy , Stomach Neoplasms/drug therapy , Adenocarcinoma/genetics , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Boronic Acids/administration & dosage , Boronic Acids/adverse effects , Bortezomib , Camptothecin/administration & dosage , Camptothecin/adverse effects , Camptothecin/analogs & derivatives , Esophageal Neoplasms/genetics , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Irinotecan , Male , Middle Aged , Oligonucleotide Array Sequence Analysis , Proteasome Inhibitors/administration & dosage , Proteasome Inhibitors/adverse effects , Pyrazines/administration & dosage , Pyrazines/adverse effects , Stomach Neoplasms/genetics
9.
medRxiv ; 2024 Jun 17.
Article in English | MEDLINE | ID: mdl-38947080

ABSTRACT

Circulating tumor cells (CTCs) captured from the bloodstream of patients with solid tumors have the potential to accelerate precision oncology by providing insight into tumor biology, disease progression and response to treatment. However, their potential is hampered by the lack of standardized CTC enrichment platforms across tumor types. EpCAM-based CTC enrichment, the most commonly used platform, is limited by EpCAM downregulation during metastasis and the low EpCAM expression in certain tumor types, including the highly prevalent and lethal NSCLC. In this study we demonstrate that Transferrin Receptor (TfR) is a selective, efficient biomarker for CTC identification and capture in patients with prostate, pancreatic and NSCLC. TfR identifies significantly higher CTC counts than EpCAM, and TfR + -CTC enumeration correlates with disease progression in metastatic prostate and pancreatic cancers, and overall survival and osimetrinib-resistance in non-small cell lung cancer (NSCLC). Profiling of TfR + -CTCs provides a snapshot of the molecular landscape of each respective tumor type and identifies potential mechanisms underlying treatment response to EGFR TKi and immune checkpoint inhibitors in NSCLC. One sentence summary: Transferrin Receptor identifies circulating tumor cells in solid tumors.

10.
Res Sq ; 2024 Jul 25.
Article in English | MEDLINE | ID: mdl-39108491

ABSTRACT

Colorectal carcinoma (CRC) is a heterogeneous group of tumors with varying therapeutic response and prognosis, and evidence suggests the tumor immune microenvironment (TIME) plays a pivotal role. Using advanced molecular and spatial biology technologies, we aimed to evaluate the TIME in patients with CRC to determine whether specific alterations in the immune composition correlated with prognosis. We identified primary and metastatic tumor samples from 31 consented patients, which were profiled with whole-exome sequencing and bulk RNA-seq. Immune cell deconvolution followed by gene set enrichment analysis and unsupervised clustering was performed. A subset of tumors underwent in situ analysis of the TIME spatial composition at single-cell resolution through Imaging Mass Mass Cytometry. Gene set enrichment analysis revealed two distinct groups of advanced CRC, one with an immune activated phenotype and the other with a suppressed immune microenvironment. The activated TIME phenotype contained increased Th1 cells, activated dendritic cells, tertiary lymphoid structures, and higher counts of CD8+ T cells whereas the inactive or suppressed TIME contained increased macrophages and a higher M2/M1 ratio. Our findings were further supported by RNA-seq data analysis from the TCGA CRC database, in which unsupervised clustering also identified two separate groups. The immunosuppressed CRC TIME had a lower overall survival probability (HR 1.66, p=0.007). This study supports the pertinent role of the CRC immune microenvironment in tumor progression and patient prognosis. We characterized the immune cell composition to better understand the complexity and vital role that immune activity states of the TIME play in determining patient outcome.

11.
Cancer Med ; 12(17): 18269-18280, 2023 09.
Article in English | MEDLINE | ID: mdl-37551156

ABSTRACT

PURPOSE: Most patients with cancer lack the prognostic understanding necessary to make informed decisions. We tested the feasibility and acceptability of the Oncolo-GIST ("Giving Information Strategically and Transparently, GIST") intervention and explored its associations with patients' improved prognostic understanding. METHODS: The Oncolo-GIST intervention distills prognostic discussions into easy-to-understand talking points. Patients with metastatic cancers that progressed on ≥1 line of chemotherapy and not expected to survive 12 months (n = 31) were recruited from October 2020 through November 2022. We compared patients who discussed their progressive scans with an oncologist trained in the GIST technique or not (i.e., usual care). A primary outcome was prognostic understanding (e.g., patients reporting a life-expectancy of months) assessed within a week of the scan discussion visit. RESULTS: Oncologists (n = 4) appeared receptive to the Oncolo-GIST intervention and scored nearly perfectly on post-training tests of material mastery after a < 2-h tutorial. Post-scan discussion visit, 100% of patients who met with an Oncolo-GIST-trained clinician understood that their cancer was considered incurable (a 31% improvement from pre-visit) compared with 91% of patients meeting with usual care oncologists (an 18% improvement); 33% of patients who met with an Oncolo-GIST-trained oncologist understood that they likely had months, not years, compared to 18% in the usual care group. No statistically significant differences emerged for these changes, nor for therapeutic alliance, anxiety, or depression scores between groups. CONCLUSION: Oncolo-GIST appears to be an easily learned approach to improve prognostic understanding that neither undermines therapeutic alliances nor increases patients' anxiety or depressive symptoms. Efficacy testing in a larger trial is warranted.


Subject(s)
Neoplasms , Humans , Prognosis , Pilot Projects , Neoplasms/therapy , Anxiety/etiology , Anxiety Disorders
12.
Oncogene ; 42(44): 3252-3259, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37731056

ABSTRACT

In patients with locally advanced cancer without distant metastases, the neoadjuvant setting presents a platform to evaluate new drugs. For mismatch repair proficient/microsatellite stable (pMMR/MSS) colon and rectal cancer, immunotherapy has shown limited efficacy. Herein, we report exceptional responses observed with neoadjuvant botensilimab (BOT), an Fc-enhanced next-generation anti-CTLA-4 antibody, alongside balstilimab (BAL; an anti-PD-1 antibody) in two patients with pMMR/MSS colon and rectal cancer. The histological pattern of rapid immune response observed ("inside-out" (serosa-to-mucosa) tumor regression) has not been described previously in this setting. Spatial biology analyses (RareCyte Inc.) reveal mechanisms of actions of BOT, a novel innate-adaptive immune activator. These observations have downstream implications for clinical trial designs using neoadjuvant immunotherapy and potentially sparing patients chemotherapy.


Subject(s)
Colorectal Neoplasms , Rectal Neoplasms , Humans , DNA Mismatch Repair , Neoadjuvant Therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics
13.
Cancer ; 118(22): 5497-506, 2012 Nov 15.
Article in English | MEDLINE | ID: mdl-22569804

ABSTRACT

BACKGROUND: It has been demonstrated that the humanized clivatuzumab tetraxetan (hPAM4) antibody targets pancreatic ductal carcinoma selectively. After a trial of radioimmunotherapy that determined the maximum tolerated dose of single-dose yttrium-90-labeled hPAM4 ((90) Y-hPAM4) and produced objective responses in patients with advanced pancreatic ductal carcinoma, the authors studied fractionated radioimmunotherapy combined with low-dose gemcitabine in this disease. METHODS: Thirty-eight previously untreated patients (33 patients with stage IV disease and 5 patients with stage III disease) received gemcitabine 200 mg/m(2) weekly for 4 weeks with (90) Y-hPAM4 given weekly in Weeks 2, 3, and 4 (cycle 1), and the same cycle was repeated in 13 patients (cycles 2-4). In the first part of the study, 19 patients received escalating weekly (90) Y doses of 6.5 mCi/m(2) , 9.0 mCi/m(2) , 12.0 mCi/m(2) , and 15.0 mCi/m(2) . In the second portion, 19 additional patients received weekly doses of 9.0 mCi/m(2) or 12.0 mCi/m(2) . RESULTS: Grade 3/4 thrombocytopenia or neutropenia (according to version 3.0 of the National Cancer Institute's Common Terminology Criteria for Adverse Events) developed in 28 of 38 patients after cycle 1 and in all retreated patients; no grade >3 nonhematologic toxicities occurred. Fractionated dosing of cycle 1 allowed almost twice the radiation dose compared with single-dose radioimmunotherapy. The maximum tolerated dose of (90) Y-hPAM4 was 12.0 mCi/m(2) weekly for 3 weeks for cycle 1, with ≤9.0 mCi/m(2) weekly for 3 weeks for subsequent cycles, and that dose will be used in future trials. Six patients (16%) had partial responses according to computed tomography-based Response Evaluation Criteria in Solid Tumors, and 16 patients (42%) had stabilization as their best response (58% disease control). The median overall survival was 7.7 months for all 38 patients, including 11.8 months for those who received repeated cycles (46% [6 of 13 patients] ≥1 year), with improved efficacy at the higher radioimmunotherapy doses. CONCLUSIONS: Fractionated radioimmunotherapy with (90) Y-hPAM4 and low-dose gemcitabine demonstrated promising therapeutic activity and manageable myelosuppression in patients with advanced pancreatic ductal carcinoma.


Subject(s)
Deoxycytidine/analogs & derivatives , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/radiotherapy , Radioimmunotherapy , Yttrium Radioisotopes/therapeutic use , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/therapeutic use , Antimetabolites, Antineoplastic/therapeutic use , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/radiotherapy , Combined Modality Therapy , Deoxycytidine/therapeutic use , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Neutropenia/etiology , Radiation Dosage , Radiation-Sensitizing Agents/therapeutic use , Thrombocytopenia/etiology , Yttrium Radioisotopes/adverse effects , Gemcitabine
14.
JMIR Cancer ; 8(1): e31388, 2022 Mar 24.
Article in English | MEDLINE | ID: mdl-35323123

ABSTRACT

BACKGROUND:  There is a growing interest in the pattern of consumption of health-related information on social media platforms. OBJECTIVE: We evaluated the content of discussions around pancreatic cancer on Twitter to identify subtopics of greatest interest to health care providers and the general public. METHODS:  We used an online analytical tool (Creation Pinpoint) to quantify Twitter mentions (tweets and retweets) related to pancreatic cancer between January 2018 and December 2019. Keywords, hashtags, word combinations, and phrases were used to identify mentions. Health care provider profiles were identified using machine learning and then verified by a human analyst. Remaining user profiles were classified as belonging to the general public. Data from conversations were stratified qualitatively into 5 domains: (1) prevention, (2) survivorship, (3) treatment, (4) research, and (5) policy. We compared the themes of conversations initiated by health care providers and the general public and analyzed the impact of the Pancreatic Cancer Awareness Month and announcements by public figures of pancreatic cancer diagnoses on the overall volume of conversations. RESULTS:  Out of 1,258,028 mentions of pancreatic cancer, 313,668 unique mentions were classified into the 5 domains. We found that health care providers most commonly discussed pancreatic cancer research (10,640/27,031 mentions, 39.4%), while the general public most commonly discussed treatment (154,484/307,449 mentions, 50.2%). Health care providers were found to be more likely to initiate conversations related to research (odds ratio [OR] 1.75, 95% CI 1.70-1.79, P<.001) and prevention (OR 1.49, 95% CI 1.41-1.57, P<.001) whereas the general public took the lead in the domains of treatment (OR 1.63, 95% CI 1.58-1.69, P<.001) and survivorship (OR 1.17, 95% CI 1.13-1.21, P<.001). Pancreatic Cancer Awareness Month did not increase the number of mentions by health care providers in any of the 5 domains, but general public mentions increased temporarily in all domains except prevention and policy. Health care provider mentions did not increase with announcements by public figures of pancreatic cancer diagnoses. After Alex Trebek, host of the television show Jeopardy, received his diagnosis, general public mentions of survivorship increased, while Justice Ruth Bader Ginsburg's diagnosis increased conversations on treatment. CONCLUSIONS: Health care provider conversations on Twitter are not aligned with the general public. Pancreatic Cancer Awareness Month temporarily increased general public conversations about treatment, research, and survivorship, but not prevention or policy. Future studies are needed to understand how conversations on social media platforms can be leveraged to increase health care awareness among the general public.

15.
Cancer Med ; 11(22): 4169-4181, 2022 11.
Article in English | MEDLINE | ID: mdl-35499204

ABSTRACT

BACKGROUND: This trial explores SM-88 used with methoxsalen, phenytoin, and sirolimus (MPS) in pretreated metastatic pancreatic ductal adenocarcinoma (mPDAC) METHODS: Forty-nine patients were randomized to daily 460 or 920 mg oral SM-88 with MPS (SM-88 Regimen). The primary endpoint was objective response rate (RECIST 1.1). RESULTS: Thirty-seven patients completed ≥ one cycle of SM-88 Regimen (response evaluable population). Disease control rate (DCR), overall survival (OS), and progression-free survival (PFS) did not differ significantly between dose levels. Stable disease was achieved in 9/37 patients (DCR, 24.3%); there were no complete or partial responses. Quality-of-life (QOL) was maintained and trended in favor of 920 mg. SM-88 Regimen was well tolerated; a single patient (1/49) had related grade 3 and 4 adverse events, which later resolved. In the intention-to-treat population of 49 patients, the median overall survival (mOS) was 3.4 months (95% CI: 2.7-4.9 months). Those treated in the second line had an mOS of 8.1 months and a median PFS of 3.8 months. Survival was higher for patients with stable versus progressive disease (any line; mOS: 10.6 months vs. 3.9 months; p = 0.01). CONCLUSIONS: SM-88 Regimen has a favorable safety profile with encouraging QOL effects, disease control, and survival trends. This regimen should be explored in the second-line treatment of patients with mPDAC. CLINICALTRIALS: gov Identifier: NCT03512756.


Subject(s)
Adenocarcinoma , Pancreatic Neoplasms , Humans , Methoxsalen/therapeutic use , Phenytoin/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Sirolimus/adverse effects , Quality of Life , Pancreatic Neoplasms/pathology , Adenocarcinoma/pathology , Pancreatic Neoplasms
16.
J Thromb Haemost ; 20(9): 2046-2057, 2022 09.
Article in English | MEDLINE | ID: mdl-35652416

ABSTRACT

BACKGROUND: Patients with cancer and acute ischemic stroke (AIS) face high rates of recurrent thromboembolism or death. OBJECTIVES: To examine whether hematologic and embolic biomarkers soon after AIS are associated with subsequent adverse clinical outcomes. METHODS: We prospectively enrolled 50 adults with active solid tumor cancer and AIS at two hospitals from 2016 to 2020. Blood was collected 72-120 h after stroke onset. A 30-min transcranial Doppler (TCD) microemboli detection study was performed. The exposure variables were hematologic markers of coagulation (D-dimer, thrombin-antithrombin), platelet (P-selectin), and endothelial activation (thrombomodulin, soluble intercellular adhesion molecule-1 [sICAM-1], soluble vascular cell adhesion molecule-1 [sVCAM-1]), and the presence of TCD microemboli. The primary outcome was a composite of recurrent arterial/venous thromboembolism or death. We used Cox regression to evaluate associations between biomarkers and subsequent outcomes. RESULTS: During an estimated median follow-up time of 48 days (IQR, 18-312), 43 (86%) participants developed recurrent thromboembolism or death, including 28 (56%) with recurrent thromboembolism, of which 13 were recurrent AIS (26%). In unadjusted analysis, D-dimer (HR 1.6; 95% CI 1.2-2.0), P-selectin (HR 1.9; 95% CI 1.4-2.7), sICAM-1 (HR 2.2; 95% CI 1.6-3.1), sVCAM-1 (HR 1.6; 95% CI 1.2-2.1), and microemboli (HR 2.2; 95% CI 1.1-4.5) were associated with the primary outcome, whereas thrombin-antithrombin and thrombomodulin were not. D-dimer was the only marker associated with recurrent AIS (HR 1.2; 95% CI 1.0-1.5). Results were generally consistent in analyses adjusted for important prognostic variables. CONCLUSIONS: Markers of hypercoagulability and embolic disease may be associated with adverse clinical outcomes in cancer-related stroke.


Subject(s)
Ischemic Stroke , Neoplasms , Thromboembolism , Adult , Antithrombins , Biomarkers , Humans , Ischemic Stroke/diagnosis , Neoplasms/complications , P-Selectin , Thrombin , Thrombomodulin
17.
Commun Biol ; 4(1): 785, 2021 06 24.
Article in English | MEDLINE | ID: mdl-34168263

ABSTRACT

Quantitation of androgen receptor variant (AR-V) expression in circulating tumor cells (CTCs) from patients with metastatic castration-resistant prostate cancer (mCRPC) has great potential for treatment customization. However, the absence of a uniform CTC isolation platform and consensus on an analytical assay has prevented the incorporation of these measurements in routine clinical practice. Here, we present a single-CTC sensitive digital droplet PCR (ddPCR) assay for the quantitation of the two most common AR-Vs, AR-V7, and AR-v567es, using antigen agnostic CTC enrichment. In a cohort of 29 mCRPC patients, we identify AR-V7 in 66% and AR-v567es in 52% of patients. These results are corroborated using another gene expression platform (NanoStringTM) and by analysis of RNA-Seq data from patients with mCRPC (SU2C- PCF Dream Team). We next quantify AR-V expression in matching EpCAM-positive vs EpCAM-negative CTCs, as EpCAM-based CTC enrichment is commonly used. We identify lower AR-V prevalence in the EpCAM-positive fraction, suggesting that EpCAM-based CTC enrichment likely underestimates AR-V prevalence. Lastly, using single CTC analysis we identify enrichment for AR-v567es in patients with neuroendocrine prostate cancer (NEPC) indicating that AR-v567es may be involved in lineage plasticity, which warrants further mechanistic interrogation.


Subject(s)
Neoplastic Cells, Circulating/chemistry , Prostatic Neoplasms/pathology , Receptors, Androgen/genetics , Cell Line, Tumor , Humans , Male , Neoplasm Staging , Prostatic Neoplasms/chemistry , RNA-Seq , Receptors, Androgen/analysis , Receptors, Androgen/physiology
18.
Cancer Prev Res (Phila) ; 14(11): 1021-1032, 2021 11.
Article in English | MEDLINE | ID: mdl-34625409

ABSTRACT

Up to 10% of patients with pancreatic ductal adenocarcinoma (PDAC) carry underlying germline pathogenic variants in cancer susceptibility genes. The GENetic Education Risk Assessment and TEsting (GENERATE) study aimed to evaluate novel methods of genetic education and testing in relatives of patients with PDAC. Eligible individuals had a family history of PDAC and a relative with a germline pathogenic variant in APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, or TP53 genes. Participants were recruited at six academic cancer centers and through social media campaigns and patient advocacy efforts. Enrollment occurred via the study website (https://GENERATEstudy.org) and all participation, including collecting a saliva sample for genetic testing, could be done from home. Participants were randomized to one of two remote methods that delivered genetic education about the risks of inherited PDAC and strategies for surveillance. The primary outcome of the study was uptake of genetic testing. From 5/8/2019 to 5/6/2020, 49 participants were randomized to each of the intervention arms. Overall, 90 of 98 (92%) of randomized participants completed genetic testing. The most frequently detected pathogenic variants included those in BRCA2 (N = 15, 17%), ATM (N = 11, 12%), and CDKN2A (N = 4, 4%). Participation in the study remained steady throughout the onset of the Coronavirus disease (COVID-19) pandemic. Preliminary data from the GENERATE study indicate success of remote alternatives to traditional cascade testing, with genetic testing rates over 90% and a high rate of identification of germline pathogenic variant carriers who would be ideal candidates for PDAC interception approaches. PREVENTION RELEVANCE: Preliminary data from the GENERATE study indicate success of remote alternatives for pancreatic cancer genetic testing and education, with genetic testing uptake rates over 90% and a high rate of identification of germline pathogenic variant carriers who would be ideal candidates for pancreatic cancer interception.


Subject(s)
BRCA1 Protein/genetics , BRCA2 Protein/genetics , Genetic Predisposition to Disease , Genetic Testing/methods , Germ-Line Mutation , Pancreatic Neoplasms/genetics , Risk Assessment/methods , Adolescent , Adult , Aged , Aged, 80 and over , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/therapy , Female , Humans , Male , Middle Aged , Models, Genetic , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/therapy , Patient Participation , Risk Factors , Surveys and Questionnaires , Telemedicine , Young Adult
19.
Mol Cancer Ther ; 19(5): 1148-1156, 2020 05.
Article in English | MEDLINE | ID: mdl-32156785

ABSTRACT

KRAS mutation is a negative predictive biomarker of anti-EGFR agents in patients with metastatic colorectal cancer (mCRC), and remains an elusive target. Pelareorep, a double-stranded RNA virus selectively replicates in KRAS-mutated cells, and is synergistic with irinotecan. A dose escalation trial of FOLFIRI/bevacizumab [irinotecan (150-180 mg/m2) and pelareorep (1 × 1010 TCID50-3 × 1010 TCID50)] was implemented in adult patients with oxaliplatin refractory/intolerant, KRAS-mutant mCRC. Pelareorep was administered intravenously over 1 hour on days 1-5 every 4 weeks. Additional studies included pharmacokinetics, tumor morphology, and immune responses. Among FOLFIRI-naïve patients, the highest dose of FOLFIRI/bevacizumab (180 mg/m2 irinotecan) and pelareorep (3 × 1010 TCID50) was well tolerated, without a dose-limiting toxicity. At the recommended phase II dose, 3 of 6 patients (50%) had a partial response; the median progression-free and overall survival (PFS, OS) were 65.6 weeks and 25.1 months, respectively. Toxicities included myelosuppression, fatigue, and diarrhea. Transmission electron microscopy revealed viral factories (viral collections forming vesicular structures), at various stages of development. Immunogold staining against viral capsid σ-1 protein demonstrated viral "homing" in the tumor cells. The nucleus displayed sufficient euchromatin regions suggestive of active transcription. Flow cytometry revealed rapid dendritic cell maturation (48 hours) with subsequent activation of cytotoxic T cells (7 days). The combination of pelareorep with FOLFIRI/bevacizumab is safe. The PFS and OS data are encouraging and deserve further exploration. Pelareorep leads to a clear recurrent immune stimulatory response with cytotoxic T-cell activation, and homes and replicates in the tumor.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/therapy , Mutation , Oncolytic Viruses/metabolism , Proto-Oncogene Proteins p21(ras)/genetics , Adult , Aged , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Apoptosis , Bevacizumab/administration & dosage , Biomarkers, Tumor/genetics , Cell Proliferation , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Combined Modality Therapy , Female , Humans , Irinotecan/administration & dosage , Male , Maximum Tolerated Dose , Mice , Mice, Nude , Oncolytic Viruses/genetics , Prognosis , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
20.
Clin Cancer Res ; 26(18): 4756-4766, 2020 09 15.
Article in English | MEDLINE | ID: mdl-32641434

ABSTRACT

PURPOSE: We examined cabazitaxel, a novel next-generation taxoid, in patients with metastatic gastric cancer in a multicenter phase II study. PATIENTS AND METHODS: Patients who have progressed on one or more prior therapies for locally advanced, unresectable, or metastatic disease were eligible, and prior taxane therapy was allowed. Taxane-naïve and pretreated cohorts were analyzed independently for efficacy. The primary endpoint for both cohorts was progression-free survival (PFS) using RECIST 1.1, using a Simon's two-stage design (10% significance and 80% power) for both cohorts. Comprehensive molecular annotation included whole exome and bulk RNA sequencing. RESULTS: Fifty-three patients enrolled in the taxane-naïve cohort (Arm A) and 23 patients in the prior-taxane cohort (Arm B), from January 8, 2013, to April 8, 2015: median age 61.7 years (range, 35.5-91.8 years), 66% male, 66% Caucasian. The most common adverse events included neutropenia (17% Arm A and 39% Arm B), fatigue/muscle weakness (13%), and hematuria (12%). In Arm A, the 3-month PFS rate was 28% [95% confidence interval (CI), 17%-42%] and did not meet the prespecified efficacy target. The 3-month PFS rate in Arm B was 35% (95% CI, 16%-57%) and surpassed its efficacy target. HER2 amplification or overexpression was associated with improved disease control (P = 0.003), PFS (P = 0.04), and overall survival (P = 0.002). An M2 macrophage signature was also associated with improved survival (P = 0.031). CONCLUSIONS: Cabazitaxel has modest activity in advanced gastric cancer, including in patients previously treated with taxanes. Her2 amplification/overexpression and M2 high macrophage signature are potential biomarkers for taxane efficacy that warrant further evaluation.


Subject(s)
Adenocarcinoma/drug therapy , Esophageal Neoplasms/drug therapy , Receptor, ErbB-2/genetics , Stomach Neoplasms/drug therapy , Taxoids/administration & dosage , Tumor-Associated Macrophages/immunology , Adenocarcinoma/genetics , Adenocarcinoma/immunology , Adenocarcinoma/mortality , Adult , Aged , Aged, 80 and over , Esophageal Neoplasms/genetics , Esophageal Neoplasms/immunology , Esophageal Neoplasms/mortality , Esophagogastric Junction/pathology , Female , Gene Amplification , Gene Expression Regulation, Neoplastic , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Progression-Free Survival , Receptor, ErbB-2/analysis , Response Evaluation Criteria in Solid Tumors , Stomach Neoplasms/genetics , Stomach Neoplasms/immunology , Stomach Neoplasms/mortality , Taxoids/adverse effects
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