CX1003 quantification by ultra-performance LC–MS/MS in human plasma and its application to a pharmacokinetic study in solid tumor patients

Bioanalysis ◽  
2019 ◽  
Vol 11 (16) ◽  
pp. 1483-1493
Author(s):  
Yu Li ◽  
Qian Zhao ◽  
Pei Hu ◽  
Ji Jiang
Keyword(s):  
Cancer Patients ◽  
Human Plasma ◽  
Solid Tumors ◽  
Pharmacokinetic Study ◽  
Solid Tumor ◽  
Receptor Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Chinese Patients ◽  
Good Sensitivity ◽  
Tumor Patients

Aim: CX1003 is a novel multitargeted receptor tyrosine kinase inhibitor targeting cancer patients with relapsed or metastatic malignant solid tumors. The study aimed to develop a robust and rapid assay approach to quantify CX1003 in human plasma. Methodology & results: Samples of plasma were purified by SPE where the diluted eluates were then separated by a Waters Acquity CSH C18 column and thereafter detected using positive electrospray ionization via an ultra performance LC–MS/MS. Conclusion: The method to quantify CX1003 in human plasma was first exploited and validated with good sensitivity and specificity, and successfully fulfilled the requirement of the first-in-human clinical pharmacokinetic study of CX1003 in Chinese patients with relapsed or metastatic malignant solid tumors.

Characteristics and outcomes of cancer patients ≥80 years treated with chemotherapy at a comprehensive cancer center

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 8548-8548
Author(s):  
P. Jiang ◽  
M. Choi ◽  
D. Smith ◽  
L. Heilbrun ◽  
S. M. Gadgeel
Keyword(s):  
Cancer Patients ◽  
Solid Tumors ◽  
Solid Tumor ◽  
Hematologic Malignancy ◽  
Survival Rates ◽  
The United States ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
Tumor Patients ◽  
Hematologic Cancer

8548 Background: The percentage of cancer patients ≥ 80 years old is expected to rise in the United States. However data are limited on use of chemotherapy in this group of patients. Methods: Retrospective identification of patients who received systemic chemotherapy at our cancer center between 1/1/2000 to 12/31/2004 was performed using the computer generated pharmacy data and medical records. Patients who had diagnosis of cancer and ≥ 80 years were included in the study; patients receiving only supportive care, hormonal therapy, or oral chemotherapy were excluded. The protocol for this study was approved by the Wayne State University IRB. Results: A total of 133 patients ≥ 80 years who received chemotherapy was analyzed. The median age was 83 and 31% of the patients were ≥ 85 years. There were more females (61%) than males (39%). The gender distribution was more even (47% v. 53%) after excluding gender specific tumors. The racial distribution was diverse- Whites 65 (49%); Blacks 41 (31%); Other 18 (13%); Unknown 9 (7%). 16% of the patients had hematologic malignancy and 84% had solid tumors. Gynecological cancers (32%) followed by aerodigestive cancers (26%) were the most common solid tumors. Solid tumor patients primarily had regional (48%) or distant (45%) disease. During the first regimen, 512 cycles of chemotherapy was delivered with a median of 3 cycles per patient (range 1–24 cycles); 40% of patients received only 2 cycles of chemotherapy. 64% of patients were able to receive chemotherapy without 2nd cycle delay. The distribution of single or multidrug regimens was fairly similar; Solid tumors 52% v. 48%; Hematologic cancers 43% v. 57%. Carboplatin and paclitaxel (22%) was the most common regimen among solid tumor patients. 26% of all patients received a second regimen. The 1 year survival rates among hematologic cancer and solid tumor patients were 65% and 48%, respectively. Stage of disease was the only statistically significant factor predicting survival. Conclusions: In this diverse group of cancer patients ≥ 80 years old and selected for chemotherapy, the treatment was feasible. The survival outcomes in this elderly population were comparable to those of a younger patient population suggesting that the treatment is beneficial. No significant financial relationships to disclose.

The alteration of TERT in 10,000 Chinese patients with solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13655-e13655
Author(s):  
Jie Lin ◽  
Yuehua Li ◽  
Hao Zou ◽  
Li Zhang ◽  
Yanbin Xiao ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Biliary Tract ◽  
Solid Tumor ◽  
Promoter Region ◽  
Chinese Patients ◽  
Tumor Patients ◽  
Lung Cancers ◽  
Liver Cancers ◽  
Biliary Tract Tumors ◽  
And Gender

e13655 Background: The reactivation of telomerase reverse transcriptase ( TERT) is one of the characters that make cancer cells immortal. TERT expression has been shown in various human cancers.However, the landscape of TERT alterations in Chinese patients with solid tumors still remains unclear. Here, we illustrated the profile of TERT variations of Chinese solid tumor patients by using next generation sequencing (NGS)-based targeted sequencing. Methods: Formalin fixed, paraffin embedded (FFPE) tumor tissues and matching blood samples were collected from 9874 Chinese patients and subjected to a NGS-based panel at a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. All classes of alterations were assessed. Results: FFPE samples from 9874 Chinese solid tumor patients included lung cancers (39.7%), liver cancers (12.5%), colorectal cancers (10.8%), gastric cancers (5.7%), pancreatic cancers (4.9%), biliary tract tumors (4.6%), and other 18 cancer types (21.7%) were assessed. And 1187 (12.0%) out of 9874 cancer samples had TERT variations. TERT variations occurred in all types of cancer with various frequencies: urothelial neoplasms (52.0%), central nervous system tumors (40.0%), melanomas (38.9%), liver cancers (30.7%), thyroid tumors (24.3%), cervical cancers (20.6%), biliary tract tumors (16.3%), head and neck tumors (14.6%), soft tissue tumors (12.2%) and lung cancers (10.3%). Substitution was the most common variation of TERT and accounted for 58.7% of all the alterations, followed by gene amplification (38.8%) and fusions (2.4%). There were 86.8% of substitution variations presented in TERT promoter region comprising of c.-124C > T (70.7%) and c.-146C > T (13.1%). Patients with TERT alterations included 414 females and 773 males with a median age of 59 years old (range: 8-88). Tumors included stage IV (34.0%), stage III (22.2%), stage II (12.7%), stage I (18.7%) and stage 0 (12.3%). TERT variations were correlated with patients’ age (p = 0.00083) and gender (p = 5.59×10−7). There was no significant correlation of TERT alterations with the highly mutated TP53. The frequencies of TERT alterations were similar in patients with mutated and wild type TP53 (12.7% vs 11.1%). Conclusions: Our study revealed that 12.0% Chinese solid tumor patients harbored TERT alterations, especially two hotspots mutations (c.-124C > T and c.-146C > T) in the promoter region. TERT variations had a correlation with patients’ age and gender, but no correlation with hotspot TP53 mutations.

Updated safety and efficacy of MSB2311 (an anti-programmed death-ligand 1 antibody) in Chinese patients with advanced solid tumors and hematological malignancies from a phase 1 study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14547-e14547
Author(s):  
Lin Shen ◽  
Jifang Gong ◽  
Jian Zhang ◽  
Dongmei Ji ◽  
Haijun Zhong ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Solid Tumor ◽  
Phase 1 ◽  
Chinese Patients ◽  
Binding Property ◽  
Advanced Solid Tumors ◽  
Tumor Patients ◽  
Durable Response ◽  
Programmed Death ◽  
Grade 3

e14547 Background: MSB2311 is a novel humanized PD-L1 antibody with a unique pH-dependent antigen binding property that enables intra-tumor recycling and potentiates tumor penetration. Methods: Patients with metastatic solid tumors or selected lymphoma progressed on or after standard treatments were enrolled in this phase I study. In dose escalation part, MSB2311 was given at dose levels of 3, 10, and 20 mg/kg intravenously every 3 weeks. At the dose expansion part, patients with enriched biomarker expression, including EBV+, PD-L1+ (TPS≥50%), MSI-High or TMB-High (≥10muts/Mb), were dosed at 20mg/kg Q3W or 10mg/kg Q2W. Primary objectives are to evaluate the safety and tolerability and to identify MTD and RP2D. Secondary objectives include the assessment of pharmacokinetic parameter, immunogenicity, and preliminary anti-cancer activity per RECIST1.1. Results: As of data cutoff by Aug 31, 2020, 33 Chinese patients had been treated, including 27 heavily pre-treated solid tumor patients and 6 lymphoma patients. No dose limiting toxicity was reported and MTD has not been reached. The most common AEs (>20%) included: anemia, hypothyroidism, aspartate aminotransferase elevated, proteinuria, weight loss. 13 patients (39.4%) experienced grade 3 AEs, and 6 patients (18.2%) experienced SAEs. No treatment related grade 4 or 5 event was reported. Of the 17 efficacy evaluable solid tumor patients with biomarker selection, 6 achieved confirmed partial response with 35% ORR: 2/8 (25%) at 10 mg/kg Q2W and 4/9 (44%) at 20 mg/kg Q3W. Additionally, one patient achieved sustained iPR via iRECIST. 4 out of 7 responding patients (including one iPR) achieved tumor shrinkage of more than 50%, 3 of them got durable response (≥24 weeks).1 out of 6 lymphoma patients achieved PR. Conclusions: MSB2311 demonstrated a manageable safety profile and promising preliminary antitumor activity in patients with advanced solid tumors and selected lymphomas. Clinical trial information: NCT04272944.

Oncogenic FGFR3 gene fusions in solid tumors among Chinese cancer patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15072-e15072
Author(s):  
Libin Xu ◽  
Ming Liu ◽  
Jingxian Duan ◽  
Tao Wang
Keyword(s):  
Cancer Patients ◽  
Solid Tumors ◽  
Solid Tumor ◽  
Coiled Coil ◽  
Genetic Alterations ◽  
Chinese Patients ◽  
Driver Mutations ◽  
Gene Fusions ◽  
Fgfr3 Gene ◽  
Tumor Types

e15072 Background: Oncogenic FGFR3 (fibroblast growth factor receptor 3) gene fusions have been identified as driver mutations that lead to the activation of FGFR3 in many solid tumor types and serve as a novel therapeutic target for FGFR inhibitors in clinical development. TACC3 (transforming acid coiled coil 3) is the most common partner of these FGFR3 fusions. Methods: The study enrolled over ten thousand cases of Chinese patients with different types of solid tumors. We performed targeted sequencing assay with our 605 gene panel that covered all the exon and intron regions of the FGFR3 gene, so that we could identify nearly all the FGFR3 translocation events. Results: The prevalence and form of FGFR3 fusions in different tumor types were shown in Table. We identified seven patients harboring FGFR3 fusion events, with six cases of FGFR3-TACC3 and one case of FGFR3-UBE2K. In the seven patients, three of them were also harbored concomitant TP53 gene mutations, and six of them were microsatellite stability (MSS), and one was microsatellite instability-low (MSI-L). Conclusions: FGFR3 gene rearrangements were identified in different solid tumor types in our study, and they were relatively rare compared to other novel mutations. However, clinical testing for the identification of FGFR3 fusions should be prioritized in bladder cancer patients. Consistent with other studies, the most common FGFR3 fusion form was FGFR3-TACC3. Co-occurring genetic alterations in FGFR3 gene fusions cases were also common. From our limited number of cases, most of FGFR3 gene fusions patients were MSS.[Table: see text]

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.

scholarly journals Co-expression of HIF-1α, MDR1 and LAPTM4B in peripheral blood of solid tumors

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e6309 ◽  
Author(s):  
Zaira Rehman ◽  
Ammad Fahim ◽  
Attya Bhatti ◽  
Hajra Sadia ◽  
Peter John
Keyword(s):  
Colon Cancer ◽  
Multidrug Resistance ◽  
Disease Progression ◽  
Cancer Patients ◽  
Solid Tumors ◽  
Solid Tumor ◽  
Peripheral Blood ◽  
Chemotherapy Resistance ◽  
Advanced Tumor Stage ◽  
Tumor Patients

The hypoxic tumor microenvironment is the major contributor of chemotherapy resistance in solid tumors. One of the key regulators of hypoxic responses within the cell is the hypoxia inducible factor-1α (HIF-1α) that is involved in transcription of genes promoting cell survival and chemotherapy resistance. Multidrug resistance gene-1 (MDR1) and Lysosome-associated protein transmembrane 4B-35 (LAPTM4B-35) are among those notable players which augment their responses to cellular hypoxia. MDR1 is the hypoxia responsive gene involved in multidrug resistance phenotype while LAPTM4B-35 is involved in chemotherapy resistance by stabilizing HIF-1α and overexpressing MDR1. Overexpression of HIF-1α, MDR1 and LAPTM4B has been associated with poor disease outcome in many cancers when studied individually at tissue level. However, accessibility of the tissues following the course of chemotherapy for ascertaining chemotherapy resistance is difficult and sometimes not clinically feasible. Therefore, indication of hypoxic biomarkers in patient’s blood can significantly alter the clinical outcome. Hence there is a need to identify a blood based marker to understand the disease progression. In the current study the expression of hypoxia associated chemotherapy resistance genes were studied in the peripheral blood lymphocytes of solid tumor patients and any potential correlation with disease progression were explored. The expression of HIF-1α, MDR1 and LAPTM4B was studied in blood of 72 breast, 42 ovarian, 32 colon and 21 prostate cancer patients through real time PCR analysis using delta cycle threshold method. The statistical scrutiny was executed through Fisher’s Exact test and the Spearman correlation method. There was 12–13 fold increased in expression of HIF-1α, two fold increased in MDR1 and 13–14 fold increased in LAPTM4B mRNA level in peripheral blood of breast, ovarian, prostate and colon cancer patients. In the current study there was an association of HIF-1α, MDR1 and LAPTM4B expression with advanced tumor stage, metastasis and chemotherapy treated group in breast, ovarian, prostate and colon cancer patients. The Spearman analysis also revealed a positive linear association among HIF-1α, MDR1 and LAPTM4B in all the studied cancer patients. The elevated expression of HIF-1α, MDR1 and LAPTM4B in peripheral blood of solid tumor patients can be a predictor of metastasis, disease progression and treatment response in these cancers. However, larger studies are needed to further strengthen their role as a potential biomarker for cancer prognosis.

The landscape of gene fusions and the correlation with immunotherapy biomarkers in Chinese patients with advanced solid tumor.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15039-e15039
Author(s):  
Wenshuai Liu ◽  
Yifan Zhou ◽  
Bei Zhang ◽  
Yuezong Bai ◽  
Yueqi Wang
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patients ◽  
Solid Tumor ◽  
Chinese Patients ◽  
Fisher Exact Test ◽  
Gene Fusions ◽  
Advanced Solid Tumor ◽  
Tumor Patients ◽  
Potential Biomarker ◽  
Colorectal Cancer Patients

e15039 Background: Due to the U.S. Food and Drug Administration approval of larotrectinib, a tumor or tissue-agnostic cancer treatment, gene fusions and fusion-driven cancer were identified as indications. Exploration of the gene fusions might be essential in both target therapy and immunotherapy in advanced solid tumor. However, the landscape of gene fusions in Chinese solid tumor patients is poorly reported. Methods: Tissue samples were obtained from 7514 Chinese patients with advanced solid tumor. Genomic alterations were identified via the next generation sequencing (NGS) with a validated commercial 381-cancer-gene panel (panel size over 0.5 MB), including 100 MSI loci. TMB was calculated according to NGS results. Statistical analysis was performed by Fisher exact test using R 3.6.1. Results: There were 162 pathologic or very like pathologic gene fusions observed in 249 (3.31%) patients, covering 30 cancer types. Top frequent fusion genes were ALK (93), RET (32), FGFR2 (26), FGFR3 (13), ROS1 (10), TMPRSS2 (10) and NTRK1 (9). Their main partner genes were EML4 (66/ 93), KIF5B (15/32), BICC1 (5/26), TACC3 (13/13), CD47 (3/10), ERG (9/10) and TPM3 (5/9), respectively. Mostly, only one fusion was detected in one patient. Three patients harbored 3 gene fusions and 35 patients harbored 2 gene fusions, among which 21 patients were observed harboring both fusion and its reciprocal fusion. In the group of patients harboring gene fusions, the prevalence of MSI-H was 4.0% (10/ 249). Especially, the prevalence was significant high (41.2%, 7/ 17) in colorectal cancer patients (P < 0.001). In MSI-H colorectal cancer patients, 4 carried NTRK1 fusions, 2 RET fusions and 1 ALK fusion. And all of them had high tumor mutation burden (TMB). As another immunotherapy response predictor, TMB was low in most solid tumor patients in this study, except for the patients harboring gene fusions involving NTRK1, NTRK2 or STK11, whose TMB-H proportion were 67%, 50% and 33%, respectively. Conclusions: Gene fusions might be associated with MSI-H. In colorectal cancer patients, gene fusions involved either NTRK1 or NTRK2 might be associated with TMB-H, which revealed a potential biomarker for both target and immunotherapy.

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