bluuebunny/crossref_metadata_2025_split huggingface dataset:
A study of US-based Indian and Pakistani population with cancer diagnosis reported in the SEER database from 1988 to 2002
Authors: Hossain A. , Sehbai A. , Abraham J. 
Published: March 2020

20116 Background: Southeast Asian population comprises about 1.5% of the US population and one of the rapidly growing ethnic groups. This is the first study in US-based Indian and Pakistani patients with new diagnosis of cancer analyzing the epidemiologic data. Methods: SEER cancer incidence database have reported cancer incidence from 13 SEER registries from 1973 to 2002. Frequency sessions were performed and descriptive parameters were calculated regarding age, sex, marital status, vital statistics, stage, grade, tumor sites and other diagnostic tests employed. Results: About 11% of the estimated Indian and Pakistani population live in the 13 SEER registry areas. A total of 4,229 cases were reported since 1988 in this subcategory, which is about 0.03% of the total reported cases. 2148 (50.8%) were male and 2081 (49.2%) were female (p = 0.821). Average age at diagnosis was 51 years in male and 53 years in female (p = 0.7295). Table shows the incidence of different cancers compiled from American Cancer Society (ACS) (2005)1, SEER2 and World Health Organization (WHO) (2002)3 databases. Conclusions: Oral cavity cancer in males, and Breast and cervical cancer in females are common malignancies in India and Pakistan. Our study shows that prostate and breast cancer are most common in males and females in US-based Indian and Pakistani population respectively. Immigrants change their demographics regarding cancers and these differences could be attributed to multiple factors. This data may also have implications in terms of earlier screening of cancer in this population and earlier intervention. [Table: see text] No significant financial relationships to disclose.
Association of molecular markers with toxicity outcomes in a randomized trial of chemotherapy for advanced colorectal cancer (FOCUS)
Authors: Seymour M. T. , Braun M. S. , Richman S. D. , Daly C. , Thompson L. C. , Meade A. , Parmar M. , Allan J. M. , Selby P. , Quirke P. 
Published: March 2020

2022 Background: We present data on putative markers of chemotherapy toxicity from patients randomized to receive fluorouracil alone (FU), or FU+irinotecan (Ir), or FU+oxaliplatin (Ox). Methods: 1188 patients randomized to the FOCUS trial (ASCO 05 #3518) were analyzed. First-line therapy was FU in two thirds of patients, and FU+ either Ir or Ox in one third. Second-line Ir and Ox were administered to 29% and 14% of patients respectively. DNA was extracted from formalin-fixed, paraffin embedded (FFPE) blocks. Assessed DNA polymorphisms included TSER, TS1494, DPD IVS14 + 1G>A, MTHFR C667T, MLH1 -93, UGT1A1*28, ABCB1 C3435T, GSTP1 105Val, XRCC1 Q399R and ERCC2 K751Q. The primary endpoint was chemotherapy delay or dose-reduction due to toxicity during the first 12 weeks of treatment. The secondary endpoint was incidence of CTC toxicity. The Chi-squared test was used to assess for associations. Results: In this exploratory analysis no molecular factors were observed to be associated with the primary endpoint (all p values >0.1). Furthermore, no polymorphism predicted severe CTC toxicity in patients receiving FU alone (all p values >0.1). XRCC1 variant allele carriers were at increased risk of severe CTC toxicity from Ir. Combined analysis of patients treated with first and second-line Ir appeared to show a significant association between toxicity and the presence of the variant XRCC1 allele across genotypes (57% versus 52% versus 38%; p=0.006). The UGT1A1*28 was not associated with Ir toxicity. No oxaliplatin markers predicted CTC toxicity. Conclusions: None of the assessed polymorphisms were significantly associated with the primary endpoint. Our results do not support the use of pharmacogenomics in routine clinical practice. In contrast to other studies the UGT1A1*28 VNTR was not associated with irinotecan toxicity . However, the XRCC1 Q399R polymorphism was associated with increased toxicity in patients receiving irinotecan, and these data may warrant further investigation, and independent confirmation. No significant financial relationships to disclose.
Pharmacokinetic and pharmacodynamic analysis of topotecan administered in combination with PS 341 in patients with advanced malignancy
Authors: Tomita M. , Xin L. , Freeman B. , Twomey S. , Pizzorno G. , Murren J. R. 
Published: March 2020

2033 Background: In vitro exposure to camptothecin results in down-regulation of the target enzyme, topoisomerase I (topo) via multi-ubiquitination and proteasomal degradation of the protein-linked DNA breaks. To prevent loss of topo, and thus circumvent a possible mechanism of resistance to the topo inhibitors, we conducted a dose escalating phase I study of topotecan in combination with the proteosome inhibitor PS 341. We now report the pharmacokinetic and pharmacodynamic analysis of the trial. Methods: Patients with advanced cancer were treated with topotecan alone at the following dose escalating levels: 0.75, 1.0,1,25 and 1.5 mg/m2 as a 60 min infusion d x 5 during cycle 1. In subsequent cycles (21 days), cohorts of 3–6 patients received PS 341 as a 30 min infusion on days 1, 4, 8 and 11 at the following dose levels: 0.6, 0.8, 1.0 and 1.3 mg/m2. Topo expression was determined by western blot on peripheral blood mononuclear cells (PBMCs) sampled throughout the first 5-day treatment period of cycles #1 and 2. Total topotecan plasma pharmacokinetics were studied with the first doses of topotecan on cycle #1 (topotecan alone) and cycle #2 (topotecan after PS 341). Results: Samples were collected from 22 patients and 38 patient-cycles. In the first week of cycle #1, 9 of 22 (41 %) patients demonstrated a significant decrease in topo expression (range 0.2 - 1 fold) compared with the baseline level. Topo levels did not change (7/22, 32%) or increased (6/22, 27%) in the remaining patients. After administration of PS 341 during cycle #2, PBMC from 10 of 17 patients (59 %) analyzed showed a greater than 0.3 fold increase (range: 0.32 to 63) in topo concentration, and topo levels in 4 patients (23 %) were unchanged. Preliminary pharmacokinetic analysis indicates that PS 341 may interact with topotecan. Conclusions: There is a heterogeneous response in PBMC topo levels following administration of topotecan. However, addition of PS 341 to topotecan stabilized or increased PBMC topo I levels in the majority of patients, suggesting a possible role for PS341 in inhibiting camptothecin-induced topo protein degradation. Further studies combining proteasome inhibitors with topotecan to overcome drug resistance based on topo degradation are warranted. No significant financial relationships to disclose.
A phase I trial of TAS-102 administered on a three times a day schedule in patients with solid tumors
Authors: Wolff R. A. , Hoff P. M. , Mita A. , Fukushima M. , Blais J. C. , Abbruzzese J. L. , Xiong H. Q. 
Published: March 2020

2053 Background: TAS-102 consists of trifluorothymidine (FTD) and an inhibitor of thymidine phosphorylase (TP). FTD, like 5-fluorouracil, is an inhibitor of thymidylate synthase. However, when orally administered, FTD is rapidly degraded to an inactive form, primarily by TP. Co-administration of FTD with an inhibitor of TP elevates FTD concentrations. Since tumor xenograft models demonstrated greater anti-tumor activity with divided daily dosing of TAS-102, and a phase I trial of once-daily TAS-102 showed a short FTD half-life, this trial was designed to explore a three times a day dosing schedule. Methods: Patients with advanced solid tumors having received prior therapy, with adequate organ function, and performance status Zubrod 0–2, were eligible. TAS-102 was administered orally three times a day for 5 days a week for two weeks, followed by two weeks off. Courses were repeated every 4 weeks. Results: A total of 15 patients (8 female, age 37–72 years) were enrolled into the study; three at 60 mg/m2/day, 6 each at 70 mg/m2/day and 80 mg/m2/day. Nine patients had colorectal cancer, 2 carcinoma of unknown primary, 2 pancreatic cancer, one each medullary thyroid cancer and cholangiocarcinoma. Toxicity was assessed throughout all courses of therapy. Grade 3 and 4 hematological toxicities were the most common, including 3 episodes of grade 3 neutropenia at 60 mg/m2/day, 5 at 70 mg/m2/day, 5 at 80 mg/m2/day with only 1 instance of grade 3 thrombocytopenia at 80 mg/m2/day. Non-hematological grade 3 toxicities included nausea/vomiting (1 at 70 mg/m2/day), colitis, gout, and hematuria (1 each at 70 mg/m2/day), and fatigue (1 at 70 mg/m2/day and 2 at 80 mg/m2/day) Two episodes of dose-limiting toxicity were observed at 80 mg/m2/day: grade 3 fatigue and grade 4 neutropenia. Although there were no objective responses, nine patients (60%) maintained stable disease with a median duration of disease stabilization of 4.3 months (range, 1.9 to 8.6 months). Conclusions: TAS-102 is well tolerated with manageable hematologic toxicity and few non-hematological toxicities. The most common grade 3 or 4 toxicity was neutropenia. The suggested phase II dose of TAS-102 is 70 mg/m2/day when administered orally three times a day for 5 days a week for two weeks followed by two weeks off every 4 weeks. [Table: see text]
Dihydropyrimidine dehydrogenase deficiency (DPD) in GI malignancies: Experience of 4 years
Authors: Mehra R. , Mattison L. K. , Ledbetter L. , Ezzeldin H. , Diasio R. B. , Saif M. W. 
Published: March 2020

2056 Background: 5-Fluorouracil (5-FU) is an integral part of treatment of GI malignancies. While normal DPD enzyme activity is rate limiting in 5-FU catabolism, its deficiency could increase concentrations of bioavailable 5-FU anabolic products leading to 5-FU related toxicity syndrome. With DPD deficiency, 5-FU is discontinued. Data regarding safety of capecitabine (CAP) in this population is scarce. Methods: Patients were tested for DPD deficiency after excessive toxicities from 5-FU and CAP at UAB between 2001 and 2005. DPD activity was evaluated by PBMC radio assay, genotyping of DPYD gene by DHPLC, or 2-13C uracil breath test (UraBT). Results: Of 23 patients with GI malignancies (small intestine, gastric, pancreatic, HCC, and colorectal) evaluated, 7 (30%) were DPD deficient. Among these 7 patients, DPD activity ranged from 0.064 - 0.18 nmol/min/mg. Age ranged from 51–75 years, M:F ratio = 1.3:1, and ethnicities included Caucasian (71%), African-American (14%) and South-Asian (14%). Four were treated with 5-FU/LV (2 Roswell; 2 Mayo); 2 CAP (1800mg/m2); and 2 high dose bolus 5-FU (1400mg/m2) + PN401 (tri-acetyluridine). Toxicities included mucositis (71%), diarrhea (43%), nausea (29%), memory loss/altered mental status (43%), cytopenias (43%), hypotension (14%), respiratory distress (14%), acute renal failure (14%), and severe skin rashes (43%). Re-challenge with CAP in 1 patient after the Mayo regimen caused grade 3 HFS only on dorsal surfaces of hands. One patient on PN401 had a grade 3 facial rash as the worst toxicity. Genotypic analysis of the DPYD gene in the second on PN401, who had severe leucopenia, demonstrated a heterozygous mutation (IVS14+1 G>A, DPYP*2A). UraBT in 2 patients revealed 1 to be DPD-deficient (DOB50 of 112.8; PDR of 49.4%) and borderline normal values (DOB50 of 130.9; PDR of 52.5%) in a second patient. There were 2 toxicity-related deaths (28%): 1 on CAP and 1 on 5-FU + PN401. Conclusions: DPD deficiency was observed in several ethnicities. Patients with CAP toxicities should also be tested for DPD deficiency. Role of PN401 in rescuing 5-FU toxicity in DPD deficiency is not clear. Screening patients for DPD deficiency prior to administration of 5-FU or CAP, using UraBT, could potentially lower risk of toxicity. Future studies should validate this technique. [Table: see text]
Distribution of UGT1A1 (TA) polymorphisms in Caucasian and Asian subjects
Authors: Liu J. , Qu K. , Ren Y. , Sferruzza A. , Bender R. A. 
Published: March 2020

2063 Background: The hepatic isoform 1A1 of uridine diphosphate glucuronosyltransferase (UGT) is responsible for glucuronidation and detoxification of SN-38, the active metabolite of irinotecan. The presence of an additional TA repeat in the TATA sequence of the UGT1A1 gene is a common polymorphism, leading to a significant decrease in SN-38 glucuronidation. Patients with the UGT1A1 (TA)7 allele (either [TA]6/7 or [TA]7/7 ) are more likely to experience severe neutropenia and diarrhea following irinotecan chemotherapy. We assessed the distribution of the UGT1A1 (TA) polymorphism in Caucasian and Asian subjects. Methods: We used a fluorescent PCR-based assay to detect UGT1A1 (TA) polymorphisms in 129 healthy subjects (52 Caucasian, 34 Chinese, 36 Filipino, and 7 Japanese). The chi-square test was used to assess between-group differences in the distribution of UGT1A1 (TA) genotypes. Results: UGT1A1 (TA) genotype distribution differed significantly between Caucasian and Asian subjects (P = 0.003). The UGT1A1 (TA)6/7 and (TA)7/7 genotypes were more common in Caucasians than Asians. Genotype distributions did not differ significantly between men and women in either group ( Table ). Conclusions: The frequency of the deleterious UGT1A1 (TA)7 polymorphism was greater in Caucasians than in Asians; genotype frequencies were consistent with previous reports. In both groups, UGT1A1 (TA) genotype distributions were similar in men and women. [Table: see text] No significant financial relationships to disclose.
Phase I study of trabectedin (T) in combination with docetaxel (D) in patients with advanced malignancies
Authors: Von Mehren M. , Buck D. , Temmer E. , Elsayed Y. A. , Cohen R. B. 
Published: March 2020

2068 Background: T is a novel cytotoxic agent that binds to the DNA minor groove and is active in several tumor types. The objective of this study is to determine the maximum tolerated dose (MTD) of the combination. Other objectives include safety and efficacy. Methods: Eligible patients (pts) had advanced cancer, PS 0–1 and adequate organ function. Restricted pts were limited to 1 prior cytotoxic regimen, while unrestricted pts had no limit. On day 1 of each cycle, Pts received D starting at 60 mg/m2 over 1 hour followed by T starting at 0.4 mg/m2 over 3 hours. Dosing was repeated q 3 weeks. Incremental doses of both drugs were explored. PK samples were collected. A standard “3+3” dose escalation, definitions of dose limiting toxicity (DLT), and dose modifications were implemented. Results: To date, 31 pts have been treated, receiving 147 cycles (Range 1–28, median 6). At dose level 2 (D 60 mg/m2 + T 0.6 mg/m2), 2/4 unrestricted pts and 3/5 restricted pts developed DLT (grade IV neutropenia and/or febrile neutropenia) requiring institution of prophylactic filgrastim. Therapy was well tolerated after institution of filgrastim and no DLTs have been observed through the current dose level 6 (D 60 mg/m2 + T 1.3 mg/m2). Most frequently related grade 3 and 4 adverse events (AE) were: neutropenia (51%), elevated liver enzymes (3.7%), DVT (3.7%), and hyponatremia (3.7%). The most frequently related grade 1and 2 AEs were: fatigue (56%), neutropenia (56%), nausea (55%), and anemia (40%). Anti-tumor activity included a complete response in a pt with peritoneal Ca and durable prolong stable disease (SD) in 2 pts with sarcoma (20 + and 10 + months) and a pt with prostate Ca (8+ months). Another pt with gastric Ca achieved SD lasting 8 months. PK evaluations of D and T are ongoing. Conclusions: The combination of T and D with filgrastim support is safe and well-tolerated. Preliminary data suggest that this regimen is active in pts with advanced cancers. Additional cohorts are planned giving D 75 mg/m2 and T 1.3 mg/m2. [Table: see text]
Phase I clinical and pharmacological trial of trabectedin (T) in 3 hour infusion every 3 weeks (3h/q3w) in patients with advanced cancer and hepatic function disorder
Authors: Salazar R. , Pardo B. , Majem M. , García M. , Montes A. , Cuadra C. , Ciruelos E. , Cortés-Funes H. , Lebedinsky C. , Paz-Ares L. 
Published: March 2020

2080 Background: Trabectedin (ET-743) is a marine-derived DNA and transcription interacting agent with activity in pretreated soft tissue sarcoma, breast, prostate and ovarian cancer. T is associated with 2 types of liver function alterations: a frequent acute and reversible elevation of ALT and AST and a less frequent cholestasis, usually reflected by low grade increases in alkaline phosphatase (AP) and bilirubin (B). The main predictors of dose limiting toxicity (DLT) or T-related serious adverse events appear to include elevated baseline or intercycle peaks of AP, B and ALT > 5 × ULN (Gomez J, ASCO 2000). The objectives of this trial are to determine the maximum tolerated dose (MTD) and pharmacokinetics (PK) of T 3h/q3w in patients (pts) with advanced cancer and baseline liver dysfunction. Methods: All pts are stratified according to basal liver function as follows: STRATUM (S) I: ULN < AP ≤ 1.5 × ULN S II: 1.5 × ULN < AP ≤ 2.5 × ULN S III: AP > 2.5 × ULN All pts had to have AST and ALT ≤ 2.5 × ULN, albumin > 2.5 g/dl and B < 2.5 mg/dl. T concentrations in plasma are determined using a validated LC-MS/MS method. PK parameters were calculated by non-compartmental methods. Results: 32 pts were recruited.Median age: 54 years (26–76); PS≤1:28 pts; prior chemotherapy (CT): 31 pts (97%); median number of prior CT: 2 (1–6); B > ULN: 0 pts. In S I, T was administered at 1.1 mg/m2 (3 pts) and 1.3 mg/m2 (13 pts). Two DLTs were reported at 1.3 mg/m2: neutropenia G4 > 5 days with febrile neutropenia and G3 ALT not recovered by day +28. In S II no DLT occurred in 4 pts at T 0.9 mg/m2 nor 3 pts at T 1.1 mg/m2, 1 out of 4 pts at 1.3 mg/m2 suffered DLT: G3 AST not recovered by day +24. In S III one out of 2 pts at 0.9 mg/m2 had DLT: AP increase. Initial PK evaluation from S I and II (8 from each) showed a long half life (geometric mean (GM) S I: 124.6 h, S II: 118.8 h) and wide distribution (GM Vss S I: 2366 l/m2, S II: 3830 l/m2). GM clearance: 18.3 l/(hr*m2) in S I; 26.3 l/(hr*m2) in S II. Clearance is somewhat lower than in normal liver function population (GM under equal dexamethasone treatment 33.8 l/hr*m2) in study ET-B-010. Conclusions: The recommended dose (RD) of T for pts with mild AP elevations (< 1.5 ULN) and B levels < ULN is 1.3 mg/m2 3h/q3w. The study is ongoing to define the RD for S II and III [Table: see text]
Phase II trial of extended dose anti-CTLA-4 antibody ipilimumab (formerly MDX-010) with a multi-peptide vaccine for resected stages IIIC and IV melanoma
Authors: Weber J. S. , Targan S. , Scotland R. , Snively J. , Garcia M. , Yellin M. , Fischkoff S. , Nichol G. 
Published: March 2020

2510 Background: Ipilimumab is a human anti-CTLA-4 antibody shown to have clinical activity in melanoma and renal cancer that is associated with inflammatory-type adverse events termed immune breakthrough events (IBEs). Methods: 25 patients with resected stages IIIC/IV melanoma received MART-1/gp100/tyrosinase peptides with adjuvant Montanide ISA 51 12 times injected subcutaneously with Ipilimumab at 3 mg/kg intravenously every eight weeks for 12 months. The primary endpoints were toxicity and the achievement of a 40% rate of tolerable IBEs, and 20% or less rate of intolerable adverse events. Immune responses measured by ELISPOT and peptide-tetramer assays, and time to relapse were also assessed. The three melanoma peptides differed from wild type by one amino acid modification to increase HLA binding, and were administered at 1000 mcg/dose each. Results: Median age was 55, with 13 men and 12 women. 15 patients had stage IV, and 10 had stage IIIC resected disease. Thus far, 12/25 (48%) patients had grades 2–3 IBEs; 5 (20%) were dose limiting; 7 had GI toxicity, of which 2 were dose limiting; four had skin toxicity, of which 2 were dose limiting; one patient had hypopituitarism, which was also dose limiting. No patient with dose limiting toxicity required hospitalization and all returned to baseline status with the use of systemic steroids. Serologic assays of IBD-related microbial and auto-antibodies showed that seven of eight patients tested had increases in ANCA IgG or I2 IgA, and 5/8 had increases in ASCA IgA. Four of 25 patients have relapsed with a median of 10 months of follow-up. Two were again rendered NED surgically. The two remaining patients were treated with biochemotherapy, with one CR and one PR. All 25 patients are alive, one with disease. No patient with grade 2–3 IBEs has relapsed. ELISPOT assays showed that 10/11 patients tested responded in fresh PBMC to MART-1 and gp100. Conclusions: These data suggest that IBEs are associated with clinical benefit in patients with resected high-risk melanoma receiving Ipilimumab at 3 mg/kg with a peptide vaccine, and support testing the current regimen in a larger randomized trial. [Table: see text]
Clinical and immune responses of WT1-peptide vaccination in patients with acute myeloid leukemia
Authors: Keilholz U. , Letsch A. , Asemissen A. , Hofmann W. , Uharek L. , Blau W. , Thiel E. , Scheibenbogen C. 
Published: March 2020

2511 Background: The transcription factor Wilms tumor protein (WT) 1 belongs to a new generation of tumor antigens, as it is essential for tumor cell proliferation. WT1 is highly expressed both in myeloid leukemias and many carcinomas. This phase 2 proof-of-concept trial was initiated to determine immunogenicity and toxicity of vaccination with a novel HLA-A2-restricted WT1 peptide vaccine. Methods: Sixteen HLA-A2-positive patients with acute myeloid leukemia and one patient with myelodysplasia received 3–18 vaccinations (median 8) of WT1. 126–134 peptide (0.2 mg) together with the T helper protein keyhole limpet hemocyanin (1 mg) and in addition GM-CSF (75 mcg for four days) and. Twelve patients had elevated blast counts at study entry and 5 patients complete remission with high risk for relapse. Results: Six of 12 patients with presence of leukemic blasts had evidence of antileukemic activity. One patient achieved complete remission for 12 months. The patient with myelodysplasia RAEB II had a major response of neutrophils and platelets. Two patients had minor responses with transient clearance of peripheral blasts or improvement of hematopoiesis, and two patients achieved disease stabilization for 3 and 14 months. WT1 transcripts as molecular disease marker decreased in 5 of these 6 patients and also in 4 of 5 high-risk patients. No significant toxicity occurred. The generation of a WT1-specific T cell response in peripheral blood and bone marrow was detected in 9 of 13 patients by tetramer analysis and 8 of 13 patients by intracellular cytokine staining. Conclusion: These results show that WT1 vaccination can induce functional T cell responses associated with antileukemic activity and warrant trials of WT1 vaccination in patients at high risk of relapse and with WT1-expressing carcinomas. No significant financial relationships to disclose.