bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II trial of nemorubicin hydrocloride (nemorubicin) in combination with cisplatin (cDDP) in patients (pts) with hepatocellular carcinoma (HCC): First step results
Authors: Izzo F. , Catino A. M. , Vogl T. J. , Middleton M. , Valle J. W. , Fiore F. , Gadaleta C. D. , Pirotta R. M. , Martignoni M. , Laffranchi B. 
Published: August 2020

4593 Background: Nemorubicin is a novel DNA-intercalator, mainly metabolized in liver by CYP3A4 enzyme and showing synergic antitumor activity with cDDP. The objective of this study was to evaluate the efficacy and adverse effects of nemorubicin administered by intra-hepatic artery in combination with cDDP to unresectable HCC pts. Methods: The study was in two HCC pt populations: intermediate risk (IRP) (CLIP 0–1, bilirubin < 1.5 x upper normal limit, no portal vein thrombosis [PVT]) and advanced risk (ARP) (CLIP 2, bilirubin < 2.5 mg/dL, PVT admitted). Treatment was repeated every 4–6 weeks for a maximum of six courses, if no toxicity and disease progression occurred. A single-arm, Simon's minimax two-stage design was adopted to evaluate the primary endpoint of tumour response (WHO criteria). In the first step >5/18 responses (IRP) and >2/10 responses (ARP) are needed to proceed with the second step. Results: Twenty-three IRP pts (13 evaluable) and 13 ARP pts (10 evaluable) were enrolled. The median number of treatments was 3 (range 1–6) in IRP (dose 600 mcg/m2 nemorubicin and 60 mg/m2 cDDP) and 4 (range 1–4) in ARP (dose 400 mcg/m2 nemorubicin and 60 mg/m2 cDDP). In IRP, so far 1 pt (8%) achieved complete response, 3 pts (23%) had partial response (PR), 5 pts (38%) had minor response (MR)/disease stabilization (SD) >3 months. In ARP, 2 pts (20%) had PR, satisfying the first step efficacy criteria. Also, 2 ARP pts (20%) had MR/SD. Overall, the main grade 3 and 4 hematological toxicities were thrombocytopenia (47%), leukopenia (42%), anemia (12%) and neutropenia (6%). Grade 3 and 4 biochemical alterations were aspartate aminotranferase (29%) alanine transferase (24%) and bilirubin increase (12%). The most frequent adverse events were fatigue (35%), vomiting (29%), diarrhoea (24%) and nausea (18%). Conclusions: Hepatic arterial infusion of nemorubicin with cisplatin showed promising activity in the first step of the study and it was a well tolerated regimen. These encouraging results warrant further development in HCC pts. No significant financial relationships to disclose.
Impact of lymph node evaluation on survival for small bowel adenocaricnoma: Analysis of the Surveillance, Epidemiology and End Results (SEER) database
Authors: Overman M. J. , Hu C. , Wolff R. A. , Chang G. J. 
Published: August 2020

4596 Background: Small bowel adenocarcinoma is a rare malignancy and is often associated with poor outcome. The impact that the number of positive and negative lymph nodes (LN) have upon survival following curative resection has not been studied. Methods: Patients aged 18–90 with adenocarcinoma of the small intestine diagnosed between 1988 and 2005 were identified from SEER data (ver. 2008). Disease-specific survival (DSS) outcomes were determined through 12/2005. Cox proportional hazards regression analyses were performed after adjusting for age, sex, race, T stage, grade, and primary site. Stage I-II cases were categorized by total LN examined (1–8, 9–12, and >12). Stage III cases were evaluated using cut-point analysis to determine the number of positive LN that predicted outcomes. This result was then compared to the predictive value of the ratio of positive to total LN (LNR) using the chi-square statistic. Results: 1,991 patients were identified in the SEER database. Survival among stage I/II patients (n=1,216) was dependent upon the total number of LN assessed. 5-year DSS for stage II patients was 66%, 82% (HR 0.52 95% CI .33-.84), and 88% (HR 0.38, 95% CI .23-.61) for 1–8, 9–12, >12 LN, respectively. The optimal cutpoint of positive LN for stage III disease (n=775) was <3 compard to ≥3 with 5 year DSS of 58% vs. 37% (HR 1.49, 95% CI 1.15–1.92, P=0.002), respectively. Among stage III patients, the LNR was even more predictive of survival than stratification by the number of positive lymph nodes as demonstrated by an improved chi-square statistic for the multivariate model (78.8 vs 63.1, P=0.0005). Conclusions: As noted in colon cancer, the total number of LN assessed has considerable influence upon survival in stage I, II and III small bowel adenocarcinoma. Stratifying stage III small bowel adenocarcinoma into those with <3 and ≥3 positive lymph nodes significantly improves prognostication for these patients and future staging systems should incorporate the number of positive nodes into nodal staging. The use of LNR may provide additional prognostic information. No significant financial relationships to disclose.
A randomized phase III study of gemcitabine (G) versus GV1001 in sequential combination with G in patients with unresectable and metastatic pancreatic cancer (PC)
Authors: Buanes T. , Maurel J. , Liauw W. , Hebbar M. , Nemunaitis J. 
Published: August 2020

4601 Background: A phase I/II study with GV1001, a telomerase peptide vaccine, showed a median overall survival (OS) of 8.6 months in non-resectable PC (Bernhardt SL et al, Br J Cancer. 2006;95:1474–1482). This phase III trial was conducted to determine the impact on overall survival of G monotherapy vs. GV1001 in sequential combination with G in unresectable and metastatic PC. Methods: Eligible patients (pts) had chemotherapy-naive, advanced PC and ECOG performance status 0–1. Pts were randomized 1:1 to receive arm A: G (1,000 mg/m2 30 min i.v.) weekly for 7 weeks (w), 1w off and then 3w during 4-weekly cycles, or arm B: GV1001 0.56 mg s.c. plus GM-CSF as immune adjuvant on days 1, 3, 5, 8, 15, 22, 36, then every 4 weeks. Patients who progressed clinically or radiologically during GV1001 continued on GV1001 and concomitant gemcitabine. CT scans were performed every 8 weeks. The primary end-point was OS. A sample size of 520 patients allowed the detection of a hazard ratio (HR) of 0.73 (B/A), with 2α = 0.05 and 90% power. Results: Between June 2006 and May 2008, 365 pts were enrolled (A / B; 182 / 183). The study was stopped prematurely due to a preliminary analysis with 178 events showing no survival benefit of GV1001. Pts were well balanced for baseline characteristics: male 59.3% / 62.8%; median age 61y / 61y; ECOG PS 0 34.3% / 36.7%; locally advanced 22.4% / 20.7%. As of August 2008, 238 pts (A / B : 114 / 124) had died. Median OS was 7.3 / 5.9 months (HR 0.8; 95% CI 0.6–1.0). Median progression-free survival (PFS) was 3.7 / 1.9 months (HR 0.5; 95%CI 0.4–0.7). Grade 3–4 AEs: gastrointestinal 6% / 8%, infection 5% / 5%, vascular disorders 2% / 3%, neutropenia 6% / 3%. Conclusions: GV1001 did not show efficacy in sequential combination with G in advanced PC. The advantage of G monotherapy over the sequential combination may be due to the delayed treatment with G in arm B. [Table: see text]
Preclinical identification of biomarkers of response to mTOR inhibitors and subsequent application in a phase II trial of sirolimus in pancreatic cancer patients refractory to gemcitabine
Authors: Garrido-Laguna I. , Rudek M. , Tan A. , Uson M. , Iacobuzio-Donahue C. , Angenendt M. , Jimeno A. , Laheru D. , Barret M. , Hidalgo M. 
Published: August 2020

4612 Background: Treatment for advanced pancreatic cancer refractory to gemcitabine has not been defined. We conducted an efficacy study in pancreatic cancer xenografts to identify biomarkers of response to mTOR inhibition and attempted to translate the results by conducting a phase II trial of sirolimus in this patient population. Methods: 19 direct pancreatic xenografts were treated with temsirolimus (20mg/Kg IP daily) for 28 days. Tumors were profiled with array CGH and gene expression arrays at baseline. TGI were calculated at 28 days. Patients refractory to gemcitabine were included in the clinical trial. Sirolimus was administered at 5mg/day for 28 days. Primary endpoint was 6 month survival rate (6mSR). Secondary endpoints included: baseline evaluation of AKT pathway activation, pharmacodynamic assessment of p-S6K in PBMC, pharmacokinetics and toxicity analysis. Results: In the preclinical study, mTOR sensitive tumors showed upregulation of genes involved in the renal cell cancer pathway. CGH identified focal gains in N-Ras and K-Ras and homozygous deletions of FHIT in sensitive cases. Overall, these genetic changes induced AKT pathway activation, and led us to explore high baseline p-S6K expression as a predictor of outcome in the clinical phase. Patient characteristics: Median age: 64 (39–77). 11 patients had received ≥ 2 prior lines of chemotherapy. 6mSR was 20%. 6mSR in the subgroup of patients who received rapamycin as first line chemotherapy after progression to gemcitabine was 34%. Baseline tumor p-S6K was not predictive for survival. Early pharmacodynamic changes in p-S6K in PBMC 6 hours after treatment initiation were correlated with survival (R2= 0.65). Treatment was well tolerated. The most common grade 3 adverse event was hyperglycemia in 10% of the patients. 7 (23%) patients achieved stable disease. Conclusions: Rapamycin is well tolerated in this setting. Early pharmacodynamic changes in p-S6K in PBMC were correlated with survival. Preclinical findings leading to activation of the AKT pathway in all sensitive cases warrants further validation studies. Efficacy data is limited by the selection of a heavily pretreated and poor prognosis population (DFS≤47 days). No significant financial relationships to disclose.
GOFURTGO trial (GFG): An AGITG multicenter phase II study of fixed dose rate gemcitabine-oxaliplatin (Gem-Ox) integrated with concomitant 5FU and 3-D conformal radiotherapy (5FU-3DRT) for the treatment of locally advanced pancreatic cancer (LAPC)
Authors: Goldstein D. , van Hazel G. , Selva-Nayagam S. , Ackland S. , Shapiro J. , Carroll S. , Cummins M. , Brown C. , Simes R. J. , Spry N. 
Published: August 2020

4616 Background: Our previous study of Gem with sandwich 5FU-3DRT for LAPC was encouraging (Br J Cancer 2007: 97, 464–471). Gem-Ox has higher response rate than Gem, improved progression free survival (PFS) but not overall survival (OS). Its use in LAPC may improve local control (LC) and delay systemic spread. GFG is a study of induction (ind) Gem-Ox, then 5FU-3DRT, then consolidation (con) Gem-Ox. Primary outcome is feasibility using proportion of patients (pts) receiving > 80% planned dose for each component. Secondary outcomes are safety, activity and QOL. Methods: Pts with previously untreated inoperable LAPC, M0, measurable disease, ECOG 0–2 were given Gem (1000mg/m2 d1 + d15 q28), Ox (100mg/m2 d2 + d16 q28) in both ind (1 cycle) & con (3 cycles), & 5FU 200mg/m2/d over 6 weeks during RT of 54Gy in 30 fractions of 1.8Gy. Results: 48 pts were enrolled, median age 61y (44–81y), PS 0/1=96%, regional lymph nodes=44%, T4=46%. Worst grade (G) for anaemia (10%); fatigue, nausea (8%); diarrhoea, vomiting, neutropenia, infection (4%); stomatitis, anorexia (2%) was G3. Thrombocytopenia was G3=2% G4=2%; liver function was G3=23% G4=6%; late radiation toxicity was G3=2% G4=2% (both gastric bleeding). Half of all pts completed all planned cycles (24 pts); 29% of pts received >80% of all treatment (14 pts); 70% of pts received >80% of all chemoradiation (33 pts). Pts ceased treatment for toxicity (16%), PD (21%) or doctor/pt preference (4/2%). Global QOL did not significantly change from baseline. Median duration of LC, PFS, OS were 15.8, 9.9, 15.4m at median follow up of 29.7m. Exploratory analysis of age, disease stage, PS, CA19–9 or WCC found no univariate predictors of PFS or treatment completion. 8/48 pts survived >24m. Conclusions: Compared to our previous study using the same radiation schedule, addition of oxaliplatin was associated with improved LC, PFS & OS (prev. 11.9, 7.1 & 11.7m) without significant offset by toxicity. The extended duration of LC and a subset who had a very prolonged benefit may be due to patient selection but equally may suggest an incremental benefit from more intensive systemic therapy requiring further study in controlled trials. [Table: see text]
Detection of circulating hypoxia-regulated miR-210 in pancreatic adenocarcinoma patients
Authors: Ho A. S. , Huang X. , Cao H. , Koong A. C. , Le Q. T. 
Published: August 2020

4624 Background: MicroRNAs (miRs) are small non-coding transcripts involved in many cellular mechanisms, including tumorigenesis. miR-210, in particular, has been shown to be induced by hypoxia, over-expressed in several different cancers, and correlated with adverse outcomes in breast cancer. Moreover, since pancreatic adenocarcinomas have been previously shown to be extremely hypoxic, we hypothesized that miR-210 may be elevated in the plasma of these patients compared to non-cancer controls. Here, we compared the circulating plasma levels of miR-210 in pancreatic cancer patients and controls using a novel miRNA extraction approach and quantitative PCR. Methods: Pretreatment EDTA plasma samples were obtained from pancreatic cancer patients and age-matched non-cancer controls. miRNA was extracted from 40ul of plasma and reverse transcribed to cDNA. A known quantity of c. elegans miR-54 was added to the sample as a normalization control. miR-210 and cel-miR-54 were then quantified using TaqMan MicroRNA Assays. The procedure was performed on the initial 11 pairs of age-matched pancreatic cancer patients and non- cancer controls, then validated with a second cohort of 12 pancreatic cancer patients and 11 controls. Results: miR-210 was reliably detected and quantified in small amounts of plasma using the approach developed in our study. There is a statistically significant four-fold increase of mir-210 expression in pancreatic cancer patients compared to normal controls (Student's t-test, p <0.0001). This difference was confirmed in the validation group (Student's t-test, p<0.05). Conclusions: Circulating miR-210 levels can be readily measured from a small quantity of plasma using a novel extraction method. Its expression is significantly higher in the blood of pancreatic cancer patients compared to controls and may potentially serve as a useful biomarker for pancreatic cancer diagnosis. No significant financial relationships to disclose.
Pharmacodynamic (PD) study of pre-prostatectomy rapamycin in men with advanced localized prostate cancer (PC): A DOD Prostate Cancer Clinical Trials Consortium Trial
Authors: Netto G. , Armstrong A. , Wood D. , Creel P. , Partin A. , Jimeno A. , Rudek M. , George D. , Gurganus R. , Carducci M. A. 
Published: August 2020

5001 Background: Rapamycin is an orally bioavailable and generic mTOR inhibitor with an MTD of 6 mg daily and anticancer activity in solid tumors. We sought to determine the optimal biologic dose (OBD) in the pre-operative setting in men with PC. Methods: We explored the safety and PD activity of 3 and 6 mg of daily oral rapamycin for 14 days prior to radical prostatectomy (RP) in cohorts of 21 men with intermediate risk localized PC. Ten untreated control subjects were included using identical inclusion criteria. Men had Gleason >6 PC involving multiple cores. PD markers in pre-treatment prostate biopsies and RP specimens included p-S6 and p-Akt, 4EBP-1, PTEN, p27, Ki-67, and cleaved caspase-3. Tissue and whole blood sirolimus levels were measured. A Simon 2-stage design using PD efficacy (tumor S6 inhibition > 60%) was utilized. Results: 32 subjects were accrued to this 2 stage pharmacodynamic trial, including 10 control subjects. Median pre-treatment PSA was 6.4 ng/dl, age 60y, Gleason 7 in 85%. 20 accrued to the 3 mg cohort without DLT. However, 2/2 men enrolled at the 6 mg dose level experienced DLT consisting of thrombocytopenia leading to a delay in surgery (<100K) and fever with grade 3 stomatitis. AEs observed in the 3 mg cohort included stomatitis (2), rash (1), post-operative ileus (2), and mild neutropenia (2). One post-operative ileus was observed among control patients. PD studies demonstrated tumor S6 inhibition in >50% of subjects (median 60% decline, p=0.026 vs. baseline) with no negative effect on the state of Akt phosphorylation (p=0.82) or p27 levels (p=0.10). Prostate sirolimus levels (range 7.1–47.2 ng/g) were two-fold higher than whole blood concentrations (range 3.2–19.2 ng/ml). There was no effect of rapamycin on rates of post-operative wound healing or bleeding. PBMC S6 activity inhibition did not correlate with tumor S6 inhibition. Conclusions: The MTD/OBD of daily rapamycin in the pre-operative or prevention setting is 3 mg. This dose demonstrated downstream mTOR inhibition in tumor tissue and achieved adequate prostate tissue levels. Additional PD and genomic studies will be presented. Conducted through the DOD PCCTC and registered at clinicaltrials.gov as NCT00311623 . [Table: see text]
Increased expression of androgen receptor (AR) and enzymes involved in androgen synthesis in metastatic prostate cancer: Targets for novel personalized therapies
Authors: Mitsiades N. , Schultz N. , Taylor B. S. , Hieronymus H. , Satagopan J. , Scardino P. T. , Reuter V. E. , Sander C. , Sawyers C. , Scher H. I. ,   Prostate Cancer Genome Project Group
Published: August 2020

5002 Background: Androgen receptor (AR) signaling remains active in castration-resistant prostate cancer (CRPC) despite castrate levels of circulating androgens. This is indicated by continuous expression of androgen-responsive genes and is due to mechanisms that include: increased AR expression; AR mutations allowing promiscuous activation by alternative ligands; and increased intratumoral androgen levels, resulting from in situ steroidogenesis. Methods: Gene expression profiles of 30 normal prostate tissue samples, 131 primary prostate carcinomas (PCas) and 16 metastatic PCas, generated using Affymetrix Exon arrays, were interrogated for levels of 40 mRNAs encoding AR, SHBG, 28 enzymes involved in androgen synthesis and 10 enzymes involved in androgen inactivation. For individual tumors, a transcript was considered to be overexpressed or underexpressed when its levels were >2 SDs higher or lower, respectively, than its average levels in normal tissue. Results: Metastatic PCas expressed higher average transcript levels for AR and several steroidogenic enzymes, including SRD5A1 and SRD5A3, than primary PCas and normal prostate tissue. Expression of SRD5A2, CYP3A4, CYP3A5, and CYP3A7 mRNAs was decreased both in primary and metastatic tumors compared to normal prostate tissue. In analysis involving AR and 28 steroidogenic transcripts in individual tumors, all (16/16) metastatic PCas overexpressed at least one transcript (range: 2–14, median: 5 transcripts) compared to normal tissue, while 100/131 (76%) primary PCas overexpressed at least one transcript (range: 2–16, median: 2). Conclusions: Metastatic PCas overexpress AR and several steroidogenic enzymes, while they express lower levels of the androgen-inactivating enzymes CYP3A4, CYP3A5, and CYP3A7. These data highlight the role of AR and the androgen synthetic pathway as a therapeutic target in CRPC. Novel antiandrogens (MDV3100) and CYP17 inhibitors (abiraterone) are already in clinical trials in CRPC. Overexpression of AR or steroidogenic enzymes may serve as a biomarker (e.g. by detection via RT-PCR in circulating tumor cells) to predict for sensitivity to these agents and guide patient selection for participation in clinical trials. No significant financial relationships to disclose.
VEGF single nucleotide polymorphisms (SNPs) and correlation to sunitinib-induced hypertension (HTN) in metastatic renal cell carcinoma (mRCC) patients (pts)
Authors: Kim J. J. , Vaziri S. A. , Elson P. , Rini B. I. , Ganapathi M. K. , Ganapathi R. 
Published: August 2020

5005 Background: VEGF SNPs (-634 C/C and -1498 T/T) have been associated with protection from grade III/IV HTN in breast cancer pts receiving bevacizumab plus paclitaxel (J Clin Oncol. 26:4672–4678). The aim of this study was to retrospectively evaluate the association among VEGF SNPs and the development of HTN in mRCC pts receiving sunitinib. Methods: mRCC patients receiving sunitinib (50mg 4/2) with available blood pressure (BP) data and germline DNA were retrospectively identified. All BP measurements were recorded in clinic approximately every 4 weeks. Genomic DNA was isolated from peripheral blood lymphocytes. VEGF SNP's -634 C/G (5’UTR polymorphism, NCBI reference sequence #2010963), and -1498 C/T (promoter polymorphism NCBI reference sequence #833061) were amplified using primers designed to flanking sequences for the respective SNPs. Genotypes were assigned following sequence analysis. Data were analyzed using parametric and non-parametric methods. Results: Sixty-four patients were identified of which 63 had available SNP data; 78% were male; median age was 60 (range 35–80); 67% ECOG performance status of 0; 89% prior nephrectomy and 63% previously treated with cytokines (48%) and/or a TKI (24%). Median systolic and diastolic BPs at baseline were 139 mmHg (range, 93–190) and 80 mmHg (range, 47–103), respectively; 57% of patients were being treated with anti-hypertensive therapies at baseline. The distribution of pts for the VEGF-634 genotype was C/C (10%), C/G (33%) and G/G (57%). VEGF-634 C/C < C/G < G/G genotypes were associated with increasing frequency and duration of HTN (diastolic > 90 mmHg and/or systolic > 150 mmHg) during treatment with sunitinib (p = 0.03 and p = 0.007, respectively) and remained significant adjusting for baseline BP and use of anti-HTN meds (p = 0.05 and 0.02, respectively). Similar correlations were not found for VEGF-1498 genotypes. There was no association between VEGF SNPs and tumor volume reduction or PFS. Conclusions: VEGF SNP-634 G/G genotype is correlated with HTN during treatment with sunitinib in mRCC pts. [Table: see text]
Outcomes of conservatively managed localized prostate cancer
Authors: Lu-Yao G. , Albertsen P. C. , Moore D. F. , Lin Y. , Shih W. , Barry M. J. , Zietman A. , O’Leary M. , Walker-Corkery E. , DiPaola R. S. , Yao S. 
Published: August 2020

5010 Background: The natural history of screen-detected prostate cancer has not been well described. Methods: Cancer-specific and overall mortality, assessed through competing risk analyses, were determined for 14,516 men aged 65 years or older diagnosed between 1992–2002 and did not receive surgery or radiation within 6 months of cancer diagnosis. The population-based cohort was identified from US cancer registries, which had 98% completeness in case ascertainment. Results: Compared to earlier era studies, survival has improved considerably for conservatively managed patients diagnosed in the contemporary prostate specific antigen (PSA) era ( Table ). Conclusions: Men diagnosed with prostate cancer in the PSA era have survival outcomes significantly better than those in the past. Patients and healthcare providers may need to reassess some treatment options in light of these data. [Table: see text] No significant financial relationships to disclose.