bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intratumoral lactate dehydrogenase 5 (LDH5) protein expression is associated with expression of angiogenesis markers and hypoxia in patients with colorectal cancer (CRC)
Authors: Koukourakis M. I. , Giatromanolaki A. , Sivridis E. , Gatter K. C. , Harris A. L. , Trarbach T. , Folprecht G. , Shi M. M. , Meinhardt G. 
Published: March 2020

4107 Background: Recent clinical trials (CONFIRM 1 and CONFIRM 2) have shown that metastatic CRC patients (pts) with high serum lactate dehydrogenase (LDH) derive the greatest therapeutic benefit from PTK787/ZK 222584 (PTK/ZK). PTK/ZK is a novel, oral tyrosine kinase inhibitor (TKI), which blocks all known VEGF receptors (VEGFR). From previous studies, total LDH and isoenzyme LDH5 have been associated with tumor aggressiveness and hypoxia. In the present study, we tested whether CRC pts with high levels of tumor LDH5 have increased expression of proteins involved with hypoxia (hypoxia inducible factors [HIF1a and 2a], pyruvate dehydrokinase [PDHK]), increased vessel density (VD), angiogenesis (VEGFA; phosphorylated VEGFR2 [pKDR]), acidity (carbonic anhydrase 9 [CA9]), and others. Methods: Baseline sections from either primary or metastatic tumor sites from 42 pts of the CONFIRM 1 and 2 trials were analysed with immunohistochemistry utilizing an established nominal scoring system. The degree of association between the scores of protein expressed was estimated by the phi-coefficient (correlation coefficient) and assessed by means of p-values from pairwise Fisher’s exact test (two- sided). Results: Associations were observed between LDH5 and the following: pKDR (Phi=.53; p<.001), VEGF (Phi=.41; p=.006), HIF-1a (Phi=.56; p<.001), VD (Phi=.34; p=.052), and PDHK (Phi=.58; p=.014), respectively. HIF-1a associated with pKDR (Phi=.38; p=.027), VD (Phi=.34; p=.045), and VEGFA (Phi=.33; p=.067). VEGFA associated with PDHK (Phi=.52; p=.035). Conclusions: Our results demonstrate that mCRC patients with high level of intratumoral protein expression of LDH5 have elevated HIF-1a, pKDR, VEGFA, PDHK expression and VD. These results support the concept that tumor hypoxia and angiogenesis are associated and that elevated LDH protein expression may serve as a surrogate marker for activated HIF-1a pathway. No significant financial relationships to disclose.
Quantitative multiplex PCR analysis for large rearrangements in the MLH1 and MSH2 genes for hereditary non- polyposis colorectal cancer
Authors: Roa B. , Judkins T. , Hendrickson B. , Eliason K. , Schoenberger J. , Rajamani S. , Scholl T. , Colvin C. 
Published: March 2020

4109 Background: Hereditary non-polyposis colon cancer (HNPCC) is caused by germline mutations in the mismatch repair genes MLH1, MSH2, MSH6 and PMS2. HNPCC patients have ∼80% increased risk of colon cancer, and elevated risk for cancers of the endometrium, ovary, stomach, small intestine and upper urinary tract. Molecular genetic testing in HNPCC families showed that ∼90% of cases are due to MLH1 and MSH2, 7–10% to MSH6, and <5% to PMS2. The majority are point mutations detectable by sequencing; however, about 5% and 20% of mutations in MLH1 and MSH2, respectively, are large rearrangements that require other detection techniques such as Southern blot or multiplex ligation-dependent probe amplification (MLPA). Our laboratory had previously developed and implemented a quantitative multiplex PCR (QMPCR) endpoint assay for clinical testing for large rearrangements in the BRCA1 and BRCA2 genes. We have developed a similar assay for the MLH1 and MSH2 genes in HNPCC which we refer to as CART (Colorectal cancer Rearrangement Test). Methods: CART consists of 9 multiplexes of 8–12 amplicons each, with at least 2 amplicons targeting each coding exon, promoter, and 3’UTR of both genes. Copy numbers are normalized against MLH1, MSH2, and two unlinked control genes. Internally developed software provides automated analysis and statistical confidence levels for the presence or absence of large rearrangements. Results: Initial validation of CART has been performed on 14 MLH1 or MSH2 rearrangement-positive and 30 negative DNA samples. Results were 100% concordant with previous Southern blot data, as well as supplemental MLPA studies. CART has greatly improved turnaround time, accuracy, and consistency compared to Southerns and MLPA. Conclusions: QMPCR is a superior diagnostic tool for detecting large rearrangements in disease genes. Validation of CART for MLH1 and MSH2 rearrangements is underway on a larger set of previously genotyped samples in a blinded manner. In conjunction with sequencing of the MLH1 and MSH2 genes, the CART assay is expected to improve molecular diagnostic testing on individuals at risk for HNPCC. No significant financial relationships to disclose.
Statin use is associated with a reduced risk of colon cancer recurrence
Authors: Anderson D. M. , Jackson J. , Butani A. , Asche S. , Rolnick C. 
Published: March 2020

4114 Background: A significant body of data suggests that statin use reduces the risk of developing colon and other cancers, although other data have not confirmed these findings. We examined whether statin use helps prevent recurrence of colon cancer in patients with resected disease. Methods: We conducted a retrospective analysis of patients treated for stage I, II, and III colon cancer in a Minneapolis/St. Paul health system. Incident cases of colon cancer between 1995 and the present were identified through a hospital tumor registry. All identified cases were then cross-checked against an HMO membership database. Data regarding statin use was pulled from the HMO outpatient pharmacy database. For each patient all available data from a 5-year window prior to first diagnosis of cancer until either recurrence or most recent data available was obtained. Demographic data and survival data from the tumor registry were then combined with pharmacy data regarding statin use in a single database for analysis. Recurrence and time to recurrent disease were compared in statin users and non-users. Results: A total of 358 colon cancer cases were available for analysis. Median follow up of patients after diagnosis of colon cancer was 49 months. 89 patients (24.9%) used statin drugs for some period of time with a median of 780 days of use. Median age of all patients enrolled was 69 (range 24–95). Statin use was higher in patients ages 61–75 (33%) than in those aged 24–60 (22%) or those aged 76–95 (19%) (p=0.02). There was no association between statin use and stage at diagnosis. 6 of 89 patients (6.7%) with any statin use relapsed as opposed to 43 of 269 (16%) of patients with no statin use (Fisher’s exact p=0.03). Kaplan-Meier analysis of relapse curves found a significant difference in relapse between groups with a two year recurrence rate of 3.7% among statin users and 10.1% among non users (Log Rank p=0.03, using age stratification). Conclusions: Statin use was associated with a decreased risk of recurrence in patients diagnosed with stages I-III colon cancer in this study. Further study of statin use in the prevention of colon cancer recurrence is warranted. No significant financial relationships to disclose.
Use of sex-specific genomic profile to predict clinical outcome in metastatic colorectal cancer (mCRC) patients treated with 5- fluorouracil/oxaliplatin
Authors: Gordon M. A. , Zhang W. , Yang D. , Nagashima F. , Chang H. , Lurje G. , Borucka E. , Lenz H. J. 
Published: March 2020

4122 Background: There is increasing evidence that gender plays a significant role in the development and progression of colorectal cancer (CRC). Rates of CRC incidence are higher among males, and it has been shown that hormone replacement therapy in postmenopausal women reduces the risk of developing CRC, indicating a protective effect of female hormones. These findings indicate that physiological differences between the sexes may contribute to differential tumor development and progression. In the current study, we tested the hypothesis whether males and females would have different genomic profiles that would predict clinical outcome in 5-FU/oxal-treated mCRC. Methods: One hundred seventy-three patients were enrolled in this phase II study. One hundred fifty-two patients were evaluable for genotyping and statistical analysis. There were 74 females and 78 males, and median age was 60 (range 25–87). Twenty-four polymorphisms in 12 genes involved in cancer progression were tested by PCR. CART analysis was used to test for association of polymorphisms with overall survival (OS), time to tumor progression (TTP), and tumor response. Separate regression trees were developed for males and females. Results: Median follow-up was 18.6 months, response rate 19%, median time to tumor progression 4.2 months and median survival 10.3 months. CART analysis by gender generated significantly different regression trees for men versus women. For TTP, males carrying polymorphisms in the ER-β and SCN1A genes had improved TTP, while females carrying polymorphisms in the XPD and EGFR genes had improved TTP. For OS, male patients carrying ER-β and MTHFR polymorphisms had improved OS, while female patients carrying polymorphisms in SCN1A and PLA2 had improved OS. It is notable that analysis of males and females in combination produced a different regression tree than when separated by gender. Conclusions: Our results suggest for the first time that genomic profiling to predict clinical outcome of patients with mCRC depends on gender. Taking gender into account when examining the genetic profile of patients may help to more specifically identify those who will benefit from 5-FU/oxal chemotherapy. No significant financial relationships to disclose.
Safety of panitumumab, a fully human monoclonal antibody against the epidermal growth factor receptor (EGFr), in patients (pts) with metastatic colorectal cancer (mCRC) across clinical trials
Authors: Peeters M. , Van Cutsem E. , Berlin J. , Hecht J. R. , Ruiz R. , Navale L. , Amado R. , Meropol N. J. 
Published: March 2020

4138 Background: Panitumumab is indicated in pts with EGFr-expressing mCRC refractory to chemotherapy. We present a summary of safety with panitumumab monotherapy in mCRC pts across 10 clinical trials. Methods: Data were pooled from pts enrolled in 10 clinical trials (including 2 extension studies). Pts received at least 1 dose of panitumumab at 2.5 mg/kg QW, 6 mg/kg Q2W, or 9 mg/kg Q3W. Adverse events were graded using NCI-CTC or CTCAE criteria. Results: A total of 920 mCRC pts were included in this analysis: 60% were male; 88% were white; median age (range) was 61 (20, 88) years. All pts had prior therapy; 77% had failed prior fluoropyrimidine, irinotecan, and/or oxaliplatin. Most (80%) pts received panitumumab 6 mg/kg Q2W; 17% and 3% of pts received panitumumab 2.5 mg/kg QW and 9 mg/kg Q3W, respectively. Median (range) follow-up time was 21 (1–124) weeks. A total of 7264 panitumumab infusions were administered with a median (range) of 5 (1–94) infusions/pt. Treatment-related adverse events (AE) were experienced by 94% (grade = 3, 20%) of pts. All pts had = 1 AE. The most common AEs were skin-related and GI toxicities ( table ). Skin-related AEs resulted in discontinuation in 2% of pts. Overall, 12% of pts discontinued panitumumab due to toxicity. Four (0.4%) pts had grade = 3 infusion reactions. In pts with postdose samples (n = 613), increased and persistent postdose levels of anti-panitumumab antibodies were detected in 0.5% of pts by ELISA and in 4.6% of pts by Biacore assay. Conclusions: Skin toxicity was common, but rarely treatment-limiting. Most AEs were mild to moderate and infrequently resulted in discontinuation. Infusion reactions and formation of anti-panitumumab antibodies were rare. The safety profile of 9 mg/kg Q3W panitumumab appeared consistent with other dosages; however, because of the small pt size further evaluation is needed. Panitumumab at 2.5 mg/kg QW and 6 mg/kg Q2W was well tolerated across 10 clinical studies. [Table: see text] No significant financial relationships to disclose.
Phase II trial of irinotecan/docetaxel for advanced pancreatic cancer with randomization between irinotecan/docetaxel and irinotecan/docetaxel plus C225, a monoclonal antibody to the epidermal growth factor receptor (EGF-r) : Eastern Cooperative Oncology
Authors: Burtness B. A. , Powell M. , Berlin J. , Liles D. , Chapman A. , Mitchell E. , Benson A. B. ,   Eastern Cooperative Oncology Group
Published: March 2020

4519 Background: Gemcitabine (G) is standard for metastatic pancreatic cancer (PC), with median survivals of 6 months (m). Second cytotoxic or biologic agents do not substantially advance survival. EGFR is expressed on PC and a phase II trial of G plus cetuximab (C) resulted in favorable 1 year survival. A phase II trial of irinotecan/docetaxel (I/D) chemotherapy reported a median survival for metastatic patients (pts) of 9 m. We conducted this randomized phase II trial to confirm the activity of this non-G regimen, and determine whether combining it with C was feasible and active. The primary endpoint was response. Methods: Pts required histologic confirmation of adenocarcinoma of the pancreas, evidence of distant metastases, ECOG PS 0–1, normal bilirubin, written informed consent, and were randomly assigned to Arm A (N=47) or B (N=45). Imaging with CT or MR within 4 weeks (wk) was used for tumor measurement. Dexamethasone was given 12 hours (h), 1 h before and 12 h after chemotherapy. Pts on Arm A received D 35 mg/m2 over 1 h and I 35 mg/m2 over 30 minutes weekly x 4 in a 6 wk cycle. Pts on Arm B received the same therapy, but C (loading dose 400 mg/m2 wk 1, 250 mg/m2 weekly thereafter) was given before D. Pts not receiving therapeutic anticoagulation received enoxaparin 40 mg per day. Pts were restaged (RECIST) after 2 cycles. Results: Median age Arm A: 59.9, Arm B: 60.2 years. Arm A 55% male, 32% PS 0, 97% EGFR immuno+. Arm B 84% male, 42% PS 0, 97% EGFR +. Median number of cycles for each arm 2 (1 -10). >4 cycles were delivered to 10.5% of pts Arm A, 20.9% Arm B. Grade ¾ neutropenia 26% Arm A, 33% Arm B. Grade 3 nausea 28% Arm A, 18% Arm B; Grade ¾ diarrhea 33% Arm A, 44.4% Arm B. 1 treatment-related death per arm. Median overall survival (OS), with 70.2% of pts known to have died, 6.5m [(95% CI (4.8, 8.6)] in Arm A. With 86.7% of pts known to have died in Arm B, OS 7.4 m [95% CI (4.4, 10.7)]. Response/progression data will be available at time of presentation. Conclusions: Weekly I/D ± C is associated with high rates of grade ¾ neutropenia/diarrhea. Median survival is 6.5m for I/D and 7.4m for I/D/C. Non-G containing therapy is active in metastatic PC. [Table: see text]
Post-resection CA 19–9 predicts overall survival (OS) in patients treated with adjuvant chemoradiation: A secondary endpoint of RTOG 9704
Authors: Berger A. C. , Winter K. , Hoffman J. , Regine W. , Abrams R. , Safran H. , Konski A. , Benson A. , MacDonald J. , Willet C. 
Published: March 2020

4522 Background: CA 19–9 is an important tumor marker in pancreatic adenocarcinoma. Several single institutional studies have demonstrated post-resection CA 19–9 to be an important prognostic factor. A secondary endpoint of RTOG 9704, a phase III adjuvant chemoradiation trial for pancreatic cancer, was to prospectively evaluate the ability of post-resectional CA 19–9 to predict survival. Methods: A total of 538 patients were accrued to this trial, of which 385 had evaluable CA 19–9 levels. These were analyzed using ELISA GI-MA kits provided by Diagnostic Products Corporation, a Siemens Company. CA 19–9 expression was analyzed as a dichotomized variable (<180 vs. =180). Cox proportional hazards models were utilized to characterize the contribution of CA 19–9 expression on OS. The following additional variables were included in the multivariate analysis: treatment, nodal involvement, tumor diameter (< or > 3cm), and margin status. Actuarial estimates for OS were calculated using Kaplan-Meier methods. Results: Most patients had CA 19–9 < 180 (n=220, 57%), while 34% were Lewis Antigen negative (unable to express CA 19–9) and 33 (9%) patients had levels >180. Survival was statistically significantly improved among patients with CA 19–9 <180 compared with those whose CA 19–9 =180 (HR=3.58(95% CI=2.40–5.34), p<0.0001) ( table ). This corresponds to a 72% reduction in the risk of death. This improvement was observed among patients with pancreas head and non-head tumors when analyzed separately. The multivariate analysis confirms that CA 19–9 is a highly significant predictor of OS in patients with resected pancreatic cancer. Conclusions: This prospective analysis of CA 19–9 in 385 patients treated with adjuvant chemoradiation definitively confirms the importance of post-resectional CA 19–9 in pancreatic cancer patients who have undergone resection. Patients with post-resection CA 19–9 >180 should be considered for additional therapy. [Table: see text] No significant financial relationships to disclose.
Impact of radiation (RT) regimen on palliative procedures (PP) for patients with resectable locally advanced esophageal cancer treated with exclusive chemoradiation (CRT) or preoperative chemoradiation (CRT+S): results from a phase III trial of the Federation Francophone de Cancerologie Digestive (FFCD 9102)
Authors: Crehange G. , Bonnetain F. , Seng S. , N'guyen T. , Mirabel X. , Marchal C. , Verrelle P. , Roullet B. , Maingnon P. , Bedenne L. 
Published: March 2020

4531 Background: The FFCD 9102 trial demonstrated that CRT is an alternative to CRT+S for responding patients. We investigated the type of PP in the follow-up (FU) period, according to the RT scheme: protracted (P-RT) vs. split course (SC-RT). Methods: Resectable T3 N0–1 M0 thoracic esophageal carcinoma were included. First sequence : 2 cycles of cisplatin and 5-FU (day (d)1 - d22) combined with RT. Two schemes of RT were allowed: P-RT (46 Gy / 4.5 weeks (w), 2 Gy / f) or SC-RT (2 one-week courses of 15 Gy, 3 Gy / f). For CRT, the same chemotherapy was given on d43, d64 and d92 combined with 20 Gy / 2w (P-RT) or 15 Gy / 1w (SC-RT). Responding patients after the first sequence were randomized between CRT and CRT+S. The impact of SC-RT vs. P-RT on PP in the FU period was explored using a Mann-Whitney test. Results: From February 1993 to December 2000, 451 pts were registered and 446 were eligible. P-RT: 161 pts, SC-RT: 285 pts. After a median FU of 47.4 months, 2-year overall survival and local relapse-free survival were for P-RT vs. SC-RT: 37.1% vs. 30.5% (p = 0.25) and 76.7% vs. 56.8% (p = 0.002), respectively. P-RT vs. SC-RT: mean length of hospital stay: 48 d vs. 60.5 d (p= 0.0003). Mean number of dilatation sessions: 0.56 vs. 0.66 (p= 0.43). Mean number of stents: 0.21 vs. 0.34 (p= 0.03). Mean number of any PP: 1.01 vs. 1.50 (p= 0.001). Mean dysphagia grade: 2.99 vs. 3.12 (p= 0.21). In the CRT+S-group, P-RT vs. SC-RT: mean length of hospital stay 55.0d vs. 68.7d (p =0.051). Mean number of dilatation sessions: 0.74 vs. 0.74 (p= 0.77). Mean number of stents: 0.09 vs. 0.18 (p= 0.44). Mean number of PP: 1.00 vs. 1.37 (p= 0.054). In the CRT-group, P-RT vs. SC-RT, mean length of hospital stay: 42.6d vs 54.0d (p= 0.053). Mean number of dilatation sessions : 0.38 vs. 0.67 (p= 0.12). Mean number of stents: 0.31 vs. 0.50 (p= 0.03). Mean number of PP: 0.83 vs. 1.86 (p= 0.0005). Conclusions: Stents, rate of PP and length of hospital stay were significantly increased with SC-RT. Dysphagia score was similar between SC-RT and P-RT at last FU. No significant financial relationships to disclose.
Predictive factors of transcatheter arterial chemoembolization for hepatocellular carcinoma
Authors: Ishii H. , Furuse J. , Nakachi K. , Suzuki E. , Shimizu S. , Yoshino M. , Satake M. , Hayashi T. 
Published: March 2020

4541 Background/Aim: Although transcatheter arterial chemoembolization (TACE) has been widely used for the treatment of unresectable hepatocellular carcinoma (HCC), the optimal indication of the TACE has not been fully elucidated. Methods: The treatment outcomes after TACE were analyzed retrospectively to determine predictive factors of anti-cancer effect on HCC. The patient (pts) selection criteria were: 1) admission between 1992 and 2005, 2) diagnosis of fresh HCC, 3) no extrahepatic metastasis and 4) primary treatment with TACE. TACE was performed by selectively introducing a catheter into the hepatic artery and injecting gelatin sponge particles following an emulsion consisting of 2–5 ml of iodized oil (Lipiodol) and 20–50 mg doxorubicin hydrochloride. Lipiodol accumulation in tumors was regarded as an indication of necrosis. We defined complete response (CR) as disappearance or 100% necrosis of all tumors, and partial response (PR) as more than 50% reduction and/or more than 50% necrosis. Results: There were 270 pts who fulfilled the above criteria. According to Japan Integrated Staging, the number of T1, T2, T3 and T4 was 10, 59, 171 and 30, respectively. There were 52 CRs, 113 PRs, 77 who remained SD and 28 who showed PD/NE. The median survival months of CR, PR, SD and PD/NE were 50, 30, 15 and 5, respectively, and there was a significant differences between them. The logistic regression analysis revealed tumor multiplicity and vascular invasion (VI) were significantly associated with the objective response (CR or PR). The response probability of patients with solitary tumor without VI was 85%, that with multiple tumors without VI was 63%, that with solitary tumor with VI was 33% and that with multiple tumors with VI was 16%. The small tumor (<5 cm) was another favorable factor which was significantly associated with CR. Among 231 patients without VI, the CR probability of patients with a solitary tumor <5 cm or >5 cm was 46% or 40%, respectively; although that of those with multiple tumors <5cm or >5cm was 21% or 5%, respectively. Conclusion: TACE is recommended for HCC patients without VI, and is optimally indicated for those with a solitary tumor or those with multiple tumor <5 cm among them. No significant financial relationships to disclose.