bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognosis prediction of stage II colon cancer by gene expression profiling
Authors: Barrier A. , Brault D. , Houry S. , Dudoit S. , Lemoine A. , Flahault A. , Boelle P. 
Published: March 2020

3565 Background: The aims of the present study were: 1) to identify a prognosis signature (PS), based on microarray gene expression measures, in stage II colon cancer patients and to assess its accuracy with resampling techniques ; 2) to assess the accuracy, also with resampling techniques, of a previously proposed 23-gene PS. Methods: Colon tumor mRNA samples from 50 patients were profiled using the Affymetrix HGU133A GeneChip (22283 sequences). In a first part, the 50 patients were randomly divided into 2 groups (G1 and G2) of equal size that were considered alternately as training and validation sets. In a second part, the 50 patients were randomly divided into 1600 training (size=n) and validation (size=50-n) sets. Informative genes were selected on the training set by taking the 30 most differentially expressed genes between patients who recurred and those who remained disease-free; the accuracy of this PS was assessed by comparing the predicted prognosis (using a diagonal linear discriminant analysis (DLDA)) and the actual evolution for all the validation set patients. Using the same random splits, the accuracy of the 23-gene PS was assessed with a DLDA that used learning set patients as reference samples. Results: The 30-gene PS that was identified from G1 (G2) patients yielded a 80% (84%) prognosis prediction accuracy when applied on G2 (G1) patients. With resampling techniques, the prediction accuracy regularly increased with the learning set (LS) size: 65.5% (range=52.5–75%) with LS of size 10, and 82.7% (range=60–100%) with LS of size 40. Comparisons of compositions of the 100 PS for a given value of n suggested a high instability of informative genes; with LS of size 10, 7 genes were part of at least 10% of signatures; with LS of size 40, 7 genes were part of all the 100 signatures. The accuracy of the previously proposed 23-gene PS also increased with the learning set size. Conclusion: Microarray gene expression profiling represents a promising technique to predict the prognosis of stage II colon cancer patients. The present study also outlines the high instability of informative gene selection and suggests the usefulness of resampling techniques to obtain an honest assessment of prognosis prediction accuracy. No significant financial relationships to disclose.
Neoadjuvant XELOX vs. XELIRI in combination with concomitant boost 3D-conformal radiotherapy in locally advanced rectal cancer (LARC)
Authors: Privitera G. , Spatola C. , Acquaviva G. , Di Franco G. , Raffaele L. , Salamone V. , Ettorre G. C. 
Published: March 2020

3570 Background: While several randomized trials have shown that preoperative chemoradiation reduces local recurrence in LARC, there is no standard chemoradiation schedule. The aim of this study was to compare capecitabine + oxaliplatin (XELOX) vs. capecitabine + irinotecan (XELIRI) in association with high-dose radiotherapy. Methods: Patients (pts) with histologically proven uT3–4 N-/+ or uT2 N+ LARC were randomized to receive capecitabine 1250mg/m2 bid d1–14 before chemoradiation and then 825mg/m2 bid d22–55 plus either oxaliplatin 130mg/m2 d1,22&43 (18 pts) or irinotecan 180mg/m2 d1,22&43 (18 pts). On d22 pts also received radiotherapy administered to the whole pelvis (maximum 45Gy; 1.8Gy/fraction), with a concomitant boost to the CTV (maximum 9Gy; 1.5Gy/fraction) during the last 6d of treatment with a 6h inter-fraction interval. Surgery was carried out 6–8w after chemoradiation by the same surgical team. Results: 36 pts (23M/13F, median age 59 years, ECOG PS 0–1) were enrolled between Jan03 and Jun05. No pt had systemic disease at the time of diagnosis. One pt in the XELIRI group discontinued chemoradiation because of GI toxicity; the other 35 pts (18 XELOX, 17 XELIRI) received 95% and 92% of the planned chemotherapy doses, respectively. The most common adverse event was grade 3/4 diarrhea (6% XELOX, 18% XELIRI). There was no relevant neurotoxicity. 12 pts (67%) on XELOX and 12 pts (71%) on XELIRI had clinical and pathological downstaging. There were no treatment-related deaths. A complete pathological remission was seen in 4 pts (22%) on XELOX and 5 pts (29%) on XELIRI. 25 pts (71%; 13 XELOX, 12 XELIRI) underwent sphincter-saving surgery and 10 pts had Miles abdomino-perineal resection. All pts are alive after a median follow-up of 20 months (range 7–36 months), but 4 (2 in each group) have developed distant metastases. Conclusions: XELOX and XELIRI are feasible and effective, with high efficacy comparable to that observed with other neoadjuvant regimens. XELOX was better tolerated, as diarrhea was seen more frequently in the XELIRI arm. Further studies of these regimens are warranted in this setting. No significant financial relationships to disclose.
Long-term follow-up of colorectal cancer (CRC) patients treated with neoadjuvant chemotherapy with irinotecan and fluorouracil plus folinic acid (5-FU/FA) for unresectable liver metastases
Authors: Pozzo C. , Basso M. , Quirino M. , Schinzari G. , Astone A. , Trigila N. , D’Argento E. , Sponziello F. , Cassano A. , Barone C. 
Published: March 2020

3576 Background: In a prospective study, neoadjuvant therapy with irinotecan and 5-FU/FA (modified FOLFIRI) enabled a significant proportion of CRC patients (pts) with initially unresectable liver metastases (LM) to undergo potentially curative surgical resection (Annals of Oncology 15:933–939, 2004). Here we report data on survival and time to progression (TTP) from long-term follow-up. Methods: Forty patients received irinotecan 180 mg/m2 IV on day 1, FA 200 mg/m2 IV on days 1 and 2, 5-FU IV bolus 400 mg/m2 on days 1 and 2, and 5-FU 48-h continuous IV infusion 1200 mg/m2 on day 1. Treatment was repeated every 2 wks, with response assessed every 12 wks (6 cycles), and continued until an objective response (OR), indicating suitability for surgery, disease progression, or unacceptable toxicity. Pts undergoing liver resection received a further 6 cycles postoperatively. Results: Nineteen (47.5%) of 40 pts had OR; 13 (33%) underwent resection. Treatment was well tolerated, with adverse events typical of agents used. As of June 30, 2005, median follow up was 30.4 months (mo). Median survival for all pts was 30.1 mo; median survival in nonresected pts was 24 mo, and overall survival (OS) in resected pts was not reached. TTP was 14.3 mo for all pts and 5.2 mo for nonresected pts. Disease-free (DF) survival in resected pts was 28.2 mo. Of resected pts, all were alive and 9 were DF at 1 y, all were alive and 6 were DF at 2 y, and 9 were alive and 6 DF at last follow-up. Conclusion: Surgical resection of LM after neoadjuvant treatment with modified FOLFIRI in CRC pts was followed by favorable DF and OS times. These data encourage use of irinotecan in pts with unresectable LM. Forthcoming studies should include arms with irinotecan-based combination regimens. [Table: see text]
Preliminary results from a phase II study of infusional 5-FU, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab as first-line treatment for metastatic colorectal cancer (mCRC)
Authors: Kopetz S. , Abbruzzese J. L. , Eng C. , Adinin R. B. , Morris J. , Wolff R. A. , Lin E. , Chang D. Z. , Hoff P. , Bogaard K. 
Published: March 2020

3579 Background: Irinotecan (I) plus bolus 5-FU (F) and leucovorin (L) comprise the IFL regimen, a very active treatment in mCRC when combined with bevacizumab (B). The response rate (RR) for IFL-B given as first-line treatment is 45%, with a median progression-free survival (PFS) of 10.6 months and a median survival of 20.3 months. The IFL regimen is now considered inferior to infusional 5-FU regimens, such as FOLFIRI, which have less toxicity and improved efficacy. Methods: We designed a 43 patient (pt), single-arm phase II trial of FOLFIRI-B with B (5mg/kg), I (180mg/m2), bolus of F (400mg/m2) and L (400mg/m2) followed by a 46-hour infusion of F (2400mg/m2), with a primary endpoint of progression-free survival (PFS). Chemotherapy naïve mCRC patients (pts) with adequate organ function and performance status 0–2 received B alone on Day minus 14, starting FOLFIRI + B on Day 1. DCE-MRI and laboratory correlates were completed before and after B alone and cycle 1. Once cycle is equivalent to two weeks. Results: 21 pts, median age 59 y/o (range 26–75), M:F = 15:6, 4 with prior F in adjuvant setting, have been enrolled to date. 20 pts are evaluable for response. One pt is too early. A total of 215 cycles have been administered (median 11). Median PFS has not been reached after a median follow-up of 8 months. By intent-to-treat analysis, there were 14 PRs (70%), and 5 (25%) pts with stable disease observed (including 1 unconfirmed PR). PRs were observed from 9 to 35 weeks after the first cycle (median: 18 weeks). 9 pts remain on treatment (1–12 months); 12 pts are off study (3 for progressive disease, 1 withdrew, 4 sent for curative surgery, 2 for toxicity, 2 sent for surgery unrelated to cancer). Toxicity included 10 cases of grade 3 neutropenia, including 1 febrile neutropenia, 4 venous thrombi, and 6 cases of hypertension requiring medication change. One pt included in the analysis developed peritonitis, considered a possible microperforation, after B alone and never received FOLFIRI. No ≥ grade 3 diarrhea was observed. Analysis of correlative studies will be presented at a later date. Conclusion: Our preliminary results indicate that FOLFIRI-B is well tolerated and an excellent choice as a first-line treatment for mCRC. [Table: see text]
Effective salvage therapy of liver-only colorectal cancer metastases with chronomodulated irinotecan-fluorouracil-oxaliplatin via hepatic artery infusion
Authors: Bouchahda M. , Adam R. , Giacchetti S. , Li X. M. , Castaing D. , Gholam D. , Kunstlinger F. , Jasmin C. , Machover D. , Lévi F. 
Published: March 2020

3585 Background: Cell cycle and pharmacology genes are controlled by the molecular clock in normal liver but not in tumors (Filipski et al. JNCI 2005). As a result, circadian-based hepatic artery infusions of 3 main active drugs (ChronoHAI) could improve both tolerability and efficacy in patients (pts) with liver metastases from colorectal cancer. Methods: The therapeutic potential of 3-drug chronoHAI was evaluated in 28 heavily pretreated non hospitalized pts with metastatic colorectal cancer (MCC). They received 5-day (d) q21 d courses (c) with d1 irinotecan (160 mg/m2 from 2 to 8 am, peak at 5 am) and d2–5 oxaliplatin (20 mg/m2/d from 10 am to 10 pm, peak at 4 pm) and 5-fluorouracil (600 mg/m2/d from 10 pm to 10 am, peak at 4 am). 149 courses (c) were given (median, 5 ; 1–15) using a multichannel pump (Mélodie, Aguettant, F). Toxicity was assessed q21 d and response q3 c with CT scan. Results: Pt characteristics: prior chemotherapy lines 1/2/3/4+: 3/4/8/13 pts; WHO Performance Status 0/1/2/3 : 12/9/6/1 pts; median age: 63 years (32–73); liver only: 21 pts; liver and lung: 7 pts. Treatment was withdrawn for thrombosis (6 pts) and/or Grade (gr) 3 abdominal pain (3 pts). Grade 3–4 diarrhea and vomiting respectively occurred in 6 pts (21%) and 4 pts (14%) and were the main toxicities. Leucopenia, anemia and thrombocytopenia were respectively encountered in 5, 2 and 1 pt (< 18%). NCIC gr 3 sensory neuropathy occurred in 4 pts and alopecia in 3 pts. Of 25 pts with measurable lesions, disease progressed in 11 pts (exclusively outside the liver for 3 pts) and was controlled in 14 pts (56%), including 8 objective responses - 32% [95% C.L. 13.4 to 50.6]. Partial hepatectomy was performed in 3 pts with measurable disease (12%): R0 (2 PR) and R1 (1 SD). Median Progression free survival is 5 months [2.5 to 7.5] and median survival is 18.4 mo [10.5 to 26.3]. Five pts are alive at 2 to 51 mo. Conclusions: 3-drug chronoHAI is safe in heavily pretreated pts and achieves consistent activity against colorectal cancer liver metastases despite prior failure to oxaliplatin, irinotecan and fluorouracil. The addition of systemic molecular targeted therapy could be useful for preventing extra hepatic dissemination. Supported by ARTBC, Hôpital P. Brousse, Villejuif, France No significant financial relationships to disclose.
Chemo-immunotherapy regimen with gemcitabine + FOLFOX 4 (GOLF) followed by subcutaneous (sc) granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2). Results from a multicenter phase II trial in colon carcinoma patients
Authors: Correale P. , Remondo C. , Montagnani F. , Rotundo M. S. , Marsili S. , Laplaca M. , Tassone P. , Tagliaferri P. , Venuta S. , Francini G. 
Published: March 2020

3587 We have recently described a poly-chemotherapy (GOLF) regimen that: A) is active in colon carcinoma patients as second line of therapy; B) induces high levels of necrosis and apoptosis in colon cancer cells; C) up-regulates the expression and release of heat shock proteins (HSP)-70 and -90 and tumour-associated antigens (2,3); and D) down-regulates tumour cell resistance to the death signals of cytotoxic-T-lymphocytes.These effects represented the rationale for projecting GOLFIG regimen. Here we describe the results of a multi-center translational phase II trial designed to evaluate the toxicity, anti-tumour activity of a novel regimen designated as GOLFIG-1, composed by the GOLF poly-chemotherapy followed by the subcutaneous (sc.) administration of GM-CSF and low-dose IL-2 in colorectal carcinoma patients. The study involved 37 patients (21M and 16F, mean age 62.5 years), 24 of whom had received a previous line of treatment, and 24 had liver involvement. All the patients received biweekly chemotherapy with gemcitabine (1g/m2, day 1 and 15), oxaliplatin (85 mg/m2, day 2 and 16), levo-folinic acid (100 mg /m2, day 1, 2, 15, 16) and 5-Fluorouracil (400 mg/m2 as a bolus, and 800 mg/m2 as 24 hour infusion, days 1, 2, 15, 16). These patients also received sc GM-CSF (100 μg, day 3 to 8) followed by sc IL-2 (0.5 X 106 IUs twice a day from day 9 to 14 and from 17 to 29). The treatment was well tolerated and very active in colon carcinoma patients, with high objective response (64.9%) and disease control rates (97.3%), with an average time to progression of 12.94 months (CI 95%: 9.98–15.91). An immunological study confirmed the immunological response to colon carcinoma antigen, a significant reduction in suppressive regulatory T lymphocytes (CD4+CD25+T-reg) and a significant reduction of VEGF levels reported in a previous study. In conclusion, these results suggest that the GOLFIG regimen exerts strong immunological and anti-tumour activity in colorectal cancer patients. A randomized phase III trials aimed to compare the efficacy of GOLFIG-1 with FOLFOX-4 regimen in patients with advanced colorectal carcinoma is presently ongoing. No significant financial relationships to disclose.
Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms associated with overall survival in women with metastatic colon cancer
Authors: Press O. A. , Zhang W. , Yang D. , Haiman C. A. , Gordon M. , Schultheis A. M. , Nagashima F. , Sherrod A. , Iqbal S. , Lenz H. 
Published: March 2020

3600 Background: Methylenetetrahydrofolate Reductase (MTHFR) is a key enzyme regulating intracellular folate pool, which affects DNA synthesis and methylation. Recent studies found folate deficiency induces DNA damage because of impaired nucleotide-excision repairs in mouse model. Two MTHFR gene polymorphisms, C677T and A1298C are linked to altered enzyme activity. Numerous studies have shown these two polymorphisms associated with colon cancer risk and response to fluorouracil-based treatment in advanced colon cancer patients. One epidemiology study also demonstrated 1298CC genotype to be associated with a significantly lower risk of colon cancer in women, but not men. We tested whether these two polymorphisms were associated with clinical outcome in metastatic colon cancer patients treated with 5-FU/Oxaliplatin. Methods: Between 1992 and 2003, a total of 318 patients with metastatic colon cancer treated at the University of Southern California/Norris Comprehensive Cancer Center (USC/NCCC) or the Los Angeles County/University of Southern California Medical Center (LAC/USCMC), were eligible for this study. Peripheral blood samples were collected from each patient and genomic DNA was extracted from white blood cells using the QiaAmp kit (Qiagen, Valencia, CA). Two MTHFR gene polymorphisms (C677T, A1298C) were tested by PCR-RFLP method. Results: MTHFR A1298C gene polymorphism showed statistically significant differences in overall survival (OS) in female patients with metastatic colon cancer (P=0.025, logrank test). Patients with the AA genotype had an 18.7 months median OS compared with the heterozygous AC genotype, which had a 14.3 months median OS and the CC genotype, which had a 15.9 months median OS. Conclusions: There is no significant difference in clinical outcome in male patients. However, female metastatic colon cancer patients with a MTHFR A1298C polymorphism AA genotype have significantly better overall survival than those with heterozygous AC genotype or CC genotype. This data supports the role of MTHFR polymorphisms as an independent prognostic marker in female patients with metastatic colon cancer. Further prospective study is needed to confirm these preliminary findings. [Table: see text]
Impact of biomarker dynamic profile and pathological response induced by neoadjuvant chemoradiotherapy in rectal cancer
Authors: Gentile A. L. , Pinto C. , Ceccarelli C. , Di Fabio F. , Funaioli C. , Longobardi C. , Tardio M. L. , Cuicchi D. , Iacopino B. , Martoni A. A. 
Published: March 2020

3614 Background: The aim of this study was to evaluate the correlation among biomarkers, pathological response and clinical outcomes in patients (pts) with rectal cancer submitted to neoadjuvant chemoradiotherapy. Methods: Pts entering the study had rectal adenocarcinoma, uT3/4N-/+ or uT2N-/+ with inferior location. Chemotherapy consisted of oxaliplatin 60 mg/m2 weekly infusion IV for 6 times and 5-fluorouracil 225 mg/m2/die continuous infusion IV d 1–38. Radiotherapy was delivered up to a dose of 50.4 Gy in daily fractions of 1.8 Gy d 1–38. Rectal surgery with TME was performed 6–8 weeks after neoadjuvant treatment. Immunohistochemical determination of Ki67, p53, bcl2, TS, EGFR, MLH1 and MSH2 was performed in pretreatment biopsy and operative specimen. Results: Between March 2002 and May 2005, 32 pts had completed neoadjuvant therapy and surgery. Pt characteristics: 24 (75%) men and 8 (25%) women; median age 64 (33–80) years; stage uT2N-M0 3 (9.4%) pts, uT3N-M0 14 (43.8%), uT3N+M0 10 (31.2%), uT3NXM0 2 (6.2%), uT4N+M0 3 (9.4%). Surgery consisted of abdominal-perineal amputation in 12 (37.5%) and low-anterior resection in 17 (53.1%) pts, with negative circumferential resection margins in 86.2%. Laparoscopic local excision was performed in 3 (9.4%) pts. Pathological down-staging occurred in 18 (56.2%) pts, including 7 (21.9%) pT0N0, with sphincter preservation in 40%. Tumor Regression Grade (TRG) (according to Mandard) evaluation of operative specimen was: 7 TRG1, 11 TRG2, 11 TRG3 and 3 TRG4. Expression mean value in pretreatment biopsy and operative specimen was: Ki67 88.8% and 31.7%; p53 49.7% and 40.7%; TS 12.6% and 10.0%; MLH1 89.7% and 76.4%; MSH2 84.3% and 72.2%. The evaluation of biomarker profile in operative specimen of TRG2 pts vs TRG3–4 showed: Ki67 16.6% vs 46.2% (p=0.03); TS 4.5% vs 12.9% (ns); MSH2 82.3% vs 65.6% (ns); p53 52.3% vs 34.8% (ns). Median DFS was 19 (3–35) months. At a median follow-up of 22 (5–41) months, 100.0% of TRG1 pts, 90.9% of TRG2, 73.3% of TRG3–4 had no-evidence of disease relapse. Conclusions: These preliminary results suggest a correlation between Ki67 and pathological response in rectal cancer pts treated with neoadjuvant therapy. Moreover, DFS appears to be related to TRG. No significant financial relationships to disclose.
Randomized phase II trial of neoadjuvant vs. adjuvant docetaxel plus cisplatin in patients with locally advanced gastric carcinoma: An interim analysis
Authors: Chun J. , Park S. , Kim H. , Kim Y. , Ryu K. , Lee J. , Lee J. , Kim C. , Lee J. , Bae J. 
Published: March 2020

4030 Background: The perioperative treatment strategy for locally advanced gastric cancer (LAGC) has not been clearly established. We conducted a randomized phase II study of neoadjuvant vs. adjuvant docetaxel/cisplatin (DC) chemotherapy in LAGC. Methods: LAGC was radiographically defined by CT and PET. Pts were randomized to receive neoadjuvant or adjuvant DC (docetaxel 36 mg/m2 + cisplatin 40 mg/m2 on D1, D8, q 3 wks X 3 cycles) according Japanese staging system (IIIa, IIIb, IV M-, and IV with a single M+ node). Results: All planned 88 pts in 44 per each arm were enrolled between Jan 2003 and Nov 2005. One pt was not eligible. The median age was 57 yrs vs. 58 yrs, PS 1 90.7% vs. 84.1%, and stage III/IV 72.1%/27.9% vs. 70.5%/29.5% in the neoadjuvant and adjuvant arm, respectively. Clinical response rate of 42 evaluable pts in neoadjuvant arm according to WHO criteria was 64.3% (95% CI 49.8–78.8%) with CR 2.4%, PR 61.9%, SD 31.0%, and PD 4.7%. There was no treatment related death. Comparison of G3/4 adverse events in neoadjuvant vs. adjuvant arm were; leukopenia 14.0% vs. 32.4% (p=0.04), neutropenia 37.2% vs. 62.2% (p=0.02), febrile neutropenia 0% vs. 2.7%, diarrhea 2.3% vs. 10.8%, stomatitis 2.3% vs. 8.1% (p=NS). There were no difference in the postoperative morbidity and the duration of hospital stay between both arms, but surgery was delayed in one pt who developed tuberculosis during neoadjuvant chemotherapy. Downstaging of the T stage could be obtained in 6 (14.3%) among 42 evaluable pts in neoadjuvant arm, according to EUS. Conclusions: Both neoadjuvant and adjuvant DC chemotherapy were relatively well tolerated in LAGC, with the lower incidence of G3/4 toxicities in neoadjuvant arm. Neoadjuvant DC showed a high response rate and a modest downstaging effect. (Supported by National Cancer Center Grant; Docetaxel was provided by Sanofi Aventis Korea) [Table: see text] No significant financial relationships to disclose.