bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bisphosphonates and esophageal cancer: A RADAR report.
Authors: Edwards Beatrice J. , Nardone Beatrice , Raisch Dennis W , Mckoy June M. , Belknap Steven M , Holbrook Jaimee S , Garg Vishvas , Shen Xian , Godinez-Puig Victoria , Trifilio Steven M , Emmanuel Romala , West Dennis P. , Rosen Steven T. 
Published: March 2020

4063 Background: In 2009, the US Food and Drug Administration (FDA) reported on 23 patients who had developed distal esophageal cancer, with alendronate (ALN) within 2 years of initiation of therapy. Similarly, 31 cases of esophageal cancer were reported from Europe and Japan. Esophagitis has been associated with oral BPs. Erosive esophagitis and persistent mucosal abnormalities have been noted with crystalline material (similar to ground ALN). Our objective was to assess the FDA Adverse event reporting system (FDA AERS) for a safety signal. Methods: The FDA Adverse Event Reporting System (AERS) database was searched using terms related to esophageal cancer combined with all drug names for bisphosphonates (search period:1996-2010). Disproportionality ratios were calculated: Proportional reporting ratio (PRR) and Empiric Bayes Geometric Mean (EBGM) determining that the esophageal cancer cases were more common with bisphosphonates than with other drugs in the database. Results: We identified 128 cases of bisphosphonate-associated esophageal cancer; 114 (89%) female and 14 male (11%), mean age 72 ± 12 yrs; the drugs included alendronate (n=96, 75%), risedronate sodium (n=14, 11%), ibandronic acid (n=10, 7.8%), zoledronic acid (n=7, 5.4%) and pamidronate (n=1, 1%). Barrett’s esophagus was listed in 3 cases of esophageal carcinoma. A significant safety signal was found only for alendronate with a PRR= 6.4 (95% C.I. 5.29, 7.730; p=0.001), EBGM = 6.3 (95% C.I. 5.1, 7.6 p=0.001). Conclusions: Our analysis of FDA AERS identifies a larger number of cases of esophageal cancer than previously described, and a significant safety signal with alendronate use. Avoidance of oral bisphosphonates in patients with Barrett’s esophagus, and persistent mucosal abnormalities is recommended. Increased awareness and vigilance is needed for patients receiving oral bisphosphonate therapy.
Does in-house availability of multidisciplinary teams increase survival in upper GI cancer?
Authors: Kersten Christian , Cvancarova Milada , Boehler Geir , Mjaaland Svein , Mjaaland Odd 
Published: March 2020

4066 Background: Treatment of esophageal, gastric and pancreatic cancers (UGI) is recommended to be discussed by a multidisciplinary team (MDT), despite lack of evidence that this approach leads to increased survival. In 2001, a cancer centre with irradiation and chemotherapy facilities was established in the Norwegian county of West Agder (WA), providing the potential for local in-house MDT meetings. Our primary objective was to evaluate the effect of the establishment of in-house MDT availability (iMDTa) on survival in a cohort of UGI patients in WA. We compared survival figures for WA with those of other Norwegian counties with complete, less complete and without iMDTa. Methods: We defined “iMDTa” as a single administrative institution with all departments on one campus, serving the population of one county. We compared cause-specific survival rates for 2000-04 and 2005-08 for UGI patients living in counties with (MDT-Yes), without (MDT-No) and with a mix (MDT-mix) of iMDTa, with the county of WA which had a change in iMDTa (MDT-Change) during the study period. Crude survival was modelled with Kaplan-Meier method and Cox regression analysis was used to adjust for age and region (sex and stage distributions were similar in all counties). Results: We analyzed 12530 UGI patients living in five Norwegian regions. Median age was 74 (17-98) yrs and median follow-up was 5 (0-138) months. The regions with the highest level of iMDTa achieved the largest increases in survival, compared to the counties with limited or no iMDTa. Median overall survival for all UGI patients in WA/MDT-Change increased from 129 to 300 days from 2000-8, p=0.001. Compared to the county with MDT-Mix, the county with MDT-Change reached a statistically significant reduction in the risk of death (HR) for both esophageal (1.12- 0.60) and stomach cancers (0.87-0.63), but not for pancreatic cancers (1.04-1.01). Conclusions: In parallel with an increasing use of in-house MDT, we found a striking and more than two-fold increase in survival in the Norwegian county of WA/MDT-Change. This survival gain is partly explained by increased use of chemotherapy. During the same time period, no increase in survival was found in the MDT-No or MDT-Mix counties.
NeoFLOT: Multicenter phase II study of perioperative chemotherapy in resectable adenocarcinoma of the gastroesophageal junction or gastric adenocarcinoma.
Authors: Schulz Christoph , Kullmann Frank , Kunzmann Volker , Schepp Wolfgang , Geissler Michael , Vehling-Kaiser Ursula , Stauder Heribert , Wein Axel , Al-Batran Salah-Eddin , Kubin Thomas , Schaefer Claus , Held Swantje , Stintzing Sebastian , Boeck Stefan Hubert , Haas Michael , Forstpointner Roswitha , Ridwelski Karsten , Heinemann Volker 
Published: March 2020

4072 Background: The rationale of the NeoFLOT-trial was the intensification of neoadjuvant chemotherapy (NACT) by prolongation of preoperative treatment. This strategy is based on the notion that while perioperative treatment is notably beneficial in locally advanced gastroesophageal cancer (GEC), postoperative chemotherapy can only be applied in a fraction of patients (pts). Methods: Pts with T3, T4 and/or N+ adenocarcinoma (GEC) were eligible for this multicenter phase II trial. NACT consisted of 6 cycles of oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, fluorouracil 2600 mg/m2 and docetaxel 50 mg/m2 (FLOT) applied q 2 wks. Staging was performed after 3 cycles to select pts with progressive disease (PD) for immediate surgery. Primary endpoint was the R0-resection rate. Secondary endpoints included the pathological complete response rate (pCR), histologic tumor regression grade (Becker 2003), safety, and progression-free survival (PFS). Results: From 10/2009 to 06/2011, 59 pts were enrolled of whom 58 pts were assessable for safety. Median age was 61 years (range: 32-79), 58.6% (34/58) had tumors of the gastroesophageal junction. 50 pts underwent surgery and were assessable for the primary endpoint. R0-resection rate was 86.0% (43/50). pCR was achieved in 20.0% (10/50) of pts. During NACT, 6.9% (4/58) of pts developed progressive disease. Dose reduction was performed in 43.1% (25/58) of pts resulting in a median dose intensity of 89.2%. Grade 3/4 neutropenia was observed in 29.3% (17/58) of pts, febrile neutropenia grade 3/4 in 1.7% (1/58). Common grade 3/4 non-hematologic adverse events were diarrhea (13.8% (8/58)) and mucositis (6.9% (4/58)). Treatment related mortality was 3.4% (2/58) with 2 cases of sepsis. After a median follow-up of 9.1 months, median PFS and OS have not been reached. Conclusions: These data indicate that NACT with 6 cycles FLOT is well-tolerated and highly effective in resectable GEC.
Association of clinical complete response (cCR) after preoperative chemoradiation and pathological complete response (pathCR) in patients with gastroesophageal cancer (GEC) and indispensability of trimodality therapy (TMT).
Authors: Cheedella Naga K Sucharita , Suzuki Akihiro , Correa Arlene M , Hofstetter Wayne Lewis , Mehran Reza J. , Rice David C. , Maru Dipen M , Vaporciyan Ara A. , Taketa Takashi , Blum Mariela A. , Welsh James , Lin Steven H. , Lee Jeffrey H , Bhutani Manoop S. , Weston Brian , Walsh Garrett L , Swisher Stephen , Ajani Jaffer A. 
Published: March 2020

4086 Background: TMT strategy has the highest level-1 evidence for treating localized GEC. High rates of cCR (defined as post-chemoradiation negative endoscopic biopsy and physiologic uptake on PET) are common and have questioned the benefit from surgery in patients with cCR after chemoradiation. We hypothesized that cCR would be associated with a high rate of pathCR than < cCR. Methods: The data were analyzed retrospectively in 563 patients who had esophagectomy for GEC in between 2002 and 2010 at UTMDACC. Among them, 284 had TMT and post-chemoradiation endoscopic biopsies and PET (before surgery). Multiple statistical methods were used. Results: Of these 284 TMT patients, 218 (77%) patients achieved a cCR. However, only 67 (31%) of 218 had a pathCR. The sensitivity of cCR for pathCR was 97.1 % (67/69) but the specificity was low, 29.8 % (64/215). Intriguingly, 66 patients who had < cCR, only 2 patients (3%) had a pathCR. The difference in the rate of pathCR between the cCR and < cCR groups was significant (P < 0.001). Conclusions: Our data show that cCR is frequent after chemoradiation but the pathCR rate is not high and it is associated with specificity that is too low for clinical implementation. Therefore, all TMT-eligible patients, irrespective of the achievement of cCR or < cCR must be encouraged to undergo surgery. Therapies that overcome chemoradiation resistance and could increase the pathCR rate are needed for esophageal preservation in select GEC patients. Supported by UTMDACC and generous donors. [Table: see text]
A prospective trial for defining a subset of patients with limited metastatic gastric cancer who may be candidates for bimodal treatment strategies: FLOT3.
Authors: Al-Batran Salah-Eddin , Hofheinz Ralf , Homann Nils , Illerhaus Gerald , Martens Uwe Marc , Stoehlmacher-Williams Jan , Schmalenberg Harald , Luley Kim Barbara , Prasnikar Nicole , Egger Matthias , Probst Stephan , Hartmann Joerg Thomas , Moehler Markus Hermann , Arnold Dirk , Fischbach Wolfgang , Pauligk Claudia , Hozaeel Wael , Moenig Stefan Paul , Hölscher Arnulf H , Jäger Elke ,   Arbeitsgemeinschaft Internistische Onkologie (AIO)
Published: March 2020

4090 Background: The utility of surgery for metastatic gastric cancer is debated. A prospective trial was performed to evaluate a prognostic model for selecting patients (pts) treated with systemic chemotherapy (ct) who may also be candidates for surgical intervention. Methods: Using a predefined algorithm pts with untreated gastric cancer were prospectively stratified into 3 groups: operable (OD), limited metastatic (LD), or extensive metastatic (ED) disease and treated with 5-FU, oxaliplatin, leucovorin and docetaxel (FLOT). LD was defined as: distant intra-abdominal lymph node metastases only or/and a maximum of 1 organ involved, normal serum alkaline phosphatase, < 5 liver lesions, no visible carcinomatosis (peritoneum or pleura), and ECOG ≤ 1. All other metastatic pts were ED. Pts with OD received 4 preoperative ct cycles followed by surgery and 4 postoperative cycles. Pts with LD received 8 cycles with surgery allowed for complete macroscopic resection. Pts with ED received 8 cycles with surgery allowed for palliation only. The study had 80% power to detect a HR of 0.55 for overall survival in favor of the LD group (vs. ED group; 2-sided log-rank p=0.05). Results: 238 of 252 pts included were eligible (OD/LD/ED: 51/60/127). LD pts had distant lymph nodes only (41%), liver (22%), lung (17%), localized peritoneal involvement (7%), or others (13%). A median of 8 ct cycles was applied to all groups. Median OS was 22.9 vs. 10.7 months in pts with LD vs. ED, respectively (HR 0.37; 95% CI, 0.25 – 0.56; p <0.001). LD was the strongest predictor of OS in the multivariate analysis including all single determinants of LD status (p=.002). Surgical resection was conducted in 96%, 62%, and 12% in the OD, LD, and ED groups, of which R0 resection (primary) was achieved in 82%, 81% and 33%, respectively. Within the LD arm, operated pts had better outcome than non-operated pts (median OS 31.3 vs. 15.9 months; p=.004) and pts with lymph node only involvement had best outcome. Conclusions: This clinical model identifies a subset of pts with (limited) metastatic gastric cancer who have a favorable outcome and who may be candidates for bi-modal treatment strategies.
Serum folate, LINE-1 hypomethylation, and overall survival in a prospective cohort of hepatocellular carcinoma patients.
Authors: Siegel Abby B. , Goyal Abhishek , Hidalgo Rosa , Brown Robert S , Neugut Alfred I. , Verna Elizabeth , Emond Jean , Samstein Benjamin , Kato Tomoaki , Gamble Mary , Dove Lorna , Santella Regina 
Published: March 2020

4101 Background: Folate plays a central role in DNA methylation reactions, but the relationship between folate and methylation status has not been studied in HCC patients. We hypothesized that low folate levels would correlate with global hypomethylation, and worsened survival in HCC patients. Methods: 72 newly-diagnosed HCC patients were enrolled in a prospective study, beginning 10/08, and followed until 9/11. We excluded those with previous malignancy, and uncompensated Child Pugh (CP) B or C disease. We used pyrosequencing to evaluate quartiles of LINE-1 methylation in plasma as a surrogate for global tumor hypomethylation. We evaluated the relationship between folate deficiency (serum folate levels < 6ng/mL), DNA hypomethylation (LINE-1 methylation < 25th percentile i.e., < 69.4%), and overall survival in our cohort. Results: Median age was 60; 82% were men and 67% had hepatitis C. Mean serum folate levels were 12.1 ng/mL (SD = 5.3 ng/mL), while mean % LINE-1 methylation was 69.9 (SD = 4.6). In a univariate analysis, folate deficiency and LINE-1 hypomethylation were significant predictors of poor overall survival (HR = 3.77; 95% CI: 1.37, 10.41, and HR=3.50; 95% CI: 1.51, 8.13, respectively). These markers remained independent predictors of survival in a multivariate model including age, CP class, AJCC stage and AFP. HR for folate deficiency in this model was 3.52 (95% CI: 1.16, 10.70), and HR for LINE-1 hypomethylation was 2.74 (95% CI: 1.10, 6.85). We also found a significant association between folate deficiency and LINE-1 hypomethylation (p = 0.04). Conclusions: We provide novel data that folate deficiency is an independent predictor of worsened overall survival in patients with HCC in a multivariate model. Further, we show that global changes in DNA methylation assesed in plasma correlate with folate levels, supporting a possible mechanistic link between the two. Folate supplementation, and the use of other agents which modulate methylation, deserve further study in HCC.
Efficacy, safety, tolerability, and PK of the HDAC inhibitor resminostat in sorafenib-refractory hepatocellular carcinoma (HCC): Phase II SHELTER study.
Authors: Bitzer Michael , Horger Marius , Ganten Tom M , Lauer Ulrich M , Woerns Marcus A , Siveke Jens T , Dollinger Matthias M. , Gerken Guido , Wege Henning , Giannini Edoardo G , Zagonel Vittorina , Cillo Umberto , Trevisani Franco , Santoro Armando , Montesarchio Vincenzo , Hauns Bernhard , Asche Julia , Jankowsky Rüdiger , Mais Anna , Hentsch Bernd ,   Shelter Study Group
Published: March 2020

4115 Background: Resminostat (R), an oral HDAC inhibitor, was studied in the SHELTER trial evaluating safety, PK and efficacy in HCC patients (pts) refractory to sorafenib (S). R was explored as monotherapy and within a novel resensitization approach to overcome tolerance to S by the combination of both drugs. Methods: Pts with advanced HCC (BCLC B/C) were included in a multi-center, two-arm trial. Radiologic progression under S firstline therapy had to be confirmed by central review (RECIST) prior to study entry. A dose escalation of R (range 200 to 600 mg) combined with S (400 or 800 mg) was performed. Arm A investigated the drug combination (R+S), Arm B the monotherapy of R (600 mg). Primary objective was the progression-free survival rate (PFSR) after 12 weeks (w). Secondary objectives included safety, tolerability, tumor response, PFS, TTP, OS and the analyses of PK and biomarkers (BM), incl. AFP, VEGF, HDAC enzyme inhibition, histone acetylation and gene expressions in peripheral blood. Results: 50 pts were enrolled, dose escalation determined 600 mg R and 400 mg S for Arm A. Clinical activity results of 15 evaluable pts from combination treatment revealing a PFSR of 66.6% after 12 w, not all patients in Arm B already reached the 12 w staging. Most frequent AE were CTC grade 1-2 GI complaints (nausea, vomiting) and skin disorders (rash, pruritus, HFSR). Grade 3-4 toxicity (SAE reports) consisted mainly of non-hematological events mostly related to tumor disease. Plasma concentrations of both drugs correlated with administered doses and were in the expected range without obvious influence of preexisting liver disease. BM investigations revealed effective target modulation by R in both arms. Conclusions: The primary study objective was achieved for both treatment arms. R demonstrated a favorable PK, safety and tolerability profile, even in combination with S and despite preexisting liver disease, includig cirrhosis. The observed clinical activity emphazises the resensitizing activity of R by an epigenetic mode-of-action to overcome tolerance to S and warrants further development, in particular for combination therapy in both, first and second line HCC treatment.
Prevalence and prognostic significance of FGF receptor 2 (FGFR2) gene amplification in Caucasian and Korean gastric cancer cohorts.
Authors: Kilgour Elaine , Su Xinying , Zhan Ping , Gavine Paul , Morgan Shethah , Womack Chris , Jung Eun-Jung , Bang Yung-Jue , Im Seock-Ah , Kim Woo Ho , Grabsch Heike 
Published: March 2020

4124 Background: Gastric adenocarcinoma is the 4th most common cancer, and many patients present with metastatic or recurrent disease. The prognosis for these patients is poor, with median survival times of 11–12 months. Hence there is a need for identification of potential new drug targets. We have determined the prevalence of FGFR2 gene amplification (FGFR2amp) and its relationship to clinicopathological parameters and survival in Caucasian (n=408) and Korean (n=356) gastric cancers (GC) and determined the overlap with HER2 or cMET gene amplification. Methods: FGFR2, HER2 and cMET gene amplification was assessed by fluorescence in situ hybridisation in GC tissue microarrays from Caucasian and Korean surgically resected gastric carcinomas. Gene amplification was defined as a gene/centromeric probe ratio of ≥2.0 after measuring at least 50 tumour cells. Results: 7% (30/408) of Caucasian and 4% (15/356) of Korean GC showed FGFR2amp, and the incidence was not significantly different between these cohorts (p=0.092). FGFR2amp was significantly associated with lymph node status in both cohorts (p<0.0007, multivariate analysis), and in the Korean cohort with diffuse-type histology, but not with depth of tumour invasion, age or gender. Patients with FGFR2amp showed significantly shorter overall survival in both the Caucasian (HR 2.37, 95% CI 1.6–3.5; p=0.0001) and Korean (HR 2.33, 95% CI 1.28–4.25; p=0.0129) cohorts, by multivariate analysis. There was no overlap between FGFR2amp and HER2 or cMET amplification in the Korean cohort, but two of twenty-six FGFR2amp Caucasian gastric tumours also showed HER2 amplification. Conclusions: This is the first study to demonstrate FGFR2amp, at a prevalence of 4% and 7%, in two large GC cohorts of Asian and Caucasian origin and that FGFR2amp is prognostic and significantly associated with lymph node metastasis. Furthermore, FGFR2amp is generally mutually exclusive with HER2 and cMET amplifications. Based on these observations, FGFR2 inhibitors warrant further investigation in the treatment of FGFR2 amplified GCs.
Cardiac safety analysis for a phase III trial of sunitinib (SU) or sorafenib (SO) or placebo (PLC) in patients (pts) with resected renal cell carcinoma (RCC).
Authors: Haas Naomi B. , Manola Judith , Ky Bonnie , Flaherty Keith T. , Uzzo Robert G. , Wood Christopher G. , Kane Christopher J , Jewett Michael A. S. , Atkins Michael B. , Dutcher Janice P. , DiPaola Robert S. ,   Eastern Cooperative Oncology Group
Published: March 2020

4500 Background: We performed a cardiac analysis of E2805, a well population of pts with resected high risk RCC. The objectives were to determine if pts treated with SU or SO had clinically significant decreases in left ventricular (LV) ejection fraction (EF) and to describe the frequency of clinically significant heart failure (HF). We also report the frequency of other events including (un)stable angina or myocardial infarction. Methods: EF was measured by multiple gated acquisition scan (MUGA) at baseline, 3, 6, and 12 months (mo), and end of treatment, if symptoms developed, and 3 mo after the last abnormal assessment. The primary cardiac endpoint was defined as an EF decline < the institutional lower limit of normal (ILN) that was a ≥ 16% decline from baseline, and that occurred ≤ 6 mo into therapy. Clinically significant HF was ≥ Grade 3 LV systolic or diastolic dysfunction (severe symptoms with any activity or from drop in EF responsive (Grade 3) or refractory (Grade 4) to therapy. Late LVEF events were a drop in LVEF of ≥ 16% occurring after 6 mo of therapy. Event rates on each treatment arm were calculated, with 90% exact binomial confidence intervals (CI). Results: Post-baseline MUGAs are available for 1589 of 1943 total pts accrued. 1293 pts had MUGA assessment ≥ 6 mo. 21 pts had primary events (Table). 71 pts had worst LVEF declines of ≥16% from baseline, including 52 of which occurred ≤ 6 mo from baseline, with the majority not meeting full primary event criteria. There were 11 reported grade 3 LV systolic events (5 SU, 4 SO and 2 PLC). 8 pts had cardiac ischemia possibly or probably from agent. Only one grade 4 event followed a primary LVEF event. 4 of 7 pts who began treatment with LVEF <ILN had primary LVEF events. Conclusions: In detailed followup of SU and SO use, cardiac function in pts starting with normal EF, was not impaired significantly over placebo. Ischemic events were uncommon and not clearly associated with treatment. The data demonstrate that SU or SO for adjuvant therapy will likely not cause significant cardiac toxicity. [Table: see text]