bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression of Claudin 18.2 and HER2 in gastric, gastroesophageal junction, and esophageal cancers: Results from the FAST study.
Authors: Schuler Martin H. , Al-Batran Salah-Eddin , Zvirbule Zanete , Manikhas Georgy , Lordick Florian , Rusyn Andriy V. , Vynnychenko Ihor , Dudov Assen , Bazin Igor , Melichar Bohuslav , Dhaene Karl , Wiechen Kai , Maurus Daniel , Tureci Özlem , Sahin Ugur 
Published: September 2018

4038 Background: Claudin 18.2 (CLDN18.2), a gastric mucosa tight junction protein, is aberrantly expressed in various cancers. In the FAST Phase 2 trial (NCT01630083), IMAB362, an anti-CLDN18.2 monoclonal antibody, administered in combination with EOX chemotherapy, prolonged survival compared to EOX alone in patients with advanced/recurrent gastric, gastroesophageal junction (GEJ), and esophageal cancers ineligible for trastuzumab. The aim of the present analysis was to assess tumor CLDN18.2 expression and co-expression with HER2 in the FAST population. Methods: Tumor tissue samples from patients screened for inclusion into the FAST trial were analyzed for CLDN18.2 expression using a CE-marked, validated immunohistochemistry (IHC) assay. CLDN18.2 expression was centrally scored based on staining intensity and percentage of stained tumor cells. In a subset of tissue samples with known HER2 status, overall HER2 expression and co-expression with CLDN18.2 were determined. Results: Tissue samples from 730 patients with gastric, GEJ, and esophageal cancer were screened for the FAST study. Of these 730 samples, 685 (94%) were assessed by central IHC; 49% (n=333/685) met the FAST CLDN18.2 expression criterion (≥2+ intensity in ≥40% of tumor cells) for inclusion. Across the 154 tissue samples with known HER2 status, the majority (84%; n=129/154) were HER2–. Furthermore, 94 of these 154 samples (61%) met the FAST CLDN18.2 expression criterion, of which 14% (n=13/94) co-expressed HER2 (Table). Conclusions: In tissue samples from patients screened for the FAST trial, nearly half met CLDN18.2 expression inclusion criterion. In samples with known HER2 status, co-expression of CLDN18.2 and HER2 occurred in 14% of the samples that met study eligibility. These data suggest CLDN18.2 may serve as a non-HER2 overlapping targetable alteration in a distinct subpopulation of patients with gastric, GEJ, or esophageal cancers. Clinical trial information: NCT01630083. [Table: see text]
Cardiac death rates after irradiation for esophageal cancer: An epidemiologic study among esophageal cancer survivors.
Authors: Molenaar Remco Jurriaan , Radivoyevitch Tomas , Hulshof Maarten , Van Laarhoven Hanneke W.M. 
Published: September 2018

4049 Background: Esophageal cancer is frequently treated with radiation in addition to surgery and/or chemotherapy. Long-term survivors that received radiation may be at risk for radiation-induced cardiotoxicity. Methods: Esophageal cancer survivors (defined as surviving > 5 yrs after diagnosis) from all 18 Surveillance Epidemiology and End Results (SEER) registries from 1973 to 2013 were queried for irradiation status, cause of death and survival using SEERaBomb, a package for the R statistical programming language. Results: 6,514 esophageal cancer survivors were identified, of whom 2,892 (44%) received no radiation therapy and 3,448 (53%) received external beam radiotherapy. Mean age at the time of esophageal cancer diagnosis was 64.0 yrs in the no radiation group and 63.0 yrs in the radiation group. Median person years of follow up after esophageal cancer diagnosis was 8.6 yrs (interquartile range [IQR]: 7-12) in pts receiving no radiation and 7.9 yrs (6-11) in pts receiving radiation. A total of 590 esophageal cancer survivors died of cardiac disease; 254 received no radiation and 336 did receive radiation. Median time to cardiac death after esophageal cancer diagnosis was 32.2 yrs (IQR: 19-38) in pts that received no radiation and 25.3 years (15-30) in pts that received radiation (log-rank P< 0.001). Compared with unirradiated pts, irradiated pts had an increased risk of dying of cardiac disease (hazard ratio [HR] = 1.47; 95% confidence interval [CI]: 1.2-1.7, Cox regression P< 0.001). The association between radiation and cardiac death was the strongest in esophageal cancer pts diagnosed before 1995 (HR = 1.75; 95% CI: 1.4-2.2, P< 0.001) and in squamous cell carcinoma of the esophagus (HR = 1.9; 95% CI: 1.4-2.6, P< 0.001) but not in adenocarcinoma (HR = 1.04; 95% CI: 0.8-1.4, P= 0.8). Conclusions: 5-year esophageal cancer survivors that were treated with radiotherapy have an increased risk of dying of cardiac disease, compared with unirradiated counterparts. This association was strongest in pts treated before 1995 and in squamous cell carcinoma pts. This may be due to late radiation-induced cardiotoxicity, decreasing with the use of heart-sparing radiation techniques after 1995.
Pathophysiology and therapeutic strategies for peritoneal recurrence after gastric cancer surgery.
Authors: Murata Satoshi , Takebayashi Katsushi , Yamamoto Hiroshi , Yamaguchi Tsuyoshi , Kaida Sachiko , Kodama Hirokazu , Ohtake Reiko , Shimizu Tomoharu , Mori Tsuyoshi , Kawai Yuki , Kitamura Naomi , Miyake Toru , Akabori Hiroya , Iida Hiroya , Ueki Tomoyuki , Sonoda Hiromichi , Mori Haruki , Nitta Nobuhito , Naka Shigeyuki , Tani Masaji 
Published: September 2018

4050 Background: We recently showed that cancer cells, with proliferative and tumorigenic potential, can spill into the peritoneal cavity during curative (R0) gastric cancer (GC) surgery, which is associated with peritoneal recurrence (PM). To elucidate the pathophysiology of PM, the relationship between spilled cancer cells and cancer stem cells was evaluated. Furthermore, to identify a therapeutic strategy for PM, the prognostic impact of hyperthermic intraperitoneal chemotherapy (HIPEC) following GC surgery with spillage of cancer cells was evaluated. Methods: Patients with advanced GC (≥pT2 [MP]) who underwent R0 gastrectomy between 2010 and 2015 were enrolled. Ninety-four consecutive patients with negative results in peritoneal cytology and cancer cell culture (CCC [-]) following peritoneal washing (PW) before GC surgery were included. Spilled cancer cells in PW after GC surgery (PW-Post) were examined to identify any CD44-positive cancer stem-like cells associated with cancer metastasis. Based on the PW-Post CCC results, associations between HIPEC and recurrence-free survival (RFS), or overall survival (OS) were evaluated. HIPEC was performed following GC surgery using CDDP, MMC, and 5-FU in 5 L saline maintained at 42˚C for 30 min. Results: Spilled cancer cells included CD44+ cancer stem-like cells. In 48 patients with PW-Post positive CCC (CCC [+]), the number of patients with pStage I, II, and III were 4, 7, and 15, respectively, in those who received HIPEC (n = 26), and 3, 9, and 10, respectively, in those who did not (n = 22). Among patients with CCC (+), the 5-year peritoneal RFS, hepatic RFS, and lymph node RFS rates were 93.3%, 100%, and 68.5%, respectively, in patients who received HIPEC, and 56.7%, 35.6%, and 66.7%, respectively, in those who did not ( P = 0.008, P = 0.008, and P= 0.24, respectively). Among patients with PW-Post CCC (-), none developed recurrence, regardless of whether they received HIPEC (n = 28) or not (n = 18). Conclusions: The results show that PW-Post CCC is a promising predictive biomarker for recurrence after R0 GC surgery. Adjuvant HIPEC performed with R0 GC surgery showed preventive effects on peritoneal and hepatic recurrence and survival benefits for patients with PW-Post CCC (+).
Long-term outcomes with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal carcinomatosis from appendiceal cancer: An 18-year experience.
Authors: Munoz-Zuluaga Carlos A. , Sardi Armando , Sittig Michelle , Eskay Victoria , Nieroda Carol Ann , El-Sharkawy Farah , Sipok Arkadii , Gushchin Vadim 
Published: September 2018

4098 Background: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) have become standard of care for patients with peritoneal carcinomatosis (PC) from appendiceal cancer (AC). We reviewed our experience and outcomes. Methods: A retrospective review of 614 CRS/HIPEC procedures from 1998-2016 was performed. Patient characteristics, surgical variables, and postoperative outcomes of first CRS/HIPEC were analyzed. Results: Two hundred ninety patients with PC from AC underwent 334 CRS/HIPEC’s. Median age at diagnosis and surgery was 52 (22-79) and 53 (23-81) years, respectively; 65% (187) were female. Prior surgical score was 0, 1, 2, and 3 in 20%, 38%, 37%, and 5%, respectively. Prior systemic chemotherapy was reported in 30% of patients. Median time from diagnosis to CRS/HIPEC was 4 months (0-182). Pre-operative tumor markers (CEA, CA-125, CA-19-9) were positive in 48% with one, two, and three positive markers in 21%, 15%, and 13% patients, respectively. Median Peritoneal Cancer Index was 29. Mitomycin-C was the HIPEC agent of choice. Mean operative time was 10 hours (R: 4-19) and median length of stay was 10 days (R: 4-93). Histology included 59% (171) peritoneal mucinous carcinomatosis (PMCA), 41% (119) disseminated peritoneal adenomucinosis (DPAM). Lymph nodes were positive in 47% PMCA. Complete cytoreduction rate was 87% (84% PMCA, 92% DPAM [p = 0.048]). Grade III-V complications occurred in 21%, with one 30-day mortality (0.3%). Overall, median progression-free survival (PFS) was 84 months with 5-year PFS of 56%. Median PFS was 43 months in PMCA and not reached in DPAM. Five year PFS was 40% PMCA and 82% DPAM (p < 0.001). Median overall survival (MOS) was 139 months with 61% 5-year OS. MOS was 53 months in PMCA and not reached in DPAM. Five year OS was 47% PMCA and 85% DPAM (p < 0.001). At 42-month median follow-up, 68% were alive (92 PMCA/103 DPAM) with 84% disease free (72 PMCA/92 DPAM), 28% died of disease (73 PMCA/7 DPAM). Conclusions: CRS/HIPEC is an effective treatment for patients with PC from AC providing meaningful long term survival in low and high grade tumors and should be considered the standard of care.
Potential role of circulating tumor DNA (ctDNA) in the early diagnosis and post-operative management of localised pancreatic cancer.
Authors: Lee Belinda , Cohen Joshua , Lipton Lara Rachel , Tie Jeanne , Javed Ammar Asrar , Li Lu , Goldstein David , Cooray Prasad , Nagrial Adnan , Burge Matthew E. , Tebbutt Niall C. , Nikfarjam Mehrdad , Harris Marion , O'Broin-Lennon Anne Marie , Wolfgang Christopher Lee , Tomasetti Cristian , Papadopoulos Nickolas , Kinzler Kenneth W. , Vogelstein Bert , Gibbs Peter 
Published: September 2018

4101 Background: Pancreatic cancer remains a devastating disease, with the diagnosis typically being made late. ctDNA has shown promise as a screening test for various tumor types. The detection of ctDNA post curative intent surgery has been associated with a high risk of recurrence in multiple solid tumors. We explored the potential of ctDNA to improve pancreatic cancer outcomes. Methods: Data from separate US and Australian series were combined. Plasma samples were collected prior to surgery in both studies and post-operative samples were collected in Australia from cases undergoing curative intent surgery. Clinicians were blinded to ctDNA results and adjuvant therapy was at clinician discretion. Tissue samples from both series were analyzed at Johns Hopkins University. Next generation sequencing was used to search for somatic KRAS mutations in the primary tumors and in cell-free DNA in the plasma. Clinico-pathologic, treatment and outcome data were collected. Results: 119 pts had a ctDNA sample at diagnosis (median age 67 years, 56.3% male). Sixty six pts (55.5 %) had detectable ctDNA, including 3/7 (42.9%) with stage I disease, 54/99 (54.5%) with stage II disease, 4/8 (50%) with stage III disease and 5/5 (100%) with metastases. Specific codon 12 KRAS (G12D, G12V or G12R) mutations were identified in the tumor tissue of 12/16 (75%) patients who had a ctDNA sample collected post-surgery. At a median follow-up of 15.2 months, 7/12 (58.3%) pts had recurred, including 3/8 (37.5%) with no detectable ctDNA and 4/4 (100%) with detectable ctDNA post-surgery (HR 4.9, p = 0.04). Detectable ctDNA post-surgery was significantly associated with poor overall survival (HR 6.93, p = 0.006), with a median of 8 months for pts with detectable ctDNA. Conclusions: ctDNA shows promise as a pancreatic cancer screening test, being detectable in a high proportion of pts with early stage disease. The detection of ctDNA post operatively predicts a very high risk of recurrence. The clinical utility of ctDNA to guide adjuvant therapy decision making, and its potential as a real-time marker of treatment effect, are being explored in further studies. Clinical trial information: ACTRN12612000763842.
Preliminary safety data from a randomized multicenter phase Ib/II study of neoadjuvant chemoradiation therapy (CRT) alone or in combination with pembrolizumab in patients with resectable or borderline resectable pancreatic cancer.
Authors: Katz Matthew H. G. , Varadhachary Gauri R. , Bauer Todd W. , Acquavella Nicolas , Merchant Nipun B. , Le Tri Minh , Javle Milind M. , Shroff Rachna T. , Overman Michael J. , Fogelman David R. , Petroni Gina R. , Slingluff Craig L. , Rahma Osama E. 
Published: September 2018

4125 Background: Pancreatic cancer (PC) is a challenging target for immunotherapy.Tumor-infiltrating lymphocytes (TILs) do not reach the PC cells in significant numbers due to the presence of stroma and a suppressive microenvironment. Neoadjuvant chemoradiation (CRT) can increase the presence of TILs in the PC microenvironment. We hypothesized that combination of CRT and pembrolizumab can lead to further increase in TILs and their activation. Methods: Patients with resectable or borderline resectable PC have been randomized 2:1 to the investigational treatment (Arm A) to receive pembrolizumab 200mg IV every 3 weeks on days 1, 22, and 43 during concurrent CRT with capecitabine (825 mg/m2 orally twice daily, Monday-Friday, on days of radiation only) and radiation (50.4 Gy in 28 fractions over 28 days) or Arm B to receive only concurrent CRT with capecitabine. Restaging CT scan or MRI is performed at 4-6 weeks after completion of neoadjuvant treatment, and patients with resectable disease will undergo surgical resection. Here we report the preliminary safety data based on 22 enrolled patients. Results: As of February 3-2017,22 patients have been enrolled (14 Arm A and 8 Arm B). 50% of the patients had resectable disease (7 arm A; 4 arm B) and the other 50% had borderline resectable disease (7 Arm A; 4 arm B). Post-neoadjuvant therapy, 6 patients had unresectable disease (3 on each arm), and 14 patients underwent surgery (10 arm A and 4 arm B). There were 7 grade 3 treatment-related toxicities in Arm A (5 patients): 2 grade 3 diarrhea attributed to CRT; 4 grade 3 lymphopenias attributed to pembrolizumab, CRT or the combination; and one patient had elevated alkaline phosphatase probably related to the combination that met the definition of DLT and resolved after holding the treatment and receiving steroids. There was only one grade 3 toxicity on Arm B: lymphopenia attributed to CRT. No grade 4 toxicities have been reported on either arm. There were no major surgical complications reported within 30 days post-surgery. Conclusions: The combination of CRT and pembrolizuamb is safe based on the presented data. Clinical trial information: NCT02305186.
Biomarker findings and mature clinical results from KEYNOTE-052: First-line pembrolizumab (pembro) in cisplatin-ineligible advanced urothelial cancer (UC).
Authors: O'Donnell Peter H. , Grivas Petros , Balar Arjun Vasant , Bellmunt Joaquim , Vuky Jacqueline , Powles Thomas , Plimack Elizabeth R. , Hahn Noah M. , De Wit Ronald , Pang Lei , Savage Mary J. , Lunceford Jared K. , Keefe Stephen Michael , Bajorin Dean F. , Castellano Daniel 
Published: September 2018

4502 Background: Comorbidities and renal impairment preclude many with advanced UC from receiving chemotherapy. Initial results from the phase 2 KEYNOTE-052 (NCT02335424) trial suggested first-line pembro is active and safe in cisplatin-ineligible advanced UC. We present updated efficacy and safety data (all pts have ≥6 mo follow-up) and evaluate biomarkers correlated with outcomes. Methods: Eligibility criteria included cisplatin-ineligible (ECOG PS 2, CrCl ≥30- < 60 mL/min, grade ≥2 neuropathy/hearing loss, NYHA Class 3 heart failure), advanced UC, and no prior systemic chemotherapy. Pts received pembro 200 mg IV Q3W. Imaging was performed at wk 9, then Q6W for the first year, and Q12W thereafter. Primary end point was confirmed ORR (RECIST v1.1, independent review). Efficacy and safety were assessed in the 370 pts with ≥1 pembro dose. The associations of an 18-gene expression profile (GEP) and IHC PD-L1 combined positive score (CPS) with ORR were evaluated. Results: As of the Dec 19, 2016, data cutoff, ORR was 29% (95% CI, 24-34): 25 (7%) and 81 (22%) pts achieved complete and partial responses. Another 69 pts (19%) had stable disease as best response, for a clinical benefit rate of 47%. Median time to response was 2 mo (range, 1-5). At a median follow-up of 8 mo (range, 0.1-20) across all pts, median duration of response was not reached (range, 1+-18+ mo). 74% of responses were ongoing. Any-grade and grade ≥3 drug-related AEs occurred in 239 (65%) and 68 (18%) pts. Immune-mediated AEs occurred in 76 (21%) pts. Evidence supporting a positive association with response was seen in the first 100 pts for both biomarkers (GEP, n = 72, P = 0.007, ROC AUC 0.69; CPS, n = 96, P= 0.111, ROC AUC 0.58); biomarker data for all pts will be presented. ORR in the 110 pts with CPS ≥10% was 47% (95% CI, 38-57). Conclusions: Results confirm that pembro elicits clinically meaningful, durable responses in cisplatin-ineligible advanced UC. Consistent with PD-1 pathway biology, biomarkers (GEP and CPS) showed the expected trends of positive association with response to pembro. Pembro was well tolerated across cisplatin-ineligible pts, including elderly and pts with poor performance status. Clinical trial information: NCT02335424.
Epacadostat plus pembrolizumab in patients with advanced urothelial carcinoma: Preliminary phase I/II results of ECHO-202/KEYNOTE-037.
Authors: Smith David C. , Gajewski Thomas , Hamid Omid , Wasser Jeffrey S. , Olszanski Anthony J. , Patel Sandip P. , Mamtani Ronac , Schmidt Emmett V. , Zhao Yufan , Maleski Janet E. , Gangadhar Tara C. 
Published: September 2018

4503 Background: Pembrolizumab (P), a PD-1 inhibitor, is active and well tolerated in platinum-treated, advanced urothelial carcinoma (UC). Epacadostat (E) potently and selectively inhibits indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan-catabolizing enzyme that suppresses T-cell–mediated immune surveillance. IDO1 overexpression is associated with tumor progression and shortened patient (pt) survival. ECHO-202/KEYNOTE-037 is an open-label, phase I/II study of E + P in pts with advanced tumors. We report phase I/II efficacy and safety outcomes for the UC cohort at an October 29, 2016 data cutoff. Methods: Adult pts with advanced UC, prior platinum therapy (adjuvant or advanced disease setting) or alternative therapy (if platinum was not appropriate), and no prior checkpoint inhibitor therapy were eligible to participate. In phase I, pts received E (25, 50, 100, or 300 mg PO BID) + P (2 mg/kg or 200 mg IV Q3W); MTD was not exceeded. E (100 mg BID) + P (200 mg Q3W) dosing was selected for phase II. Response was assessed in RECIST 1.1–evaluable pts. Safety was assessed in pts receiving ≥1 E + P dose. Results: A total of 40 pts (phase I, n = 5; phase II, n = 35) were evaluated. Median age was 67 years, 75% were men, 88% were white, 100% had prior platinum therapy, and 75% had 0–1 prior line of therapy for advanced disease. Preliminary ORR (CR+PR) and DCR (CR+PR+SD) for all efficacy-evaluable pts were 35% (13/37; all PR) and 57% (21/37; 13 PR, 8 SD), respectively; for pts with 0–1 prior line of therapy for advanced disease, ORR and DCR were 37% (10/27) and 63% (17/27). At data cutoff, 12/13 responses were ongoing (range, 1+ to 652+ days). PFS and biomarker analyses are ongoing. The most common TRAEs (≥10% of 40 pts) were fatigue (28%), rash (18%), and increased amylase (10%; asymptomatic). Grade ≥3 TRAEs occurred in 20% of pts (rash was the only grade ≥3 TRAE to occur in > 1 pt [n = 3]). Three pts discontinued due to TRAEs (grade 3 rash [n = 1]; grade 3 COPD exacerbation [n = 1], grade 2 diarrhea [n = 1]). Conclusions: E + P was generally well tolerated and associated with increased response compared with previously reported PD-1 inhibitor monotherapy in pts with advanced UC. A phase III UC study is planned. Clinical trial information: NCT02178722.
First-line avelumab + axitinib therapy in patients (pts) with advanced renal cell carcinoma (aRCC): Results from a phase Ib trial.
Authors: Choueiri Toni K. , Larkin James M. G. , Oya Mototsugu , Thistlethwaite Fiona C. , Martignoni Marcella , Nathan Paul D. , Powles Thomas , McDermott David F. , Robbins Paul B. , Chism David D. , Cho Daniel C. , Atkins Michael B. , Gordon Michael S. , Gupta Sumati , Uemura Hirotsugu , Tomita Yoshihiko , Compagnoni Anna , di Pietro Alessandra , Rini Brian I. 
Published: September 2018

4504 Background: Combining an immune checkpoint inhibitor with a targeted antiangiogenic agent may leverage complementary mechanisms of action for treatment of aRCC. Avelumab is a fully human anti–PD-L1 IgG1 antibody with clinical activity in various tumor types; axitinib, a VEGF receptor inhibitor, is approved for second-line treatment of aRCC. JAVELIN Renal 100 (NCT02493751) is a phase Ib study evaluating safety and clinical activity of avelumab + axitinib in treatment-naïve pts with aRCC; updated results are reported here. Methods: Eligible pts had confirmed clear-cell aRCC, ≥1 measurable lesion, fresh or archival tumor specimen, ECOG PS ≤1, and no prior systemic therapy. Pts received avelumab 10 mg/kg IV Q2W + axitinib 5 mg orally BID until progression, unacceptable toxicity, or withdrawal. Endpoints included safety (NCI CTCAE v4.03) and objective response (RECIST v1.1). Results: As of Dec 30, 2016, 55 pts (median age 60.0 yrs [range 42.0–76.0]; 76.4% male; 34.5% ECOG PS = 1) were enrolled. 54 pts were treated with avelumab for a median of 24.1 wks (range 2.0–62.0); 55 pts were treated with axitinib for a median of 25.3 wks (range 3.0-61.0). 51 pts (92.7%) had an avelumab-related adverse event (AE) with the therapy combination, the most common (≥30% any grade) were fatigue and diarrhea (30.9% each). 10 pts (18.2%) had a max grade 3 and 1 pt (1.8%) had a max grade 4 avelumab-related AE. 52 pts (94.5%) had an axitinib-related AE with the therapy combination; the most common (≥30% any grade) were diarrhea (52.7%), hypertension (45.5%), dysphonia (43.6%), and fatigue (43.6%). 24 pts (43.6%) had a max grade 3 and 5 pts (9.1%) had a max grade 4 axitinib-related AE. 2 deaths occurred in the study during the reporting period: 1 due to progression and 1 related to both treatments (myocarditis). An AE led to discontinuation of avelumab in 5 pts (9.1%) and axitinib in 4 pts (7.3%). Confirmed ORR was 54.5% (95% CI 40.6–68.0) based on 2 CR and 28 PR. Unconfirmed ORR was 60.0% (95% CI 45.9–73.0). Conclusions: The safety profile of the combination of avelumab + axitinib appears manageable and consistent with those agents administered as monotherapy, and early encouraging antitumor activity was observed. Follow-up is ongoing. Clinical trial information: NCT02493751.