bluuebunny/crossref_metadata_2025_split huggingface dataset:
Isolated chemotherapeutic perfusion as neoadjuvant therapy for advanced/unresectable plevic malignancy.
Authors: Wanebo Harold J. , DiSiena Michael Ross , Belliveau James , Gustafson Eric 
Published: March 2020

e13561 Background: Isolated pelvic perfusion (IPP) may have value in therapy of recurrent pelvic malignancy following previous surgery and chemoradiation. We performed 113 IPP in 78 such pts (34 palliation, and 44 pre op) using a simplified balloon occlusion technique. Methods: Of 42 patients (pts) with recurrent rectal cancer (ca), 26 had preop and 16 had palliative IPP. Other pelvic cancers included anal canal (8 pts), pelvic sarcoma (5 pts), melanoma (M) (4 pts), endometrial ca (EC) 2 pts, ovarian ca (OC) 2 pts, and bladder ca (BC) 1 pt. Chemo agents included Paclitaxel, 5FU, cisplatinum, or Oxaliplatin and mitomycin for epithelial cancer and (Doxorubicin, Ifosamide, Phenyl Alanine Mustard (PAM) for remaining tumors. High dose IPP with PAM, Paclitaxel and Cisplatin was given in 6 pts, 3 with stem cell support. Results: Palliative IPP in advanced rectal cancer (AdRca) pts relieved narcotic resistant pain (2-4 mos) in 11/16 pts (69%). Preop IPP in 26 AdRca achieved path CR in 2 pts and partial regression in 11 pts; 7 had RO resection. Of 5 other pts, 3 refused resection, 2 were inoperable. Median survival was 17 mos in 12 resectable pts and 30 mos in 7 resected pts and 8 mos in 12 non resectable pts. It was 30 months in 8 pts with anorectal ca (1>90 mos), 20 mos in 4 endometrial/ovarian ca pts, (1 died NED >48 mos), 13 mos in 4 M pts and 5 (4-34) mos in 5 pelvic sarcoma pts. Overall 17 of 44 (39%) were resected and 24 were palliated with IPP. Conclusions: IPP has value in palliating or augmenting resectability and survival in advanced pelvic cancer patients not amenable to conventional chemoradiation and surgery.
Evaluation of KPT-SINE (Selective Inhibitors of CRM1-Mediated Nuclear Export) in AML and T-ALL.
Authors: Etchin Julia , Kentsis Alex , Sanda Takaomi , Kung Andrew L. , Stone Richard M. , McCauley Dilara , Kauffman Michael , Shacham Sharon , Look A. Thomas 
Published: March 2020

e13586 Background: CRM1 is the major nuclear exporter that mediates transport of a variety of molecules, including proteins involved in tumor suppressor and cellular proliferation pathways. The crystal structure of CRM1, in complex with its export cargo, Snurportin 1, has been recently resolved. The molecular understanding of the CRM1-cargo binding interface has led to the development of novel small molecule inhibitors of CRM1-cargo interaction, termed KPT-Selective Inhibitors of Nuclear Export (SINE). KPT-SINE are potent, drug-like CRM1 inhibitors that irreversibly inactivate the CRM1-directed protein export by covalent modification of the essential CRM1-cargo binding residue Cys528. The inhibition of the CRM1 nuclear export has been shown to lead to selective apoptosis in cancer cells when compared to normal cells. Here, we assess the efficacy of the KPT-SINE in human AML, T-ALL, and normal hematopoietic cells. Methods: The viability of a panel of human AML and T-ALL cell lines upon treatment by the KPT-SINE was assessed. Dose-response measurements were done using serial dilutions of KPT-SINE from 1 µM to 0.3 nM and luminescent cell viability assay. Apoptosis was measured using Annexin V staining and TUNEL assays. Results: KPT-SINE induces rapid apoptosis in 10 of 14 AML and 12 of 15 T-ALL cell lines with IC50s of 15-100 nM. In the KPT-SINE-sensitive cell lines, BCL2 overexpression suppresses KPT-SINE-induced apoptosis, indicating its intrinsic pathway mediation. Importantly, KPT-SINE compounds, either KPT-251 at 75 mg/kg or KPT-330 at 15 or 25 mg/kg, induced remarkable growth suppression in MV4-11 human AML cells engrafted into immunodeficient NSG mice with minimal toxicity to normal mouse hematopoietic cells after 35 days of treatment. Bone marrow biopsies of KPT-treated mice were remarkable in that they showed normal hematopoietic cell morphology and cellularity after 35 days of treatment. Xenograft studies to address the potency of the KPT-251 and KPT-330 on MOLT-4 human T-ALL cells in vivo are ongoing. Conclusions: These studies emphasize the clinical promise of the KPT-SINE as a novel and selective drug candidate for the treatment of AML and T-ALL.
Pharmacodynamic evaluation of pCDC2 as the target engagement biomarker to assess activity of MK-1775 a Wee1 tyrosine kinase inhibitor.
Authors: Rose Shelonitda , Cheng Jonathan D. , Viscusi Johnny , Iannone Robert , Schellens Jan HM , Leijen Suzanne , Shapiro Geoffrey , Pavlick Anna C. , Oza Amit M. , Rosen Lee S. , Tosolini Alessandra , Lam Raymond , Demuth Tim 
Published: March 2020

e13598 Background: Wee1 kinase regulates the G2 checkpoint through phosphorylation of CDC2. MK-1775 is a first-in-class inhibitor of Wee1, and thereby reduces pCDC2 levels relative to CDC2. pCDC2therefore can be used as a target engagement (TE) biomarker to assess activity of MK-1775. This was investigated in a phase I first-in-man clinical trial of MK-1775. Methods: This is a multicenter, open-label, non-randomized phase I dose escalation study in patients with locally advanced or metastatic solid tumors. MK-1775 was administered orally in escalating doses as monotherapy, and either single dose or multi-dose in combination with chemotherapy including cisplatin, carboplatin and gemcitabine. Serial skin biopsies were performed at baseline and either 8, 24 or 48 hours following MK-1775 administration and analyzed by IHC for CDC2 and pCDC2. Based on preclinical efficacy experiments, TE was defined as a decrease of pCDC2 of at least 50% (or fold change > 0.50) from pre- to post-dose MK-1775. Results: To date a total of 176 patients have received at least one dose of MK-1775 either as monotherapy or in combination (single or multi-dose MK-1775) with chemotherapy at doses ranging from 25 mg to 1300 mg to define maximum tolerated dose. Dose dependent decreases in pCDC2 were observed in skin biopsies between pre-dose and post-dose treatment in all treatment groups. TE with monotherapy was achieved at 325 mg. TE with multi-dose MK-1775 in combination with cisplatin and carboplatin were achieved at 125 mg BID and 225 mg BID. Gemcitabinecombination treatment is on-going. In contrast, chemotherapy alone resulted in an increase of pCDC2. Conclusions: Based on preclinical data, in this first-in-man clinical trial of MK-1775, we were able to demonstrate TE required for maximal efficacy at tolerable doses of MK-1775 either as a single agent or in combination with chemotherapy. [Table: see text]
A phase I dose escalation study of oral MK-2206 (allosteric Akt inhibitor) with oral selumetinib (AZD6244; ARRY-142866) (MEK 1/2 inhibitor) in patients with advanced or metastatic solid tumors.
Authors: Khan Khurum Hayat , Yan Li , Mezynski Janusz , Patnaik Amita , Moreno Victor , Papadopoulos Kyriakos P. , Garrett Chris R. , Ong Michael , Shannon Keith A. , Morosky Anne , Rubin Eric H. , Tetteh Ernestina , Skolnik Jeffrey , Smith Ian C. , Smith Paul D. , De Bono Johann Sebastian , Tolcher Anthony W. 
Published: March 2020

e13599 Background: Simultaneous inhibition of both the PI3K-Akt and RAF/MEK/ERK pathways may yield greater benefits than inhibiting either pathway alone. This phase I study (NCT01021748) examined the safety, pharmacokinetics (PK), pharmacodynamics (PD), maximal tolerated dose (MTD), and preliminary antitumor activity of the combination of a MEKi (selumetinib) and AKTi (MK-2206). Methods: Eligible patients (pts) with advanced solid tumors were treated with MK-2206 either every other day (QOD) or once weekly (QW), in combination with selumetinib administered either once daily (QD) or twice daily (BID). Results: 51 pts with advanced solid tumors (15 colon, 8 NSCLC, 6 ovarian, 5 pancreatic, 3 breast and 14 others) were treated across 9 dose levels. There were 2 confirmed partial response (PR) (1 NSCLC, ongoing > 52 wks; 1 ovarian, on treatment for 47 weeks; both KRAS mutation positive), 1 unconfirmed PR (pancreatic, on treatment 20 wks), and 24 pts with stable disease (ranged from 6 to 47 wks). Preliminary assessment of PK data suggested no apparent drug-drug interactions with unaltered PK profiles of each drug when administered in combination. Conclusions: In combination the maximum tolerated doses of MK-2206 and selumetinib are 135 mg QW and 100 mg QD, respectively. This combination of investigational agents demonstrated preliminary antitumor activity in pts with advanced cancer. [Table: see text]
A phase I study of MDM2 antagonist RG7112 in patients (pts) with relapsed/refractory solid tumors.
Authors: Kurzrock Razelle , Blay Jean-Yves , Bui Nguyen Binh , Wagner Andrew J. , Maki Robert G. , Schwartz Gary K. , Patnaik Amita , Gore Lia , Wu Lin , Vassilev Lyubomir T , Ding Michelle , Geho David , Zhi Jianguo , Middleton Steven , Nichols Gwen L. 
Published: March 2020

e13600^ Background: RG7112 is a small molecule MDM2 antagonist, designed to non-genotoxically activate p53. A phase I dose escalation (DE) was performed, followed by a sarcoma biomarker extension (EXT) in pts with wild type TP53. Methods: 106 pts (58M, 48 F), median age 57.9 yrs (range 22-84) participated; 76 in 9 cohorts (DE) from 20 to 1800 mg/m2, orally QD x 10 q28 days. 30 pts with sarcoma were treated at MTD (2500 mg) (EXT) with pre-and on dose (d5+/-2) biopsies. Analyses included TP53 mutation (AmpliChip), MDM2 amplification (ISH), p53 and p21 IHC, MDM2 RT-PCR, Ki-67, TUNEL and [18F]-FLT-PET. Blood was obtained for PK and MIC-1, a PD marker of p53 activation. Results: DE: MTD was1440 mg/m2/d (2500 mg flat dose). PK was ~dose linear (t½ 1-1.5 d) with high variability (CV~70%) in AUC and Cmax . Adverse events included nausea/GI and exposure-related neutropenia/thrombocytopenia. 3 DLTs: diarrhea, pancytopenia, hyponatremia occurred (at ≥ 640 mg/m2). Evidence of activity included: 1) concentration dependent increase in plasma MIC-1 (% baseline), 2) decrease in [18F]-FLT PET and PR each in liposarcoma pts at 1800 mg/m2 and 1440 mg/m2, respectively. EXT: Grade3/ 4 cytopenias at MTD precluded subsequent cycles in 6/8 pts (10 day schedule). Dosing was changed to 5 days, and only 3 patients had Gr3/4 cytopenias. 8/22 pts remained on study for >4 cycles, including 2 pts with SD for 7 and 9 cycles respectively. 3 of 4 EXT pts had decreased [18F]-FLT-PET activity. Biopsies (pre- and on treatment) demonstrated: 1) increase in p53 (median 1.5 fold change (X) by IHC, n=15); 2) increase in p21 (median 2.7X by IHC, n=14); 3) increase in MDM2 (median 2.5X by RT-PCR, n = 27); 4) decrease in % Ki-67(+) cells (median % change from baseline -65.4%, range -91% to +275%, n=17 ); 5) increase in TUNEL(+) cells of 9.0 (density of + cells/mm2, range -26.2 to +45.5, n=22). These results were seen both in tumors with and without MDM2 gene amplification, and in multiple sarcoma subtypes. Conclusions: RG7112 has manageable AEs (GI ) and cytopenias correlating with AUC. Single agent disease control, and biomarker activity was seen in both MDM2 amplified and non-amplified, heavily pretreated soft tissue sarcoma pts, with changes reflecting activation of p53-related pathways.
Relationship of loss of miRNA-296 in the circulation and clinical outcome in patients receiving systemic chemotherapy for metastatic colon cancer.
Authors: Mikhail Sameh , Shivapurkar Narayan , Bai Wei , Marshall John , Hwang Jimmy J. , Pishvaian Michael J. , Wellstein Anton , He Aiwu Ruth 
Published: March 2020

e14009 Background: Several studies highlighted the potential for serum microRNA (miRNA) as prognostic and/or predictive markers. We describe an association between miR-296 and outcomes in a phase II trial of sunitinib and capecitabine in first line treatment of patients with metastatic colorectal cancer. Methods: Serum samples were obtained from subjects at (1) Screening (2) Prior to start of study drug (3) Every four weeks while on study. We compared miRNA levels and response to treatment at baseline and at four weeks. Results: Serum from seven patients was used to run miRNA array (382 miRNAs). Among the seven patients, three patients had decrease in the level of miR-296 at 4 weeks (Table). These patients were on the study treatment for a mean duration of 2.5 months (median 1.9). They had a mean survival from the time of diagnosis of 10.5 months (median 10.4) and a mean survival from time of enrollment of 7.5 months (median 8.7). Four patients had increase in the level of miR-296 at 4 weeks. These four patients were on the study treatment for a mean duration of 5 months (median 5). They had a mean survival from the time of diagnosis of 22.8 months (median 22) and a mean survival from study entry of 17.1 months (median 18.3). The duration on study treatment and the difference in survival from diagnosis, between the two groups were statistically significant (p=0 .014 and p=0.0025, respectively). Patients with shorter survival and poor clinical outcome had decrease in the level of miR-296 at four weeks from the start of treatment (0.43 versus 28 for patients with better clinical outcome; p=0.035). Conclusions: In our study, miR-296, served as a predictive and prognostic marker for clinical outcome of patients receiving systemic treatment for advanced colorectal cancer. Further studies are needed to confirm our results in a larger population. [Table: see text]
A phase II multicenter trial of mFOLFOX6 as adjuvant treatment after resection of liver metastases from colorectal cancer (Miyagi-HBPCOG Trial-001): The final data of progression-free survival.
Authors: Katayose Yu , Yamamoto Kuniharu , Takemura Shinichi , Takahashi Michinaga , Nakamura Ryuji , Shimamura Hiromune , Asanuma Taku , Uchiyama Tetsuyuki , Endo Kojin , Oikawa Masaya , Shiiba Kenichi , Nakagawa Kei , Egawa Shinichi , Unno Michiaki ,   Miyagi-HBPCOG
Published: March 2020

e14011 Background: Perioperative chemotherapy with FOLFOX4 reduces the progression-free survival of patients with liver metastases from colorectal cancer. However, the benefit of adjuvant treatment after hepatectomy has not been clarified yet. Here, we evaluated the efficacy of treatment with mFOLFOX6 in a postoperative adjuvant setting. Methods: We recruited 49 patients from 17 hospitals (Japan) between July 2006 and June 2009 who were histologically proved to have colorectal cancer. The primary tumor had to be resected with R0 or R1 resection, and no detectable extrahepatic metastases. This report is the trial’s final data for progression-free survival (PFS) in all enrolled cases, while overall survival is still being monitored. The regimen was 12 cycle of mFOLFOX6. The primary endpoint was progression-free survival. This study was planned to detect a 20% increase in median PFS from 40% to 60% in all assigned patients based on the data of several previous surgeries, and the set of 50 cases. Results: 1 patient did not start the protocol treatment because liver metastases were detected before starting. 48 patients started the protocol treatment. 4 patients committed a protocol violation. Excluding this 4 violation cases from the 49 cases, 33 cases (75%) received 10 course (83.3%) of mFOLFOX6. The dose intensities of oxaliplatin, leucovorin, and 5-FU were 75.9%, 80.5%, 78%, respectively in all enrolled cases. The PFS at 2 years was 59.2%. The median survival time was 49 months. The PFS for single liver metastasis was better than that for multiple metastases (Wilcoxon test: p<0.05). Overall survival was 72%. There were no Grade 4 adverse events (AE) or deaths related to chemotherapy. In Grade 3 AE, neutropenia, sensory disturbance, thrombocytopenia, and allergy were 37.5%, 8.3%, 8.3%, and 8.3%, respectively. Conclusions: Adjuvant treatment with mFOLFOX6 is feasible and could greatly improve the PFS without biologics. The benefit of this therapy with mFOLFOX6 as an adjuvant treatment needs to be evaluated further as compared to perioperative chemotherapy.
Identification of the biomarkers for the prediction of efficacy in the first-line chemotherapy of metastatic colorectal cancer patients using SELDI-TOF-MS and artificial neural networks.
Authors: Yuan Ying , Shen Hong , Li Mo-Dan , Tan Chun-Wen , Yu Jie-Kai , Fang Xue-Feng , Zheng Shu 
Published: March 2020

e14026 Background: For patients with metastatic colorectal cancer, both FOLFOX regimen and FOLFIRI regimen are considered as first-line choices. However, only about half of patients could have an obvious response, and there are no clinically useful markers that could predict the response to these regimens respectively. A major clinical challenge is to identify the subset of patients who could benefit from those regimens. We aimed at identifying serum protein patterns which could predict the efficacy of chemotherapy. Methods: Serum from 70 patients diagnosed as metastatic colorectal cancer before first-line chemotherapy were collected and analyzed for protein patterns using artificial neural networks (ANN) analysis of surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). Among the 70 cases, 44 patients received FOLFOX chemotherapy, while the other 26 patients received FOLFIRI chemotherapy. After four cycles of the treatment, RECIST criteria were used to define the responders (R) and non-responders (NR). Results: With the method of SELDI-TOF-MS,a potential predicting pattern consisting of 6 biomarkers (9,298m/z, 9,282m/z, 4,606m/z, 9,198m/z, 7,775m/z and 2,266m/z) was identified in the patients receiving FOLFOX chemotherapy. Using this predicting pattern, the responders could be separated from the non-responders with a sensitivity of 92.9%, and a specificity of 81.3%. Another potential predicting pattern that consisted of 7 biomarkers (4,321m/z, 4,305m/z, 2,648m/z, 2,952m/z, 4,121m/z, 4,292m/z and 3,980 m/z) was identified in the patients who have received FOLFIRI chemotherapy. Using this predicting pattern, the responders could be separated from the non-responders with a sensitivity of 92.3% and a specificity of 92.3 %. Conclusions: Two potential patterns for the prediction of efficacy of FOLFOX or FOLFIRI chemotherapy were established in this preliminary study. These protein patterns could be helpful for oncologists to make a decision in selecting suitable first-line regimens for metastatic colorectal cancer patients.
Frequency of second- and third-line treatment among elderly Medicare stage IV colon cancer patients.
Authors: Mullins C. Daniel , Bikov Kaloyan A , Onukwugha Ebere , Seal Brian S. , Hanna Nader 
Published: March 2020

e14035 Background: Stage IV colon cancer (CC4) patients may receive multiple lines of chemotherapy and/or biologics as treatment (TX) to improve survival or quality of life, yet elderly patients generally receive less aggressive cancer TX. Methods: Elderly (65+) SEER-Medicare patients diagnosed with CC4 in 2003-7 were followed through death or 2009 to examine variation across sub-groups in the number of TX lines. TX included 5-fluorouracil and (levo)leucovorin-based (5FU/LV); irinotecan (IRI) and/or oxaliplatin (OX) with/out 5FU/LV; bevacizumab, cetuximab, or panitumumab (MNCLA), alone or in combination with chemotherapy; and other TX. A hierarchy categorized treatments as: 1) IROX (IRI+OX); 2) IRI or OX; 3) 5FU/LV; 4) MNCLA without chemotherapy; and 5) other TX. Gaps in TX or changes from OX or IRI to 5FU/LV were not considered new lines. Results: Of 7,937 elderly CC4 patients, 3,263 (41%) received any TX, while 1,541 (19%) and 570 (7%) received second and third line TX, respectively. Among the TX group, younger (p<0.01), married (51 vs. 42%, p < 0.01) and male (49 vs. 45%, p = 0.02) patients were more likely to go on to second line TX. Medicare buy-in coverage, which generally indicates dual Medicaid-Medicare coverage (42 vs. 48%, p = 0.03), lowered the likelihood of second line TX. Having comorbidities impacted initial TX (CCI=0: 44.5%, CCI=1: 41.9%, CCI=2: 28.4% ; p<0.01) more so than the likelihood of second (CCI=0: 48.6%, CCI=1: 45.9%, CCI=2: 42.4% ; p=0.06) or third (CCI=0: 37.2%, CCI=1: 39.9%, CCI=2: 29.9% ; p=0.09) line TX conditional upon receipt of prior line treatment. There was no significant association between second line TX and race/ethnicity, urbanicity or year of cancer diagnosis. Among those with second line TX, only age (p=0.05) and urbanicity (38 urban vs. 25% non urban, p < 0.01) were significantly associated with higher likelihood of third line TX. Conclusions: Among CC4 patients with TX, married patients and men receive more TX lines, while number of treatment lines decreases with age. Tendency to use less aggressive treatment with elderly CC4 patients, combined with our observed results, suggests that a substantial proportion of elderly CC4 patients receive fewer TX lines than equivalent younger patients.
Effect of brain-derived neurotrophic factor/TrkB axis on cancer progression in colorectal cancer.
Authors: Inoue Yasuhiro , Okugawa Yoshinaga , Saigusa Susumu , Hiro Junichiro , Toiyama Yuji , Tanaka Koji , Mohri Yasuhiko , Kusunoki Masato 
Published: March 2020

e14039 Background: Brain-derived neurotrophic factor (BDNF) is one of the member of the neurotropin family known to activate the high affinity tyrosine kinase B (TrkB) receptor together with the pan-neurotropin low-affinity coreceptor p75 (p75NTR). TrkB activation by BDNF has been shown to facilitate the progression of several cancers, however, no reports have shown the clinical and biological effects of BDNF/TrkB axis expression in colorectal cancer(CRC). Methods: A total of 223 consecutive patients undergoing surgery for CRC were enrolled. We analyzed BDNF/TrkB mRNA levels by real-time reverse transcription PCR in CRC tissues, and their relationships with clinicopathological findings including survival were investigated. BDNF and TrkB expression were also evaluated by immunohistochemistry. To investigate the biological role of the BDNF/TrkB axis, recombinant human BDNF and Trk antagonist K252a were used for proliferation, migration, and anoikis assays in CRC cell lines. Results: The mean BDNF level in CRC tissue was 94.3 (0-1326.8). One hundred five of 223 patients (47.1%) showed detectable BDNF levels, whereas the remainder had no detectable. BDNF positive expression was significantly associated with undifferenciated histological type, lymph node metastasis, and hepatic metastasis. In addition, increased BDNF/TrkB axis expression associated with lymph node metastasis, hepatic metastasis, and peritoneal disseamination. Immunohistochemical analysis indicated intense BDNF expression in the cytoplasm of cancer cells, and intense TrkB expression in the nuclei of cancer cells, respectively. In vitro, administration of recombinant human BDNF promoted proliferation, anoikis resistance, and partial migration. These effects were generally inhibited by Trk antagonist K252a. Conclusions: We demonstrated the clinical and biological function of BDNF/TrkB axis in CRC. BDNF/TrkB axis appears to play an important role in cancer progression, and blocking this pathway might be clinically useful in developing therapies for patients with CRC.