tbuckley/cabot-search huggingface dataset:
Chemoradiation for the treatment of locoregional squamous cell carcinoma of the anal canal: A single center retrospective analysis in Japan.
Authors: Ryo Takahashi, Takeru Wakatsuki, Eiji Shinozaki, Senzo Taguchi, Yoshiya Fujimoto, Hiroki Osumi, Yumiko Ota, TOMOHIRO MATSUSHIMA, Mariko Ogura, Takashi Ichimura, Daisuke Takahari, Mitsukuni Suenaga, Keisho Chin, Masahiko Oguchi, Masashi Ueno, Kensei Yamaguchi
Journal: Journal of Clinical Oncology (2018)

851 Background: Squamous cell carcinoma of the anal canal (SCCA) is a rare malignancy. In western countries, chemoradiotherapy (CRT) has become the standard treatment for locoregional SCCA according to National Comprehensive Cancer Network guidelines. But only some small amount case reports have been found about CRT for SCCA in Japan. We retrospectively evaluated the results of CRT for SCCA at a single center in Japan. Methods: We had treated 33 patients with the concurrent CRT at the Cancer Institute Hospital between 2007 and 2017. RT consisted of 45.0 to 59.4 Gy given in 5 to 7 weeks, with a daily dose of 1.8 Gy. Chemotherapy was given during RT: 1000mg/m 2 daily fluorouracil (FU) as a continuous infusion on day 1 to 4 and 29 to 32, and a single dose of mitomycin C (MMC) 10mg/m 2 administered on day 1 and 29. Data on relapse and deaths were obtained until August 2017. Results: Of 33 patients who were treated with CRT, the median age was 59 (range 35-82) years. Male to female sex ratio was 1:4.5. Patients who had Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 were 88% and patients who had ECOG PS 1 were 12%. The clinical stages before CRT were cStage I in 9 (27%), II in 4 (12%), IIIA in 6 (18%) and IIIB in 14 (42%). Although clinical complete response (CR) was observed in 29 patients of 33 (88%), 5 patients of 29 recurred. No patients recurred in cStage I and II. SCCA remained or recurred in 2 patients of 6 in cStage IIIA and 7 patients of 14 in cStage IIIB. 3-year disease free survival (DFS) was 71.3% (95%CI: 52.0-84.0%), and 3-year overall survival was 81.8% (95%CI: 55.1-92.8%). Conclusions: CRT for SCCA resulted in clinically meaningful impact on DFS and OS in our hospital. Therefore, CRT may be the standard of treatment also in Japan.
Mechanisms of Acquired Resistance to Gilteritinib Therapy in Relapsed and Refractory FLT3 -Mutated Acute Myeloid Leukemia
Authors: Christine M. McMahon, Jonathan Canaani, Bryan Rea, Rachel Lynn Sargent, Jennifer J.D. Morrissette, David B. Lieberman, Christopher Watt, Gregory W. Schwartz, Robert B. Faryabi, Timothy T. Ferng, Neil P. Shah, Catherine C. Smith, Martin Carroll, Alexander E. Perl
Journal: Blood (2017)
Combination between a long-acting engineered cytokine (NKTR-214) and checkpoint inhibitors anti-CTLA-4 or anti-PD1 in murine tumor models.
Authors: Seema S. Kantak, Steve Lee, Murali Addepalli, Ute Hoch, Rhoneil Pena, Yolanda Kirksey, Deborah H. Charych, Stephen K. Doberstein
Journal: Journal of Clinical Oncology (2014)

3082 Background: Durability of response is the hallmark of immunotherapy but only a fraction of patients experience this prolonged benefit. Recent studies suggest more patients may benefit from combining agents with complementary immunological mechanisms. NKTR-214 is an engineered form of IL-2 that directly activates cytotoxic T cells by targeting the IL-2 receptor beta subunit and exhibits a pharmacokinetic profile that is more like an antibody than a cytokine. Anti-CTLA-4 and anti-PD1 are antibodies that block negative regulation of T cells. Here we show that combining either antibody with NKTR-214, provides significant tumor growth inhibition in resistant mouse models. Methods: For combination studies, BALB/c mice bearing established CT-26 (Colon Carcinoma) or EMT6 (Mammary Carcinoma) tumors were treated with single agent NKTR-214, murine anti-CTLA-4 antibody, murine anti-PD-1 or the two agents in combination. Results: NKTR-214 exhibits a plasma and tumor exposure that is 600-fold and 500-fold greater respectively, than an equivalent dose of the original IL-2 cytokine. The optimized PK profile allows q9d dosing schedule instead of bid; the latter being typical for cytokines. In both the EMT-6 and the CT-26 models, the combination of NKTR-214 with anti-CTLA-4 provided 10/12 and 8/12 tumor-free animals respectively, up to 40 days after the last dose and showed clear synergy compared to either agent alone. The combination with anti-PD1 was also synergistic and showed tumor regression in 5/10 animals. Single agent administration did not show any significant tumor growth inhibition in these models. The combinations were well tolerated with no body weight loss or other clinical signs. Conclusions: NKTR-214 directly stimulates cytotoxic T cells and is therefore complementary to the mechanism of checkpoint inhibition using antibodies. The favorable pharmacokinetics of NKTR-214 enables dosing schedules that are more like an antibody allowing convenient combination with other antibodies. Combining NKTR-214 mediated T cell activation with CTLA-4 or PD1 blockade is synergistic in murine models of cancer and holds the promise for durable responses in humans.
Respiratory Isolation Based on Rapid Molecular Testing in an Intermediate Tuberculosis-Burden Country—Reply
Authors: Lelia H. Chaisson, J. Lucian Davis
Journal: JAMA Internal Medicine (2019)

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Studies of the combination of ABT-199, a BH3 mimetic that specifically targets Bcl-2 in combination with chemotherapy and the proteosome inhibitor bortezomib in "double hit" lymphoma.
Authors: Joseph R. Bertino, Nadine Johnson-Farley, Sarathkumar Bhagavathi
Journal: Journal of Clinical Oncology (2014)

e19507 Background: Double hit lymphoma (DHL) is recently recognized as a highly proliferative subtype of Diffuse Large Cell Lymphoma characterized by over expression of cMYC and Bcl-2 with an overall survival of less than two years. Methods: We examined the cytotoxic effects of ABT-737, a Bcl-2/Bcl-XL inhibitor and ABT-199, a novel compound that selectively targets Bcl-2 against two DHL cell lines, Sc-1 and OcI-LY18 with complex karyotypes showing three way t(8,14,18) translocations and overexpression of cMyc and Bcl-2, as well as a RL cell line from a patient with Diffuse Large Cell Lymphoma (DLCL), and a Burkitt cell line, RAMOS. Results: Both ABT-737, a Bcl-2/Bcl-XL inhibitor and ABT-199, a novel compound that unlike ABT-737, does not cause thrombocytopenia and selectively targets Bcl-2, were potently cytotoxic against DHL cell lines and the RL cell line, but not the RAMOS cell line,which lacks Bcl-2 expression. ABT-199 was more potent than ABT 737 (Ic50:5nM vs 30nM). The DHL cell lines were also sensitive (< 200nM) to doxorubicin, methotrexate, cytarabine, and the proteosome inhibitor, bortezomib. Surprisingly, the DHL cell lines were also killed by low nM concentrations of the survivin and Mcl-1 inhibitor, YM-155. The combination of chemotherapy (doxorubicin or cytarabine) together with ABT-199 produced synergistic cell kill against the DHL cell lines. Synergistic cell kill also resulted when ABT-737 or ABT199 was combined with bortezomib or with YM-155. Conclusions: These results provide a rationale for additional preclinical studies that may lead to a clinical trial of ABT-199 in combination with certain chemotherapy drugs or with bortezomib in relapsed and chemotherapy refractory patients with DHL.
Lipid cell membrane composition: A novel therapeutic target in cancer.
Authors: Ravi Kiran Bobba, Monika Arya, Indira Benakanakere, Tyler Johnson, Carl Freter
Journal: Journal of Clinical Oncology (2014)

7062 Background: Cell membrane cholesterol, more specifically, the lipid composition of lipid rafts is associated with regulation of trans-membrane receptors. Methods: We tested the hypothesis that altering membrane cholesterols, via mevalonate pathway inhibitors, Ro 48-8071, TAK-475, BIBB-515 and YM-53601, may have differential effects on cancer cells in in-vitro models of Small Lymphocytic Lymphoma/ Chronic Lymphocytic Leukemia (CLL) cell lines and Peripheral blood lymphocytes of CLL patients. Results: In addition to chemo-sensitization of the cells, in-vitro results showed a statistically significant upregulation of cell surface proteins, CD20 and CD52. Treatment with cholesterol inhibitors resulted in significant upregulation of CD20 protein and glycosphingolipid-GM1 both by confocal microscopy and flow cytometry. Flow cytometry of MEC-2 and WAC-3 showed an upregulation of CD20 and CD52. Quantification of membrane lipids showed upregulation of glycosphingolipid-GM1. LysoPC (lysophosphatidylcholine) was an average of 0.0405 ± .0016 in controls was reduced to 0.0278 ± 0.0021 with BIBB-515 treatment and 0.0247 ± 0.0022 with YM-53601 treatment. PC (phosphatidylcholine) was upregulated from 1.0029 ± 0.02378 in controls to 1.0904 ± 0.04489 with BIBB-515 treatment and 1.1088 ± 0.02269 with YM-53601 treatment (P<0.05). Spingomyelin/Dihydrosphingomyelin (SM/DSM) was an average of 0.5863 ± 0.0113 in controls and was upregulated to 0.5997 ± 0.0294 with BIBB-515 treatment (P<.05) and 0.6735 ± 0.0159 in YM-53601 treatment (P<.001). Ether-linked Phosphatidylcholine (ePC) was upregulated from 0.2938 ± 0.0044 in controls to 0.3328 ± 0.0152 with BIBB-515 treatment and 0.3370 ± 0.0061 with YM-53601 treatment (P<.001). Treatment with BIBB-515 and YM-53601 did not affect membrane cholesterol levels significantly. Lovastatin significantly reduced membrane cholesterol from controls (P<0.05). Conclusions: Mevalonate pathway inhibitors lead to alterations in drug-resistant cancer cell membrane lipids by altering the cell surface receptor proteins CD 20 and upregulation of glycosphingolipid-GM1. A specific biochemical alteration in cancer cell membrane lipids represents a potential novel therapeutic approach to cancer.
Elevated LAG-3 Expression in the Tumor Microenvironement of Patients with DLBCL Is Associated with a Non-GCB Phenotype and Poor Prognosis
Authors: Colm Keane, Soi C Law, Clare Gould, Santiyagu Francis, Emad Uddin Abro, Joshua W.D. Tobin, Simone Birch, Grace Gifford, Sara Gabreilli, William S. Stevenson, Dipti Talaulikar, Anthony Gill, Sanjiv Jain, Donna Cross, Annette Hernadez, Sarah-Jane Halliday, Robert Bird, Mark Hertzberg, Maher K Gandhi
Journal: Blood (2018)
Role of FDG-PET-CT (PET) in predicting outcome of advanced hepatocellular carcinoma (aHCC) patients (pts) treated with sorafenib (SB): A prospective controlled study.
Authors: Roberto A. Pazo Cid, Javier Martinez Trufero, M. Lanzuela, Javier Fuentes, Miguel A Ubieto, Javier Banzo, Luis Sarriá, José María Artigas, Carlos Hördnler, Angel Artal, Teresa Puértolas, Alejandro Serrablo, Maite Soria, Elena Barrao, Ana Cebollero, Lourdes Calera, Isabel Pajares, Alba Hernández García, Jorge Hernando Cubero, Antonio Anton
Journal: Journal of Clinical Oncology (2014)

4104 Background: SB remains since 2007 the only drug that improves overall survival (OS) of aHCC pts. Predicting early response to SB could save costs and toxicity. PET has never been properly tested as biomarker in this setting. Methods: This prospective study recruitedaHCC pts eligible for first-line SB therapy. RECIST response to treatment was evaluated by CT scan every 6 weeks, and metabolic PET response after two weeks on SB (1999 EORTC criteria). PET response cut-off: a minimum of 15% reduction in the sum of SUVmax of up to 5 target lesions. CT (CR+PR+SD vs PD) and PET (CR+PR vs SD+PD) responses were categorized as dichotomous variables. OS and time to progression (TTP) were calculated by the Kaplan–Meier test and statistically evaluated by the log-rank test. Association between OS/TTP and several meaningful clinical variables (including PET and CT response) were evaluated using univariate Cox proportional hazards regression analysis and significant parameters were included in a multivariate analysis. Results: Accrual: 55pts Characteristics: Median age: 71 years. Male 62%. PS 0-1/2(%) 60/40. Cirrhosis etiology: HCV/HBV/Alcohol/Other/unknown(%) 34/18/20/11/17. Child-Pugh A/B(%) 75/25. Extrahepatic spread(%) yes/no 60/40. Macroscopic vascular invasion(%) yes/no 30/70. Median AFP level 24.0 (range 2.0-85520.0). BCLC stage B/C(%) 12/88. CLIP stage 0/1/2/3/4(%) 13/25/25/23/12. Baseline PET+/-(%) 86/14. SB median dose: 400mg/d. Second-line therapy (Bevacizumab): yes/no(%) 44/56. Median TTP/OS 3.7 and 7.3 months (95%CI 2.30-5.12/ 4.87-9.77). Multivariate analysis showed that CLIP stage and CT and PET responses were independent prognostic factors for TTP. For OS CLIP stage, second-line therapy and PET response retained significance but not CT response. Conclusions: Early metabolic response strongly predicted survival benefit from first-line SB therapy in aHCC pts. Clinical trial information: NCT01157013. Cox analysis TTP p HR 95%CI PET 0,005 0,292 0,123-0,693 CLIP 0,022 1,482 1,060-2,073 CT 0,048 0,376 0,143-0,991 Cox analysis OS p HR 95%CI CLIP 0,000 2,047 1,418-2,954 Second-line therapy 0,000 0,087 0,032-0,240 PET 0,004 0,253 0,099-0,650
Geno-Clinical Model to Aid in the Diagnosis of Myelodysplastic Syndrome (MDS) Versus Chronic Myelomonocytic Leukemia (CMML)
Authors: C. Beau Hilton, Mikkael A. Sekeres, Manja Meggendorfer, Wencke Walter, Stephan Hutter, Eric Padron, Michael R. Savona, Aaron T. Gerds, Yihong Guan, David A Sallman, Sudipto Mukherjee, Mrinal M. Patnaik, Brianna Smith, Yasunobu Nagata, Vera Adema, Metis Hasipek, Cassandra M. Hirsch, Bartlomiej P. Przychodzen, Rami S. Komrokji, Babal K. Jha, Claudia Haferlach, Jaroslaw P. Maciejewski, Torsten Haferlach, Aziz Nazha
Journal: Blood (2018)
Abstract 14116: POVPC Impaired Vascular Endothelial Function by Inhibiting Enos Activity and Inducing Endothelial Cell Apoptosis
Authors: Zhijun Ou, Feng-Xia Yan, Shang-Xuan Li, Wei-Ping Dai, Yan Li, Shi-Hui He, Jing-Song Ou
Journal: Circulation (2017)

Introduction: Endothelial dysfunction is the early stage of the development of atherosclerosis. Although 1-palmitoyl-2- (5-oxovaleroyl) -sn-glycero-3-phosphocholine (POVPC) is found in atherosclero...
Factors associated with efficacy of TAS-102 in patients with refractory metastatic colorectal cancer (mCRC).
Authors: Peter Grell, Josef Dvorak, Michal Vocka, Stanislav John, Helena Tuskova, Tomas Buchler, Lubos B. Petruzelka, Rostislav Vyzula, Radka Obermannova
Journal: Journal of Clinical Oncology (2018)

858 Background: TAS-102 significantly improved progression free survival (PFS) and overall survival (OS) versus placebo in patients with treatment refractory mCRC. We analyzed potential predictive and prognostic factors in patients treated with TAS-102 in real-world practice. Methods: We retrospectively evaluated the clinical data of 129 patients who received TAS-102. Different factors associated with PFS and OS were analyzed. Results: Baseline characteristics were: median age 67 (range 37-83), male 63.6%, ECOG PS 0 in 40.3% and 1 in 59.7%. Primary tumor location: right 20.2%, left 79.2%, wt RAS 45%. Median number of TAS-102 treatment line 3 (range 2-8). Prior treatment: anti-EGFR 45%, anti-VEGF 83%, and regorafenib 20.9%. Median follow-up was 9.4 months. The median number of cycles of TAS-102 was 3 (range 1-14). Best achieved response was SD in 23%. Median PFS was 3.3 months and OS was 11.1 months. Any ≥ grade 3 AE was in 45%, the most common ≥ grade 3 AEs were neutropenia (40.2%), anemia (6.2%), thrombocytopenia (4.7%), febrile neutropenia (2.3%), diarrhea (1.6%), nausea (1.6%), and asthenia (1.6%). Dose reduction was needed in 29.5% and cycle delay in 53.5%. Factors significantly associated with longer PFS were: initiation of TAS-102 treatment more than 3 months from last fluoropyrimidine therapy (p = 0.022, HR 0.633), normal baseline CRP level (p = 0.004, HR 0.479), baseline WBC &lt; 8 × 10 9 /L (p = 0.025, HR 0.641), monocytes &lt; 0.5 × 10 9 /L (p = 0.016, HR 0.522), neutropenia ≥ grade 2 during treatment (p &lt; 0.0001, HR 0.349), TAS-102 dose reduction during treatment (p &lt; 0.0001, HR 0.397), and TAS-102 cycle delay (p &lt; 0.0001, HR 0.402). Factors associated with longer OS were normal CRP (p = 0.001, HR 0.295), normal LDH (p = 0.006, HR 0.422), WBC &lt; 8 × 10 9 /L (p = 0.0001, HR 0.357), monocytes &lt; 0.5 × 10 9 /L (p = 0.016, HR 0.373), neutropenia ≥ G2 during treatment (p = 0.0002, HR 0.343), TAS-102 cycle delay (p = 0.002, HR 0.421), wt RAS (p = 0.05, HR 0.578). Conclusions: This analysis confirms that TAS-102 is effective in patients with refractory mCRC treated in a real-world setting. Factors associated with better outcomes were baseline CRP, WBC, monocytes, and neutropenia, dose reduction and cycle delays during the treatment.
The significance and long-term clinical outcome of preoperative chemoradiotherapy using S-1 plus Irinotecan for locally advanced rectal cancer.
Authors: Kei Kimura, Naohito Beppu, Kiyoshi Tsukamoto, Tomoki Yamano, Masafumi Noda, Masataka Ikeda, Naohiro Tomita
Journal: Journal of Clinical Oncology (2018)

819 Background: Preoperative chemoradiotherapy regimen using S-1 plus Irinotecan is still under clinical investigation. The aim of this study was to investigate the significance and the long-term outcomes of this regimen for locally advanced rectal cancer. Methods: Between 2009 and 2016, 81 patients underwent radical surgery after preoperative chemoradiotherapy. Radiotherapy was administered in total 45Gy with 1.8Gy/day for 25 days. S-1 was administered orally in a fixed daily dose of 80mg/m2 on days 1 to 5, 8 to 12, 22 to 26, and 29 to 33. Irinotecan was infused with dose of 80 mg/m2 on days 1, 8, 22, and 29. 6-9 weeks after the completion of the treatment, radical surgery was performed. The median follow-up was 35.3 months. Results: Of the 81 patients, 76 (93.8%) completed treatment of chemoradiotherapy. Relative dose intensity of CPT-11 was 92.8%, S-1 was 90.1%. 79 (97.5%) patients completed the radiotherapy. 18 patients (22.2%) had ≧Grade 3 hematologic toxicity (leukopenia; 15 patients, neutropenia; 16 patients ). 23 patients (28.3%) had ≧Grade 3 nonhematologic toxicity (diarrhea). In terms of the surgical procedure, 73 of 81 patients (90.1%) underwent sphincter-preserving surgery including 42 patients intersphincteric resection, and 8 patients (9.9%) underwent abdominoperineal resection. The tumor regression grade of 1/2/3(pCR) was 30/39/12(14.8%). In terms of long-term survival, 3-year local relapse-free survival rate was 96.7%, the recurrence-free survival rate was 71.6% and 3-year overall survival rate was 94.9%. Conclusions: Preoperative chemoradiotherapy using combined with Irinotecan as secondary drugs may result safe and feasible and accomplished favorable downstaging. This regimen was considered to be effective in patients with locally advanced rectal cancer.
Prognostic significance of tumor budding in resected pancreatic ductal adenocarcinoma (PDAC).
Authors: Renata D'Alpino Peixoto, Kate O'Connor, Hector Hugo Li-Chang, Steve Kalloger, Daniel John Renouf, David Schaeffer
Journal: Journal of Clinical Oncology (2014)

e15184 Background: Tumor budding (TB) is a well-established adverse prognostic factor in early colorectal cancer. However, the significance of TB in PDAC is uncertain. Methods: Archival cases of PDAC (n = 189) were assessed for TB using H and E sections only. Tumor buds were defined as single tumor cells or clusters consisting of <5 cells. The prognostic impact of TB on overall survival (OS) was assessed by Log-rank and Cox-proportional hazards tests. Results: A total of 189 pts (103 males) who underwent curative-intent surgery for PDAC were included in the analysis. Median age was 68 (range 38-89). TB was present in 165 cases (87.3%). Median OS was significantly shorter for patients with TB (15.5 versus 47.5 months, p<0.001, HR 3.11). The presence of TB was not associated with either local recurrence (p=0.564) or development of metastases (p=0.517). Only 67 pts (33.3%) received adjuvant chemotherapy (29.7% in the group with TB vs 58.3% in the group without TB, p=0.005). On multivariable analysis, TB was a prognostic factor independent of T-stage, grade, nodal status, lymphovascular invasion (LVI), perineural invasion (PNI), and adjuvant chemotherapy. Other independently prognostic variables included nodal status and adjuvant chemotherapy (see Table). Conclusions: The presence of tumor budding is a common occurrence in PDAC and represents an independent adverse prognostic factor. Characteristics Hazard ratio (95% CI) p-value Tumour budding (present vs. absent) 2.07 (1.09-3.91) 0.025 Grade (high [3] vs. low [1 and 2]) 1.24 (0.85-1.80) 0.260 T stage (pT3 vs. pT1/2 ) 0.98 (0.47-2.02) 0.964 N stage (pN1 vs. pN0) 2.07 (1.29-3.31) 0.002 LVI (present vs. absent) 1.37 (0.93-2.01) 0.103 PNI (present vs. absent) 1.91 (0.98-3.70) 0.054 Adjuvant chemotherapy (no vs. yes) 1.97 (1.33-2.90) 0.001
Hospitalising preterm infants in single family rooms versus open bay units: a systematic review and meta-analysis
Authors: Nicole R van Veenendaal, Wieke H Heideman, Jacqueline Limpens, Johanna H van der Lee, Johannes B van Goudoever, Anne A M W van Kempen, Sophie R D van der Schoor
Journal: The Lancet Child & Adolescent Health (2019)