tbuckley/cabot-search huggingface dataset:
The rationale for druggability of CCDC6-tyrosine kinase fusions in lung cancer
Authors: Aniello Cerrato, Roberta Visconti, Angela Celetti
Journal: Molecular Cancer (2018)

Gene fusions occur in up to 17% of solid tumours. Oncogenic kinases are often involved in such fusions. In lung cancer, almost 30% of patients carrying an activated oncogene show the fusion of a tyrosine kinase to an heterologous gene. Several genes are partner in the fusion with the three kinases ALK, ROS1 and RET in lung. The impaired function of the partner gene, in combination with the activation of the kinase, may alter the cell signaling and promote the cancer cell addiction to the oncogene. Moreover, the gene that is partner in the fusion to the kinase may affect the response to therapeutics and/or promote resistance in the cancer cells. Few genes are recurrent partners in tyrosine kinase fusions in lung cancer, including CCDC6, a recurrent partner in ROS1 and RET fusions, that can be selected as possible target for new strategies of combined therapy including TKi.
Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma
Authors: Alexander M.M. Eggermont, Christian U. Blank, Mario Mandala, Georgina V. Long, Victoria Atkinson, Stéphane Dalle, Andrew Haydon, Mikhail Lichinitser, Adnan Khattak, Matteo S. Carlino, Shahneen Sandhu, James Larkin, Susana Puig, Paolo A. Ascierto, Piotr Rutkowski, Dirk Schadendorf, Rutger Koornstra, Leonel Hernandez-Aya, Michele Maio, Alfonsus J.M. van den Eertwegh, Jean-Jacques Grob, Ralf Gutzmer, Rahima Jamal, Paul Lorigan, Nageatte Ibrahim, Sandrine Marreaud, Alexander C.J. van Akkooi, Stefan Suciu, Caroline Robert
Journal: New England Journal of Medicine (2018)

The programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma.Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated.At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) and in the subgroup of 853 patients with PD-L1-positive tumors (1-year rate of recurrence-free survival, 77.1% [95% CI, 72.7 to 80.9] in the pembrolizumab group and 62.6% [95% CI, 57.7 to 67.0] in the placebo group; hazard ratio, 0.54; 95% CI, 0.42 to 0.69; P<0.001). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group.As adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified. (Funded by Merck; ClinicalTrials.gov number, NCT02362594 ; EudraCT number, 2014-004944-37 .).
Combinatorial IL13Rα2 chimeric antigen receptor-T cells plus checkpoint blockade to treat solid tumors in murine and canine models.
Authors: Yibo Yin, Alina Boesteanu, Chong Xu, Avery Posey, Danielle Cook, Kristin Blouch, Bevin McGettigan-Croce, Nicola Mason, Carl H. June, Zhiguo Lin, Laura A. Johnson
Journal: Journal of Clinical Oncology (2017)

152 Background: Glioblastoma (GBM) is a deadly cancer, with a 5-year survival rate of less than 10%. T cells can be redirected to kill cancer cells using chimeric antigen receptors (CAR), a promising method to treat solid tumors. IL13Rα2 is expressed in many solid tumors but not normal tissues, and provides a target for CAR T cells as a powerful immunotherapy treatment. Methods: Human and canine tumors were screened for IL13Rα2 expression by flow cytometry and RT-PCR. Different IL13Rα2 single-chain variable fragments (scFv) were tested in CARs in vitro against human and canine recombinant IL13Rα2 protein to identify a cross-reactive clone. IL13Rα2 CARs expressed in human and canine T cells and showed antigen-specific stimulation by cytokine secretion and target cell lysis. Solid tumors were used to establish in vivo subcutaneous and orthotopic xenograft models in NSG mice. Mice received a single treatment of 2-5 million CAR T cells IV with or without anti PD-1, CTLA-4 or TIM3 mAb checkpoint blockade. Results: IL13Rα2 was detected on three human GBM (D270, U251 and U87), four canine osteosarcomas (BW-, CS-, MC- and SK-KOSA) and two canine lung cancer cell lines (Cacal3, Cacal5). Two different IL13Rα2 CAR were generated that recognized human IL13Rα2 and not IL13Rα1, one also recognized canine IL13Rα2. Five million IL13Rα2 CAR T-cells delivered IV were able to eliminate established GBM tumors. Use of fewer CAR T cells initially controlled tumor growth, followed by tumor outgrowth correlated with expression of T cell exhaustion markers. Combined treatment with CARs plus checkpoint blockade mAb delivered IP had synergistic effects, restoring anergic T-cell function and improving tumor treatment. Conclusions: IL13Rα2 is highly expressed on human and canine tumors, but not normal tissues. IL13Rα2 specific CAR T cells successfully respond to human and canine tumors and treat GBM in a xenograft mouse model, although this effect was transient at lower treatment doses. Addition of checkpoint blockade mAbs to CAR therapy was beneficial for the treatment of solid tumors. We plan to utilize this treatment in a canine spontaneous cancer preclinical model and translate into clinical trials for patients with GBM.
SCOT: Tumor sidedness and the influence of chemotherapy duration on DFS.
Authors: Mark P. Saunders, James Paul, Jana Crosby, Gordon Brown, Timothy Iveson, Rachel Kerr, Andrea Harkin, Karen Allan, John McQueen, Sarah R Pearson, James Cassidy, Louise C. Medley, Sherif Raouf, Mark Harrison, Alison Brewster, Charlotte Rees, Richard Ellis, Anne L. Thomas, Mark Churn, Noori Maka
Journal: Journal of Clinical Oncology (2018)

558 Background: Patients with R-sided tumours who develop metastatic disease have a worse prognosis compared to patients with L-sided tumours. The latter may also have a greater benefit from treatment with EGFR inhibitors. In general, registry studies and meta-analyses have shown that patients with loco-regional R-sided tumours have a worse overall survival (OS). This has recently been confirmed by the PETACC8 study but only after they had relapsed. There was not a significant difference in disease free survival (DFS). Methods: The SCOT study showed that 3-months of oxaliplatin-containing adjuvant chemotherapy (OxFp) was non-inferior to 6-months for patients with stage III and high-risk stage II colorectal cancer. Here we divide the population into left and right-sided tumours to see whether sidedness had an impact on DFS. We also evaluated whether sidedness impacted on the 3 vs. 6-months comparison in SCOT. Results: 6088 patients with Stage III/high risk Stage II cancers or the colon or rectum were randomised between March 27, 2008 and November 29, 2013 from 244 centres (164 UK, 32 Australia, 19 Spain, 14 Sweden, 10 Denmark and 5 New Zealand). In February 2017 (3-years FU) information on sidedness was available for 3219 patients (1207 R-sided, 2012 L-sided). Characteristics: Right: median age: 65, Male: 53%, T4 41%, Stage II: 17%; Left: median age: 65, Male: 66%, T4 24%, Stage II: 21%). Patients with R-sided tumours had a significantly worse DFS (3-year DFS right: 73% (se=1%), left: 80% (se=1%). HR 1.401 (95% CI 1.216-1.615; p=0.000004). Adjusting for T and N-stage reduced the HR to 1.215 (95% ci 1.051-1.404, p=0.009). The data did not suggest that sidedness affected the impact of chemotherapy duration on 3-year DFS (R: HR (3 month/6 month) 1.049 (0.849 -1.296) L: 0.910 (0.753-1.099). Test for homogeneity, p=0.327). Further sub-set analysis was limited due to cohort size. Conclusions: This is the first study to show that unselected patients with R-sided tumours had a worse DFS compared to L-sided tumours. This implies that prognosis is influenced primarily by greater recurrence rather than the contributing factors that influence OS. Tumour sidedness did not impact on the 3-months vs. 6-months comparison in SCOT. Clinical trial information: ISRCTN59757862.
Predictors of recurrence in patients with surgically resected pancreatic neuroendocrine tumors.
Authors: Cynthia Harris, Michelle Kang Kim, Kiwoon Joshua Baeg, Mi Ri Lee, Julie Starr, Lauren K. Brais, Stephen Ward, Kristen Stashek, Jennifer A. Chan, Daniel M. Labow, Umut Sarpel, Myron E. Schwartz, Max W. Sung, Juan P. Wisnivesky, Richard R. P. Warner, David C. Metz, Matthew H. Kulke
Journal: Journal of Clinical Oncology (2018)

408 Background: Current surveillance guidelines regarding follow up of patients with resected pancreatic neuroendocrine tumors (PNETs) are based on limited data, and there have been few studies evaluating recurrence risk in such patients. We assessed disease-free survival (DFS) in a large, multi-institutional cohort of patients with resected PNETs. Methods: Patients with surgically resected, non-metastatic PNETs between 1990-2017 were identified using institutional databases at three institutions: Mount Sinai Hospital, Dana-Farber Cancer Institute, and University of Pennsylvania. Recurrence date was defined as the imaging date documenting first recurrence (n = 56); if an imaging date was not available, then July 1 of that year was used in calculations (n = 9). Kaplan-Meier analysis was used to estimate DFS; multivariate Cox regression analysis was used to assess DFS adjusted for patient and disease-related characteristics, including tumor stage and grade. Results: We identified a total of 418 patients with surgically resected, non-metastatic PNETs between 1990-2017. Of these patients, 299 patients had complete stage and tumor grade information and were used for subsequent analysis. Patients were 48.6% male with a median age of 57.5 years at time of surgery. The distribution of AJCC stage and grade was as follows: 170 (56.9%) patients were stage I, 129 (43.1%) were stage II; 167 (55.9%) had grade 1, 121 (40.5%) had grade 2, and 11 (3.7%) had grade 3 tumors. Median follow-up was 2.6 years (interquartile range = 4.2); during this time, 65 (21.7%) patients developed disease recurrence. After adjusting for potential confounders, patients with more advanced stage and higher tumor grade were significantly more likely to develop disease recurrence (Hazard Ratio (HR): 6.9, 95% CI: 2.5-19.1 for stage II; HR 4.0 (1.7-9.5) for grade 2; HR 2.6 (0.4-17.8) for grade 3). Both higher stage and tumor grade were associated with decreased DFS (p &lt; 0.0001 for both). Conclusions: In surgically resected PNETs, with a median follow-up time of 2.6 years, both higher stage and higher grade are associated with decreased DFS. Further follow up of this cohort is planned.
Does a Newly Characterized Cell From the Bone Marrow Repair the Heart After Acute Myocardial Infarction?
Authors: Steven R. Houser
Journal: Circulation Research (2018)

Axis Mediates Homing of Muse Cells Into Damaged Heart for Long-Lasting Tissue Repair and Functional Recovery After Acute Myocardial Infarction" suggests that injection of isolated multilineage-differentiating stress enduring (MUSE) cells into the venous circulation 24 hours after acute myocardial infarction (AMI) reduces scar size and adverse ventricular remodeling and improves cardiac pump function.
A randomized, controlled trial evaluating the efficacy and safety of BTH1677 in combination with bevacizumab, carboplatin, and paclitaxel in first-line treatment of advanced non-small cell lung cancer
Authors: Walburga Engel-Riedel, Jamie Lowe, Paulette Mattson, J. Richard Trout, Richard D. Huhn, Michele Gargano, Myra L. Patchen, Richard Walsh, My My Trinh, Mariève Dupuis, Folker Schneller
Journal: Journal for ImmunoTherapy of Cancer (2018)

<h3>Background</h3> BTH1677, a beta-glucan pathogen-associated molecular pattern molecule, drives an anti-cancer immune response in combination with oncology antibody therapies. This phase II study explored the efficacy, pharmacokinetics (PK), and safety of BTH1677 combined with bevacizumab/carboplatin/paclitaxel in patients with untreated advanced non-small cell lung cancer (NSCLC). <h3>Methods</h3> Patients were randomized to the BTH1677 arm (<i>N</i> = 61; intravenous [IV] BTH1677, 4&nbsp;mg/kg, weekly; IV bevacizumab, 15&nbsp;mg/kg, once each 3-week cycle [Q3W]; IV carboplatin, 6&nbsp;mg/mL/min Calvert formula area-under-the-curve, Q3W; and IV paclitaxel, 200&nbsp;mg/m<sup>2</sup>, Q3W) or Control arm (<i>N</i> = 31; bevacizumab/carboplatin/paclitaxel as above). Carboplatin/paclitaxel was discontinued after 4-6&nbsp;cycles and patients who responded or remained stable received maintenance therapy with BTH1677/bevacizumab (BTH1677 arm) or bevacizumab (Control arm). Efficacy assessments, based on blinded central radiology review, included objective response rate (ORR; primary endpoint), disease control rate, duration of objective response, and progression-free survival. Overall survival and adverse events (AEs) were also assessed. <h3>Results</h3> ORR was higher in the BTH1677 vs Control arm but the difference between groups was not statistically significant (60.4% vs 43.5%; <i>P</i> = .2096). All other clinical endpoints also favored the BTH1677 arm but none statistically differed between arms. PK was consistent with previous studies. Although a higher incidence of Grade 3/4 AEs occurred in the BTH1677 vs Control arm (93.2% vs 66.7%), no unexpected AEs were observed. Serious AEs and discontinuations due to AEs were lower in the BTH1677 vs Control arm. <h3>Conclusions</h3> Improvements in tumor assessments and survival were observed with BTH1677/bevacizumab/carboplatin/paclitaxel compared with control treatment in patients with advanced NSCLC. <h3>Trial registration</h3> ClinicalTrials.gov registration ID: NCT00874107. Registered 2 April 2009. First participant was enrolled on 29 September 2009.
Epidemiology of pediatric nickel sensitivity: Retrospective review of North American Contact Dermatitis Group (NACDG) data 1994-2014
Authors: Erin M. Warshaw, Kelly A. Aschenbeck, Joel G. DeKoven, Howard I. Maibach, James S. Taylor, Denis Sasseville, Donald V. Belsito, Joseph F. Fowler, Kathryn A. Zug, Matthew J. Zirwas, Anthony F. Fransway, Vincent A. DeLeo, James G. Marks, Melanie D. Pratt, Toby Mathias
Journal: Journal of the American Academy of Dermatology (2018)
Abstract 14093: Kidney Transplantation From Non-Hypertensive Unrelated Donor: Correction of Post-Transplant Hypertension
Authors: Ekamol Tantisattamo, Wasawat Vutthikraivit, Weera Sukhumthammarat, Prapaipan Putthapiban
Journal: Circulation (2016)

Introduction:  Hypertension (HTN) is a very common even after successful kidney transplantation.   Hypothesis:  Since hypertensive genotype may be transferred in kidney diseases, kidney from non-hypertensive donors may correct post-transplant HTN.   Method:  A 103 kidney transplant recipients were review. There were 32 living-donor renal transplant (LDRT; 15 living-related and 17 living-unrelated) and 12 deceased donor renal transplant (DDRT) recipients, who received paired deceased donor kidneys (derived from the same donor transplanted to different recipients) leading to 5 “mate” recipient pairs.   Results:  Of 44 recipients, mean age was 53.3 yrs old (21.4-79.5) and 57% were female. Median duration of follow-up was 8.2 mo (0.6-16.3). Mean serum creatinine (SCr) was 1.4±0.1 (LDRT 1.23±0.05 vs. DDRT 1.95±0.29, p=0.0006). Up to 93% had pre-transplant HTN, and 45% was non-hypertensive post-transplant (SBP≤140, DBP≤90, or being on ≤2 BP agents regardless SBP or DBP). Mean post-transplant SBP was not significantly lower than mean pre-transplant SBP(132.07±2.63 vs. 135±2.42, p=0.3526) as same as DBP(76.7±1.7 vs. 80±2.13,p=0.2406). Among 13 LRRT recipients with pretransplant HTN, 5 patients were non-hypertensive post-transplant; whereas 16 of 29 (55%) recipients of unrelated recipients (LURT+DDRT) became non-hypertensive (Figure1). Among 11 DDRT recipients with pretransplant HTN, only 4 patients (2 mate pairs) had the same post-transplant BP outcomes. The recipients with pre-transplant diabetes (DM) was account for 18%, and appears to have higher prevalence of post-transplant HTN compared to the non-DM recipients (75% vs. 39%, p=0.1148).   Conclusions:  Pre-transplant HTN may be corrected by unrelated-donor kidney transplantation (LURT and DDRT). Un-expressed hypertensive phenotype of living-related donors may exist and using kidneys from living-related donors should be caution with the potential developing post-donation HTN in these donors.
A pilot study to assess the efficacy, safety, and pharmacodynamic effects of pembrolizumab and BL-8040 in patients with metastatic pancreatic cancer.
Authors: David R. Fogelman, Steven Matthew Townson, Gauri R. Varadhachary, Milind M. Javle, Rachna T. Shroff, Robert A. Wolff, Michael J. Overman, Linus Ho, Abi Vainstein Haras, Tzipora M Lustig, Ella Sorani, Maureen E. Lane, David Ross Kaufman, James C. Yao
Journal: Journal of Clinical Oncology (2018)

TPS533 Background: Checkpoint inhibitors such as pembrolizumab are active against a variety of tumor types; however, pancreatic cancer patients generally do not see improvements in their disease from single agent treatment. Blocking CXCR4 may potentiate the activity of checkpoint inhibitors by (1) increasing mobilization of lymphocytes from bone marrow, (2) blocking production of SDF-1, in turn allowing better penetration of immune cells into the tumor, (3) reducing the entry of suppressor T cells into tumor, and (4) upregulating CCL20 in the tumor microenvironment, which may help attract dendritic cells into the tumor. We have launched a study combining BL8040, a CXCR4 antagonist, with pembrolizumab in order to determine the efficacy of this combination. Methods: Major inclusion criteria require patients with pancreatic adenocarcinoma whose tumors have progressed through at least one line of therapy. There must be sufficient disease to allow for pre- and post-treatment biopsy as well as measurement of response by RECIST criteria. Patients must be age 18 or older and ECOG 0-1. Liver function, renal, and hematologic criteria are fairly rigorous. Major exclusion criteria include patients with viral infections or those who require supraphysiologic steroid use. Treatment includes a two week cycle of single agent BL-8040 given on days 1-5 and 8-12. Cycles 2 and beyond include treatment on day 1 with pembrolizumab, 200 mg flat dose, plus BL-8040 given SQ on days 1,4,8, and 11 of a two week cycle. The primary endpoint is response rate; other major clinical objectives include progression free and overall survival. Scientific correlates include assessments of immune cell infiltrates into tumor via histology and immunoflourescence, histological assessment of stromal components, and gene expression signatures. Blood is likewise being collected for serum cytokine analysis, circulating free DNA analysis, circulating tumor cells, and exosome analysis. Clinical trial information: NCT02907099.
105P Feasibility study of adjuvant chemotherapy with cisplatin and pemetrexed short hydration regimen for completely resected non-small cell lung cancer
Authors: R. Dokuni, M. Tachihara, S. Tokunaga, K. Okuno, M. Yamamoto, K. Kobayashi, Y. Tanaka, Y. Funada, Y. Maniwa, Y. Nishimura
Journal: Journal of Thoracic Oncology (2018)
Immunomodulation of pembrolizumab (pembro) treated metastatic melanoma patients (pts) after progression with sequential temozolomide (TMZ): A case series.
Authors: Umang Swami, Varun Monga, Yousef Zakharia, Mohammed M. Milhem
Journal: Journal of Clinical Oncology (2017)

123 Background: Regulatory T cells are increased in melanoma pts and are postulated to impair objective response to immune therapies. Pembro blocks programmed death receptor-1, reverses T-cell suppression and induces antitumor activity. Continuous low dose TMZ has immunomodulatory effects resulting in selective CD4+ lymphopenia of which the T-reg population of CD4+/CD25+ T cells could be decreased significantly. TMZ has demonstrated dramatic responses after IL-2 in metastatic melanoma pts. We evaluated responses with sequential TMZ after progression on pembro in pts with metastatic melanoma. Methods: Medical records of pts with metastatic melanoma treated with pembro and TMZ at Holden Comprehensive Cancer Center between 1/1/2011 and 8/31/2016 were reviewed. Recorded data included BRAF mutation status, treatment doses, serological markers, duration of treatment and treatment related responses (immune RECIST and RECIST 1.1). Results: Overall 10 pts (7 males, 3 females) with metastatic melanoma received sequential pembro followed by TMZ after disease progression or unacceptable toxicity. Eight were BRAF negative and 7 were pretreated with ipilimumab. Median age at time of initiating pembro (2 mg/kg every 3 weeks) was 64 years (range 33-75). Pts received a median of 4 doses (2-19). Median duration of treatment was 88 days (41-464) with stable disease in 3, progressive disease (PD) in 6 and 1 not evaluable for response. All pts thereafter received TMZ (75 mg/m2 daily for 6 weeks on 8 week cycle except 1 who received 200 mg/m2 for 5 days every 4 weeks) after a median of 21.5 days (12-34) from last pembro dose. Median duration on treatment with TMZ was 75 days (20-198) resulting in 1 complete response, 1 partial response, 6 PD and 2 not evaluable for response. Pts with response to TMZ had a higher median baseline lymphocyte count at the time of initiation of pembro (4131 vs. 1715 k/uL, p &lt; 0.05) as well as TMZ (2335 vs. 965 k/uL, p = 0.08) as compared to pts without a response. Conclusions: TMZ is an interesting alternative for metastatic melanoma pts with disease progression on pembro. Our results show a 25% response rate. Further studies in this setting are warranted.