tbuckley/cabot-search huggingface dataset:
Using elongated microparticles to enhance tailorable nanoemulsion delivery in excised human skin and volunteers
Authors: Miko Yamada, Hossam Tayeb, Hequn Wang, Nhung Dang, Yousuf H. Mohammed, Sam Osseiran, Paul J. Belt, Michael S. Roberts, Conor L. Evans, Frank Sainsbury, Tarl W. Prow
Journal: Journal of Controlled Release (2018)

This study demonstrates, for the first time, clinical testing of elongated silica microparticles (EMP) combined with tailorable nanoemulsions (TNE) to enhance topical delivery of hydrophobic drug surrogates. Likewise, this is the first report of 6-carboxyfluorescein (a model molecule for topically delivered hydrophobic drugs) AM1 & DAMP4 (novel short peptide surfactants) used in volunteers. The EMP penetrates through the epidermis and stop at the dermal-epidermal junction (DEJ). TNE are unusually stable and useful because the oil core allows high drug loading levels and the surface properties can be easily controlled. At first, we chose alginate as a crosslinking agent between EMP and TNE. We initially incorporated a fluorescent lipophilic dye, DiI, as a hydrophobic drug surrogate into TNE for visualization with microscopy. We compared four different coating approaches to combine EMP and TNE and tested these formulations in freshly excised human skin. The delivery profile characterisation was imaged by dye- free coherent anti-Stoke Raman scattering (CARS) microscopy to detect the core droplet of TNE that was packed with pharmaceutical grade lipid (glycerol) instead of DiI. These data show the EMP penetrating to the DEJ followed by controlled release of the TNE. Freeze-dried formulations with crosslinking resulted in a sustained release profile, whereas a freeze-dried formulation without crosslinking showed an immediate burst-type release profile. Finally, we tested the crosslinked TNE coated EMP formulation in volunteers using multiphoton microscopy (MPM) and fluorescence-lifetime imaging microscopy (FLIM) to document the penetration depth characteristics. These forms of microscopy have limitations in terms of image acquisition speed and imaging area coverage but can detect fluorescent drug delivery through the superficial skin in volunteers. 6-Carboxyfluorescein was selected as the fluorescent drug surrogate for the volunteer study based on the similarity of size, charge and hydrophobicity characteristics to small therapeutic drugs that are difficult to deliver through skin. The imaging data showed a 6-carboxyfluorescein signal deep in volunteer skin supporting the hypothesis that EMP can indeed enhance the delivery of TNE in human skin. There were no adverse events recorded at the time of the study or after the study, supporting the use of 6-carboxyfluorescein as a safe and detectable drug surrogate for topical drug research. In conclusion, dry formulations, with controllable release profiles can be obtained with TNE coated EMP that can effectively enhance hydrophobic payload delivery deep into the human epidermis.
Exercise counseling in integrative oncology: Patient characteristics and effects on self-reported symptoms.
Authors: Gabriel Lopez, Carol A Eddy, Yisheng Li, Minxing Chen, Lorenzo Cohen
Journal: Journal of Clinical Oncology (2018)

10089 Background: Physical activity and exercise have shown benefits for cancer prevention and contribute to improved treatment related outcomes. We reviewed the characteristics of cancer patients referred for physical therapist-led exercise counseling at a comprehensive cancer center and its effects on self-reported symptoms. Methods: Patients presenting for an exercise counseling consultation and follow up encounter at an Integrative Medicine Center outpatient clinic from Feb 2016 to May 2017 completed the Edmonton Symptom Assessment Scale (ESAS; 0-10 scale, 10 most severe) pre/post-encounter; a PROMIS 10 global health assessment was also completed within 30 days of each encounter. Exercise counseling was provided by a physical therapist. ESAS individual items and subscales of Physical Distress (PHS), Psychological Distress (PSS), and Global Distress (GDS) were analyzed. We used paired t-tests with a p-value correction (i.e., p < .001) to examine symptoms before and after each encounter. Results: Data were available for 367 participants; 68 (18.5%) had at least one follow up encounter at 56.1 days (mean). Most were female (77.7%), caucasian (66.2%) with breast (43%), gastrointestinal (15.8%), or gynecologic (6.8%) cancer. Highest and most frequently reported (%) symptom scores at baseline included poor sleep (63.2%; 3.55), fatigue (59.9%; 3.19), and poor well-being (62.4%; 3.17). Pre/post change for one encounter was statistically and clinically significant for the ESAS GDS subscale (-3.36, SD 6.54, p < 0.001). ESAS change (n = 40) between baseline and first follow up within 60 days was statistically and clinically significant for improvement in fatigue (-1.35, p = 0.006), GDS (-4.55, p = 0.008), and PHS (-3.15, p = 0.016). PROMIS10 scores (n = 321) at baseline included global health 31.34. For the follow up group (n = 67), significant improvements were observed for mental health (p = 0.015) and global health (p = 0.024), not physical health (p = 0.07). Conclusions: Patients presenting for an exercise consultation had a moderate symptom burden with global health scores lower than the population mean, with improvements observed in global distress, physical distress, and fatigue after one encounter.
Metabolic syndrome in adult survivors of childhood cancer.
Authors: Aruna Alahari Dhir, Anuprita Daddi, Sheela Sawant, Maya Prasad
Journal: Journal of Clinical Oncology (2018)

e22102 Background: Metabolic syndrome (MS) is a group of disorders related to insulin resistance, characterized clinically by central obesity, hyperglycemia, dyslipidemia and hypertension. There is a growing body of evidence indicating that pediatric cancer survivors are at a greater risk of developing metabolic syndrome than the general population . We studied the prevalence of metabolic syndrome in adult survivors of childhood cancer(CCS). Methods: This is a prospective observational study . CCS with age > or = 18 years and at least 5 years in remission were included in the study .Details of cancer treatment , history of hypertension(HT), diabetes mellitus (DM) , cardiovascular disease and family history of HT and DM was noted . Blood pressure and body mass index was recorded. Fasting blood sugar and lipid profile were done. We used IDF (International diabetes federation) criteria to diagnose metabolic syndrome . This study was approved by our institute ethics comittee. The data was analyzed using the Statistical Package for Social Sciences (IBM SPSS 24). Results: 130 CCS were included in this study. Males were predominant 114(87.7%). Median age at follow up was 24 years ( Range 18-50 years) and median follow up time was 13 years (range 5-35 years) .Most were treated for Hodgkin’s disease 46(35.4% ) followed by acute lymphoblastic leukemia 26 (20%) . 11.5 % of total population satisfied the criteria of metabolic syndrome. The gender, cancer diagnosis, cranial RT did not affect the risk of MS . 23.8 % had generalized obesity of these 25.8 % had metabolic syndrome .20% survivors were hypertensive and 6.2 % had diabetes mellitus .77.7% of the study group had one or more risk factors for MS Conclusions: We have documented an increased proportion of metabolic syndrome in CCS. It is important to screen for components of MS in CCS in order to prevent cardiovascular events and type 2 diabetes.
A pilot study on cisplatin-based transarterial chemoembolization combined with systemic cisplatin plus gemcitabine for advanced or metastatic intrahepatic cholangiocellular carcinoma.
Authors: Sadahisa Ogasawara, Yoshihiko Ooka, Eiichiro Suzuki, Harutoshi Sugiyama, Akinobu Tawada, Yuji Sakai, Tetsuhiro Chiba, Fumihiko Kanai, Toshio Tsuyuguchi, Osamu Yokosuka
Journal: Journal of Clinical Oncology (2017)

e15629 Background: Systemic cisplatin plus gemcitabine (CisGem) is the standard treatment for patients with advanced or metastatic intrahepatic cholangiocellular carcinoma (ICC). Transarterial chemoembolization (TACE) is a treatment procedure for patients with liver cancer. This prospective study was to evaluate the safety and efficacy of cisplatin-based TACE combined with systemic CisGem in patients with ICC. Methods: Eligibility criteria were histologically or cytologically confirmed, unresectable, recurrent or metastatic mass-forming type ICC; Eastern Cooperative Oncology Group performance status 0–2; and an adequate major organ function. Patients may have had prior treatment, including surgery, but no prior CisGem therapy. Cisplatin (25 mg/m2) plus gemcitabine (1000 mg/m2) were intravenously administered on days 1 and 8 of a 21-day cycle for 12 cycles. Three sessions of TACE were scheduled—before first, fifth, and ninth cycle of CisGem. A suspension of CDDP-powder 35 mg/m2 and lipiodol was injected through tumor-feeding branch of intrahepatic lesions, and embolization of the feeding arteries was performed using gelatin sponge (UMIN000004776). Results: Of 14 patients enrolled between December 2010 and December 2013, 7 (50%) completed treatment schedule, whereas 4 (29%) and 3 (21%) discontinued due to disease progression and adverse events (one patients each due to allergic reaction, platelet count reduction, and hepatic infection), respectively. The most common severe adverse events were elevated aspartate aminotransferase (86%) and alanine aminotransferase (71%) levels; reduced neutrophil (36%), platelet (36%), and white blood cell (28%) counts; and hepatic infection (21%). Eleven patients (79%) were evaluated for objective response (RECIST version 1.1): 9 were observed to have a partial response and 2 had a stable disease. The 6-month progression-free survival rate was 64%, and median overall survival was 25.8 months. Conclusions: Cisplatin-based TACE combined with CisGem is a feasible treatment option; however, a randomized clinical trial for comparison with CisGem is required in future. Clinical trial information: UMIN000004776.
Comparing the impact of dose reductions and delays on ovarian cancer patient outcomes with three-weekly versus dose dense carboplatin and paclitaxel regimens in the national prospective OPAL cohort.
Authors: Tharani Sivakumaran, Linda R. Mileshkin, Peter T. Grant, Michael Friedlander, Penelope M Webb, George Au-Yeung
Journal: Journal of Clinical Oncology (2018)

5568 Background: To determine if chemotherapy dose reductions and delays in the adjuvant setting impact ovarian cancer pt outcomes. Secondary objective is comparing deliverability of three weekly and dose dense chemotherapy. Methods: OPAL is a national prospective study involving 958 pts with newly diagnosed epithelial ovarian (or peritoneal, fallopian tube) cancer. All pts who commenced 3 weekly Carboplatin (AUC 5/6) and Paclitaxel 175mg/m2 (3CP) or Carboplatin (AUC 5/6) and weekly Paclitaxel 80mg/m2(CddP) were identified from the OPAL study database. Information regarding patient demographics, treatment doses, adverse effects and clinico-pathological characteristics had been collated from medical records were identified. Results: Five hundred and fifty-two pts were identified from the database with 262 commencing 3CP and 290 commencing CddP. The median age at diagnosis was 62 yrs (range 21-79). The most common pathology was serous (74%) with most high grade (77%). Six cycles of chemotherapy were completed by 200 (76%) and 128 (44%) pts (p < 0.001) in the 3CP and CddP groups respectively. There was at least one treatment delay in 125 (48%) and 143 (49%) pts in the 3CP and CddP groups respectively. The 3CP and CddP groups had 46 (18%) and 91 (31%) pts respectively requiring at least a 15% dose reduction for Carboplatin; and 47 (18%) and 94 (32%) patients for Paclitaxel respectively. Severe haematological toxicity was experienced in 8% and 16% of pts in the 3CP and CddP group respectively and 7% experienced severe neurological toxicity in both groups. Mean relative dose intensities of Carboplatin was 93% and 85% for the 3CP and CddP group respectively; and for Paclitaxel was 86.5% and 75.5%. The median progression free survival (mPFS) was 23.3 mo vs 20.1 mo for 3CP and CddP groups (p = 0.0012). The mPFS in 3CP was 23.7 mo vs 26.5 mo in the dose reduction and no dose reduction group respectively; and for CddP group was 20.1 mo vs 20.4 mo. Conclusions: Dose reductions did not have an impact on mPFS. CddP had more treatment delays, dose reductions, haematological toxicities and lower completion rates than the 3CP group.
Fusion analysis of solid tumors to reveal novel rearrangements in breast carcinomas.
Authors: Igor A. Astsaturov, Phil Ellis, Jeffrey Swensen, David Arguello, Sandeep K. Reddy, Zoran Gatalica, Wafik S. El-Deiry
Journal: Journal of Clinical Oncology (2016)

11504 Background: Gene fusions are important mutations in cancer development. In NSCLC, ALK- and ROS1-rearrangements led to creation of agents that block further tumor progression. Some fusions are considered unique to a specific cancer subtype (“translocation-defined” cancer types). The purpose of this study is to report fusion testing results performed at a multi-omic tumor profiling facility to identify novel or uncommon fusions in a variety of tumor types. Methods: In total, 1282 solid tumor specimens were profiled using the ArcherDx FusionPlex Assay at a CLIA-certified laboratory (Caris Life Sciences). Commonly profiled cancer specimens included colorectal adenocarcinoma (n = 243), non-small cell lung carcinoma (n = 215), breast adenocarcinoma (n = 109), and glioblastoma multiforme (n = 76). Results: Overall, 13.4% (172/1282) of specimens analyzed contained a previously reported or novel fusion. Fusions were more frequently detected in glioblastoma multiforme (26.3%, 20/76), soft tissue sarcoma (23.5%, 8/34), prostatic adenocarcinoma (20.0%, 5/25), NSCLC (16.7%, 36/215), gastric adenocarcinoma (15.2%, 5/33) and invasive breast carcinoma (7.3%, 8/109) specimens. A common cis-spliced fusion of two adjacent genes (ADCK4-NUMBL) was identified in 6.1% overall (78/1282), followed by the FGFR3-TACC3 (0.5%, 7/1282). Overall, sixty-five unique fusions were identified. In a sub-analysis of breast carcinomas of common histologic subtypes (e.g. ductal), eight distinct gene fusions were detected (ADCK4-NUMBL, CCDC6-RET, ESR1-ATP2B2, ETV6-RUNX1, FCGR2C-MAST2, FGFR2-CCDC3, FGFR3-TACC3, and PRKCG-PRKCB). Conclusions: Our analysis reveals fusions, such as FGFR, that are potentially targetable and these results could be useful to direct patients to clinical trials for relevant drugs. Our analysis indicates gene fusions are not restricted to special subtypes of breast carcinoma. For example, ETV6 gene rearrangement is not restricted to secretory carcinoma as it was detected in a metastatic ductal carcinoma, NOS. In addition, we report ETV-RUNX1, a well-known fusion associated with childhood ALL, in a breast carcinoma. Further studies are warranted to explore the role of fusions in driving various cancers.
Airway Microbiota Dynamics Uncover a Critical Window for Interplay of Pathogenic Bacteria and Allergy in Childhood Respiratory Disease
Authors: Shu Mei Teo, Howard H.F. Tang, Danny Mok, Louise M. Judd, Stephen C. Watts, Kym Pham, Barbara J. Holt, Merci Kusel, Michael Serralha, Niamh Troy, Yury A. Bochkov, Kristine Grindle, Robert F. Lemanske, Sebastian L. Johnston, James E. Gern, Peter D. Sly, Patrick G. Holt, Kathryn E. Holt, Michael Inouye
Journal: Cell Host & Microbe (2018)
P01.018 Mismatch repair deficiency (MMRd) in glioma patients (PTS): frequency and correlation with clinical, histological and molecular characteristics
Authors: G Lombardi, M Caccese, M Simonelli, M Fassan, P Persico, E Lorenzi, R Bertorelle, M Gardiman, L Bellu, A Pambuku, A Santoro, V Zagonel
Journal: Neuro-Oncology (2018)

Immune-checkpoint inhibitors (ICI) represent a new interesting approach in oncology. The presence of DNA MMRd would seem to be a predictor of ICI efficacy. We analyzed MMRd frequency in glioma PTS and its correlation with clinical, histological and molecular characteristics. From July 2017 to May 2018, we prospectively analyzed histologically confirmed glioma PTS for the presence of MMRd by immunohistochemistry (IHC): MSH2, MSH6, PMS2, MLH1. Clinical, histological and molecular characteristics (MGMT methylation and IDH mutational status, PD-L1 expression) were recorded. Chi-square test was used for analyzing their correlations with MMRd. 167 PTS were enrolled: 78% glioblastoma (GBM), 14% anaplastic astrocytoma (AA), 1% ependymoma, 2% anaplastic oligodendroglioma (OD) and 5% LGG. The analyses were assessed on tissue samples of first (82% of the cases), second surgery (18%). All PTS performing a second surgery received radiotherapy and temozolomide as first-line therapy. 134 PTS were analyzed for IDH status: 99 were IDH wt; 117 for MGMT status: 68 were methylated.27 PTS (16%) showed MMRd by IHC (MSH2 in 48%, MSH6 in 55.6%, PMS2 in 18.5% and MLH1 in 14.8%): 33% of AA, 14% of GBM, 33% of OD and 0% of LGG (p=0.2). MMRd was found in 13% and 32% on first and second surgery samples (p=0.03). PD-L1 expression analysis was performed in 60 cases: no expression was showed in 58% of cases, ≥ 1% and <50% in 38%, > 50% in 10%. MMRd was not correlated with PD-L1 expression (p=0.3). MMRd was found in 10% and 29% of IDHwt and IDHmut gliomas(p=0.008); MMRd was showed in 10% and 21% of PTS with unmet and metMGMT (p=0.1). Among MMRd tumors, 7 were also investigated by molecular analysis (PCR) of mononucleotide markers: in only 1 PT (14%) was confirmed MMRd in agreement with IHC analysis (p=0.1.). We showed a small group of glioma PTS have MMRd by IHC, expecially at second surgery. Correlation was observed between IHC MMRd and IDH mutational status. No association was demonstrated between IHC MMRd and histology, MGMT status, PD-L1 expression or molecular analysis of MMRd. A prospective study analyzing ICI efficacy in MMRd PTS should be warranted.
Single agent activity of U3-1402, a HER3-targeting antibody-drug conjugate, in breast cancer patients: Phase 1 dose escalation study.
Authors: Takahiro Kogawa, Kan Yonemori, Norikazu Masuda, Shunji Takahashi, Masato Takahashi, Hirotaka Iwase, Takahiro Nakayama, Toshiaki Saeki, Tatsuya Toyama, Toshimi Takano, Hiroshi Onuma, Hayao Ogawa, Yoshimi Tanaka, Yoshiko Igari, Masahiro Sugihara, Michele Vigliotti, Channing Yu, Martin Sebastian Olivo, Suguru Ueno, Hiroji Iwata
Journal: Journal of Clinical Oncology (2018)

2512 Background: U3-1402 is a human epidermal growth factor receptor 3 (HER3)-targeting antibody-drug conjugate (ADC) of high drug-to-antibody-ratio (DAR: 7 to 8) with a novel linker and topoisomerase I inhibitor payload. HER3 is overexpressed in a variety of cancers, including breast, lung, colorectal, ovarian, prostate and urothelial cancer. This ongoing, Phase 1/2 study (NCT02980341) of U3-1402 in HER3-expressing metastatic breast cancer (MBC) is divided into three parts: dose escalation (Part 1), dose finding (Part 2), and dose expansion (Part 3). Methods: In Part 1 of the ongoing study, the dose of U3-1402 was escalated based on dose-limiting toxicity data, guided by the modified Continuous Reassessment Method (mCRM). U3-1402 was administered via intravenous (IV) infusion in 21-day cycles. The primary objectives are to determine safety and tolerability of U3-1402, the maximum tolerated dose (MTD), and the recommended dose for Phase 2. AEs, PK, ORR per RECIST v1.1, and durability of responses were assessed. Efficacy-evaluable patients (pts) received at least one dose of U3-1402 and had pre- and post-treatment tumor assessments. Results: As of December 28, 2017, 21-evaluable pts (female, median age 59 years, ECOG 0-1, and ≥ 2 previous treatment regimens) have received U3-1402 at dose levels between 1.6 mg/kg to 8.0 mg/kg. Reversible Grade 3/4 thrombocytopenia, and Grade 3/4 liver enzyme increase as dose-limiting toxicities were observed in 4 (19%) and 2 (9.5%) pts respectively. The most common treatment-related adverse events were nausea (71.4%), vomiting (47.6%), and decreased appetite (47.6%). ORR was 33% and DCR (CR+PR+SD) was 95%. Three pts (14%) discontinued due to PD and 1 pt discontinued due to Grade 2 pneumonitis. Seventeen pts (80%) remain on treatment, including 6 pts (28%) who have remained on treatment for more than 6 months. HER3 IHC has been evaluated in 294 breast cancer pts, 87 (30%) showed high levels of HER3 expression. Conclusions: In a preliminary analysis of 21 pts, U3-1402 exhibits antitumor activity in previously treated HER3 expressing MBC pts and treatment is associated with a manageable safety profile. Clinical trial information: NCT02980341.
Prognostic markers for progression free survival (PFS) to anti PD-1 therapies in metastatic melanoma.
Authors: Umang Swami, Varun Monga, Tina Knutson, Aaron D. Bossler, Yousef Zakharia, Mohammed M. Milhem
Journal: Journal of Clinical Oncology (2018)

e21527 Background: Anti PD-1 therapies are the front-line treatment for metastatic melanoma. However, it is not known who will benefit from them. Herein we report results for prognostic factors from our institution. Methods: Patients (pts) data enrolled in Melanoma Skin & Ocular Tissue Repository at Holden Comprehensive Cancer Center from 8/1/2012 to 7/31/2017 was reviewed. Reviewed data included baseline characteristics, mutational status, baseline hematological parameters, PFS, radiation therapy 3 months prior or during treatment and antibiotic exposure 2 months before or after starting anti PD-1 therapy. Kaplan-Meier analysis and t-test were performed. Results: Total 199 pts (all white, non-Hispanic) with metastatic melanoma received anti PD-1 therapy. Demographics as below. Pts with cutaneous melanoma had a better median PFS as compared to choroidal and mucosal melanoma (338 vs. 126 vs. 133 days, p < 0.05). Pts with cutaneous melanoma and PFS > 180 days, when compared to pts with PFS < 90 days had a significantly higher baseline median lymphocyte count (1580 vs. 1360/mm3), albumin (4.2 vs 3.95 g/dl) and lower platelet to eosinophil ratio (1268 vs 1593), absolute neutrophil count (ANC) to lymphocyte ratio (2.88 vs.3.63), ANC to eosinophil ratio (25.74 vs. 33.85), LDH (194 vs.243 U/L) and lower incidence of radiation therapy (13% vs. 45%) (p < 0.04 for all). Prior ipilimumab use, line of therapy, smoking history, BRAF V600E, NRAS and antibiotic exposure were not statistically significant as prognostic markers. On sub-group analysis, in pts 65 years or older, a lower PFS was associated with NRAS mutation (88 days vs undefined, HR 3.78 95%CI 1.1-12.97, p < 0.035) and antibiotic exposure (89 vs. 943 days, HR 4.06 95% CI 1.78 to 9.25, p < 0.001). Conclusions: Our study demonstrates multiple hematological prognostic markers as above. In pts 65 years or older, NRAS mutation and antibiotic exposure 2 months prior or after starting anti PD-1 therapy was associated with poor PFS. Total subjects, n = 199 Subjects≥65 years, n = 90 Male 124 60 Female 75 30 Median age (Range) years 63 (25-98) 75 (65-98) Ocular 19 6 Mucosal 11 9 Cutaneous + others 169 75 Single agent vs. combination 127 vs. 72 61 vs. 29 Anti PD-1 as first line vs. later 123 vs. 76 58 vs. 32