tbuckley/cabot-search huggingface dataset:
Treatment of hepatocellular carcinoma and liver metastases with hafnium oxide nanoparticles activated by SBRT: A phase I/II trial.
Authors: Nicolas Jaksic, Marc Pracht, Yann Rolland, Thierry De Baere, Jerome Durand-Labrunie, France Nguyen, Jean-Pierre Bronowicki, Veronique Vendrely, Antonio Sa Cunha, Valérie Croisé-Laurent, Emmanuel Rio, Samuel Le Sourd, Patricia Said, Sebastian Freund, Edwina Baskin-Bey, Pierre Gustin, Christophe Perret, Didier Peiffert, Eric Deutsch, Enrique Chajon
Journal: Journal of Clinical Oncology (2020)

537 Background: Treatment of unresectable liver cancer or liver metastases (mets) by stereotactic body radiotherapy is well tolerated but limited by the need to preserve liver function. Increasing energy deposition in the tumor while at the same time maintaining the dose in healthy tissue remains a major challenge in radiation oncology that could be achieved by NBTXR3 (hafnium oxide nanoparticles) when activated by radiotherapy (RT). NBTXR3 augments energy dose deposit within tumor cells, increasing tumor cell death compared to RT alone, while sparing healthy tissues. Patients (pts) with hepatocellular carcinoma (HCC) or liver metastasis (mets) may benefit from the mode of action of NBTXR3. A phase I/II clinical trial has been conducted to evaluate NBTXR3 activated by SBRT in these pts [NCT02721056]. Methods: The Phase I used a 3+3 dose escalation scheme with 5 NBTXR3 dose levels: 10, 15, 22, 33, and 42% of baseline tumor volume. NBTXR3 was administered by intratumoral injection (ITI) followed by SBRT (45 Gy / 3 fractions / 5 to 7 days or 50 Gy / 5 fractions / 15 days). Primary endpoints were identification of the recommended Phase II Dose and early DLTs. Secondary endpoints included safety profile, liver function evaluated by Child-Pugh score (CPS), AST to Platelet Ratio Index (APRI), and early efficacy by response rate (mRECIST/RECIST 1.1). Results: The dose escalation levels of 10, 15, 22 and 33% are completed (n = 17): 6 pts at 10% (2 SBRT doses tested due to organ constraints), 4 pts each at 15% and 22% (due to fiducial displacement and ITI shift) and 3 pts at 33%. No early DLT was observed and only one SAE (bile duct stenosis) related to NBTXR3 and RT occurred. CPS and APRI did not show clinically meaningful changes post-treatment and CT-scan showed no leakage of NBTXR3 into surrounding tissues. Best response for HCC (n = 8) were 5CR, 3PR and for mets (n = 6) the results were: 3 PR, 3SD. Conclusions: ITI of NBTXR3 is feasible, demonstrated a very good safety and tolerability profile up to the 33% dose level. Recruitment needs to be finalized at the 42% dose level. Based on early efficacy results NBTXR3 has the potential to address an unmet medical need in pts with unresectable primary or metastatic liver cancer. Clinical trial information: NCT02721056.
Plasma VEGF-D and PlGF levels according to prior use of biologics among metastatic colorectal cancer: Preliminary results from GI-SCREEN CRC-Ukit study.
Authors: Hiroya Taniguchi, Satoshi Yuki, Manabu Shiozawa, Toshiki Masuishi, Tomohiro Nishina, Yoshinori Kagawa, Naoki Takahashi, Hisateru Yasui, Tadamichi Denda, Yu Sunakawa, Kentaro Yamazaki, Taito Esaki, Hisato Kawakami, Takeshi Kato, Kazuhiro Yoshida, Atsuo Takashima, Hiroko Ohmiya, Shogo Nomura, Atsushi Ohtsu, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2020)

178 Background: Plasma vascular endothelial growth factor-D (VEGF-D) level is a potential predictor for ramucirumab efficacy in patients (pts) with metastatic colorectal cancer (mCRC), while a high VEGF-A and placental growth factor (PlGF) level in bevacizumab naïve pts receiving 2nd-line FOLFIRI plus aflibercept may suggest relatively higher activity. However, there are a few data associating 1st-line antiangiogenic treatments as well as anti-EGFR with angiogenic factors. Methods: This prospective longitudinal study aims to investigate an association between plasma angiogenesis-related mediators and clinical outcomes in mCRC. Serial plasma collections were done at time points of pre- and post-treatments of either 1st- or 2nd-line. Comprehensive measurements of 17 mediators were analyzed by the multiplex assay with Luminex technology. Here we report an association between levels of VEGF-D, PlGF and patient backgrounds. Results: From Sep 2017 to Aug 2019, 375 samples from 317 pts were enrolled in this analysis. Baseline characteristics were follows; 169 samples at pre-1st-line (pre-1L), 151 with prior bevacizumab treatment (post-bev) and 55 with prior anti-EGFR antibody (post-EGFR); median age, 66 years; male gender, 58%; RAS mutant, 46%; left-sided primary, 76%. In pre-1L, the median values of VEGF-D/ PlGF were 264/ 7.21 pg/mL without a clear association between the two in each patient (r = 0.094) and any baseline characteristics. Compared to pre-1L, the values of VEGF-D/ PlGF showed significantly higher in post-bev (median VEGF-D/ PlGF; 346/ 23.5 pg/mL, respectively). Moreover, there was no clear relationship between the two cytokines in each patient (r = 0.190). In 37 pts with serial blood collection, VEGF-D/ PlGF levels showed similar trends. In addition, VEGF-D/ PlGF levels in post-EGFR tended to be higher than those in pre-1L (median VEGF-D/ PlGF; 395/ 9.11 pg/mL, respectively). Conclusions: The VEGF-D/ PlGF may be separately induced by bev treatment as well as anti-EGFR therapy, suggesting the possibility of usefulness for selecting a better antiangiogenic inhibitor by measuring baseline VEGF-D/ PlGF. Clinical trial information: UMIN000028616.
Estrogen/progesterone receptor and HER2 discordance between primary tumor and brain metastases in breast cancer and its effect on treatment and survival
Authors: Paul W Sperduto, Shane Mesko, Jing Li, Daniel Cagney, Ayal Aizer, Nancy U Lin, Eric Nesbit, Tim J Kruser, Jason Chan, Steve Braunstein, Jessica Lee, John P Kirkpatrick, Will Breen, Paul D Brown, Diana Shi, Helen A Shih, Hany Soliman, Arjun Sahgal, Ryan Shanley, William Sperduto, Emil Lou, Ashlyn Everett, Drexell Hunter Boggs, Laura Masucci, David Roberge, Jill Remick, Kristin Plichta, John M Buatti, Supriya Jain, Laurie E Gaspar, Cheng-Chia Wu, Tony J C Wang, John Bryant, Michael Chuong, James Yu, Veronica Chiang, Toshimichi Nakano, Hidefumi Aoyama, Minesh P Mehta
Journal: Neuro-Oncology (2020)

Breast cancer treatment is based on estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2). At the time of metastasis, receptor status can be discordant from that at initial diagnosis. The purpose of this study was to determine the incidence of discordance and its effect on survival and subsequent treatment in patients with breast cancer brain metastases (BCBM).A retrospective database of 316 patients who underwent craniotomy for BCBM between 2006 and 2017 was created. Discordance was considered present if the ER, PR, or HER2 status differed between the primary tumor and the BCBM.The overall receptor discordance rate was 132/316 (42%), and the subtype discordance rate was 100/316 (32%). Hormone receptors (HR, either ER or PR) were gained in 40/160 (25%) patients with HR-negative primary tumors. HER2 was gained in 22/173 (13%) patients with HER2-negative primary tumors. Subsequent treatment was not adjusted for most patients who gained receptors-nonetheless, median survival (MS) improved but did not reach statistical significance (HR, 17-28 mo, P = 0.12; HER2, 15-19 mo, P = 0.39). MS for patients who lost receptors was worse (HR, 27-18 mo, P = 0.02; HER2, 30-18 mo, P = 0.08).Receptor discordance between primary tumor and BCBM is common, adversely affects survival if receptors are lost, and represents a missed opportunity for use of effective treatments if receptors are gained. Receptor analysis of BCBM is indicated when clinically appropriate. Treatment should be adjusted accordingly.1. Receptor discordance alters subtype in 32% of BCBM patients.2. The frequency of receptor gain for HR and HER2 was 25% and 13%, respectively.3. If receptors are lost, survival suffers. If receptors are gained, consider targeted treatment.
Provider perspective: The clinical value of a novel digital medicine program in gastrointestinal oncology.
Authors: Edward Greeno, Paul Morales, Daniel Beiswenger, Xue Wang, Ellen Travis, R. Scooter Plowman
Journal: Journal of Clinical Oncology (2020)

76 Background: The differences in colorectal cancer (CRC) treatment between infusion and oral chemotherapy have challenged clinical teams to maintain clinical quality and patient communications with self-administered therapies. The complexity of many regimens, such as capecitabine, creates challenges with dosing and adverse event (AE) management. The first novel Digital Medicine Program (DMP), aimed at providing support to patients and providers, was integrated into CRC treatment at Fairview Health Services and University of Minnesota Health. The DMP consists of DigiMeds (medications co-encapsulated with ingestible sensors), a wearable patch, and a mobile app to facilitate passive collection of actual medication ingestion data and biometrics over time. Methods: Beginning in September 2018, patients with CRC were offered the DMP to augment standard of care. Clinical pharmacists monitored medication adherence and biometrics in near real-time through a secure web portal. This data was used to address barriers to adherence and adjust therapy when appropriate. Qualitative data regarding provider experiences with the DMP and their interactions with patients were collected via a 5-question survey. Results: Eleven patients used the DMP (age: 66.9 ± 9.9 years (mean ± SD); patch wear: 89.9 ± 11.6%; average adherence: 91.0 ± 5.6%) for 140 ± 137 days. Providers reported that the DMP enabled data-driven decision-making by helping identify non-adherence, prompted timely dose modification for AE management, and allowed personalized care and targeted counseling. Integration of the DMP data into the Electronic Medical Record system improved utility, but providers called the DMP a “time-saver”, creating a “proactive rather than reactive” care process in “ways no other technology can do”. Providers stated patients felt more ownership of their care, and that DMP revealed newly “quantifiable positive changes” in their cancer care. Conclusions: Use of the DMP in this small cohort enabled proactive decision-making and facilitated patient-focused and efficient care. Future pragmatic, large real-world studies are underway to assess the impact of DMP on adherence, AE management, and clinical and economic outcomes.
Pancreatic cancer intratumoral microbiome and characteristics within paired patient samples.
Authors: Sonal Suresh Noticewala, Daniel Lin, Ramez Kouzy, Anirban Maitra, Lauren Elizabeth Colbert, Cullen M. Taniguchi
Journal: Journal of Clinical Oncology (2020)

744 Background: While most studies evaluating the microbiome in gastrointestinal cancers analyze stool, little is known about the microbiota of the peri-tumoral and intra-tumoral environment. Here, we evaluated the intra-tumoral and peri-tumoral (duodenum and normal pancreas) microbiome for paired duodenal, normal pancreas and resected tumor specimens from pancreatic cancer patients. The purpose of this study was to describe the similarities and differences within patient microbiota. Methods: Fifteen specimens from 5 patients with pancreatic cancer were collected during surgical resection. Genomic bacterial DNA was extracted from these specimens and underwent 16S rRNA sequencing. Alpha (Inverse Simpson) and beta diversity were calculated, and relative abundances of individual bacterial species were compared. Sorensen distance was used the evaluate the spread in beta diversity between paired sample types. Results: Of the five patients who underwent resection, the following baseline characteristics were obtained: median age = 65 years (range 55 -80 years), 2/5 patients were treated with gemcitabine/abraxane, 3/5 patients were treated with oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX); 4/5 patients received pre-operative radiation. 16s sequencing analysis of the pancreatic tumor showed the dominant genus to be Escherichia/Shigella (10.6%). Bradyrhizobium (10.1 %) was dominant in the normal pancreas . Escherichia/Shigella (14.3%) was abundant in the duodenum. There was a trend towards higher alpha diversity in tumor vs. normal duodenum/ pancreas (p = 0.12). Sorensen distance was statistically different between sample types (p = 0.004), with duodenal samples most consistent (distance = 67.82), and tumor vs. normal pancreas (81.86) and tumor vs. other tumor samples the most heterogeneous (78.5). Conclusions: This pilot data suggests that the pancreatic tumor microbiome is distinct from the normal pancreas and duodenal microbiome, which indicates tumor specific bacteria should be studied. In future studies, intra-tumoral microbiome may be more relevant to associations with outcomes and treatment response than stool or intestinal microbiome studies.
Efficacy and safety of larotrectinib in patients with TRK fusion gastrointestinal cancer.
Authors: Jordan Berlin, David S. Hong, John F. Deeken, Valentina Boni, Do-Youn Oh, Jyoti D. Patel, Shivani Nanda, Nicoletta Brega, Barrett H. Childs, David Michael Hyman, Alexander E. Drilon
Journal: Journal of Clinical Oncology (2020)

824 Background: Tropomyosin receptor kinase (TRK) fusions arise from rearrangements of the neurotrophic tyrosine receptor kinase ( NTRK) 1, 2, or 3 genes and an unrelated gene, creating constitutively active oncogenic drivers that have been detected in a range of adult and pediatric malignancies, but are generally rare in patients with gastrointestinal (GI) cancer. Larotrectinib is a selective TRK inhibitor approved for the treatment of adult and pediatric patients with TRK fusion cancer. Here, we report efficacy and safety data for patients with TRK fusion GI tumors. Methods: Patients with a TRK fusion GI cancer treated with larotrectinib in a phase II clinical trial, NAVIGATE (NCT02576431), were included in this analysis. Larotrectinib was administered at 100 mg twice daily, until disease progression, unacceptable toxicity, death, or withdrawal. Response was assessed by the investigator using RECIST v1.1. Results: As of February 19, 2019, 14 patients with TRK fusion GI cancer (median age 68 y, range 32–84 y) were enrolled. GI tumor types were colon (8), cholangiocarcinoma (2), pancreas (2), appendix (1), and hepatic (1). Fusions involved NTRK1 (n = 12) and NTRK3 (n = 2). Nine patients had ≥2 prior lines of therapy. The best response on last prior therapy was 1 partial response (PR). Overall best responses on larotrectinib were: colon cancer, 4 patients had a PR and 4 had stable disease (SD); pancreatic cancer, 1 patient had a PR and 1 had SD; cholangiocarcinoma, 1 patient had a PR and 1 had progressive disease; appendix cancer, 1 patient had SD; response in 1 patient with hepatic cancer was not determined. Median time to response was 1.8 months (range 1.7–2.1). With 5 patients ongoing and censored, the median progression free survival was 5.3 months (95% CI 2.2–9.0). Median overall survival was 33.4 months (95% CI 2.8–36.5). Larotrectinib was well tolerated, with most adverse events being grade 1 or 2. Conclusions: Although the sample size is limited, there is evidence of clinical activity with larotrectinib in TRK fusion GI cancer, with a manageable safety profile. TRK fusion GI cancer may represent an under-diagnosed subset of patients with viable treatment options. Clinical trial information: NCT02576431.
Phase III study of pembrolizumab (pembro) versus best supportive care (BSC) for second-line therapy in advanced hepatocellular carcinoma (aHCC): KEYNOTE-240 Asian subgroup.
Authors: Masatoshi Kudo, Ho Yeong Lim, Ann-Lii Cheng, Yee Chao, Thomas Yau, Sadahisa Ogasawara, Masayuki Kurosaki, Naoki Morimoto, Kazuyoshi Ohkawa, Tatsuya Yamashita, Kyung-Hun Lee, Erluo Chen, Abby B. Siegel, Baek-Yeol Ryoo
Journal: Journal of Clinical Oncology (2020)

526 Background: Pembro received accelerated approval for second-line therapy in aHCC based on KEYNOTE-224 (phase 2). KEYNOTE-240 (NCT02702401) is a randomized, phase 3 study of pembro v BSC in previously treated aHCC. We report outcomes for the Asian subgroup. Methods: Pts with a radiographic/pathologic HCC diagnosis, radiographic progression with/intolerance to sorafenib, Child-Pugh A disease, and ECOG PS 0/1 were randomized 2:1 to pembro (200 mg) + BSC or PBO + BSC Q3W (≤35 cycles or until confirmed PD/unacceptable toxicity). Pts were stratified by geographic region (Asia without Japan; non-Asia with Japan), AFP, and macrovascular invasion. Response was assessed Q6W (RECIST v1.1, central review). Primary end points: OS, PFS; secondary end points: ORR, DOR, safety. Data cutoff: Jan 2, 2019. Results: 413 pts were randomized (overall cohort: n = 278 pembro, n = 135 PBO; Asian subgroup [Hong Kong, Japan, Philippines, S Korea, Taiwan, Thailand]: n = 107, n = 50). HBV+ status and BCLC stage C were higher in Asian subgroup (HBV+: 51% v 24.5% overall; stage C: 86.6% v 79.4%). Median follow-up: pembro (21.3 mo overall; 23.5 mo); PBO (21.5 mo overall; 23.0 mo). Pembro improved OS v PBO (median OS [95% CI]: 13.9 [11.6-16.0] v 10.6 [8.3-13.5] mo; HR: 0.781; 95% CI, 0.611-0.998; P = 0.0238) and PFS (HR: 0.718; 0.570-0.904; P = 0.0022) for overall cohort and Asian subgroup (median OS: 13.8 [10.1-16.9] v 8.3 [6.3-11.8] mo; HR: 0.548; 0.374-0.804; P = 0.0009; PFS: HR: 0.475; 0.324-0.696; P &lt; 0.0001). Differences did not meet prespecified significance level for overall cohort. ORR in overall cohort was 18.3% (14.0-23.4) for pembro; 4.4% (1.6-9.4; P = 0.00007) for PBO; in Asian subgroup, 20.6% (13.4-29.5) and 2.0% (0.1-10.6; P = 0.00135). Safety was consistent with that previously reported in pembro studies. No HBV/HCV flares were identified. Conclusions: Pembro reduced risk for death by 22% in overall cohort and 45% in Asian subgroup and improved PFS v PBO. Safety was comparable to that of pembro monotherapy. Results are consistent with KEYNOTE-224 and magnitude of OS benefit was enhanced in Asian subgroup, supporting a favorable risk-benefit balance for second-line pembro in HCC. Clinical trial information: NCT02702401.
A phase II trial of pharmacological ascorbate, gemcitabine, and nabpaclitaxel for metastatic pancreatic cancer.
Authors: Pashtoon Murtaza Kasi, Kellie Bodeker, Daniel James Berg, Chandrikha Chandrasekharan, Saima Sharif, Brian J. Smith, Sandy Vollstedt, Heather Brown, Meghan Chandler, Joseph J. Cullen
Journal: Journal of Clinical Oncology (2020)

TPS791 Background: FOLFIRINOX or gemcitabine/nab-paclitaxel are both frontline chemotherapy options for patients with metastatic pancreas cancer. For most who cannot tolerate the triplet, the latter doublet is the preferred option. Through previous work by our group, pharmacologic ascorbate is known to synergize with gemcitabine; preliminary in vitro data from our group suggests a similar synergistic response with paclitaxel. Though ascorbate has been utilized in cancer therapy, few robust trials have investigated intravenous delivery of ascorbate to deliver plasma concentrations that are cytotoxic to tumor cells. Our prior studies have demonstrated ascorbate induces oxidative stress and cytotoxicity in pancreatic cancer cells; this cytotoxicity appears to be greater in tumor vs. normal cells. We hypothesize that production of hydrogen peroxide mediates the increased susceptibility of pancreatic cancer cells to ascorbate-induced metabolic oxidative stress, resulting in improved treatment outcomes, which has led to the development of the clinical trial (NCT02905578). Methods: All participants receive gemcitabine (1000 mg/m2 weekly) and nab-paclitaxel (125 mg/m2) on cycle days 1, 8, and 15 of a 28-day cycle. Participants are randomized to ± pharmacologic ascorbate (75-gram infusion 3x weekly) in addition to chemotherapy. Study therapy continues until tumor progression. The primary objective is to determine overall survival in patients when treated with combination gemcitabine, nab-Paclitaxel and high-dose ascorbic acid compared to gemcitabine and nab-paclitaxel in patients with non-resectable pancreatic cancer. Secondary objectives include determining objective response rate as well as progression free survival using RECIST 1.1 criteria employing a blinded reviewer for RECIST measurements. The study opened to accrual in 2018 with a goal of enrolling 65 participants. Oversight.Study is conducted under IND 105715 (J. Cullen, sponsor). The University of Iowa Biomedical IRB (IRB-01) serves as the IRB of record. Clinical trial information: NCT02905578.
Slug overexpression and association with clinicopathological features in gastric cancer.
Authors: Joori Kim, In-Ho Kim, Han Hee Lee, Sung Hak Lee, Jae Myung PARK
Journal: Journal of Clinical Oncology (2020)

426 Background: Slug is a suppressive transcriptional factor of E-cadherin, acting as an activator of epithelial-mesenchymal transition(EMT). Its clinical relevance in gastric cancer(GC) is not fully known. Methods: Our study evaluated the expression patterns of EMT and cancer stem cell markers in GC patients who had clinical stage 2-3, underwent gastrectomy, D2 lymph node dissection (LND), adjuvant chemotherapy. Immunohistochemistry of E-cadherin, vimentin, CD133, ABCG2, NEDD9, SMAD4, XB130, Slug, Snail were investigated from 210 gastric cancer samples using tissue microarrays. The correlation between each markers expressed and the association with clinicopathological factors were analyzed. Results: Slug expression was more frequent in stage 3 than stage 2 (p=0.000), advanced T (p=0.007) and N stage (p=0.001), while histologic type did not make difference. Slug expression correlated with the expression of cancer stem cell marker CD133 (r=0.180, p=0.015) and CD133 expression was also related with ABCG2 (r=0.412, p=0.000). High Slug group showed shorter overall survival, compared to low Slug group (median OS 134 vs 124 months, p=0.044). The 2-year and 5-year disease-free (DF) rate for patients with high Slug and low Slug was 87.1% and 79.8%, 68.1% and 79.8%, respectively(p=0.038). The DFS curve reached an earlier plateau at 11-month in low Slug group, while in high Slug group took as long as 99 months. A multivariate analysis using the Cox proportional hazards regression model demonstrated Slug to be an independent prognostic factor for overall survival; hazard ratio 0.504 [95% CI 0.278-0.916] (p=0.025). Conclusions: In stage 2-3 GC patients who underwent gastrectomy with D2 LND and adjuvant chemotherapy, high Slug expression is associated with better disease-free and overall survival. Patients may benefit by testing Slug immunohistochemistry to predict prognosis after gastrectomy.
Tenofovir versus entecavir in prevention of hepatocellular carcinoma and mortality in patients with chronic hepatitis B
Authors: Faisal Kamal, Muhammad Ali Khan, Aijaz Ahmed, Satheesh Nair
Journal: Gut (2020)

We read with interest the study by Lee et al 1 showing no difference in risk of hepatocellular carcinoma (HCC) and mortality or liver transplantation (LT) in chronic hepatitis B (CHB) patients treated with tenofovir disoproxil fumarate (TDF) versus entecavir (ETV). We searched Medline, Embase, Scopus, Web of Science and Cochrane database to identify studies comparing TDF and ETV for prevention of HCC and mortality or LT in CHB patients. A total of 11 studies with 70 860 patients (TDF=20 105 and ETV=50 755) were included in this meta-analysis. We used adjusted HR (aHR) when reported and calculated risk ratios (RR) when adjusted effect sizes were not available. These were pooled separately using random effects model. Six studies compared TDF and ETV in propensity score (PS) matched cohorts (in addition to entire cohorts) which were created by matching two groups based on several variables (table 1) to reduce risk of bias.1–6 We …