bluuebunny/crossref_metadata_2025 huggingface dataset:
Robotic voluminous paraesophageal hernia repair: a case report and review of the literature
Authors: Tartaglia Nicola , Pavone Giovanna , Di Lascia Alessandra , Vovola Fernanda , Maddalena Francesca , Fersini Alberto , Pacilli Mario , Ambrosi Antonio
Published: February 2020

Background

The treatment for sliding esophageal hernia with mild gastroesophageal reflux is usually conservative, but surgical treatment is recommended for refractory sliding esophageal hernia, paraesophageal hernia liable to prolapse, or paraesophageal hernia with ulceration and/or stenosis. Robotic surgery overcomes laparoscopic pitfalls by providing steady-state three-dimensional visualization, augmented dexterity with endo-wrist movements, and superior ergonomics for the surgeon.

Case presentation

To investigate robotic paraesophageal hernia repair, a literature search was conducted using PubMed with the following key words: mini invasive surgery, robotic surgery, hiatal hernia, and Nissen fundoplication. We present the case of a 44-year-old Italian woman with a 20-year history of gastroesophageal reflux disease refractory to medical treatment, who underwent robotic Nissen fundoplication. In our center, we use the da Vinci® Xi™ Surgical System, which is an advanced tool for minimally invasive surgery.

Conclusions

Various reports published in the literature suggested that the robot-assisted approach was effective and was associated with very low postoperative morbidity and was accompanied by satisfactory symptomatic and anatomical radiological outcomes during a follow-up period.

The robotic approach to paraesophageal repair is safe and effective with low complication rates. With increased experience, the operative time, length of stay, and complications decrease without compromising surgical principles.
Intraday renewable electricity trading: advanced modeling and numerical optimal control
Authors: Glas Silke , Kiesel Rüdiger , Kolkmann Sven , Kremer Marcel , Graf von Luckner Nikolaus , Ostmeier Lars , Urban Karsten , Weber Christoph
Published: February 2020

As an extension of (Progress in industrial mathematics at ECMI 2018, pp. 469–475, 2019), this paper is concerned with a new mathematical model for intraday electricity trading involving both renewable and conventional generation. The model allows to incorporate market data e.g. for half-spread and immediate price impact. The optimal trading and generation strategy of an agent is derived as the viscosity solution of a second-order Hamilton–Jacobi–Bellman (HJB) equation for which no closed-form solution can be given. We construct a numerical approximation allowing us to use continuous input data. Numerical results for a portfolio consisting of three conventional units and wind power are provided.
On the prevention of kidney uptake of radiolabeled DARPins
Authors: Altai Mohamed , Garousi Javad , Rinne Sara S. , Schulga Alexey , Deyev Sergey , Vorobyeva Anzhelika
Published: February 2020

Background

Designed ankyrin repeat proteins (DARPins) are small engineered scaffold proteins (14–18 kDa) that demonstrated promising tumor-targeting properties in preclinical studies. However, high renal accumulation of activity for DARPins labeled with residualizing labels is a limitation for targeted radionuclide therapy. A better understanding of the mechanisms behind the kidney uptake of DARPins could aid the development of strategies to reduce it. In this study, we have investigated whether the renal uptake of [99mTc]Tc(CO)3-G3 DARPin could be reduced by administration of compounds that act on various parts of the reabsorption system in the kidney.

Results

Co-injection of lysine or Gelofusine was not effective for the reduction of kidney uptake of [99mTc]Tc(CO)3-G3. Administration of sodium maleate before the injection of [99mTc]Tc(CO)3-G3 reduced the kidney-associated activity by 60.4 ± 10.3%, while administration of fructose reduced it by 46.9 ± 7.6% compared with the control. The decrease in the kidney uptake provided by sodium maleate was also observed for [99mTc]Tc(CO)3-9_29 DARPin. Preinjection of colchicine, probenecid, mannitol, or furosemide had no effect on the kidney uptake of [99mTc]Tc(CO)3-G3. Kidney autoradiography showed mainly cortical accumulation of activity for all studied groups.

Conclusion

Common clinical strategies were not effective for the reduction of kidney uptake of [99mTc]Tc(CO)3-G3. Both fructose and maleate lower the cellular ATP level in the proximal tubule cells and their reduction of the kidney reuptake indicates the involvement of an ATP-driven uptake mechanism. The decrease provided by maleate for both G3 and 9_29 DARPins indicates that their uptake proceeds through a mechanism independent of DARPin structure and binding site composition.
The role of values for niche expansion: the case of solar photovoltaics on large buildings in Sweden
Authors: Warneryd Martin , Karltorp Kersti
Published: February 2020

Background

Solar photovoltaic (PV) plants can contribute to the transformation of the electricity system in Sweden not only by adding capacity, but also by forming new decentralized ownership structures and involving new actors. This article focuses on solar PV plants on larger buildings, which represent a significant share of the installed capacity (although the total capacity is still very low in Sweden) and which have a good future potential. We are interested in the reasons owners of large buildings have for investing in solar PV plants, despite the fact that they face a complex regulatory situation. The aim of this paper is, therefore, to identify added values from solar PV plants for large buildings and to see how these values contribute to the ongoing expansion of the solar PV niche in Sweden. We use sustainability transitions as the theoretical point of departure and focus particularly on the role of values in an expanding niche. Data was collected via 15 semi-structured interviews, mainly with large building owners. It provides an interesting empirical case of the pioneers within the actor group of large building owners who potentially can play an important role in the expansion of solar PV technology in Sweden. Theoretically, the article contributes to the sustainable transition research field by demonstrating how values are developed and affect the niche-regime interplay.

Results

The findings demonstrate that owning a solar PV plant adds values such as sustainability, fair cost, and induced innovativeness. These values have an effect on niche expansion by contributing for example to the development of a social network, new role development, positive niche narrative, and niche empowerment.

Conclusions

We conclude that the broad set of values added by solar PV plants on large buildings increases the desire and enhances the positive experience to take on a new role development. Furthermore, we conclude that added values contribute to developing a social identity which is important when expanding the social network around the niche. Finally, we conclude that added values shape the positive niche narrative among niche advocates and give direction for policy development related to the niche.
Does infrastructure increase exports and reduce trade deficit? Evidence from selected South Asian countries using a new Global Infrastructure Index
Authors: Rehman Faheem Ur , Noman Abul Ala , Ding Yibing
Published: February 2020

This study investigates the short- and long-run impact of infrastructure on export and trade deficit in selected South Asian countries during 1990–2017 by using Pooled Mean Group (PMG) estimator and cointegration techniques like Pedroni and Kao test. The empirical results of PMG approach confirmed the existence of significant long-run impact of aggregate and sub-indices of infrastructure (i.e., transport, telecommunication, energy and financial sector) on export and trade deficit. The findings suggested that infrastructure positively promotes exports while negatively affecting trade deficit. The relationship between infrastructure and export is worthy bulletin for South Asian economies to encourage the quantity of exports and catch-up on established economies. The control variables of exchange rate, human capital, per capita GDP and institutional quality enhance exports and retard trade deficit significantly in the long run. Furthermore, the Pedroni and Kao test indicates strong evidence of cointegration in selected variables. Fully modified ordinary least square (FMOLS) and dynamic ordinary least square (DOLS) support robust and consistent results to the main model of this study. Furthermore, the study recommended that in long run aggregate and sub-indices of infrastructure promote exports and decrease trade deficit in selected South Asian economies.
VOLTAGE-B study: Nivolumab monotherapy and subsequent curative surgery following preoperative chemoradiotherapy in patients with locally recurrent rectal cancer (LRRC) without previous radiotherapy.
Authors: Kato Takeshi , Bando Hideaki , Tsukada Yuichiro , Inamori Koji , Uemura Mamoru , Yuki Satoshi , Komatsu Yoshito , Homma Shigenori , Kotani Daisuke , Fukuoka Shota , Sasaki Takeshi , Nishizawa Yuji , Nakamura Naoki , Wakabayashi Masashi , Kojima Motohiro , Togashi Yosuke , Sato Akihiro , Nishikawa Hiroyoshi , Yoshino Takayuki , Ito Masaaki
Published: February 2020

100

Background: Chemoradiotherapy (CRT) followed by curative resection in patients (pts) with local recurrence after radical surgery for primary rectal cancer is the preferred strategy if radiotherapy (RT) was not previously performed. In VOLTAGE-A study, nivolumab plus surgery following CRT showed a promising pathologic complete response (pCR) rate of 30% in pts with microsatellite-stable (MSS) advanced primary rectal cancer. The treatment sequence was prospectively investigated in pts with Locally Recurrent Rectal Cancer (LRRC) in VOLTAGE-B. Methods: Pts with pelvic LRRC without previous RT were included. Five cycles of nivolumab (240 mg q2 weeks) plus curative surgery following CRT (50.4 Gy with capecitabine 1,650 mg/m2) were performed. The pCR rate using AJCC tumor regression grading and curative resection rate were key endpoints. Planned sample size in VOLTAGE-B was set 10 pts in an exploratory manner. Results: From May to Oct 2018, 10 pts were included. Median age was 65 and 8 were male. Curative resection was performed in nine pts with MSS. One had a newly diagnosed supraclavicular lymph node metastasis before surgery. As one pt with AJCC grade 0, seven with grade 2, and one with grade 3, were observed, pCR rate was 10%. As of cut-off date of Apr 2019, three pts showing recurrence out of the nine pts were observed. Nivolumab-related adverse events (AEs) were only one pt with grade 1 hyperthyroidism and one with grade 1 erythema. Grade 3/4 surgery-related AEs were observed in six pts, including two pts with ileus and two with pelvic infections. No treatment-related deaths were observed. Conclusions: The pCR rate of 10% with acceptable toxicity was shown in MSS LRRC pts treated with nivolumab plus curative surgery following CRT. Translational research exploring better predictors of efficacies of study treatment are ongoing. Clinical trial information: NCT02948348.
HGCSG 1301: A multicenter, double-blind, randomized controlled phase II trial comparing Hange-shashin-to versus placebo to prevent diarrhea in patients with metastatic colorectal cancer treated with IRIS/Bev as second-line therapy—Updated analysis of antitumor efficacy.
Authors: Ishiguro Atsushi , Nakatsumi Hiroshi , Muranaka Tetsuhito , Kawamoto Yasuyuki , Yuki Satoshi , Tateyama Miki , Sato Atsushi , Miyagishima Takuto , Nakamura Michio , Dazai Masayoshi , Okuda Hiroyuki , Takahashi Yasuo , Kobayashi Tomoe , Kato Takashi , Hatanaka Kazuteru , Amano Toraji , Sakata Yuh , Komatsu Yoshito
Published: February 2020

108

Background: IRIS (irinotecan plus S-1) plus bevacizumab (IRIS/Bev) is one of the standard chemotherapies in Japan for metastatic colorectal cancer (mCRC) as the first-line or second-line therapy. The most frequent non-hematological adverse event of IRIS was diarrhea. Hange-shashin-to (HST) is a Kampo medicine which is used in Japan for the treatment of gastritis, stomatitis, and diarrhea. We conducted this study to evaluate the usefulness of HST to prevent diarrhea in patients with mCRC receiving IRIS/Bev as the second-line therapy. Methods: This trial was designed as a multicenter, randomized, double-blind, placebo-controlled study. We administrated HST 2.5g or placebo PO t.i.d. x 3 months from the first treatment course of IRIS/Bev. The primary endpoint is proportion of ≥grade 3 diarrhea assessed by CTCAE v4.0. This study is registered with UMIN-CTR, number UMIN000012276. Results: Between Jan 1, 2014 and Mar 31, 2017, 59 patients from 11 institutes in Japan were randomly assigned to receive HST (n = 28, Group H) or placebo (n = 29, Group P). The proportions of ≥grade 3 diarrhea was 10.7% in Group H and 13.8% in Group P (p = 1.00). The other major adverse events of ≥grade 3 in Group H vs Group P were fatigue (3.6% vs 10.3%), anorexia (14.3% vs 10.3%), and nausea (0.0% vs 3.4%). The overall response rate was 13.6% in Group H vs 7.7% in Group P (p = 0.65). There were not statistically significant differences in median progression-free survival (mPFS), median time to treatment failure (mTTF), and median overall survival (mOS) between Group H and Group P ( mPFS 7.9 vs 5.9 months; p = 0.35; mTTF 3.8 vs 5.6; p = 0.466; mOS 17.0 vs 15.3 months; p = 0.750). Conclusions: Prophylactic HST could not reduce the severity of diarrhea during IRIS/Bev. The update analysis of anti-tumor efficacy showed that IRIS/Bev had promising survival benefit but there is not statistically significant difference between HST and placebo. Clinical trial information: UMIN000012276.
Phase I prospective trial of TAS-102 (trifluride and tipiracil) and radioembolization with 90Y resin microspheres for chemo-refractory colorectal liver metastases.
Authors: Fidelman Nicholas , Atreya Chloe Evelyn , Griffith Madeline J , Milloy Marion Alexandra , Carnevale Julia C. , Cinar Pelin , Venook Alan P. , Van Loon Katherine
Published: February 2020

110

Background: Clinical efficacy of Yttrium-90 (90Y) radioembolization (TARE) for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC) is limited by extrahepatic disease progression. TAS-102 (trifluride and tipiracil) has overall survival benefit for patients with refractory mCRC and may be a radiosensitizer. We aimed to evaluate the safety of the combination of TAS-102 and 90Y resin TARE in a Phase I dose-escalation trial. Methods: Adult patients with bilobar liver-dominant chemo-refractory mCRC were treated with sequential Y90 resin TARE (body surface area dosimetry) in combination with TAS-102 (20mg/m2, 27mg/m2, and 35mg/m2) in 28-day cycles according to 3+3 dose-escalation design. Beginning with cycle 3, TAS-102 was administered as monotherapy until disease progression or development of intolerable toxicity. Primary objectives were to determine maximum tolerated dose (MTD) of TAS-102, to assess toxicity, and to establish safety of TAS-102 in combination with 90Y TARE. Results: A total of 14 patients (10 women, 4 men) have been treated to date. Among 9 patients enrolled in the dose-escalation phase, no dose limiting toxicities were observed. The MTD of TAS-102 in combination with Y90 was 35mg/m2, which was selected for the dose expansion phase. Severe adverse events (AEs) included: neutropenia (46%); anemia (23%); and thrombocytopenia (8%), which were attributed to TAS-102. All other AEs were mild and transient. At least one follow-up imaging study has been obtained for 13 patients, and 10 patients have completed trial participation. Disease control rate in the liver was 100%. Conclusions: The combination of TAS-102 and 90Y TARE for patients with liver-dominant mCRC is safe and consistently achieved disease control within the liver. Severity and incidence of AEs is within the expected range of TAS-102 and 90Y TARE monotherapy. A dose-expansion phase with planned enrollment of 12 patients is ongoing. Clinical trial information: NCT02602327.
Safety and efficacy of trifluridine/tipiracil (FTD/TPI) plus bevacizumab in clinical practice for patients with chemorefractory metastatic colorectal cancer: A retrospective comparative study.
Authors: Kagawa Yoshinori , Nose Yohei , Hata Taishi , Kawai Kenji , Sakamoto Takuya , Murakami Kohei , Katsura Yoshiteru , Ohmura Yoshiaki , Masuzawa Toru , Takeno Atsushi , Takeda Yutaka , Murata Kohei
Published: February 2020

112

Background: Trifluridine/tipiracil (FTD/TPI) significantly improves overall survival (OS) in patients with chemorefractory metastatic colorectal cancer (mCRC). The phase I/II C-TASKFORCE study of FTD/TPI + bevacizumab (Bev) for patients with mCRC who are refractory to standard chemotherapy demonstrated promising efficacy results. FTD/TPI + Bev were linked to significant and clinically relevant improvements in progression-free survival (PFS) and OS compared with FTD/TPI monotherapy and a favorable safety profile in a Danish randomized trial. This retrospective study investigated the safety and efficacy of FTD/TPI alone or in combination with Bev for patients with refractory mCRC in clinical practice. Methods: We reviewed the outcomes of patients with chemorefractory mCRC who received FTD/TPI alone (monotherapy; 35 mg/m2, twice daily on days 1–5 and 8–12 in a 28-day cycle) or FTD/TPI + Bev (combination; 5 mg/kg, days 1 and 15) in our institution since 2014. We compared the safety and efficacy of the monotherapy and combination regimens. Adverse events were evaluated using Common Terminology Criteria for Adverse Eventsv4.0. Median PFS and OS were analyzed using the Kaplan–Meier method. Results: In total, 56 patients received chemotherapy containing FTD/TPI. Twenty-four patients were treated with monotherapy, and 32 patients received the combination regimen. The median PFS was 1.8 months in the monotherapy arm, versus 4.7 months in the combination arm (hazard ratio [HR] = 0.28; 95% confidence interval [CI] = 0.15–0.51; P < 0.0001). The median OS was 6.3 months for the monotherapy arm, versus 11.7 months for the combination arm (HR = 0.25; 95% CI = 0.13–0.48; P < 0.0001). There was no significant difference in the rates of adverse events between the groups excluding neutropenia. Neutropenia (Grade 3 or worse) developed in five patients (20.8%) in the monotherapy arm and 17 patients (53.1%) in the combination arm ( P = 0.030). There were no treatment-related deaths. Conclusions: In patients with chemorefractory mCRC, FTD/TPI + Bev significantly improved PFS and OS versus FTD/TPI monotherapy.
Efficacy and safety of regorafenib as third-line therapy in metastatic colorectal cancer: An indirect meta-analysis.
Authors: WU Yinying , Fan Yangwei , Dong Dan Feng , Dong Xuyuan , Hu Yuan , Shi Yu , Jing Jiayu , Li En Xiao
Published: February 2020

119

Background: The evidence base for optimum third-line therapy for metastatic colorectal cancer (mCRC) is not conclusive. Recent studies have demonstrated the efficacy of regorafenib as third-line therapy in mCRC. This indirect meta-analysis compared the efficacy and safety of regorafenib in comparison to other available third-line therapies in mCRC. Methods: Literature search for randomized controlled trials was conducted in PubMed, Embase and Cochrane library for studies evaluating the efficacy and safety of fruquintinib, regorafenib, TAS-102 and nintedanib as third-line therapies in mCRC patients. The primary outcomes included overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) and safety as the secondary outcome. Hazard ratio (HR) and relative risk (RR) with their respective 95% confidence interval (CI) were used for analysis of survival, clinical response and safety data, respectively. An adjusted indirect meta-analysis with placebo as the common comparator was performed. Results: We identified 8 RCTs studies comparing regorafenib (2 studies), fruquintinib (2 studies), TAS-102 (3 studies) and nintedanib (1 study) against placebo. The OS with regorafenib was significantly better when compared to nintedanib (HR= 0.66, 95% CI 0.45, 0.95, p=0.02), but was similar to that of fruquintinib (HR=1.01, 95% CI 0.67, 1.52, p=0.94) and TAS-102 (HR= 0.97, 95% CI 0.68, 1.38, p=0.88). The PFS and ORR for regorafenib were slightly better than TAS-102 (PFS: HR= 0.86, 95% CI 0.54, 1.37, p=0.5; ORR: RR= 1.13, 95% CI 0.11, 11.05, p=0.92) and nintedanib (PFS: HR= 0.68, 95% CI 0.42, 1.10, p=0.12, ORR: not reported) but was lower than fruquintinib (PFS: HR= 1.53, 95% CI 0.93, 2.52, p=0.08; ORR: RR= 0.68269, 95% CI 0.045, 10.32, p=0.79). Safety analysis showed that the relative risk of adverse events was lesser in patients treated with regorafenib in comparison to fruquintinib but was similar to that of nintedanib and TAS-102. Conclusions: Regorafenib with its efficacy and safety coupled with comprehensive continuously anti-angiogenic therapy, might be the first option in third-line mCRC. Head-on comparisons are required for further validation.
Phase I with expansion cohorts in a study of NEO-201 in adults with chemo-resistant solid tumors.
Authors: Morelli M. Pia , Houston Nicole D. , Lipkowitz Stan , Lee Jung-min , Zimmer Alexandra Dos Santos , Zia Farah Z. , Trewhitt Kathrine , Nichols Erin , Pavelova Mira , Hewitt Stephen M. , Fantini Massimo , Arlen Philip M. , Tsang Kwong Y. , Annunziata Christina M.
Published: February 2020

129

Background: NEO-201 is a humanized IgG1 monoclonal antibody (mAb) generated against tumor-associated antigens (TAA) from colorectal cancer. Our preclinical data demonstrated that NEO-201 exerts anti-tumor activity by NK-mediated ADCC and CDC against several tumor types. We identified NEO-201 antigen as a tumor-associated form of CEACAM-5 and -6, which is expressed by tumor tissue but is not present in the surrounding healthy tissue. Methods: This is a first-in-human phase 1 study to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of NEO-201 in adults with advanced solid tumors that have high likelihood of expression NEO201 antigen and have progressed to standard of treatments. This is a classic 3+3 dose escalation, with cohort expansion at the MTD. NEO-201 is administered intravenously every two weeks, and at four dose levels (DL1 = 1mg/kg, DL2 = 2mg/kg, DL3 = 4mg/kg and DL4 = 6mg/kg). Patients are evaluated for safety according to CTCAEv5.0., and for response according to RECISTv1.1. Biological samples are collected to understand NEO-201 pharmacokinetics, the effects on immune profile and the correlation with treatment toxicity and response. Results: Here we report the safety data and pharmacokinetics from DL1 and 2. A total of 9 evaluable patients were enrolled. Prolonged neutropenia, defined as ³G2 neutropenia lasting for >7 days, was observed at DL2. The cohort was expanded to a total of 6 patients and no further DLTs were observed. Seven out of nine of the patients enrolled had colon cancer, two had pancreatic cancer and one had hormone positive breast cancer. The most frequent treatment-related AEs were infusion reaction which was observed in all patients, and moderate fatigue (33%). Best response was SD observed in two patients (one on each of DL1 and DL2). Dose escalation continues on DL3 and DL4. NEO201 antigen expression in patient tumor tissue, circulating CEACAM6/CEACAM5, and MICA will be evaluated to correlate with response and toxicity. Conclusions: NEO201 has shown some promising activity. PK and PD studies are ongoing to better understand dosing schedule, toxicity profile and to identify biomarkers for patient selection. Clinical trial information: NCT03476681.
Pembrolizumab (P) in patients (Pts) with colorectal cancer (CRC) with high tumor mutational burden (HTMB): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.
Authors: Meiri Eyal , Garrett-Mayer Elizabeth , Halabi Susan , Mangat Pam K. , Shrestha Sagun , Ahn Eugene R. , Osayameh Olufunlayo , Perla Venu , Schilsky Richard L.
Published: February 2020

133

Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of CRC pts with HTMB treated with P are reported. Methods: Eligible pts had advanced CRC, no standard treatment (tx) options, measurable disease, ECOG PS 0-1, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts had HTMB, defined as ≥9 mutations/megabase (Muts/Mb) by a FoundationOne test (n=26) or other tests (n=2) approved by the Molecular Tumor Board. Pts with MSI-H tumors were ineligible. Dosing of P was 2 mg/kg (n=8) or 200 mg (n=20) IV over 30 mins, every 3 wks. Simon two-stage design was used to test a null rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have disease control (DC) (objective response (OR) or stable disease at 16+ wks according to RECIST (SD16+)), 18 more pts enrolled. If ≥7 of 28 pts have DC, the tx is worthy of further study. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: Twenty-eight pts enrolled from June 2017 to November 2018; 1 pt was ineligible and excluded. HTMB ranged from 9 to 54 Muts/Mb. Table (N=27) summarizes demographics and outcomes. Tumor MS status was reported stable for 25 pts, ambiguous for 1 pt, and not available for 1 pt. One PR (MS stable and 10 Muts/Mb) and 7 SD16+ were observed for DC and OR rates of 28% (90% CI, 16% to 45%) and 4% (95% CI, 0% to 19%), respectively. 2 pts each had grade 3 AEs at least possibly related to P including abdominal infection, anorexia, colitis, diarrhea, fatigue, nausea, and vomiting; 1 also had SAE of acute kidney injury. Conclusions: Monotherapy with P showed anti-tumor activity in heavily pre-treated CRC pts with HTMB . Additional study is warranted to confirm the efficacy of P in this population. Clinical trial information: NCT02693535.

[Table: see text]
A phase II study of FOLFOXIRI plus bevacizumab (Bmab) as initial chemotherapy for patients (pts) with untreated metastatic colorectal cancer (mCRC): TRICC1414 (Be TRI).
Authors: Yamada Takeshi , Nishina Tomohiro , Nasu Junichiro , Matsumoto Toshihiko , Yuasa Yasuhiro , Shiraishi Takeshi , Nagano Hiroaki , Moriyama Ichiro , Fujiwara Toshiyoshi , Miguchi Masashi , Yoshida Ryosuke , Nosaka Kimiyasu , Tanioka Hiroaki , Nagasaka Takeshi , Kurisu Yasuro , Kobayashi Michiya , Tsuchihashi Kenji , Inukai Michio , Kikuchi Takashi , Shinozaki Katsunori
Published: February 2020

134

Background: FOLFOXIRI-Bmab has been recognized as one of the standard first-line treatments for mCRC. We conducted a single arm, multicenter, phase II study to assess the efficacy and safety of FOLFOXIRI-Bmab in pts with untreated mCRC harboring UGT1A1(*6 and *28) wild or single hetero genotype. Methods: Pts received FOLFOXIRI-Bmab (irinotecan 165 mg/m2, oxaliplatin 85 mg/m2, l-leucovorin 200mg/m2, fluorouracil 3200 mg/m2 and Bmab 5mg/kg repeated biweekly) up to a maximum of 12 cycles, followed by the sequential therapy which consisted of the remaining drugs if any of the individual drugs were discontinued at the investigator’s discretion. Protocol therapy was continued until progressive disease, an unacceptable adverse event, tumor resection or consent withdrawal. The primary endpoint was ORR evaluated by central reviewers. Secondary endpoints include TTF, PFS, OS, R0 resection rate, relative dose intensity (RDI) and safety. The exploratory objectives were early tumor shrinkage (ETS), depth of response (DoR). Results: 47 pts were enrolled from 16 centers between April 2015 and May 2017, of whom 1 was excluded for not meeting the inclusion criteria. The full analysis set consisted of 44 pts because 2 had no target lesions that were considered measurable lesion by central reviewers. 46 pts had the following characteristics: median age 58 (29-68), 57% male, 76% PS0, 22% right-sided tumors and 52% UGT1A1 wild. RAS status was 37% wild, 52% mutant, 11% unknown. Primary endpoint was met. The ORR was 63.6% (95% CI, 47.8-77.6). ETS and DoR was 70.5%, 43.9%, respectively. R0 resection rate was 23%. Median PFS was 15.5mo (95% CI, 11.5-23.4). Median TTF was 8.1mo (95% CI, 5.3-10.1). Median OS was 34.4mo (95% CI, 26.4-not reached). The mean RDI of fluorouracil, irinotecan and oxaliplatin were 71%, 67%, and 64%, respectively. Grade 3 or higher adverse events (≥10%) were neutropenia (65.2%), febrile neutropenia (FN) (26.1%), anorexia (10.9%), nausea (10.9%), and diarrhea (10.9%). No treatment-related deaths were observed. Conclusions: Our results of FOLFOXIRI-Bmab in Japanese pts showed to be beneficial and manageable although caution to FN is required. Clinical trial information: NCT02497157.
Drug-drug interaction (DDI) potential of oral napabucasin in healthy adults.
Authors: Dai Xiaoshu , Karol Michael D. , Hitron Matthew , Hard Marjie , Goulet Matthew T. , Mclaughlin Colleen F. , Brantley Scott J.
Published: February 2020

142

Background: Napabucasin is an NQO1-bioactivatable investigational agent hypothesized to affect multiple oncogenic cellular pathways including pSTAT3 through the generation of reactive oxygen species. This phase 1 open-label study evaluated the DDI potential of napabucasin and its major metabolite (M1) with respect to 7 major human drug cytochrome P450 (CYP) enzymes and the breast cancer resistance protein (BCRP) transporter. Methods: Healthy adult subjects who initially demonstrated they could tolerate administration of 240 or 480 mg twice daily (BID) napabucasin over 2-days (D) received single doses of the CYP and transporter substrates, followed by ≥7-day washout. In the DDI portion, subjects received napabucasin 240 mg BID on D1–11 with the phenotyping cocktail administered on D6 (omeprazole [CYP2C19] 20 mg, caffeine [CYP1A2] 100 mg, flurbiprofen [CYP2C9] 50 mg, bupropion [CYP2B6] 150 mg, dextromethorphan [CYP2D6] 30 mg, and oral midazolam [CYP3A] 2 mg), intravenous (IV) midazolam 2 mg on D7, repaglinide (CYP2C8) 0.25 mg on D8, and rosuvastatin (BRCP transporter) 10 mg on D9. Results: DDI potential was evaluated in 17 subjects. Exposure to omeprazole, flurbiprofen, and oral midazolam with (test) or without (reference) napabucasin 240 mg BID were similar. Napabucasin increased exposure (area under the curve to infinity) to caffeine (124%), IV midazolam (118%), repaglinide (127%), and rosuvastatin (213%); and decreased exposure to bupropion (79%) and dextromethorphan (71%). None of these changes were expected to be clinically meaningful. The exposure of the major metabolites of the probe drugs with or without napabucasin or M1 were similar. Of the 17 subjects, 12 (70.6%) reported adverse events (AEs); 58.8% reported gastrointestinal disorders. One patient had a grade 3 AE (neutrophil count low); no serious AEs were observed. Conclusions: The data suggest minimal in vivo DDI potential for napabucasin with respect to 7 major human drug CYP enzymes and the BCRP transporter. Napabucasin 240 mg BID was generally tolerable in healthy subjects. Co-administration of napabucasin with CYP and transporter substrates was safe and tolerable. Clinical trial information: NCT03411122.
Neoadjuvant chemotherapy followed by liver resection for patients with metastatic colorectal cancer.
Authors: Jin Rui , Jin Zhaohui , Cleary Sean P. , Nagorney David M. , Smoot Rory L. , McWilliams Robert R. , Mahipal Amit
Published: February 2020

147

Background: Colorectal cancer is one of the leading causes of cancer related deaths with liver being most common site of CRC metastasis. More than 50% of the CRC patients will develop metastatic liver lesion that eventually leads to death in about 70% of them. In this retrospective review we reviewed the outcome of pts who received neoadjuvant chemotherapy followed by resection of liver lesion for metastatic colorectal cancer. Methods: 304 pts who had preoperative chemotherapy were identified from 1045 metastatic colorectal cancer patients who had liver metastasectomy at Mayo Clinic between 1997 and 2018. A retrospective review was conducted by using data from electronic medical records. Statistical analyses utilized Kaplan-Meier method, Log-rank test, and Cox proportional hazards models. Results: There were 113 (37%) female and 191 (63%) male pts. Median age at primary disease diagnosis was 56.5 yrs. Two hundred forty-nine pts presented with stage IV metastatic colorectal cancer. Primary tumor locations were: 53 right-sided, 117 left-sided and 133 rectum. 152 (50%) pts had extrahepatic metastases. Two pts were found to be MSI-H, 113 MSS, 189 unknown. BRAF mutation was found in 6 patients. RAS mutation was present in 84 patients, with 124 unknown. Pts received chemotherapy for median of 2.82 months. Single agent fluoropyrimidine was administered in 38 (12%) pts and rest receiving chemotherapy doublet or triplet with fluropyrimidine plus oxaliplatin being most common regimen. The median overall survival from primary diagnosis for the entire group was 74.5 months. Median overall survival from liver metastasectomy was 60.0 months. In univariate analysis, metachronous disease, age < 60 yrs, and an absence of extrahepatic lesions led to statistically significant improvement of overall survival from primary diagnosis. Metachronous and extrahepatic lesions remained statistically significant in multivariate analysis. Conclusions: Neoadjuvant chemotherapy followed by liver metastasectomy is beneficial for highly-selected metastatic colorectal cancer pts. Compared to a historical control of 30-36 months, our patient population had a median overall survival of about 5 years from resection.
A phase II study of durvalumab (MEDI4736) (anti-PD-L1) and trametinib (MEKi) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC).
Authors: Johnson Benny , Thomas Jane V , Dasari Arvind , Raghav Kanwal Pratap Singh , Vilar Sanchez Eduardo , Kee Bryan K. , Eng Cathy , Parseghian Christine Megerdichian , Morris Van K. , Wolff Robert A. , Shureiqi Imad , Kopetz Scott , Overman Michael J.
Published: February 2020

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Background: Monotherapy with immune checkpoint blockade (ICB) is ineffective for patients (pts) with MSS mCRC. Novel approaches to modulate the tumor microenvironment (TME) are needed. Here, we investigate whether the combination of trametinib (T) with durvalumab (D) can alter the immune TME by successfully priming and activating T-cells. Methods: An open-label, single center phase II trial with primary endpoint of immune-related response rate for T+D in refractory MSS mCRC pts (NCT03428126). T is 2mg/day orally starting 1 week prior to D, which is given 1500mg intravenously every 4 weeks. Dose de-escalation strategy performed to identify maximum tolerated dose (MTD). Simon 2-stage design utilized with plans to enroll 29 pts into the first stage, requiring response in 2 or more pts to proceed to stage 2 (n = 15). Results: Demographics for 29 treated pts: 48% female, median age 48 years (range 28-75), and median prior therapies was 2 (range 1-5). No grade (G) 4 treatment-related adverse events (TRAE). The most common G3 TRAE included autoimmune hepatitis (14%) and acneiform rash (10%). G1/2 TRAE included acneiform rash (69%), fatigue (24%) and anemia (21%). No fatal TRAE and 4 pts discontinued treatment due to TRAE. 1 of 29 pts had confirmed partial response (PR) lasting 9.3 months (mo) for an ORR of 3.4%. This pt had an ATM E221fs*14 mutation. 7 pts had stable disease (SD) with median time to progression (TTP) of 5.4 mo (range 3.9-9.3 mo). 1 pt remains on active therapy with SD ( > 10 mo). 5 pts (1 PR, 4 SD) demonstrated decrease in total CEA ng/mL (best percentage reduction: 94%, 95%, 42%, 34% and 21.6% respectively). Median TTP for the entire cohort was 3.2 mo (range 1.1-9.3 mo). Consensus molecular subtypes (CMS) were performed on the primary CRC in 23 pts: 12 CMS2, 2 CMS3, and 9 CMS4. 4 SD pts were CMS2, 1 SD pt was CMS4 and the CMS status of the pt with a PR was unknown. Conclusions: The combination of T+D did not meet efficacy criteria to proceed to the second stage of the study. Analysis of 15 paired on-treatment biopsies is ongoing and will be presented. Utilization of CMS characterization in mCRC clinical trials is feasible and may provide an improved biological understanding of treatment activity. Clinical trial information: NCT03428126.
Leveraging the integrated EHR for trial matching across a nationwide network.
Authors: Yeatman Timothy Joseph , Watson Mark , Chasse Adam
Published: February 2020

165

Background: The Guardian Research Network (GRN) is a nationwide consortium of integrated health systems, who share their electronic health records (EHR) to democratize clinical trial access through improvements in “process”. The GRN is a unique-in-class, free-to join, non-exclusive consortium leveraging the digital EHR---including labs, medications, demographics and non-discrete data (all text) data--- mining nightly for clinical trial candidates. Using a suite of NLP and AI tools, the GRN dramatically improves the efficiency of the clinical research staff, by electronically searching all records for the I/E criteria for trials. The GRN uses a central IRB, one contract and legal review, promising to revolutionize the trial accrual process and speed drug development. Methods: With a database of > 1.0M patients, the GRN reviews all active cancer records nightly from > 110 member hospitals to produce lists of trial candidates. Comprehensive electronic screens were filtered by manual reviews to rapidly find best candidates. Results: Our data collected over 10 mo suggest comprehensive electronic queries examining hundreds of thousands of records daily eliminate > 90% of ineligible patients in minutes. Manual review further refines eligible list. This is vastly different from current opportunistic screening approaches that examine only a tiny fraction of potential trial candidates (last week's new patients). Conclusions: The GRN has executed an all-inclusive approach to trial accrual, embedding a scalable database search technology within an integrated trial network. The novel approach seeks to exponentially expand operational capabilities of CTOs with limited staff, review all eligible patients, and solve for a large unmet need for democratizing trial access in the community.

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RAS status in circulating-tumor DNA (ctDNA) and outcomes during rechallenge treatments with anti-EGFR antibodies in metastatic colorectal cancer (mCRC).
Authors: Sunakawa Yu , Nakamura Masato , Ishizaki Masahiro , Kataoka Masato , Satake Hironaga , Kitazono Masaki , Yanagisawa Hideyuki , Kawamoto Yasuyuki , Kuramochi Hidekazu , Ohori Hisatsugu , Nakamura Michio , Maeda Fumiyo , Komeno Chihiro , Takeuchi Masahiro , Fujii Masashi , Yoshino Takayuki , Ichikawa Wataru , Tsuji Akihito
Published: February 2020

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Background: We have evaluated rechallenge treatment with irinotecan plus cetuximab (JACCRO CC-08, n = 36) or panitumumab (JACCRO CC-09, n = 25) in patients (pts) with KRAS wild-type mCRC [Tsuji A, WCGC 2018], and the primary endpoint of PFS rate at 3 months was met in both trials. RAS status in ctDNA may potentially predict responders of the rechallenge treatment in mCRC resistant to anti-EGFR antibody [Cremolini C, JAMA Oncol 2018]. Methods: A post-hoc biomarker study was performed to investigate an association between RAS status in ctDNA and clinical outcomes in the JACCRO phase II trials comprised mCRC pts who achieved a clinical benefit from 1st-line anti-EGFR antibody-based therapy, then had a disease progression at 2nd-line treatment. RAS status in ctDNA was analyzed at the time points of baseline, 8 weeks, and progression using OncoBEAM RAS CRC Kit for specific KRAS/ NRAS mutations, using cut-off value defined as the number of beads with amplified-mutant molecules specifically set per each codon. Results: Sixteen pts (median 67.5-y old, 50% of PS0, 25% of right-sided primary, cet/pani: 4/12) were enrolled in this study, with response rate of 0% and disease control rate (DCR) of 62.5%. RAS mutations (mt) were found at the baseline in 6 out of 16 pts (all left-sided pts with KRAS codon 12, codon 61 and/or NRAS codon 61 mt simultaneously). Pts without RAS mt at baseline experienced longer PFS in 1st-line treatment (11.5 vs. 9.0 m). The DCR was 33% in pts with RAS mt in ctDNA, while it was 80% in pts without RAS mt at baseline. Pts with RAS mt at baseline had significantly shorter PFS and OS than pts without RAS mt [median PFS 2.3 vs 4.7 m, HR 6.2 (95%CI 1.6-30.5), p = 0.013; median OS 3.8 vs. 16.0 m, HR 12.4 (95%CI 2.7-87.7), p = 0.0028]. Six of 10 pts without RAS mt at baseline acquired RAS mt ( KRAS/ NRAS codon 12 or 61) in ctDNA at progression, however there was no difference in survival between pts with/without RAS mt at progression. Conclusions: Our study demonstrated that RAS status in ctDNA using OncoBEAM RAS CRC Kit predicts survival of rechallenge treatment with anti-EGFR antibody in mCRC pts. These data can support the application of RAS monitoring into clinical practice. Clinical trial information: UMIN000015914/UMIN000015916.
CD3+ tumor-infiltrating lymphocytes (TILs) as prognostic in patients (pts) with stage II colon cancer (CC) not treated with adjuvant chemotherapy (ADJ).
Authors: Francini Edoardo , Ou Fang-Shu , Lazzi Stefano , Petrioli Roberto , Multari Andrea Giovanni , Pesola Guido , Messuti Luciana , Colombo Elena , Livellara Virginia , Bazzurri Serena , Cherri Sara , Salvatora Miano , Wolfe Eric , Alberts Steven R , Hubbard Joleen Marie , Yoon Harry H. , Francini Guido
Published: February 2020

167

Background: Previous studies have reported high TILs are a favorable prognostic factor in stage II CC. However, whether the impact of TILs on overall survival (OS) differs among pts who did or did not receive ADJ is still to be determined. We assessed the prognostic value of CD3+ TILs in pts with stage II CC according to whether they received ADJ or not (no-ADJ). Methods: Pts treated with curative surgery for stage II CC (2002-2013) were identified through the Santa Maria alle Scotte Hospital database. CD3+ TILs at the invasive front, center of tumor, and stroma, were determined by immunohistochemistry and manually quantified as the rate of TILs/total tissue areas. High TILs (H-TILs) was defined as > 20%. Pts were classified as high or low TILs (L-TILs) and ADJ or no-ADJ. Cox models were used to assess OS with hazard ratio estimates (95% CI). Results: Of the 678 pts included (356 deaths), 137 (20%) received ADJ while 541 (80%) did not. ADJ comprised fluoropyrimidine +/- oxaliplatin. Median follow-up was 8.5 years. The distributions of the 4 groups were: 16% (L-TIL/ADJ), 64% (L-TIL/no-ADJ), 5% (H-TIL/ADJ), 15% (H-TIL/no-ADJ). Compared to H-TILs/no-ADJ, ADJ pts had a significantly longer OS (P < .0001) regardless of the TILS rate while L-TILs/no ADJ had significantly shorter OS and higher risk of death (HR = 1.41; 95% CI, 1.06-1.88; P < .0001) [See table]. On multivariable analysis, adjusting for perforation, obstruction, T-stage, grade, < 12 lymph nodes resected, lymphovascular and perineural invasion, the adverse prognostic impact of L-TILs (vs H-TILs) in no-ADJ pts was confirmed (HR = 1.36; 95% CI 1.02, 1.82; P = .0373). Conclusions: Low CD3+ TILs rate was independently associated with shorter OS in stage II CC pts who did not receive ADJ, but was not prognostic among pts who had ADJ. These data suggest a potentially different impact of TILs in chemo-treated vs -untreated stage II CC which could affect clinical decision making.

[Table: see text]
Analysis of consensus molecular subtypes (CMS) classification in the TRICOLORE trial: A randomized phase III trial of S-1 and irinotecan (IRI) plus bevacizumab (Bmab) versus mFOLFOX6 or CapeOX plus Bmab as first-line treatment for metastatic colorectal cancer (mCRC).
Authors: Yuki Satoshi , Gamoh Makio , Denda Tadamichi , Takashima Atsuo , Takahashi Shin , Nakamura Masato , Ohori Hisatsugu , Yamaguchi Tatsuro , Kobayashi Yoshimitsu , Baba Hideo , Kotake Masanori , Amagai Kenji , Kondo Hitoshi , Shimada Ken , Sato Atsushi , Ishioka Chikashi , Komine Keigo , Ouchi Kota , Morita Satoshi , Komatsu Yoshito
Published: February 2020

169

Background: The TRICOLORE trial previously demonstrated that S-1+IRI+Bmab (Arm B) was non-inferior to mFOLFOX6/CapeOX+Bmab (Arm A) in terms of progression-free survival (PFS) as first-line treatment for mCRC, irrespective of RAS status. CMS was reported to be a prognostic factor for mCRC. Previously, it was reported that the CMS could be a predictive factor for the efficacy of oxaliplatin (OX) and IRI (Okita A, et al. Oncotarget. 2018). In this exploratory study of TRICOLORE trial, we examined if the CMS could be a predictive factor of OX and IRI regimen. Methods: We collected formalin-fixed paraffin-embedded (FFPE) primary tumor tissues and performed gene expression analysis by microarray. The subtype of CMS was determined by the CMS classifier (Guinney et al. Nature Med. 2015). PFS and overall survival (OS) were compared between arm A and B in each subtypes of CMS. Results: Total of 308 FFPE samples from 487 cases who were enrolled in the TRICOLORE study were collected. Number of patients classified into CMS1 to CMS4 were 47, 72, 99 and 90, respectively. Similar to the previous reports, the proportion of RAS mutant cases was highest in CMS3 and the most of BRAF mutant cases were classified into CMS1. The median PFS (mPFS) of arm A and B were almost same in CMS2 (16.1m vs. 17.6m, HR = 1.10, p = 0.79) and CMS3 (10.6 vs. 11.4, HR = 0.95, p = 0.81). In CMS1, mPFS of arm A was worse than that of arm B, although not statistically significant (7.4m vs. 13.2m, HR = 0.73, p = 0.35). In CMS4, mPFS of arm B was better than that of arm A, although not statistically significant again (9.7m vs. 14.1m, HR = 0.72, p = 0.15). The median OS (mOS) of both arm in CMS2-CMS4 and arm B in CMS1 were good and were 29.0m or more. On the other hand, mOS of arm A in CMS1 (18.1m) was worse than the others. Conclusions: From these results, it was not concluded that CMS was a predictor of mFOLFOX6/CapeOX+Bmab and S-1+IRI+Bmab. However, mPFS and mOS of mFOLFOX6/CapeOX+Bmab in CMS1 were poor unlike other CMS subtypes, and these were consistent with a previous report. Whereas S-1+IRI+Bmab was effective in all subtypes of CMS. Clinical trial information: UMIN000007834.
Preclinical drug testing for clinical trial planning of novel combinative therapy with PI3K and MAPK inhibitors in colorectal cancer(CRC).
Authors: Lee Cha Len , Toomey Sinead , Cremona Mattia , Workman Julie A. , Hennessy Bryan
Published: February 2020

179

Background: Combinative inhibitors with multiple actions to target downstream effectors are good strategy to reduce resistance occurrence. This is a preclinical study to evaluate efficacy of Palbociclib (P; CDK4/6 inhibitor) in combination with either Gedatolisib (G; P13K/mTOR dual inhibitors) or PD0325901 (PD; MEK 1/2 inhibitor) in CRC cell models. Methods: Five CRC cell lines with hot-spots mutations in PI3K and MAPK pathways genes are used. Cell growth assay is used to evaluate antiproliferative response to P, G and PD alone and in combination. RPPA is used to clarify the role actions of combinative drugs on resistance development and new druggable proteins. Paired t-test is used. Results: All cell lines except LS1034 (IC50=7.2µM) were sensitive to G. LS411N and SNUC4 were sensitive to P whereas Caco2, DLD1 and LS1034 were resistant (IC50>15µM). All cells lines were sensitive to PD. When tested in combination, P+G has synergistic response in all cells lines, except for LS411N (CI=0.9; p=0.02). P+G is highly synergistic in LS1034 with KRAS mutation (CI=0.1; p=0.11). P+G is also synergistic in DLD1 with co-occurring PIK3CA and KRAS mutations (CI=0.6; p=0.04). P+PD is synergistic in all cells lines except for LS411N. In SNUC4 with PIK3CA mutation, both drug combinations have equal synergism (CI=0.5; p<0.05). RPPA analysis is in progress and will be included in final abstract. Conclusions: This offers good rationale for further clinical development of P+G as beneficial therapy in treatment-resistant CRC patients. P+G offers better alternative to P+PD since MEK inhibitor resistance had been associated with tumours harbouring KRAS with(out) PIK3CA mutations. BRAFV600E and ERBB2 mutations are useful negative predictors in this cohort.

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