bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and efficacy of ONO-4578 plus nivolumab in metastatic colorectal cancer.
Authors: Kawazoe Akihito , Takashima Atsuo , Matsuoka Hiroshi , Hamamoto Yasuo , Okuno Tatsuya , Hamaguchi Tetsuya , Yamaguchi Kensei , Oki Eiji , Sugimoto Naotoshi , Tsuji Yasushi , Boku Shogen , Nishina Tomohiro 
Published: January 2024

93 Background: The prostaglandin E2-EP4 signaling is involved in immunosuppression in cancers. In the dose escalation part of the ONO-4578-01, open-label, uncontrolled phase 1 study, ONO-4578, an EP4 antagonist, plus nivolumab (4578+NIV) demonstrated manageable safety profile and antitumor activities in metastatic or advanced solid tumors. CRC cohort assessed safety, preliminary efficacy, and biomarkers of 4578+NIV in patients with metastatic colorectal cancer (mCRC). Methods: The CRC cohort was conducted at 12 sites in Japan and it included patients aged ≥20 years with mCRC; those with microsatellite-instability-high, deficient mismatch repair, or BRAF mutations were excluded. The optimal dose was determined based on the results of dose escalation part of ONO-4578-01. Patients received oral ONO-4578 (40 mg, daily) and intravenous nivolumab (480 mg, every 4 weeks) in 28-day cycles. The primary endpoint was safety. Exploratory endpoints included efficacy and biomarkers. Results: A total of 51 patients were enrolled: 24 (47.1%) were male and the median age was 59.0 (range, 33–79) years. Adverse events (AEs) occurred in 48 patients (94.1%), wherein grade 3–4 AEs occurred in 23 (45.1%). No patients died due to AEs. Serious AEs occurred in 11 (21.6%) patients. The most common AEs of any grade were rash (33.3%) and anemia (31.4%). Any-grade and grade ≥3 treatment-related AEs (TRAEs) occurred in 36 (70.6%) and 13 (25.5%) patients, respectively. Two patients achieved partial response and 18 had stable disease; the objective response rate was 3.9% (90% confidence interval [CI], 0.7–11.8) and the disease control rate was 39.2% (90% CI, 27.7–51.7). The median progression-free survival and overall survival (OS) were 1.54 (90% CI, 1.41–2.79) and 10.68 months (90% CI, 6.67–not reached [NR]), respectively. The proportion of patients continuing treatment and OS in subgroups of different PD-L1 combined positive scores (CPS) showed a tendency toward favorable efficacy in CPS-positive subgroups: the proportion of patients continuing treatment for 6 months was 4.5% (1/22) in those with CPS of 0 vs 20% (5/25) in those with CPS ≥1, and the median OS was 9.4 months (90% CI, 5.65–12.06) in those with CPS of 0 vs NR (90% CI, 10.41–NR) in those with CPS ≥1. Conclusions: 4578+NIV showed an acceptable safety profile in patients with mCRC, and no new safety signals were detected. 4578+NIV also showed antitumor activity in patients with mCRC. Favorable efficacy was observed in the PD-L1 CPS-positive subpopulation. Clinical trial information: jRCT2080223441 .
FOLFOXIRI ± molecular targeting agent (bevacizumab or panitumumab) for conversion from unresectable to resectable in the advanced/recurrent colorectal cancer.
Authors: Takemori Kodai , Kobayashi Kazuma , Inoue Yusuke , Okada Satomi , Adachi Toshiyuki , Soyama Akihiko , Adachi Tomohiko , Kanetaka Kengo , Eguchi Susumu 
Published: January 2024

99 Background: As treatment for unresectable advanced/recurrent colorectal cancer (ARCC), the introduction of doublet chemotherapy, represented by FOLFOX/FOLFIRI, and molecular-targeting agents, such as anti-VEGF antibody and anti-EGFR antibody, has given ARCC patients a more than three years’ survival. Triplet chemotherapy, such as FOLFOXIRI ± Bevacizumab or Panitumumab, has already been used in daily practice. These regimens with powerful anti-tumor effects have enabled conversion from unresectable to resectable, giving patients a longer survival than those without conversion. Therefore, we explored the ideal regimen for conversion, focusing on FOLFOXIRI ± X. Methods: We retrospectively reviewed unresectable ARCC patients treated with FOLFOXIRI ± X (X:Bmab, n=24; Pmab, n=1; alone, n=2; ) between February 2015 and December 2022. The results were compared to those of patients who received other regimens (OTHERS; n=212). Results: The median overall survival (OS) was 1072 days. Forty-nine patients acquired conversion. The patients with conversion had a longer progression-free survival and OS than those without conversion (p<0.0001 and <0.0001, respectively). Conversion rates were 37.0% in FOLFOXIRI ± X vs. 18.4% in OTHERS (p=0.0238), while response rates were 59.3% in FOLFOXIRI ± X vs. 35.8% in OTHERS (p=0.0185). The RAS wild-type group conversion rates were 30.0% in FOLFOXIRI ± X vs. 20.6% in OTHERS, while 50.0% in FOLFOXIRI ± X vs. 15.3% in OTHERS in RAS mutant group. Anti-EGFR antibody +L-OHP-based doublet chemotherapy accounted for conversion in 35.3% of the RAS wild-type group. Anti-VEGF antibody + L-OHP based doublet chemotherapy attained 29.1% conversion rate in RAS mutant group. Molecular targeting agent+doublet or triplet regimens were essential for conversion. FOLFOXIRI ± X achieved a 88.9% disease control rate, with palliation of symptoms due to a high tumor burden in 10 of 13 cases. Conclusions: Based on these results, FOLFOXIRI ± X may be an ideal candidate for achieving conversion in first-line treatment of unresectable ARCC.
Pathological complete response (pCR) to 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) with or without durvalumab (D) in resectable gastric and gastroesophageal junction cancer (GC/GEJC): Subgroup analysis by region from the phase 3, randomized, double-blind MATTERHORN study.
Authors: Janjigian Yelena Y. , Al-Batran Salah-Eddin , Wainberg Zev A. , Van Cutsem Eric , Molena Daniela , Muro Kei , Hyung Woo Jin , Wyrwicz Lucjan S. , Oh Do-Youn , Omori Takeshi , Moehler Markus , Garrido Marcelo , Oliveira Sulene CS , Liberman Moishe , Castro Oliden Victor , Bilici Mehmet , Kurland John F. , Xynos Ioannis , Mann Helen , Tabernero Josep 
Published: January 2024

LBA246 Background: FLOT was established as a perioperative therapy for GC/GEJC following the Phase 2/3 FLOT4 study conducted in Germany, with a pCR rate of 16% (Al-Batran et al, Lancet Oncol 2016). The global MATTERHORN study (NCT04592913) showed a statistically significant improvement in pCR with perioperative D + FLOT vs placebo (P) + FLOT in GC/GEJC at first interim analysis (Janjigian et al, ESMO Congress 2023). Subgroup analyses by region and country were completed to assess pCR rates with FLOT and benefit of D + FLOT across the global study population. Methods: Participants (pts) with resectable GC/GEJC were randomized 1:1 to D 1500 mg or P every 4 weeks (Q4W) on Day 1 plus FLOT Q2W on Days 1 and 15 for 4 cycles (2 doses of D or P and 4 doses of FLOT pre- and post-operative), followed by D 1500 mg or P on Day 1 Q4W for 10 further cycles. Randomization was stratified by Asia vs non-Asia. pCR (Modified Ryan; central review) was assessed in prespecified (Asia) and post hoc regional subgroups, including 6 countries with the highest numbers of randomized pts. Results: Of 948 pts randomized globally, 180 pts (19%) were in Asia. pCR outcomes with FLOT in Asia were consistent with the global outcomes. pCR rates were improved with D + FLOT vs P + FLOT in all regions (Asia, Europe, North America and South America; Table), despite some imbalances in baseline characteristics and numerical differences in pCR rates by geographic location. The pCR rate with P + FLOT in the German subgroup (13%; 95% CI, 6.1–23.0) was similar to that with FLOT in the FLOT4 study. Improvement in pCR with D + FLOT vs P + FLOT was observed across subgroups by country. Similar trends across regional subgroups were observed for combined complete and near-complete response rate. Conclusions: In MATTERHORN, pCR was consistently improved with the addition of D to perioperative FLOT in GC/GEJC across geographic regions. The study is ongoing for the primary objective of event-free survival. Clinical trial information: NCT04592913 .[Table: see text]
Sequential or up-front triple combination with durvalumab, tremelimumab, and bevacizumab for patients with unresectable hepatocellular carcinoma (HCC): MONTBLANC.
Authors: De Toni Enrico N. , Mayerle Julia , Oehrle Bettina , Seidensticker Max , Rimassa Lorenza , Ehmer Ursula , Geier Andreas , Reiter Florian P , Ettrich Thomas Jens , Philipp Alexander B , Rössler Daniel Christoph , Ben Khaled Najib 
Published: January 2024

TPS574 Background: Escalation of treatment from one to two combined immune checkpoint inhibitors (CPI) has dramatically increased objective and clinical response in advanced hepatocellular carcinoma (HCC) patients. Establishing strategies with more than two CPI agents to further increase response while maintaining a manageable toxicity is therefore a top priority. The upfront simultaneous use of three or more CPI can yield a strong initial response to treatment, but it may also increase treatment-related toxicity. An alternative approach, which prioritizes safety over immediate response, involves utilizing different CPI doublets in a sequential manner. However, this design entails switching to a different combination only after radiological progression is observed, and recurrent progressions may lead to deteriorating liver function and treatment resistance. Trials of immunotherapy of HCC conducted in recent years showed that the efficacy of CPI, when used simultaneously, outweighs the drawbacks of their combined toxicity and that early radiological response to treatment, or the lack thereof, is a predictor of clinical outcome. In addition, failure of trials using broad-spectrum tyrosine kinase inhibitors (TKI) and CPI suggest that antibodies or narrow-spectrum TKI should be used for future CPI-based combinations in HCC studies. Based on these considerations, the MONTBLANC study is the first trial to assess the effectiveness of up-front triple treatment with a combination of the three currently approved immunological agents for HCC and to implement the concept of treatment escalation determined by lack of early radiological response (as opposed to treatment progression). Methods: The MONTBLANC study is a randomized, 2-arm phase II study on the efficacy of combinations of durvalumab, tremelimumab, and bevacizumab in patients with advanced HCC. Patients with preserved liver function (Child-Pugh A) with unresectable tumors or not amenable to local or locoregional treatment are randomized to an early escalation arm (A) or a triple treatment arm (B). Patients in arm A receive combined durvalumab and tremelimumab (STRIDE regimen). Treatment is escalated by the addition of bevacizumab upon detection of disease progression or in the absence of radiological response by the 4th month of treatment. Patients in arm B receive up-front STRIDE and bevacizumab. Treatment will continue until unacceptable toxicity or progression under the Bev-containing regimen. The primary endpoint is overall response rate (ORR). Clinical trial information: NCT05844046 .
FusionVAC22_01: A phase I clinical trial evaluating a DNAJB1-PRKACA fusion transcript-based peptide vaccine combined with immune checkpoint inhibition for fibrolamellar hepatocellular carcinoma and other tumor entities carrying the oncogenic driver fusion.
Authors: Bitzer Michael , Hackenbruch Christopher , Bauer Jens , Heitmann Jonas S. , Maringer Yacine , Nelde Annika , Salih Helmut R. , Walz Juliane S. 
Published: January 2024

TPS580 Background: The DNAJB1-PRKACA fusion transcript is the driver of tumor pathogenesis in fibrolamellar hepatocellular carcinoma (FL-HCC) as well as in other tumor entities, e.g. oncocytic neoplasms of the pancreas and bile duct, thus representing a broad target for novel therapies in cancer. Recently, the DNAJB1-PRKACA fusion protein was identified as a source for HLA-presented neoepitopes that can be targeted by T-cell-based immunotherapy (Bauer et al. Nat. Commun., 2022). The DNAJB1-PRKACA fusion-derived neoepitope FusionVAC-22 is in silico predicted to bind to 1,290 HLA class II alleles and contains HLA class I ligands from 13 of the 20 most frequent HLA class I alleles that cover 93.8% of the world population with at least one HLA allotype, enabling the broad application of FusionVAC-22-based immunotherapies. The first application of FusionVAC-22-based peptide vaccines adjuvanted with the TLR1/2 agonist XS15 emulsified in Montanide ISA 51 VG in two FL-HCC patients was well tolerated and showed the induction of profound and long-lasting T-cell responses. Of note, T-cell responses were accompanied by progression-free survival of both patients for so far 32 months and 13 months, respectively. Methods: Based on these encouraging results, we established a Phase I open-label, multicentric clinical trial to evaluate the immunogenicity along with safety and toxicity, as well as first signs of efficacy of the FusionVAC-22 based peptide vaccine, combined with the immune checkpoint inhibitor (ICI) atezolizumab, in 20 patients with locally advanced or metastatic FL-HCC or other malignant diseases that carry the DNAJB1-PRKACA fusion transcript. Further, key eligibility criteria include the absence of autoimmune phenomena due to prior immunotherapy agents (≥ grade 3) as well as tissue or organ allografts. The FusionVAC-22-based peptide vaccine is applied twice in a 4-weekly interval with the opportunity of a booster vaccination after 11 months. Atezolizumab application starts on day 15 after first vaccination and is continued 4-weekly for 1 year, followed by a 6-month follow-up. The primary objectives of the trial are immunogenicity, in terms of induction of peptide specific T-cell responses until 28 days after second vaccination, as well as safety and toxicity of the peptide vaccine in combination with ICI. Safety assessment is based on the frequency of adverse events according to CTCAE v5.0. Clinical efficacy is determined by iRECIST assessment on imaging. Furthermore, disease control rate, quality of life as well as overall and progression free survival will be assessed. Clinical trial information: NCT05937295 .
Repeat Flow Diversion for Retreatment of Incompletely Occluded Large Complex Symptomatic Cerebral Aneurysms: A Retrospective Case Series
Authors: Kashkoush Ahmed , El-Abtah Mohamed E. , Davison Mark A. , Toth Gabor , Moore Nina , Bain Mark 
Published: January 2024

BACKGROUND AND OBJECTIVES:
Data regarding radiographic occlusion rates after repeat flow diversion after initial placement of a flow diverter (FD) in large intracranial aneurysms are limited. We report clinical and angiographic outcomes on 7 patients who required retreatment with overlapping FDs after initial flow diversion for large intracranial aneurysms.

METHODS:
We performed a retrospective review of a prospectively maintained database of cerebrovascular procedures performed at our institution from 2017 to 2021. We identified patients who underwent retreatment with overlapping FDs for large (>10 mm) cerebral aneurysms after initial flow diversion. At last angiographic follow-up, occlusion grade was evaluated using the O'Kelly-Marotta (OKM) grading scale.

RESULTS:
Seven patients (median age 57 years) with cerebral aneurysms requiring retreatment were identified. The most common aneurysm location was the ophthalmic internal carotid artery (n = 3) and basilar trunk (n = 3). There were 4 fusiform and 3 saccular aneurysms. The median aneurysm width was 18 mm; the median neck size for saccular aneurysms was 7 mm; and the median dome-to-neck ratio was 2.8. The median time to retreatment was 9 months, usually due to symptomatic mass effect. After retreatment, the median clinical follow-up was 36 months, MRI/magnetic resonance angiography follow-up was 15 months, and digital subtraction angiography follow-up was 14 months. Aneurysm occlusion at last angiographic follow-up was graded as OKM A (total filling, n = 1), B (subtotal filling, n = 2), C (early neck remnant, n = 3), and D (no filling, n = 0). All patients with symptomatic improvement were OKM C, whereas patients with worsened symptom burden were OKM A or B. Two patients required further open surgical management for definitive management of the aneurysm remnant.

CONCLUSION:
Although most patients demonstrated a decrease in aneurysm remnant size, many had high-grade persistent filling (OKM grades A or B) in this subset of mostly large fusiform aneurysms. Larger studies with longer follow-up are warranted to optimize treatment strategies for atypical aneurysm remnants after repeat flow diversion.
Investigation of the presence of equine herpesvirus-1 (EHV-1) in tissue samples of aborted foals by histopathological, immunohistochemical, and Real-Time PCR techniques
Authors: Deniz Sezgin , Gülçubuk Ahmet , Sönmez Kıvılcım , Altan Eda , Aytemiz Danyer Işıl , Gürel Aydın , Yılmaz Hüseyin 
Published: January 2024

Equine herpesvirus-1 (EHV-1) is a cause of pneumonia, encephalitis, and abortion in horses. Abortions occur alive or dead in the last trimester of pregnancy. The aim of this study is to investigate the incidence of EHV-1 infections in the tissue samples of aborted stillborn and live-born foals and the foals which died soon after birth and compare and correlate the conventional histopathologic diagnosis with IHC and Real-Time PCR. For this purpose, tissue samples (lung, liver, spleen, kidney, placenta, and brain) of 38 foals from Istanbul, Kocaeli, Bursa, and Eskişehir provinces of Turkey between August 2009 and March 2011 were examined Real-Time PCR revealed 52.6 % positivity (20/38), whereas 39.4 % (15/38) positivity was achieved with IHC, which indicated a correlation between these two diagnostic methods. In histopathological evaluation, the inclusion body was found in at least one of the tissue sections belonging to the lung, spleen, and mostly liver of 20 foals (52.6%). Tissue samples of the foals found to be positive by IHC and PCR revealed histopathologic findings compatible with the characteristics of the disease.
Is it worth the hype? Influence of Artificial Intelligence efforts on key financial company metrics
Authors: Maier Daniel 
Published: January 2024

Artificial Intelligence poses a consortium of multiple digital technologies able to perform tasks which were thought about that they can only be done by humans. To do so, it applies complex learning and decision-making processes based on analysis of structured and unstructured data. Currently, AI is assumed to have massive benefits in the areas of efficiency and performance of companies, although the impact on financial key performance indicators (KPI) is still unexplored. The underlying thesis of this research is that the financial impact of AI can already be seen in practice. The research question is whether there is an impact of company-driven AI efforts on financial KPI, like the return on assets (ROA) and the market capitalization.
To obtain the intended results, a theoretical and empirical analysis was chosen as particular approach. Firstly, the existing scientific research is examined regarding already measurable financial impacts of digital technologies. In a second step, a regression model for panel data will be applied on a dataset containing financial data of the forty biggest German companies and their respective AI effort per year as a binary variable over a time period of seven years.
As a result, a financial influence of AI cannot be verified yet on a statistically significant level. Despite of this, an increasing number of AI efforts over the last years can be confirmed.
Flow Allocation Games
Authors: Bertschinger Nils , Hoefer Martin , Schmand Daniel 
Published: January 2024

We study a game-theoretic variant of the maximum circulation problem. In a flow allocation game, we are given a directed flow network. Each node is a rational agent and can strategically allocate any incoming flow to the outgoing edges. Given the strategy choices of all agents, a maximal circulation that adheres to the chosen allocation strategies evolves in the network. Each agent wants to maximize the amount of flow through his or her node. Flow allocation games can be used to express strategic incentives of clearing in financial networks. We provide a cumulative set of results on the existence and computational complexity of pure Nash and strong equilibria as well as tight bounds on the (strong) prices of anarchy and stability. Our results show an interesting dichotomy. Ranking strategies over individual flow units allows us to obtain optimal strong equilibria for many objective functions. In contrast, more intuitive ranking strategies over edges can give rise to unfavorable incentive properties. Funding: This work was supported by Deutsche Forschungsgemeinschaft Research Group ADYN [411362735].
Diffuse B-cell lymphoma of the mandible disguised as acute osteomyelitis
Authors: Adalja Devina , Tagliaferri Ariana , Rezkalla Abraam , Taha Basil 
Published: January 2024

Background: Primary bone lymphoma (PBL) is a rare form of extra nodal non-Hodgkin’s lymphoma (NHL). Case description: We describe a 39-year-old-male with no medical history who presented with unilateral facial swelling following a tooth extraction. Initial diagnoses after various presentations over the course of three weeks, based on inflammatory and infectious aetiologies. However, the patient was ultimately diagnosed with diffuse large B-cell lymphoma. Discussion: Symptoms of PBL are very similar to inflammatory and infectious diseases of the bone, such as osteomyelitis or osteonecrosis. Clinical features of PBL involving the head and neck include persistent jaw pain, tooth mobility secondary to extensive destruction of bone, and in advanced cases, lip numbness and swelling. On examination it may present as an exposed necrotic bone with surrounding soft tissue oedema. Misdiagnosis of these lesions as an infectious or inflammatory aetiology may lead to an unnecessary delay in lymphoma treatment, and subsequently worsen the prognosis if caught at a later stage. Therefore, any concerning lesion, especially in the oral cavity, must be subjected to early histopathological evaluation to differentiate PBL from osteomyelitis and/or osteonecrosis. Conclusion: This case report highlights the importance of an early histopathological evaluation to prevent delay in the diagnosis of primary bone lymphomas.
Reproducing the Canon, Reproducing Inequity (Traditional Rhetoric)
Authors: Berenguer Elizabeth , Jewel Lucy , McMurtry-Chubb Teri A. 
Published: January 2024

This chapter invites readers to identify the specific ways traditional legal rhetoric does harm to the cause of social justice and equity. In this way, this chapter operates as a critical casebook, presenting several appellate opinions for readers to deeply read and digest. Rather than tell the reader how traditional legal rhetoric harms, the objective is for readers to see this for themselves. These are not especially well-known cases; they are relatively run-of-the-mill cases, representing a wide spectrum of doctrines, including immigration law, privacy law, entertainment law, obscenity law, qualified immunity / excessive force, and freedom of religion / First Amendment. Each case, however, negatively impacts justice and equity for a member of a minoritized or marginalized community. After each case, the reader will confront discussion questions that surface the social and historical context involved in the case, the role of the judge, and other ways that traditional rhetorical frameworks influenced the legal outcome in the case.