bluuebunny/crossref_metadata_2025 huggingface dataset:
Three-dimensional deformation and its uncertainty derived by integrating multiple SAR data analysis methods
Authors: Morishita Yu , Kobayashi Tomokazu
Published: January 2022

Three-dimensional (3D) surface deformation data with high accuracy and resolution can help reveal the complex mechanisms and sources of subsurface deformation, both tectonic and anthropogenic. Detailed 3D deformation data are also beneficial for maintaining the position coordinates of existing ground features, which is critical for developing and advancing global positioning technologies and their applications. In seismically active regions, large earthquakes have repeatedly caused significant ground deformation and widespread damage to human society. However, the delay in updating position coordinates following deformation can hamper disaster recovery. Synthetic aperture radar (SAR) data allow high-accuracy and high-resolution 3D deformation measurements. Three analysis methods are currently available to measure 1D or 2D deformation: SAR interferometry (InSAR), split-bandwidth interferometry (SBI), and the pixel offset method. In this paper, we propose an approach to derive 3D deformation by integrating deformation data from the three methods. The theoretical uncertainty of the derived 3D deformations was also estimated using observed deformation data for each of these methods and the weighted least square (WLS) approach. Furthermore, we describe two case studies (the 2016 Kumamoto earthquake sequence and the 2016 Central Tottori earthquake in Japan) using L-band Advanced Land Observing Satellite 2 (ALOS-2) data. The case studies demonstrate that the proposed approach successfully retrieved 3D coseismic deformation with the standard error of ~ 1, ~ 4, and ~ 1 cm in the east–west, north–south, and vertical components, respectively, with sufficient InSAR data. SBI and the pixel offset method filled the gaps of the InSAR data in large deformation areas in the order of 10 cm accuracy. The derived standard errors for each pixel are also useful for subsequent applications, such as updating position coordinates and deformation source modeling. The proposed approach is also applicable to other SAR datasets. In particular, next-generation L-band SAR satellites, such as ALOS-4 and NASA-ISRO SAR (NISAR), which have a wider swath width, more frequent observation capabilities than the former L-band satellites, and exclusive main look directions (i.e., right and left) will greatly enhance the applicability of 3D deformation derivation and support the quick recovery from disasters with significant deformation.

Graphical Abstract
Lessons from a feasibility study testing an anticipatory care planning intervention for older adults at risk of functional decline: feedback from implementing stakeholders
Authors: Corry Dagmar Anna S. , Carter Gillian , Doyle Frank , McGlade Kieran , O’Halloran Peter , Wallace Emma , Brazil Kevin
Published: January 2022

Background

Anticipatory care is becoming increasingly important in effectively managing complex multimorbidity in aging populations, preventing further functional decline, and avoiding hospital admissions. This study aimed to elicit the feedback of participating general practitioners, practice managers, nurses and an adjunct pharmacist on the implementation strengths and limitations of a nurse-led, person-centered anticipatory care planning (ACP) intervention for older people at risk of functional decline in a primary care setting. The findings have implications for a full trial and intervention design.

Methods

As part of a feasibility cluster randomized controlled trial (cRCT) testing the ACP intervention, we sought feedback from implementing stakeholders: general practitioners (N = 3), practice staff (N = 3), research nurses (N = 5), and adjunct pharmacist (N = 1) in both the Republic of Ireland (ROI) and Northern Ireland (NI), UK. Following written, informed consent, they were interviewed to investigate their experience of participating in the implementation of the ACP intervention as part of the feasibility trial, and elicit any recommendations for a full trial. Using the Consolidated Framework for Implementation Research, thematic analysis was employed to analyze data. The intervention consisted of home visits by specially trained nurses who assessed participants’ health, discussed with them their health goals and plans, and devised an anticipatory care plan following consultation with participants’ General Practitioners and the adjunct clinical pharmacist.

Results

Participating stakeholders indicated that the strengths of the implementation process included the training provided to the nurses, constructive collaboration of the research team, and structure of implementation process. Perceived limitations included the selection process and screening tool, communication between the research team and the nurses, the assessment questionnaire, and the final document left with the patient, as well as lack of access to medical records for the adjunct pharmacist. Recommendations include better communication and team-wide consensus on alterations to procedure and documents, and standardized protocols for patient selection, data collection, and reporting for research nurses.

Conclusions

The findings have identified strengths of the implementation process on which to build, and recognized limitations which can now be addressed to ensure improved efficiency and effectiveness in future trials.

Trial registration

Clinicaltrials.gov, ID: NCT03902743. Registered on 4 April 2019.
Single-nucleotide polymorphisms and activities of indoleamine 2,3-dioxygenase isoforms, IDO1 and IDO2, in tuberculosis patients
Authors: Cao Tingming , Dai Guangming , Chu Hongqian , Kong Chengcheng , Duan Huijuan , Tian Na , Sun Zhaogang
Published: January 2022

Purpose

To explore the role and effects of the single-nucleotide polymorphisms (SNPs) of the two functionally related indoleamine 2,3-dioxygenase (IDO) isoforms on IDO activity in the Chinese Han ethnic population.

Methods

A total of 151 consecutive patients of Chinese Han ethnicity (99 men and 52 women; average age 51.92 ± 18.26 years) with pulmonary TB admitted to Beijing Chest Hospital between July 2016 and February 2017 were enrolled in the study. The serum levels of tryptophan (Trp) and its metabolites, IDO1 and IDO2 mRNA levels, and the relationship of IDO1 and IDO2 SNPs with the serum Kyn/Trp ratio in TB patients and healthy controls were examined by LC/ESI–MS/MS analysis. Genomic DNA was isolated from whole blood, and the PCR products were sequenced and analyzed.

Results

In Chinese Han participants, only IDO2 had SNPs R248W and Y359X that affected IDO activity, as determined by the serum Kyn/Trp ratio. IDO1 and IDO2 mRNA levels were inversely related in TB patients and healthy controls.

Conclusions

IDO2 SNPs and the opposite expression pattern of IDO1 and IDO2 affected IDO activity in Chinese Han TB patients.
Quantitative urine proteomics in pregnant women for the identification of predictive biomarkers for preeclampsia
Authors: Joenväärä Sakari , Holm Matilda , Saraswat Mayank , Agarwal Rahul , Tohmola Tiialotta , Kajantie Eero , Räikkönen Katri , Laivuori Hannele , Villa Pia M. , Hämäläinen Esa , Renkonen Risto
Published: January 2022

Background

Preeclampsia (PE) is a life-threatening disease characterized by elevated blood pressure and proteinuria. Predictive biomarkers of PE are needed, especially those predicting PE in early pregnancy. The aim of this pilot study was to identify urine proteins that could be candidates for new non-invasive markers for PE.

Methods

Urine samples at three time points of pregnancy (12–14, 18–20 and 26–28 weeks of gestation) were prospectively collected from high-risk women who subsequently developed PE (n = 7), high-risk women who did not develop PE (n = 6), and women without known risk factors for PE (n = 4). The samples were analyzed using mass spectrometry and we subsequently quantified 361 proteins used for further analysis. Rigorous statistical analysis with multiple methods was performed to identify biomarker candidates.

Results

Of the clinical risk factors analyzed, pre-pregnancy body mass index (BMIBP) was found to be the most important predictor of PE. We identified multiple proteins that correlated with BMIBP and could improve the prediction of PE in combination with BMIBP. Other statistical analyses identified six proteins that each could differentiate women who subsequently developed PE from those who did not at all three time points.

Conclusions

We identified multiple urine proteins that could be used to predict PE in combination with BMIBP. We also identified six proteins that are strong candidates for predicting PE already in early pregnancy.
Axon guidance molecules in immunometabolic diseases
Authors: Nakanishi Yoshimitsu , Kang Sujin , Kumanogoh Atsushi
Published: January 2022

The global prevalence of metabolic diseases, such as obesity, diabetes, and atherosclerosis, is rapidly increasing and has now reached epidemic proportions. Chronic tissue inflammation is a characteristic of these metabolic diseases, indicating that immune responses are closely involved in the pathogenesis of metabolic disorders. However, the regulatory mechanisms underlying immunometabolic crosstalk in these diseases are not completely understood. Recent studies have revealed the multifaceted functions of semaphorins, originally identified as axon guidance molecules, in regulating tissue inflammation and metabolic disorders, thereby highlighting the functional coupling between semaphorin signaling and immunometabolism. In this review, we explore how semaphorin signaling transcends beyond merely guiding axons to controlling immune responses and metabolic diseases.
An environmental scan of one health preparedness and response: the case of the Covid-19 pandemic in Rwanda
Authors: Igihozo Gloria , Henley Phaedra , Ruckert Arne , Karangwa Charles , Habimana Richard , Manishimwe Rosine , Ishema Leandre , Carabin Hélène , Wiktorowicz Mary E. , Labonté Ronald
Published: January 2022

Background

Over the past decade, 70% of new and re-emerging infectious disease outbreaks in East Africa have originated from the Congo Basin where Rwanda is located. To respond to these increasing risks of disastrous outbreaks, the government began integrating One Health (OH) into its infectious disease response systems in 2011 to strengthen its preparedness and contain outbreaks. The strong performance of Rwanda in responding to the on-going COVID-19 pandemic makes it an excellent example to understand how the structure and principles of OH were applied during this unprecedented situation.

Methods

A rapid environmental scan of published and grey literature was conducted between August and December 2020, to assess Rwanda’s OH structure and its response to the COVID-19 pandemic. In total, 132 documents including official government documents, published research, newspaper articles, and policies were analysed using thematic analysis.

Results

Rwanda’s OH structure consists of multidisciplinary teams from sectors responsible for human, animal, and environmental health. The country has developed OH strategic plans and policies outlining its response to zoonotic infections, integrated OH into university curricula to develop a OH workforce, developed multidisciplinary rapid response teams, and created decentralized laboratories in the animal and human health sectors to strengthen surveillance. To address COVID-19, the country created a preparedness and response plan before its onset, and a multisectoral joint task force was set up to coordinate the response to the pandemic. By leveraging its OH structure, Rwanda was able to rapidly implement a OH-informed response to COVID-19.

Conclusion

Rwanda’s integration of OH into its response systems to infectious diseases and to COVID-19 demonstrates the importance of applying OH principles into the governance of infectious diseases at all levels. Rwanda exemplifies how preparedness and response to outbreaks and pandemics can be strengthened through multisectoral collaboration mechanisms. We do expect limitations in our findings due to the rapid nature of our environmental scan meant to inform the COVID-19 policy response and would encourage a full situational analysis of OH in Rwanda’s Coronavirus response.
Project risk management in Iranian small construction firms
Authors: Amani Nima , Safarzadeh Keyvan
Published: January 2022

The objective of this study is to evaluate RM in small projects in Iran using identification of status, barriers, and the impact of RM on project performance. In this study, theoretical foundations and research literature were first developed through library, and then a questionnaire about these variables was designed and distributed among a number of experts in the active construction companies. Data were collected from 40 projects submitted by 25 experts from 5 executive companies. According to the studies, 10 barriers are identified as major obstacles to RM implementation in such projects, prioritized as follows: (1) lack of potential benefits, (2) not economical, (3) lack of time, (4) lack of budget, (5) lack of knowledge, (6) lack of government legislation, (7) lack of manpower, (8) low profit margin, (9) complexity of analytical tools, and (10) competition among SMCs. The findings of this research can provide an in-depth understanding of RM in small projects in Iran and make benefits of RM convincing to the participants of small projects.
A Revised Measure of Acceptance of the Theory of Evolution: Introducing the MATE 2.0
Authors: Barnes M. Elizabeth , Misheva Taya , Supriya K. , Rutledge Michael , Brownell Sara E.
Published: January 2022

An updated version of the most popular survey used to measure student evolution acceptance in education studies, the Measure of Acceptance of the Theory of Evolution (MATE), is provided. Process, structural, and concurrent validity evidence for the new measure, the MATE 2.0, are supplied.
Phase-amplitude-based polarized direct envelope inversion in the time-frequency domain
Authors: Hu Yong , Wu Ru-Shan , Huang Xingguo , Long Yun , Xu Yongzhong , Han Li-Guo
Published: January 2022

Large-scale geologic structures with strong contrasts present difficulties for seismic imaging and inversion. Previously, direct envelope inversion (DEI) with ultralow frequency has been proposed to retrieve strong-contrast velocity models. However, the envelope signals lose the instantaneous phase of the original wavefield, resulting in erroneous seismic inversion results. To solve this problem, the instantaneous phase of the wavefield is encoded into envelopes for DEI. In this way, a polarized envelope is created to contain both abundant low frequencies and the instantaneous phase information of the original seismic waveform. Furthermore, to improve the resolution of deep regions underneath the strong reflections, we propose a phase-amplitude-based polarized direct envelope inversion (PA-PDEI) misfit in the time-frequency domain that uses an amplitude factor to emphasize the phase information. This makes it possible to adjust the amplitude influence and boost the low-amplitude seismic signals for deep targets. Tests on a model with a salt body and on field data show that combining the PA-PDEI with the phase-amplitude-based full-waveform inversion (PA-FWI) make it possible to reliably reconstruct velocity models, especially for deep regions, despite large and strong perturbations.
Association between a history of clinical depression and dementia, and the role of sociodemographic factors: population-based cohort study
Authors: Korhonen Kaarina , Tarkiainen Lasse , Leinonen Taina , Einiö Elina , Martikainen Pekka
Published: January 2022

Background

Depression is associated with an increased dementia risk, but the nature of the association in the long-term remains unresolved, and the role of sociodemographic factors mainly unexplored.

Aims

To assess whether a history of clinical depression is associated with dementia in later life, controlling for observed sociodemographic factors and unobserved factors shared by siblings, and to test whether gender, educational level and marital status modify the association.

Method

We conducted a national cohort study of 1 616 321 individuals aged 65 years or older between 2001 and 2018 using administrative healthcare data. A history of depression was ascertained from the national hospital register in the period 15–30 years prior to dementia follow-up. We used conventional and sibling fixed-effects Cox regression models to analyse the association between a history of depression, sociodemographic factors and dementia.

Results

A history of depression was related to an adjusted hazard ratio of 1.27 (95% CI 1.23–1.31) for dementia in the conventional Cox model and of 1.55 (95% CI 1.09–2.20) in the sibling fixed-effects model. Depression was related to an elevated dementia risk similarly across all levels of education (test for interaction, P = 0.84), but the association was weaker for the widowed than for the married (P = 0.003), and stronger for men than women (P = 0.006). The excess risk among men attenuated following covariate adjustment (P = 0.10).

Discussion

This study shows that a history of depression is consistently associated with later-life dementia risk. The results support the hypothesis that depression is an aetiological risk factor for dementia.
A randomized phase III trial of mFOLFOX7 or CapeOX plus bevacizumab versus 5-FU/l-LV or capecitabine plus bevacizumab as initial therapy in elderly patients with metastatic colorectal cancer: JCOG1018 study (RESPECT).
Authors: Hamaguchi Tetsuya , Takashima Atsuo , Mizusawa Junki , Shimada Yasuhiro , Nagashima Fumio , Ando Masahiko , Ojima Hitoshi , Denda Tadamichi , Watanabe Jun , Shinozaki Katsunori , Baba Hideo , Asayama Masako , Fukushima Tadao , Masuishi Toshiki , Nakata Ken , Tsukamoto Shunsuke , Katayama Hiroshi , Nakamura Kenichi , Fukuda Haruhiko , Kanemitsu Yukihide ,   Colorectal Cancer Study Group in Japan Clinical Oncology Group (JCOG)
Published: January 2022

10

Background: It is uncertain if the addition of oxaliplatin (OX) to fluoropyrimidine plus bevacizumab (BEV) is suitable as initial therapy in elderly patients (pts) with metastatic colorectal cancer (MCRC). Therefore, we conducted a randomized controlled trial to confirm the superiority of the addition of OX in terms of progression-free survival (PFS). This JCOG trial was originally planned as a paralell study with NCCTG, but the NCCTG trial was terminated early. Methods: Key eligibility criteria included unresectable metastatic colorectal cancer, and histologically confirmed adenocarcinoma, aged 70-74 with PS 2 or 75 or older with ECOG PS 0-2. Eligible pts were randomized (1:1) to either no addition of OX or addition. Whether using 5-FU+levoleucovorin calcium (5-FU/ l-LV) or capecitabine (CAPE) was declared before study entry; options included 5-FU/ l-LV+BEV (C), CAPE+BEV (D), mFOLFOX7+BEV (E), or CapeOX+BEV (F). 5-FU/ l-LV regimen omitted bolus 5-FU from the original sLV5FU regimen. The dose of CAPE was adjusted by estimated creatinine clearance. The primary endpoint was PFS. The planned sample size was 250 pts in total to detect a hazard ratio (HR) of 0.75, with a one-sided alpha of 5% and 70% power. The decision rule is that the primary endpoint is met, and the point estimate of HR of overall survival (OS) is less than 0.8. Results: Between Sep 2012 and Mar 2019, 251 pts were randomized. 125 pts were allocated to no addition of OX and 126 pts to addition. Median age was 79, aged 70-74/75-79/80-84/85+:5%/45%/37%/13%, PS 0/1/2:53%/39%/7%. Of 251 pts, 241 pts had PFS events and 223 pts had OS events. Median PFS (mPFS) was 9.4 months (M) (95%CI 8.3–10.3) in no addition of OX and 10.0M (9.0–11.2) in addition (HR 0.837, 90.5%CI [0.673–1.042], one-sided p = 0.086). Median OS was 21.3M (18.7-24.3) in no addition and 19.7M (15.5–25.5) in addition of OX (HR 1.054 [0.810–1.372]). Response rate was 29.5% (21.2-38.8) in no addition of OX and 47.7% (38.1-57.5) in addition. Proportion of pts whose EQ-5D scores improved from baseline to post-treatment in overall score did not differ (odds ratio 0.94 (0.51-1.75)). The deaths of 1 pt in no addition of OX and in 3 pts in addition were deemed treatment-related. Conclusions: The addition of OX has no survival benefit over no addition. OX was not recommended for elderly MCRC pts as initial therapy. Clinical trial information: UMIN000008866.[Table: see text]
Options beyond BRAF targeted therapy in second-line treatment of patients with BRAFV600E mutant (BRAFmt) metastatic colorectal cancer (mCRC).
Authors: Wong Vanessa , Hong Wei , Ananda Sumitra , Dunn Catherine , Wong Rachel , To Yat Hang , Burge Matthew E. , Nott Louise M. , Tie Jeanne , Shapiro Jeremy David , Jennens Ross , Khattak Muhammad Adnan , Roohullah Aflah , Gibbs Peter
Published: January 2022

47

Background: BRAFmt is a negative prognostic factor in mCRC but also identifies a patient population that may benefit from BRAF targeted therapy. Results from recent trials (BEACON and SWOG1406) demonstrate improved survival outcomes in second- and third-line settings when combining a BRAF inhibitor, an EGFR inhibitor (EGFRi) +/- a MEK inhibitor. In both trials, irinotecan and cetuximab was the control arm with a dismal response rate of 2-4% and progression free survival (PFS) of only 2 months. This suggests chemotherapy plus an EGFRi may not be the optimal approach where BRAF-targeted therapies are not available or have failed. Methods: Data from July 2009 to September 2021 was analysed from TRACC, a multi-site Australian mCRC comprehensive prospective registry enrolling consecutive patients. Patient characteristics, treatment and survival outcomes were examined for patients treated with chemotherapy (CT) alone, with bevacizumab (BEV) or with an EGFRi. Results: Of 2046 registry patients, 256 (13%) harboured a BRAFmt. 72 BRAFmt patients had received second-line (28%) treatment, including CT alone (n = 28), CT plus BEV (n = 26), and CT plus EGFRi (n = 18). Baseline characteristics are shown in the table. Median second-line PFS was 3.3, 4.7 and 1.8 months, for CT alone, CT plus BEV and CT plus EGFRi respectively. Median overall survival (OS) was 8.7, 7.9 and 2.5 months respectively. In multivariate analysis, PFS when treated with CT plus EGFRi trended inferior to CT alone (p = 0.054) and CT plus BEV (p = 0.061), whereas for OS, treatment with CT plus EGFRi was inferior to CT alone (p = 0.038) and CT plus BEV (p = 0.015). Poor PFS was associated with age ≥ 65 years (HR 3.03, p < 0.001) and ECOG ≥ 2 (HR 2.62, p = 0.004), but not associated with a right side primary (p = 0.17), mismatch repair (MMR) status (p = 0.86), or ≥ 3 organs with metastases (p = 0.32). Poor OS was associated with age ≥ 65 years (HR 3.11, p < 0.001), ECOG ≥ 2 (HR 7.32, p < 0.001), right side primary (HR 3.03, p = 0.002) and proficient MMR status (HR 3.57, p = 0.018), but not associated with ≥ 3 organs with metastases (p = 0.17). Conclusions: Less than one-third of BRAFmt mCRC patients received second-line therapy in a real-world setting, indicating an urgency to explore activity of BRAF targeted therapy in the first line setting. Treated patients received limited benefit, with CT plus EGFRi PFS outcomes comparable to BEACON control arm (1.8 vs 2.0 months) and trending inferior to other options. The best OS outcomes were achieved with CT alone or CT plus BEV.[Table: see text]
Determining frequency and reasons associated to refusal of colorectal cancer screening at a reference center in Mexico.
Authors: Meneses Medina Mónica Isabel , Anaya Sanchez Luis Guillermo , Hernandez-Felix Jorge Humberto , Torres Valdiviezo Lucero Itzel , Rosas Camargo Vanessa , Cedro-Tanda Alberto , Uscanga Dominguez Luis Federico , Lajous Martin , Valdovinos Aldaca Francisco , Sierra Reynerio Fagundo , Noguez-Ramos Alejandro , Huitzil Melendez Fidel David
Published: January 2022

67

Background: in Mexico, Colorectal Cancer (CRC) is a leading cause of cancer death, yet population-based screening programs are lacking. In our center, a cohort was created to validate a risk calculator to detect advanced colorectal neoplasia, and to understand barriers to implement a CRC screening program. We aimed to determine frequency and reasons associated to rejection of CRC screening in our population. Methods: from August 2019 to March 2020 (early close owing to COVID-19 pandemic) asymptomatic individuals between 50 and 75 years-old with standard-risk for CRC, without previous screening for CRC, from the outpatient internal medicine clinic at a tertiary care center in Mexico City, received standardized information on the importance of CRC screening and were invited to perform both Fecal Immunochemical Test and a screening colonoscopy within a clinical study at no cost. Individuals who rejected participation were given a 10-item questionnaire to select reasons for refusal, as many items as applied. Here we present two groups: 1) individuals who refused to receive information and to perform screening studies, and 2) individuals who refused to participate after receiving information. Results: 162 patients were invited to participate, 77 (47%) refused: 48 rejected immediately (group 1) and provided 51 reasons, and 29 declined after having received standardized information about CRC screening (group 2) and provided 30 reasons. Demographics for 77 patients were: 54 (70.1%) women, median age 66 (IQR 58-71) years. Main reasons for rejection in both groups were: “I do not have time” in 24 (29.6%) times, “I am not interested” in 23 (28.4%) times, and “I am scared” in 14 (17.3%) times (Table). Conclusions: in our cohort, we identified that nearly half of the population invited to participate in a CRC screening program refused. Main reasons were lack of time, lack of interest and fear. This may translate poor understanding on the importance of measures to prevent CRC, and absence of education programs to recall its importance. In order to increment participation in CRC screening, education and awareness campaigns should be implemented.[Table: see text]
The impact of Medicaid expansion on colorectal cancer incidence among vulnerable populations.
Authors: Qian Alexander , Nalawade Vinit , Murphy James Don
Published: January 2022

68

Background: With the Affordable Care Act (ACA), the number of uninsured patients in states that expanded Medicaid decreased more among racial/ethnic minorities and lower income adults. Increased access to care could influence colorectal cancer (CRC) incidence through increased screening. However, we lack research on whether Medicaid expansion differentially influenced CRC incidence among vulnerable patient subgroups. This population-based study examines whether Medicaid expansion with the ACA was associated with decreased CRC incidence among racial/ethnic minorities, and adults with lower income. Methods: We queried the Surveillance, Epidemiology, and End Results Program (SEER) database to calculate the age-adjusted incidence rates of CRC among patients under 65 years of age diagnosed between 2010 and 2018. We categorized states into two groups: states that expanded Medicaid on January 1, 2014, and states that did not expand Medicaid over the study period. We determined the change in CRC incidence before Medicaid expansion (2010-2013) and after Medicaid expansion (2014-2018). We used a difference-in-difference approach to determine whether changes in CRC incidence differed by expansion status among all patients and among subgroups stratified by race/ethnicity and other socioeconomic indicators. Results: Among the entire study cohort, from 2010-2013 to 2014-2018, rates of CRC (per 100,000) increased from 26.6 to 28.3, and this increasing rate did not differ by ACA expansion status (p=0.48). We found that the impact of ACA expansion on CRC incidence varied by race/ethnicity. The increase in CRC rates was higher among non-ACA expansion states compared to ACA expansion states for Hispanics (5.4 vs. 1.6 increase per 100,000; p=0.002), and Asian or Pacific Islanders (4.3 vs. 0.4 increase per 100,000; p=0.02), but not with Black (p=0.94), or non-Hispanic white patients (p=0.91). The change in CRC incidence between 2010-2013 and 2014-2018 did not differ by county-level household income, fraction under the federal poverty level, or education level (all p>0.05). Conclusions: This study found that Medicaid expansion through the ACA might differentially benefit Hispanic and Asian patients with respect to decreases in CRC incidence. This study reports on the first 5 years after the ACA, though the true benefits of increased access to care may take longer to manifest. Additional research with longer follow-up is required to fully understand the influence of Medicaid expansion.
Second cancer after adjuvant chemotherapy in patients with colon cancer.
Authors: Teufel Andreas , Li Moying , Gerken Michael , Ebert Matthias Philip , Schlitt Hans J. , Evert Matthias , Herr Wolfgang , Klinkhammer-Schalke Monika
Published: January 2022

86

Background: Adjuvant chemotherapeutic treatment of UICC-stage III/IV colon cancer with fluorouracil, leucovorin and oxaliplatin (FOLFOX) is widely accepted as the current standard after R0-resection. However, with continuous improvement of patients´ survival and life expectancy, long-term side effects of chemotherapy such as second cancer development are becoming increasingly important. Methods: We performed a retrospective analysis of clinical data derived from the population-based cancer registry at the Regensburg Tumor Center, Germany. Patients who were diagnosed with colon cancer UICC stage III and IV between 2002 and 2018 and underwent R0 surgical resection of primary tumor were included for the study. Second cancer was as defined new tumor occurrence at least 6 months after beginning of chemotherapy and in another localization compared to primary tumor. Second cancer rate was compared between patients with and patients without adjuvant chemotherapy. Results: Data of totally 2,856 Patients with UICC-stage III/IV colon cancer were analyzed, 1,520 (53.2%) of whom received adjuvant chemotherapy. Overall, 223 (7.8%) patients developed a subsequent second cancer. Most frequent second cancers were prostate cancer (18.4%), colon cancer (16.1%), breast cancers (8.1%), lung cancer (8.1%), rectal cancer (4.9%) and uterine cancer (4.9%). However, patients treated with adjuvant chemotherapy did not have a significantly increased risk for second cancer development compared to patients without adjuvant chemotherapy (Table). Interestingly, our data suggest a significantly decreased second cancer rate in patients treated with FOLFOX compared to FUFOL for adjuvant treatment. Conclusions: Second cancer development was not increased after adjuvant chemotherapy for UICC-stage III/IV colon cancer, which is a novel aspect in the ongoing discussions on reduction of adjuvant treatment to 3 months or treatment of lymph node negative patients. Primary tumor (N) Second tumor (N) Second tumor (%) Cumulative rate 60 months (%) Log-Rank p Chemotherapy Yes 1520 145 9.5% 8.8% No 1336 78 5.8% 9.0% 0.685 Total 2856 223 7.8% 8.9%
A phase 1b multitumor cohort study of cabozantinib plus atezolizumab in advanced solid tumors (COSMIC-021): Results of the colorectal cancer cohort.
Authors: Abrams Thomas Adam , Kazmi Syed Mohammad Ali , Winer Ira Seth , Subbiah Vivek , Falchook Gerald Steven , Reilley Matthew , Kunk Paul Raymond , Goel Sanjay , Garrido-Laguna Ignacio , Kochenderfer Mark D. , Werneke Scott , Andrianova Lana , Sudhagoni Ramu , Paulson Scott
Published: January 2022

121

Background: Cabozantinib, a multiple receptor tyrosine kinase inhibitor, promotes an immune-permissive environment which may enhance the activity of immune checkpoint inhibitors. COSMIC-021 (NCT03170960) is evaluating the combination of cabozantinib with atezolizumab, an anti-PD-L1 inhibitor, in patients with advanced solid tumors. Outcomes in patients (pts) with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidine-containing therapy are presented. Methods: Pts with mCRC and an ECOG PS of 0–1 who progressed during or following systemic chemotherapy including fluoropyrimidine plus oxaliplatin or irinotecan were eligible. Up to 2 prior lines of anti-cancer therapy including EGFR-targeted therapy were allowed. Microsatellite instability high (MSI-H) and/or mismatch repair (MMR)-deficient pts were excluded. Pts received cabozantinib 40 mg PO QD plus atezolizumab 1200 mg IV Q3W. The primary endpoint was objective response rate (ORR) per RECIST 1.1 by investigator. Other endpoints included safety, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). CT/MRI scans were performed Q6W for the first year and Q12W thereafter. Results: 31 pts received cabozantinib plus atezolizumab (median age, 60 y [range 31, 79]; male, 58%; ECOG PS 1, 61%; 2 prior lines of therapy, 71%; prior EGFR inhibitor, 16%; ≥3 tumor sites, 52%; tumors in left colorectum, 71%). Median follow-up was 28.1 mo (range, 24.2, 31.3) as of July 21, 2021. Cabozantinib plus atezolizumab demonstrated clinical activity in pts with mCRC (Table). Patients with wild-type RAS (n = 12) had numerically longer PFS and OS and higher ORR vs those with mutations (n = 19) (Table). Treatment-related adverse events (TRAEs) of any grade occurred in 28 (90%); the most common were diarrhea (52%), fatigue (42%), and nausea (35%). Grade 3-4 TRAEs occurred in 16 (52%); the most common were hypertension (10%), fatigue (6%), and lipase increased (6%); no Grade 5 events were reported. Conclusions: Cabozantinib plus atezolizumab demonstrated encouraging clinical activity with manageable toxicity in pts with previously treated advanced non-MSI-H/MMR-proficient CRC. Clinical trial information: NCT03170960. [Table: see text]
Effect of fruquintinib on programmed death receptor-1 blockade antitumor immune responses in colorectal cancer.
Authors: Li Qingli , Cheng Xiaojiao , Zhou Cong , Tang Yao , Li Fuli , Zhang Baiwen , Huang Tinglei , Wang Jianzheng , Tu Shuiping
Published: January 2022

150

Background:
Programmed death receptor-1 (PD-1) blockade shows little benefit in the patients with microsatellite-stable colorectal cancer (MSS-CRC).Fruquintinib, a China-made anti-angiogenic drug, applied for third line therapy in mCRC. However, the effects of combination of fruquintinib and PD-1 blockade on MSS-CRC and its relative mechanisms are not well determined.
Methods:
Syngeneic xenograft mouse models were establish using murine MC38 and CT26 colon cancer cells to assess treatment efficacy. The percentages of immune cells were detected in peripheral blood, spleen and tumor tissues in tumor-bearing mice by flow cytometry analysis. Angiogenesis in tumor tissues was detected by immunofluorescence. The safety of drug treatment was evaluated by histopathology analysis in murine main organs. The efficacy of combination of fruquintinib and sintilimab were verified in the treatment of MSS-CRC patients.
Results:
Our results showed the combination of fruquintinib and sintilimab exhibited strongest inhibition of tumor growth and achieved longest survival time in mice bearing MC38 or CT26 xenograft tumors, compared to fruquintinib and sintilimab alone. Mechanistically, the combination of fruquintinib and sintilimab reduced angiogenesis, reprogramed the vascular structure, enhanced the infiltration of CD8
+
T cells, CD8
+
TNFα
+
T cells and CD8
+
IFNγ
+
T cells and reduced the ratios of MDSCs and macrophages in mice. No obvious damage was observed in main organs in tumor-bearing mice with the combined treatment. Moreover, the treatment of combination of fruquintinib and sintilimab anti-PD-1 antibodies achieved effective response in five refractory advanced MSS CRC patients.
Conclusions:
Our results show that combination of fruquintinib and sintilimab synergistically inhibits CRC growth by alterating antitumor immune microenvironment.
Evaluation of baseline BRAF V600E mutation in circulating tumor DNA and efficacy response from the BEACON study.
Authors: Kopetz Scott , Murphy Danielle A. , Pu Jie , Yaeger Rona , Ciardiello Fortunato , Desai Jayesh , Van Cutsem Eric , Wasan Harpreet Singh , Yoshino Takayuki , Elez Elena , Golden Adele , Zhu Zhou , Zhang Xiaosong , Tabernero Josep
Published: January 2022

162

Background: In the randomized phase 3 BEACON study, encorafenib + binimetinib + cetuximab (triplet) and encorafenib + cetuximab (doublet) regimens improved overall survival (OS) and objective response rate (ORR) versus standard of care (control) in patients (pts) with previously treated BRAF V600E-mutant metastatic colorectal cancer. To identify whether detection of a BRAF V600E mutation in baseline circulating tumor DNA (ctDNA) correlated with response, we evaluated the status and allele frequency of BRAF V600E compared with clinical outcomes. Methods: Plasma samples were collected at Cycle 1 Day 1 and end of treatment for ctDNA analysis and analyzed using GuardantOMNI. Variant allele frequency (VAF) of BRAF V600E was grouped into high (> median) and low (≤median) categories. Low VAF samples included those where BRAF V600E mutation was not detected or no ctDNA was detected. ORR, based on blinded independent central review, and OS were compared between treatment arms according to VAF levels. ORR comparisons used Chi-square test and logistic regression. OS was summarized using the Kaplan-Meier method. HRs and 95% CIs were estimated using a Cox model. Additional correlation analyses between BRAF V600E status in baseline tumor tissue, as well as clonality, will be presented. Results: Baseline plasma samples were analyzed from 544 of 631 pts in the ctDNA analysis: 88.3% (196/222) in the triplet arm, 86.6% (187/216) in the doublet arm, and 83.4% (161/193) in the control arm. BRAF V600E mutations were detected in 90.4% (492/544) of pts (90.3% [177/196] triplet, 90.4% [169/187] doublet, and 90.7% [146/161] control). Pts with BRAF V600E mutations with high VAF had significantly ( P≤0.0001) increased ORR (95% CI) in the triplet and doublet arms (27.3% [19.5–36.8] and 15.9% [9.7–25.0], respectively) compared with control (0% [0.0–4.3]). Similar response trends were observed in pts with BRAF V600E mutations with low VAF (triplet: 28.9% [20.8–38.9]; doublet: 25.3% [17.7–34.6]; control: 5.3% [2.1–12.8]). OS decreased in BRAF V600E pts with high VAF (median OS [95% CI]: triplet 7.2 [6.0–8.0] months, n = 99; doublet 5.4 [4.4–6.1] months, n = 88; control 4.2 [3.4–4.8] months, n = 85) compared with pts with low VAF (triplet 14.8 [10.2–19.8] months, n = 97; doublet 14.8 [11.7–23.0] months, n = 99; control 9.3 [7.5–11.3] months, n = 76). Conclusions: ctDNA analyses showed the majority of pts in BEACON analyzed at baseline had a detectable BRAF V600E mutation. Increased response rates were observed in pts treated with triplet or doublet therapy compared with control, independent of VAF. Pts with a higher VAF for BRAF V600E may have a worse prognosis. Clinical trial information: NCT04607421.
Clinicopathological characteristics and outcomes of patients with deficient mismatch repair colorectal cancer.
Authors: Viñal David , Martinez-Perez Daniel , Martínez-Recio Sergio , Ruiz Iciar , Jiménez Bou Diego , Peña Jesus , Martin-Montalvo Gema , Rueda-Lara Antonio , Alameda Maria , Gutiérrez Sainz Laura , Custodio Ana B. , Palacios Maria Elena , Ghanem Ismael , Rodriguez Salas Nuria , Feliu Jaime
Published: January 2022

181

Background: Patients with microsatellite-instability–high (MSI-H) or deficient mismatch repair (dMMR) colorectal cancer (CRC) represent a unique subgroup of patients with evolving treatment opportunities. Methods: We included all of the patients with pathologically confirmed diagnosis of CRC at Hospital Universitario La Paz from October 2016 to September 2020. Results: A total of 1,152 patients were diagnosed with CRC. IHC for MMR was available in 1,014 patients. Of those, 100 (9,8%) patients were deficient for MLH1 and PSM2 (n = 78), MSH2 and MSH6 (n = 12), PMS2 (n =5), MSH6 (n = 4), or MSH2 (n = 1). Baseline characteristics are depicted in the table. Female sex (55% vs. 38%; p = 0,001), right primary tumor location (75% vs. 29%; p = 0,001), histological grade 3 (20% vs. 8%; p <0,001), and mucinous component (39% vs. 10%; p < 0,001), and localized disease at diagnosis (97% vs. 79% p < 0,001), were more frequent in dMMR group. Among patients with dMMR CRC, 53% were ≥75 years old. The prevalence of BRAF V600E mutation was 56%. More female sex (67% vs. 40%; p = 0,006) and BRAFV600E mutation (66% vs. 48%; p = 0,06) were found in older vs. younger dMMR patients. Six patients were diagnosed with Lynch syndrome. After a median follow-up of 24 months, 279 patients have died. Median overall survival (OS) was not reached in either group (p = 0,327). Three-year OS was 75% (95% CI: 70-80) and 69 (95% CI: 67-71) in the dMMR and pMMR, respectively. In patients with localized disease that underwent antineoplastic treatment (n = 856), median disease-free survival (DFS) and OS were not reached in either group (p =0,403 and p = 0,232). Three-year DFS in patients with stage I (n = 216) was 64% (95% CI: 46-82) and 85% (95%CI: 80-90), p = 0,055; in patients with stage II (n = 274) was 84% (95% CI: 77-91) and 70% (95% CI: 66-74), p = 0,588; and in patients with stage III (n = 366) was 79 (95% CI: 71-87) and 66% (95% CI: 62-70%), p = 0,322; in dMMR and pMMR, respectively. No baseline characteristics were associated with recurrence in patients with localized dMMR CRC. Conclusions: Patients with MSI-High/dMMR CRC display distinctive clinical and pathological features. Overall prognosis does not differ in our series, but older age of dMMR patients may have influenced the outcomes.[Table: see text]
Circulating tumor DNA dynamics on front-line chemotherapy with bevacizumab or cetuximab in metastatic colorectal cancer: A biomarker analysis for acquired genomic alterations in CALGB/SWOG 80405 (Alliance) randomized trial.
Authors: Raghav Kanwal Pratap Singh , Ou Fang-Shu , Venook Alan P. , Innocenti Federico , Sun Ryan , Lenz Heinz-Josef , Kopetz Scott
Published: January 2022

193

Background: Enhanced understanding of the evolving clonal architecture under treatment stress is crucial to optimizing care and developing effective therapies in metastatic colorectal cancer (mCRC). Emergence of genomic alterations (GAs) [mutations (muts) and amplifications (amps)] in RAS, BRAF, EGFR, ERBB2, and MET have been recognized as key resistance mechanisms to anti-EGFR therapy in later lines in mCRC. Data regarding occurrence of these GAs under selective pressure in the first line setting is lacking. Methods: CALGB/SWOG 80405 was a randomized trial of bevacizumab (bev) vs cetuximab (cet) in first line mCRC. Patients (pts) with paired plasma samples (pre-treatment and post-progression) available for circulating tumor DNA (ctDNA) testing were included in this substudy. Sequencing of ctDNA was performed by Guardant360 assay in a CLIA-certified environment to detect GAs in 73 genes. RAS/BRAF status [mut vs. wild type (wt)] was based on clonal muts [pre-defined cutoff of relative MAF (rMAF) ≥ 25%] in ctDNA. Only samples with ≥1 GA were analyzed to minimize false negatives. The primary objective was to determine and compare prevalence of acquired GAs between study arms: bev (anti-VEGF) and cet (anti-EGFR). Descriptive statistics and Fisher’s exact test were used. Results: Baseline characteristics of ctDNA cohort were similar to the 80405 population. Among 133 randomized RAS/BRAF wt pts, 11 (15.3%) and 5 (8.2%) developed acquired GAs (OR 2.0, P = 0.29), in bev and cet arm, respectively. Key comparative data for pts with regard to acquired pathogenic GAs are shown in the table. Conclusions: In this randomized mCRC cohort, the ctDNA profile of acquired GAs with front line anti-EGFR chemotherapy appears to be strikingly distinct from that seen with later lines of therapy. Acquisition of GAs, classically associated with EGFR resistance in later line, was not only rare with upfront cet-chemotherapy but also comparable to bev-containing (anti-VEGF) regimen. The mechanisms of acquired resistance appear to differ when anti-EGFR therapy is administered in combination with highly active first line chemotherapy. Our findings have critical translational relevance to the timing and value of ctDNA-guided anti-EGFR rechallenge in mCRC pts, especially in those treated with anti-EGFR therapy upfront.[Table: see text]
Safety and efficacy of encorafenib, binimetinib, plus cetuximab for BRAF V600E-mutant metastatic colorectal cancer: Results of a prospective study as an expanded access program.
Authors: Takashima Atsuo , Kotani Daisuke , Kato Takeshi , Satoh Taroh , Masuishi Toshiki , Komatsu Yoshito , Shiozawa Manabu , Esaki Taito , Izawa Naoki , Takeuchi Shinji , Bando Hideaki , Iwasa Satoru , Hasegawa Hiroko , Yamaguchi Toshifumi , Taniguchi Hiroya , Yoshino Takayuki
Published: January 2022

199

Background: The encorafenib, binimetinib, and cetuximab (triplet) regimen showed survival benefit and a higher response rate over standard chemotherapy among pretreated patients (pts) with BRAF V600E-mutant metastatic colorectal cancer (mCRC) in the phase III BEACON trial. Herein, we report the safety and efficacy of the triplet regimen in a prospective study (JapicCTI-205146) as a Japanese expanded access program (EAP). Methods: The key eligibility criteria were age ≥18 years and a diagnosis of BRAF V600E-mutant mCRC with progression observed after one or two prior systemic chemotherapy. Encorafenib (300 mg QD), binimetinib (45 mg BID), and weekly cetuximab (400 mg/m2, followed by 250 mg/m2) were administered. Patients who had received at least one dose of any study drug were included in this analysis. Adverse events were evaluated using CTCAE v4.0. The objective response rate (ORR) was evaluated using RECIST Guideline Version 1.1. Results: A total of 86 pts were enrolled from 10 Japanese institutions from February to December 2020. Safety and efficacy were evaluated in 81 pts. The median age was 60 years. Fifty-four pts (67%) had ECOG PS 0 and 50 pts (62%) received one prior chemotherapy. Treatment-related serious adverse events and grade 3 or higher treatment-related adverse events were observed in 14 (17%) and 24 (30%) pts, respectively. Treatment-related death occurred in one pts. Among the 76 pts with target lesions, 21 pts were responders, and the confirmed ORR was 27.6%. Stable disease was observed in 42 pts, resulting in a disease control rate of 82.9%. The ORR was consistent regardless of ECOG PS status, the number of prior chemotherapy lines, and the number of metastatic organs. Conclusions: The safety and efficacy of the triplet regimen in the Japanese EAP were comparable to those in the BEACON trial. These results support the triplet regimen as a new standard-of-care treatment option in the second- or third-line treatment of pts with BRAF V600E-mutant mCRC in the Japanese population, as there was a promising response without any new safety signals. Clinical trial information: JapicCTI-205146.