bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of the COVID-19 pandemic on access to the cerliponase alfa managed access agreement in England for CLN2 treatment
Authors: Mortensen Amanda , Raebel Eva M. , Wiseman Samantha
Published: January 2022

Background

Cerliponase alfa, an enzyme replacement therapy for neuronal ceroid lipofuscinosis type 2 (CLN2), is currently available in England through a managed access agreement (MAA). It is administered every 2 weeks via an intracerebroventricular device. Here we report qualitative research with families of children with CLN2 disease and healthcare professionals (HCPs) who run the MAA, to understand how access to cerliponase alfa via the MAA at Great Ormond Street Hospital (GOSH) in London, and the overall management of CLN2 disease, was affected during the coronavirus disease 2019 (COVID-19) pandemic.

Methods

Telephone interviews were conducted with nine families, representing 11 children with CLN2 disease, and two HCPs in November and December 2020.

Results

Children had received cerliponase alfa treatment for a mean (SD) of 23.1 ± 24.7 months (7.1 ± 4.6 months in the MAA). Families travelled 7–398 km for treatment (mean 210 ± 111 km). Treatment with cerliponase alfa was designated “essential” by GOSH and continued as normal during the pandemic but with extra safety precautions, and no children missed any treatments. Families were highly motivated to continue treatment, despite considerable anxiety about the risk of coronavirus infection from travelling and staying overnight but were reassured by communications from GOSH and the safety precautions put in place. Support therapy services were widely compromised, causing families concern about deterioration in their children’s condition. Families were confused about COVID-19 testing and shielding, and were unclear whether children with CLN2 disease were vulnerable to COVID-19.

Conclusions

Looking forward, advice for children with CLN2 disease should be specific and tailored, taking into account the family unit. Support therapies should be considered essential alongside cerliponase alfa treatment.
Momelotinib: an emerging treatment for myelofibrosis patients with anemia
Authors: Chifotides Helen T. , Bose Prithviraj , Verstovsek Srdan
Published: January 2022

The suite of marked anemia benefits that momelotinib has consistently conferred on myelofibrosis (MF) patients stem from its unique inhibitory activity on the BMP6/ACVR1/SMAD and IL-6/JAK/STAT3 pathways, resulting in decreased hepcidin (master iron regulator) expression, higher serum iron and hemoglobin levels, and restored erythropoiesis. Clinical data on momelotinib from the phase 2 and the two phase 3 SIMPLIFY trials consistently demonstrated high rates of sustained transfusion-independence. In a recent phase 2 translational study, 41% of the patients achieved transfusion independence for ≥ 12 weeks. In the phase 3 trials SIMPLIFY-1 and SIMPLIFY-2, 17% more JAK inhibitor-naïve patients and two-fold more JAK inhibitor-treated patients achieved or maintained transfusion independence with momelotinib versus ruxolitinib and best available therapy (89% ruxolitinib), respectively. Anemia is present in approximately a third of MF patients at diagnosis, eventually developing in nearly all patients. The need for red blood cell transfusions is an independent adverse risk factor for both overall survival and leukemic transformation. Presently, FDA-approved medications to address anemia are lacking. Momelotinib is one of the prime candidates to durably address the critical unmet needs of MF patients with moderate/severe anemia. Importantly, momelotinib may have overall survival benefits in frontline and second-line MF patients. MOMENTUM is an international registration-track phase 3 trial further assessing momelotinib’s unique constellation of anemia and other benefits in second-line MF patients; the results of the MOMENTUM trial are keenly awaited and may lead to regulatory approval of momelotinib.

Graphical abstract
Lipid reprogramming induced by the TFEB-ERRα axis enhanced membrane fluidity to promote EC progression
Authors: Mao Xiaodan , Lei Huifang , Yi Tianjin , Su Pingping , Tang Shuting , Tong Yao , Dong Binhua , Ruan Guanyu , Mustea Alexander , Sehouli Jalid , Sun Pengming
Published: January 2022

Background

Estrogen-related receptor α (ERRα) has been reported to play a critical role in endometrial cancer (EC) progression. However, the underlying mechanism of ERRα-mediated lipid reprogramming in EC remains elusive. The transcription factor EB (TFEB)-ERRα axis induces lipid reprogramming to promote progression of EC was explored in this study.

Methods

TFEB and ERRα were analyzed and validated by RNA-sequencing data from the Cancer Genome Atlas (TCGA). The TFEB-ERRα axis was assessed by dual-luciferase reporter and chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR). The mechanism was investigated using loss-of-function and gain-of-function assays in vitro. Lipidomics and proteomics were performed to identify the TFEB-ERRα-related lipid metabolism pathway. Pseudopods were observed by scanning electron microscope. Furthermore, immunohistochemistry and lipidomics were performed in clinical tissue samples to validate the ERRα-related lipids.

Results

TFEB and ERRα were highly expressed in EC patients and correlated to EC progression. ERRα is the direct target of TFEB to mediate EC lipid metabolism. TFEB-ERRα axis mainly affected glycerophospholipids (GPs) and significantly elevated the ratio of phosphatidylcholine (PC)/sphingomyelin (SM), which indicated the enhanced membrane fluidity. TFEB-ERRα axis induced the mitochondria specific phosphatidylglycerol (PG) (18:1/22:6) + H increasing. The lipid reprogramming was mainly related to mitochondrial function though combining lipidomics and proteomics. The maximum oxygen consumption rate (OCR), ATP and lipid-related genes acc, fasn, and acadm were found to be positively correlated with TFEB/ERRα. TFEB-ERRα axis enhanced generation of pseudopodia to increase the invasiveness. Mechanistically, our functional assays indicated that TFEB promoted EC cell migration in an ERRα-dependent manner via EMT signaling. Consistent with the in vitro, higher PC (18:1/18:2) + HCOO was found in EC patients, and those with higher TFEB/ERRα had deeper myometrial invasion and lower serum HDL levels. Importantly, PC (18:1/18:2) + HCOO was an independent risk factor positively related to ERRα for lymph node metastasis.

Conclusion

Lipid reprogramming induced by the TFEB-ERRα axis increases unsaturated fatty acid (UFA)-containing PCs, PG, PC/SM and pseudopodia, which enhance membrane fluidity via EMT signaling to promote EC progression. PG (18:1/22:6) + H induced by TFEB-ERRα axis was involved in tumorigenesis and PC (18:1/18:2) + HCOO was the ERRα-dependent lipid to mediate EC metastasis.
Prevalence and characterization of forgoing care: comparison of two prospective multicentre cohorts between pre-COVID-19 era and a lockdown period
Authors: Douillet Delphine , Dupont Clémence , Leloup Noémie , Ménager Grégory , Delori Maud , Soulie Caroline , Morin François , Moumneh Thomas , Savary Dominique , Roy Pierre-Marie , Armand Aurore
Published: January 2022

Background

Little is known about patients who forego healthcare, although it is an important provider of unfavorable health-related outcomes. Forgoing healthcare characterizes situations in which people do not initiate or interrupt a care process, even though they perceive the need for it, whether or not this need is medically proven. The aims of this study were to assess the prevalence and the determinants of patients who forego healthcare. The second aim was to compare the characteristics of patients who gave up healthcare during the French lockdown due to COVID-19.

Methods

We conducted two multicenter cross-sectional studies in 2017 and 2020 carried out in French patients presenting to the emergency departments. Patients who gave their consent to participate were interviewed with a standardized questionnaire. It consisted of two parts: epidemiological characteristics and health care refusal. A third part concerning the renunciation of care during the COVID-19 period was added to the second study period.

Results

A total of 1878 patients had completed the questionnaire during the interview with the physicians, 900 during the first period in 2017 (47.9%) and 978 (52.1%) during the second period. A total of 401/1878 patients reported not seeking care in the last 12 months (21.4% [95%CI: 19.5–23.3%]). In 2020, patients forewent care more during the confinement period than outside with different characteristics of the foregoing care populations.

Conclusion

Forgoing care is common in a universal health care system such as France’s and increased during the pandemic. Key public health messages targeted at the reasons for not seeking care must now be disseminated in order to combat this.
Glioblastoma vaccine tumor therapy research progress
Authors: Zhao Tong , Li Chunwang , Ge Hongliang , Lin Yuanxiang , Kang Dezhi
Published: January 2022

Glioblastoma (GBM) is the most common primary malignancy of the central nervous system in adults. The prognosis for late-stage glioblastoma (World Health Organization grade IV astrocytic glioma) is very poor. Novel treatment options are sought after and evaluated by clinicians and researchers, and remarkable advances have been made in surgical techniques, radiotherapy, and chemotherapy. However, the treatment of glioblastoma remains extremely difficult and it can extend the lives of patients by only a few months. There has been notable progress in the field of immunotherapy, particularly with the use of tumor vaccines, for treating glioblastoma; especially peptide vaccines and cell-based vaccines such as dendritic cell vaccines and tumor cell vaccines. However, the results of the current clinical trials for vaccination are not satisfactory. This article reviews the progress in the development of vaccines for glioblastoma.
Study on the characteristics of organic-rich shale in the north area of Dongying depression
Authors: Zhang Shun , Wei Xiaoliang , Wang Min , Qin Feng , Li Zheng , Bao Youshu , Liu Peng , Fu Aibing , Zhu Deyan , Yin Yan
Published: January 2022

In recent years, shale oil shows have been found in Shahejie Formation in the northern part of Dongying depression. To investigate the characteristics of shale oil in the northern part of Dongying depression, we have carried out a comparative study on the reservoir, oil bearing, and compressibility of shale in the northern steep-slope zone of Dongying depression and shale in the center of depression based on the mineral composition, reservoir physical properties, and pyrolysis experiments of drilling cores. The results find that the steep-slope zone shale and the depression central shale have good shale oil development potential. Three kinds of lithofacies developed in the steep slope and four kinds of lithofacies developed in the sag center. Interbedded sandstone with different thickness widely developed in the steep slope of Dongying depression. The development of micro-meso pores in the shale matrix and cement of interparticle pores of sandstone made shale in the sag center higher porosity than that of shale in the steep slope. However, macropores of interbedded sandstone significantly improved the permeability of shale series in the steep slope. Shale oil in the steep slope has higher gas/oil ratio, better mobility, and higher free-hydrocarbon content than the shale oil in the sag center. We predicted that the shale in the steep-slope zone has better shale oil production than the shale in sag center combined the fracturing capacity analysis.
Comparing the mental health trajectories of four different types of keyworkers with non-keyworkers: 12-month follow-up observational study of 21 874 adults in England during the COVID-19 pandemic
Authors: Bu Feifei , Mak Hei Wan , Fancourt Daisy , Paul Elise
Published: January 2022

Background

There are concerns that keyworkers may be at a greater risk for psychological distress than non-keyworkers during the COVID-19 pandemic. However, little research has included keyworkers outside of the healthcare sector or has disaggregated keyworkers into different subgroups.

Aims

To examine longitudinal changes in mental health over 12 months during the COVID-19 pandemic comparing four different groups of keyworkers with non-keyworkers.

Method

Longitudinal data were from 21 874 adults living in England (21 March 2020 to 22 February 2021). Latent growth modelling was utilised to compare growth trajectories of depressive and anxiety symptoms in non-keyworkers and four types of keyworkers: (a) health and social care workers, (b) teachers and child care workers, (c) public service workers, and (d) essential services keyworkers (such as food chain or utility workers).

Results

When accounting for both time-invariant and time-varying covariates, keyworkers in the essential services category had consistently higher levels of depressive and anxiety symptoms than non-keyworkers across the whole of the study period. There was little difference in the mental health trajectories between health/social care, teachers/child care and public service worker categories and non-keyworkers.

Conclusions

Our findings suggest that the risk for poorer mental health during the COVID-19 pandemic varies within the broad category of keyworkers generally, and that those working in utility, food chain and transport roles are especially at risk. Future research should focus on identifying which aspects of working conditions may be contributing to occupational stress in these groups.
Robotic versus laparoscopic surgery for middle and low rectal cancer (REAL): Short-term outcomes of a multicenter randomized controlled trial.
Authors: Xu Jianmin , Yuan Weitang , Li Taiyuan , Tang Bo , Jia Baoqing , Zhou Yanbing , Zhang Wei , Zhao Ren , Zhang Cheng , Cheng Longwei , Zhang Xiaoqiao , Liang Fei , He Guodong , Wei Ye , Feng Qingyang
Published: January 2022

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Background: Robotic surgery for rectal cancer is gaining popularity, but persuasive evidence on long-term oncological outcomes is lacking. This multicenter randomized controlled trial compared robotic and conventional laparoscopic surgery regarding surgical quality and long-term oncological outcomes among patients with middle and low rectal cancer. Methods: This superiority trial was undertaken at 11 hospitals in 8 Chinese provinces. Patients with middle (> 7–12 cm from anal verge) or low (0–7 cm from anal verge) rectal adenocarcinoma, cT1–T3 N0–1 or ycT1–T3 Nx after preoperative radio-/chemoradiotherapy, and no evidence of distant metastasis were enrolled and randomly assigned in a 1:1 ratio to receive robotic or conventional laparoscopic surgery. Secondary (short-term) end points (surgical quality, pathological radicality, and postoperative recovery) were compared using modified intention-to-treat (mITT) analysis. Three-year locoregional recurrence rate as the primary endpoint is expected by the end of 2023. This trial was registered with ClinicalTrials.gov (NCT02817126). Results: Between July 2016 and December 2020, 1240 patients were enrolled; 1180 were included in the mITT analysis (591 in robotic and 589 in laparoscopic group). There were significantly more sphincter-preserving surgeries (low anterior resections) performed in the robotic group (83.1% vs. 76.9%, p = 0.008). With more macroscopic complete resections (95.4% vs. 91.9%, p = 0.012), robotic surgery had better integrity of the mesorectal fascia, and had lower circumferential resection margin positivity rate (4.0% vs. 7.1%, difference = -3.1%, 95% confidence interval = -6.0% to -0.5%, p = 0.023) and more lymph nodes harvested (median, 15.0 vs. 14.0, p = 0.004). Robotic surgery also reduced the open conversion rate (1.7% vs. 3.9%, p = 0.021), estimated blood loss (median, 40.0 ml vs. 50.0 ml, p < 0.001), intraoperative complication rate (5.4% vs. 8.7%, p = 0.029), and 30-day postoperative complication rate (Clavien-Dindo grade II or higher, 16.1% vs. 22.9%, p = 0.003), leading to better postoperative recovery and shorter postoperative hospital stay (median, 7.0 days vs. 8.0 days, p < 0.001). The 30-day postoperative mortality was similar between the two groups (0.2% vs. 0.2%, p > 0.999). Conclusions: Robotic surgery for middle and low rectal cancer significantly reduced surgical injury, improved oncological radicality, and promoted postoperative recovery compared with conventional laparoscopic surgery. Clinical trial information: NCT02817126.
Association between tumor mutation profile and clinical outcomes among Hispanic-Latino patients with metastatic colorectal cancer.
Authors: Ghafouri Sayed Reshad , Philipovskiy Alexander , Dwivedi Alok Kumar , McCallum Richard , Konstantinidis Ioannis , Maegava Felipe , Gaur Sumit , Corral Javier Chavez
Published: January 2022

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Background: According to the World Health Organization GLOBOCAN database, in 2019, approximately 1.8 million new colorectal cancer cases were diagnosed, and almost 861,000 deaths were reported. In the United States, CRC is the third most frequent type of cancer and the second leading cause of cancer-related death. Although the overall incidence of CRC among the Hispanic population has been declining over the last decades, recently, a dramatic increase in CRC incidents among Hispanics younger than 50 years of age (early-onset CRC) has been reported. The increase in the incidence of early-onset CRC is markedly more significant in Hispanic-Latino (HL) patients population (45%) than in non-Hispanic Whites (NHW) (27%) and African-Americans (AA) (15%). Additionally, in contrast to NHW, Hispanics have a worse survival rate. The exact reason for these racial disparities and the biology of CRC in the HL population are not well understood. Therefore, we performed this study to better understand the biology of the disease in HL patients, which might help to identify new directions for targeted therapy. Methods: For the study, 52 formalin-fixed paraffin-embedded (FFPE) tumor tissue samples were collected and analyzed. We compared the results with individual patient clinical histories and outcomes. Of 52 patients with mCRC, 52 (100%) were identified as HL. We identified several commonly altered genes in HL patients ( APC, TP53, KRAS, GNAS, PICK3CA, and NOTCH). Compared to those in other studies. Results: Mutation frequencies in the APC gene were significantly higher among HL patients with mCRC. Moreover, the prevalence of the APC mutation was significantly higher among male HL patients compared to female patients. The combination of mutations in the APC, NOTCH, and KRAS genes in the same tumors was associated with a higher risk of progression after the first-line of chemotherapy and worse overall survival. In addition, mutations in the combination of GNAS and AURKA genes were associated with a significantly higher risk of progression after the first-line of chemotherapy. Conclusions: The data support the notion that the molecular drivers of colon cancer might be different in HL patients compared to other racial/ethnic groups.
Chemotherapy delivery in early-onset colorectal cancer is impacted by urban versus rural settings in Colorado.
Authors: Sheneman David , Hu Junxiao , Das Santi , Lieu Christopher Hanyoung
Published: January 2022

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Background: While colorectal cancer (CRC) incidence has been decreasing overall, incidence in adults under age 50 has been rising both nationally and across Colorado. National guidelines have adapted to recognize this trend, but knowledge gaps regarding early-onset CRC remain. This group has previously established rising early-onset CRC incidence in Colorado, as well as later stage at diagnosis and worse prognosis. This study examines demographics, treatment, survival, and concomitant disease among patients < 50 and diagnosed with CRC across a multicenter healthcare system in Colorado in order to better understand early-onset CRC. Methods: We analyzed 1,192 CRC cases in patients < 50 from the Colorado Health Data Compass database and cross-referenced these cases with the Colorado Central Cancer Registry to examine for association of gender, race/ethnicity, BMI, zip code, insurance type, stage, and concomitant medical conditions with overall survival and oncologic treatment modality. Logistic regressions were used to evaluate the relationships between chemotherapy and the important variables while adjusting for covariates, with 95% confidence intervals reported. Cox proportional hazard regressions were used to evaluate the relationships between overall survival and the important variables while adjusting for covariates, with 95% confidence intervals reported. Results: Overall, early-onset CRC in our population was 2.8% stage I, 6.3% stage II, 12.7% stage III, 18.5% stage IV, and 59.8% were unstageable or no stage recorded. Surgical treatment was associated with a 52% improvement in overall survival. Chemotherapy treatment was not associated with any survival changes in stage II disease. Radiation treatment, insurance type, number of concomitant conditions, geographic location, and race/ethnicity were not associated with overall survival. Upon exploring chemotherapy relationships, patients from urban areas were significantly more likely to receive chemotherapy than patients from rural areas, while adjusting for ethnicity, inpatient encounters, and stage (OR 5.55, p = 0.001). Conclusions: While less is known about CRC in patients < 50, trends are emerging that are not as well described in a traditional CRC population. The difference between urban and rural patients and their rates of chemotherapy points to a potential disparity in access to care, particularly when considering advanced stage CRC. This persisted through insurance type, indicating that distance from an infusion center, rather than ability to pay, is more likely to be driving this relationship. Further research is needed to determine if these findings are generalizable to the larger early-onset CRC population, and how access may be affecting care for this population.
Colorectal cancer biomarker, AABH (Aspartyl [Asparaginyl] β- hydroxylase), a companion imaging and treatment strategy.
Authors: Moshiri Mahmood , Moshiri Kiarash , Nazari Reza , Pishrochi Mohammad , Moshiri Arsha , Monhemi Hassan
Published: January 2022

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Background: Colorectal cancer (CRC) is the third most common type of cancer diagnosed in the US and Canada. WHO, Canadian Cancer Society (CCS), the National Comprehensive Cancer Network (NCCN) and American Cancer Society (ACS) recommend that men and women begin CRC screening at age 50 or younger if at high risk. Recommended screening procedures: Annual occult fecal blood test (OFBT), a colonoscopy every 5 years, OFBT and colonoscopy every 5 years, or a colonoscopy every 10 years. According to The Surveillance, Epidemiology, and End Results (SEER) Program, only 39% of CRC are diagnosed in stage I, 36% are diagnosed in stage II, 19% are diagnosed with metastasis. The corresponding 5-year survival rates are 89.8%, 67.7%, and 10.3%. Neither the CCS nor the ACS recommends a blood test to be done as part of screening. This is due to the fact that, until now, there has not been a blood test with adequate sensitivity or specificity for screening. Methods: In this study we discovered that aspartyl (asparaginyl) β-Hydroxylase (AABH) measurement in serum can be used as a screening test for CRC. AABH has been detected by immunohistochemical staining (IHC) on the cell surface of different cancers including CRC. It has been detected by IHC in > 97% of tumor specimens tested (n > 210) but has not been found in tissue samples from normal individuals. Results: This observation and the observation that AABH is found in the serum of patients with cancer, but not in non cancer patients, led us to develop a Sandwich ELISA Assay to measure AABH in serum. In the current study we have quantified AABH levels in CRC patients and compared it with normal individual. Increased levels of AABH were found in the serum of 99% of patients with CRC in all different stages of Cancer (n = 277). In normal individuals, AABH was essentially undetectable in serum (n = 195). AABH was identified in serum from patients with CRC irrespective of cancer stage. All serum AABH levels for stages I, II, III and IV were more than 3.0 ng/mL. Conclusions: Thus, our data indicate that by measuring AABH in the serum, we should be able to detect CC at an earlier stage than it is currently detected, resulting to a much better 5-year survival for colon cancer.
Combining the quantitative fecal immunochemical test and full blood count to rule out colorectal cancer in a symptomatic patient referral pathway.
Authors: Johnstone Mark , Burton Paul , Kourounis Georgios , Winter Jack , Crighton Emilia M. , Mansouri David , Witherspoon Paul , Smith Karen , McSorley Stephen Thomas
Published: January 2022

28

Background: The faecal immunochemical test (FIT) has proven utility for colorectal cancer (CRC) detection in symptomatic patients. Most studies have examined FIT in symptomatic patients subsequently referred from primary care. We investigated associations between CRC and FIT in both referred and non-referred symptomatic patients. Methods: A retrospective, observational study of all patients with a FIT submitted Aug’18-Jan’19 in NHS GG&C was performed. Referral to colorectal/gastroenterology and decision to perform colonoscopy were recorded. FIT results were grouped as f-Hb<10/10-149/150-399/≥400ug/g. The MCN cancer registry identified new cases of CRC. Covariables were compared using the χ2 test. Multivariate binary logistic regression identified independent predictors of CRC. Results: 4968 patients were included. Raised FIT correlated with decision to refer (p<0.001) and scope (p<0.001). With 23-month median follow-up, 61 patients were diagnosed with CRC. These patients were older (median 69 vs. 59 years, cancer and no cancer respectively, p=0.001), more likely to be male (55.7% vs. 42.1%, p=0.033) and to report rectal bleeding (51.7% vs. 36.1%, p=0.013). FIT (<10 µg/g 8.2% vs. 76.7% and ≥400 µg/g 55.7% vs. 3.8%, p<0.001) and anaemia (45.9% vs. 19.7%, p<0.001) were associated with CRC. On multivariate analysis, age (p=0.023), male sex (p=0.04), FIT (≥400 OR 54.256 (95% CI: 20.683-142.325; p<0.001)) and anaemia (OR 1.956 (1.071-3.574;p=0.029)) independently predicted CRC. 1 patient (0.04%) with a negative FIT and normal haemoglobin had CRC. Conclusions: Referral from primary care and secondary care investigation patterns were influenced by FIT. The combination of normal Hb and f-Hb excluded CRC in 99.96% of cases, providing excellent reassurance to those prioritising access to endoscopy services.
COVID-19 impact on diagnosis and staging of colorectal cancer: A single tertiary Canadian oncology center experience.
Authors: Castonguay Mathias , Richard Corentin , Vachon Marie-France , Nassabein Rami Mohamad , Charpentier Danielle , Tehfe Mustapha
Published: January 2022

33

Background: COVID-19 pandemic urged public health to imposed drastic reduction on endoscopic activities and surgery, leading to delays that still not have been caught up today. The Ministry of Health and Social Services (MSSS) of Quebec conducted a study of the impact of those measures and reported a 66% reduction of colonoscopy and a 30% reduction of colorectal cancer (CRC) surgery activities during the first wave (March to May 2020). Whether those reduction had an impact on diagnosis and staging of CRC remains unknown. Methods: Demographic information of CRC diagnosed at Centre Hospitalier de l’Université de Montréal (CHUM) between January 1 2018 and March 12 2020 (pre-pandemic period), and March 13 2020 and June 30 2021 (pandemic period) were obtained from the SARDO registry and data regarding colonoscopy, surgery and staging at diagnosis (clinical or pathological as appropriate) were collected. Priority of elective colonoscopy was defined using the MSSS grading system ranging from P1 to P5. We compared delays to colonoscopy, delays to surgery and CRC staging of the pandemic period to the pre-pandemic period using one-way ANOVA, t tests and Chi-square tests as appropriate. Only delays in elective surgeries intended as first and curative treatment were analyzed. Results: 280 CRC diagnosis were made at the pre-pandemic period compared to 127 CRC diagnosis during the pandemic period. Mean diagnosis rates of the pandemic period tend to be lower (8.3 vs. 10.5 diagnosis/month, p=0.03) compared to the pre-pandemic period. 37.6% of patient in the pandemic period had a diagnosis of CRC during a hospitalization compared to 25.9% at the pre-pandemic period (p=0.048). 51.7% of elective colonoscopy leading to a diagnostic of CRC during the pandemic period did not meet required delays according to priority compared to 38.3% (p=0.049) during the pre-pandemic period. P3 colonoscopies (mostly indicated for a positive FIT and iron deficiency anemia) were the most affected (58.9 vs. 106.5 days, p˂0.001). P2 colonoscopy (indicated for suspected colorectal cancer) did not experienced an augmentation in delays (20.9 vs. 25.2 days, p=0.39). A mean of 3.5 elective curative surgeries per month were performed during the pandemic period compared to 3.4 at the pre-pandemic period (p=0.96), and mean delays for surgery were not affected (60.4 vs. 57 days, p=0.59). Stages at diagnosis did not differ (p=0.2). Most of the delayed colonoscopies led to a stage 0 or I CRC and did not lead to a higher stage at diagnosis (p=0.2). Conclusions: In our center, the COVID-19 pandemic led to overall less CRC diagnosis and increased diagnostic endoscopic delays without a higher rate of advanced stage disease. Delays for elective surgeries were quite similar once the CRC diagnostic established.
The potential long-term comparative effectiveness of larotrectinib versus entrectinib for treatment of metastatic TRK fusion colorectal cancer.
Authors: Suh Kangho , Carlson Josh John , Xia Fang , Williamson Todd E. , Sullivan Sean D
Published: January 2022

40

Background: Commonly used systemic therapies in metastatic colorectal cancer (CRC) for patients who have progressed through available first- and second-line regimens are regorafenib or trifluridine/tipiracil. For the subset of metastatic CRC patients with neurotrophic receptor tyrosine kinase ( NTRK) gene fusions, there are two additional approved options, larotrectinib or entrectinib. Our objective was to estimate and compare expected life-years (LYs) and quality-adjusted life-years (QALYs) for metastatic TRK fusion CRC patients receiving larotrectinib versus entrectinib. Methods: We developed a partitioned survival model to project long-term comparative effectiveness of larotrectinib vs. entrectinib. Extrapolation was necessary as follow-up for both drugs was less than three years at the time of data reporting. Survival data for larotrectininb, assessed by independent review committee, were derived from a July 2020 analysis of 8 adult (≥18 years of age) TRK fusion CRC patients from the larotrectinib clinical trials program (NCT02122913, NCT02637687, and NCT02576431). Survival inputs for entrectinib were derived from 7 TRK fusion CRC patients from an October 2018 integrated analysis of three single arm trials (EudraCT 2012-000148-88, NCT02097810, and NCT02568267). Progression-free survival (PFS) and overall survival (OS) for both treatments were estimated using parametric survival distributions (Exponential, Weibull, Log-logistic, and Log-normal) fit to the available data. Exponential curves were used based on goodness-of-fit and clinical plausibility. QALYs were estimated by adjusting the time spent in the pre-progression and post-progression health states by health state utilities derived from publicly available literature. A constant discount rate of 3% was applied to LYs and QALYs. Model uncertainty was evaluated using one-way sensitivity analysis and probabilistic sensitivity analysis with 10,000 simulations. Results: Larotrectinib resulted in 2.11 LYs and 1.60 QALYs compared to 0.53 LYs and 0.41 QALYs for entrectinib. These estimates yielded additional gains for larotrectinib of 1.58 LYs and 1.19 QALYs against entrectinib. Conclusions: In metastatic TRK fusion CRC, larotrectinib may produce substantial life expectancy and quality-adjusted life-year gains compared to entrectinib. Additional data with longer follow-up times will further inform this comparison.
The potential long-term comparative effectiveness of larotrectinib versus regorafenib or trifluridine/tipiracil for treatment of metastatic TRK fusion colorectal cancer.
Authors: Suh Kangho , Carlson Josh John , Xia Fang , Williamson Todd E. , Sullivan Sean D.
Published: January 2022

41

Background: Colorectal cancer (CRC) is the third leading cause of cancer-related mortality in the US, driven primarily by those with metastatic disease. For patients with metastatic disease who have progressed through available first- and second-line options, the standard of care systemic therapies are regorafenib or trifluridine/tipiracil. Larotrectinib is approved for patients with TRK fusion advanced solid tumors including metastatic CRC. Our objective was to compare expected life-years (LYs) and quality-adjusted life-years (QALYs) for metastatic CRC patients eligible to receive larotrectinib, regorafenib or trifluridine/tipiracil. Methods: We developed a partitioned survival model to project long-term comparative effectiveness of larotrectinib vs. regorafenib or trifluridine/tipiracil. Larotrectinib survival data, assessed by independent review committee, were derived from a July 2020 analysis of 8 adult (≥18 years of age) metastatic TRK fusion CRC patients from the larotrectinib clinical trials program (NCT02122913, NCT02637687, and NCT02576431). Survival inputs for regorafenib and trifluridine/tipiracil were derived from the CORRECT trial (NCT01103323) and the RECOURSE trial (NCT01607957), respectively. Progression-free (PFS) and overall survival (OS) for larotrectinib, regorafenib, and trifluridine/tipiracil were estimated using survival distributions (Exponential, Weibull, Log-logistic, and Log-normal) fit to the available data. Exponential fits were used based on goodness-of-fit and clinical plausibility. QALYs were estimated by adjusting the time spent in the pre-progression and post-progression health states by health state utilities derived from publicly available literature. In accordance with standard practice in health economics and outcomes research on future health benefits, a constant discount rate of 3% was applied to the LYs and QALYs. Model uncertainty was evaluated using one-way sensitivity analysis and probabilistic sensitivity analysis with 10,000 simulations. Results: Larotrectinib resulted in 2.11 LYs and 1.60 QALYs compared to 0.83 LYs and 0.59 QALYs for regorafenib and 0.85 LYs and 0.60 QALYs for trifluridine/tipiracil. These estimates yielded additional gains for larotrectinib of 1.28 LYs (1.01 QALYs) and 1.26 LYs (0.99 QALYs) against regorafenib and trifluridine/tipiracil, respectively. Conclusions: In metastatic CRC, larotrectinib may produce substantial life expectancy and quality-adjusted life-year gains compared to regorafenib or trifluridine/tipiracil. Additional data with longer follow-up times will further inform this comparison.
Impact of previous adjuvant oxaliplatin combination therapy on survival in elderly colorectal cancer patients with recurrence.
Authors: Nagata Yusuke , Amano Katsushi , Mikuni Hayato , Kano Tomohiro , Ishikawa Masashi , Ishimoto Utako , Nishimura Takashi , Noguchi Masaaki , Sawada Ryoichi , Imakita Tomonori , Ohkuma Masahisa , Aoki Hiroaki , Nagasaki Eijiro , Kosuge Makoto , Hokari Atsushi , Ogawa Masaichi , Eto Ken , Saruta Masayuki
Published: January 2022

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Background: The benefit of adjuvant chemotherapy with oxaliplatin for elderly patients with colorectal cancer (CRC) remains controversial. Our study could not demonstrate the benefit of adding oxaliplatin for elderly CRC patients aged over 70 years as with the previous clinical trials. Here, we evaluated the prognosis after recurrence in the elderly patients who received adjuvant chemotherapy. Methods: This retrospective study included patients aged over 70 years who were diagnosed with high-risk stage II and stage III CRC and received adjuvant chemotherapy in our two hospitals (The Jikei University Hospital and Katsushika Medical Center) between January 2010 and December 2019. The patients were divided into two groups; patients who received fluoropyrimidine monotherapy were included in Fp group and those who received fluoropyrimidine plus oxaliplatin were included in Fp+OX group. Moreover, we evaluated patient characteristics, treatment, and survival in the patients with recurrence and compared them between two groups. Results: A total of 127 patients received adjuvant chemotherapy; 75 patients in Fp group and 52 patients in Fp+OX group. With a median follow-up time of 64.5 months, the 5-years disease-free survival and 5-years overall survival in Fp group/Fp+OX group were 70.6/67.1% (hazard ratio [HR] 1.10, 95% confidence interval [CI] 0.61–1.98) and 89.0/71.8% (HR 1.48, 95% CI 0.76–2.88), respectively. The benefit of adding oxaliplatin was not observed. Among them, 15 patients in Fp group and 14 patients in Fp+OX group were relapsed; median age was 78 (range: 72-83) and 78 (range: 72-86) years, male was 67% and 64%, PS of 0/1 was 67/33% and 86/14%, primary tumor site of right/left was 47/53% and 57/43%, and RAS mutation was 20% and 29%, respectively. Median relapse-free survival was 17.7 and 14.3 months (p = 0.453). There were no significant differences in treatment after recurrence; aggressive treatment (surgery/chemotherapy) was 73% (33/40%) and 86% (21/65%), best supportive care was 7% each, and unknown was 20% and 7%, respectively. However, the median overall survival from the date of relapse was significantly worse in Fp+OX group than Fp group (45.0 and 14.4 months, p = 0.011). Conclusions: Recurrence after receiving adjuvant oxaliplatin combination therapy was considered as one of the poor prognostic factors. It might attenuate the benefit of adding oxaliplatin in adjuvant setting in elderly patients.
An open-label, multicenter, randomized controlled study of mXELIRI versus FOLFIRI in combination with bevacizumab as the first-line treatment in metastatic colorectal cancer: A single-center report.
Authors: SUN Yongkun , Zhang Wen , Jiang Zhichao , Wang Wei , Qu Wang , Zhou Ai-Ping
Published: January 2022

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Background: The first-line treatments in metastatic colorectal cancer were FOLFOX, CAPOX, FOLFIRI and even FOLFOXIRI as basic chemotherapy regimen combined with targeted therapy. XELIRI regimen was not recommended because of the concerns about the toxicity, efficacy and controversy in optimal dosage. An increasing number of studies indicated promising efficacy with manageable safety profile of dosage and administration-adjusted XELIRI regimen. Therefore, the present study investigated the efficacy, safety and appropriate dosage of mXELIRI regimen in the first-line treatment of advanced colorectal cancer. Methods: The EXIST study was a multicenter, randomized controlled, non-inferiority study and we performed stratification based on the tumor location (left or right side). In the mXELIRI+Bev group, patients received intravenous infusion of irinotecan (a reduced dosage,150mg/m2) with bevacizumab (5mg/kg) on day 1 and oral administration of capecitabine (2000mg/m2/day) tablet on day 1-10/Q14 days. Patients in FOLFIRI+Bev group received intravenous infusion of irinotecan (180mg/m2), calcium folinate (400mg/m2) and 5-Fu (400mg/m2) bolus with bevacizumab (5mg/kg) on day 1 followed by a 46-hour continuous infusion of 5-Fu (2400mg/m2)/Q14 days. The primary endpoint was progression-free survival rate at 12 month(PFSR12m) and the secondary endpoints included ORR,OS and safety. Results: 142 patients were enrolled and randomly assigned to receive mXELIRI+Bev (n=76) or FOLIRI+Bev (n=66) in our center between May 2018 and April 2021. Baseline characteristics were well balanced between two groups. In the mXELIRI+Bev group, 70 patients were evaluable with an ORR of 60.0% (1 complete response, CR; 41 partial response, PR; 24 stable disease, SD; 4 progression disease PD). While 57 patients were evaluable in the FOLFIRI+Bev group, with an ORR of 63.2% (36 PR; 15 SD; 6 PD). The PFSR12m for two groups were 32.3% and 21.3%, the median PFS were 9.72 months and 8.77 months, respectively. For safety profiles, no statistical differences were observed in adverse events, such as nausea, vomiting, diarrhea, bone marrow suppression and abnormal liver function. While 10 serious adverse events were recorded in the mXELIRI+Bev group, including intestinal obstruction occurred in 8 patients, intestinal perforation occurred in 1 patients and venous thrombosis occurred in 1 patient. In the FOLIRI+Bev group, intestinal obstruction, venous thrombosis and pulmonary thrombosis was reported in one patient respectively. Conclusions: The modified biweekly XELIRI plus bevacizumab regimen demonstrated promising effect and could be well tolerated based on the data from a single center. Clinical trial information: NCT04247984.
Treatment patterns and outcomes of patients with metastatic colorectal cancer in third-line and beyond systemic therapy: Real-world data from a setting with limited resources.
Authors: Jácome Alexandre A. , Gil Roberto Almeida , Moraes Eduardo Dias de , Peixoto Renata D'Alpino , Canedo Jorge Alexandre , Passarini Thais , Gil Mariana , Pereira Sabrina , Amorim Larissa , Prolla Gabriel , Freitas Laura , Coelho Fernanda , Paiva Isabela , Paes Rafael , Cruz Heloisa , Costa e Silva Matheus , Ferreira Carlos Gil , Ferrari Bruno Lemos , Garicochea Bernardo , Dienstmann Rodrigo
Published: January 2022

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Background: Regorafenib and trifluridine/tipiracil (TAS-102) are the only therapeutic options for patients with chemorefractory metastatic colorectal cancer (mCRC) with demonstrated benefit in overall survival (OS). However, they are not accessible worldwide. In Brazil, they have been recently approved, but they have not yet been provided by public health system or private health insurances. We aimed to describe the treatment patterns and clinical outcomes of that population in a setting with limited access to those drugs. Methods: Retrospective study evaluating 510 patients with mCRC who were treated at five Oncoclinicas centers in Brazil from January 2011 to December 2019. Demographic and clinical data were retrieved from electronic medical records. The median OS was calculated by Kaplan-Meier method and prognostic factors were evaluated via multivariable Cox Regression, calculating the Hazard Ratio (HR) and the confidence interval (CI95%). Results: A total of 163 patients (33% of the overall population) received third-line and 73 (15%) fourth-line systemic therapy. Median age was 62 years, 59% were male. Tumors were right-sided in 19%, RAS mutated 44%, BRAF mutated 3%, and high-frequency microsatellite instability 3%. Metastasectomy prior to third-line was performed in 62% of the patients. From the start of third-line therapy, median follow-up was 9.0 months, with 67% of deaths, and median OS was 13.7 months (CI95% 11.8m–20.0m). Most adopted regimens in third-and fourth-line were (1) rechallenge with oxaliplatin-based therapy (39% and 26%, respectively); (2) rechallenge with irinotecan-based therapy (32% and 34%); (3) rechallenge with anti-EGFR monoclonal antibodies (20% and 29%); (4) regorafenib (13% and 25%); and (5) TAS-102 (2% and 4%). In multivariable model including clinical and molecular variables, prior metastasectomy was the only significant prognostic factor for OS (HR 0.51, CI95% 0.31–0.83, p=0.007). Conclusions: In real-world, a meaningful proportion of patients with mCRC are eligible for third and later lines of therapy. Rechallenge with chemotherapy and anti-EGFR agents is overused in a setting of limited access to therapies with demonstrated OS benefit, such as regorafenib and TAS-102. Barriers to drug access impair the adoption of the best evidence-based continuum of care and strategies to overcome them are urgently needed. Refractory patients in later lines of therapy derive survival benefit from prior metastasectomy.
Preferences for colorectal cancer screening of physicians and individuals at average risk in the United States: A discrete choice experiment.
Authors: Heidenreich Sebastian , Finney Rutten Lila J , Miller-Wilson Lesley-Ann , Moreno-Jimenez Cecilia , Chua Gin Nie , Fisher Deborah
Published: January 2022

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Background: Several colorectal cancer (CRC) screening options are considered in guidelines for individuals at average-risk (IAR). These options differ in aspects such as invasiveness, recommended frequency, and precision that need to be compared and weighed. This study elicited and compared the relative importance that physicians and IAR place on these screening aspects. Methods: Primary care physicians [PCPs] and gastroenterologists [GIs] who recommended/performed ≥1 screening one month prior to study and adult IAR completed a discrete choice experiment (DCE). Participants repeatedly chose between screening tests described by type of test, frequency, true-positive (TP), true-negative (TN), and adenoma TP (physicians only). The instrument was tested in qualitative (physicians: n=6; IAR: n=6) and quantitative pilots (physicians: n=100; IAR: n=202). A mixed logit model was used to estimate relative attribute importance (RAI) and predicted choice probabilities for colonoscopy, multi-target stool DNA (mt-sDNA), fecal immunochemical test (FIT), and methylated septin 9 (mSEPT9) blood test. Generalizability to the population was confirmed. Results: 1,249 IAR and 400 physicians participated. IAR were 46% male and the mean age was 58.9. Physicians were 79% male and their mean age was 53.4. Preferences were most affected by TP rates (IAR RAI=58%; physicians RAI=42%). Physicians also placed high importance (RAI=41%) on adenoma TP rates. TN rates (IAR RAI=33%; physician RAI=9%), frequency (IAR RAI=6%; physician RAI=2%) and type (IAR RAI=4%; physician RAI=6%) were less important. Despite both IAR and physicians placing most importance on precision, preferences for screening modalities differed. On average, physicians preferred colonoscopy, while IAR preferred mt-sDNA over colonoscopy (p<0.001). Both preferred mt-sDNA and colonoscopy over FIT (p<0.001), with a mSEPT9 blood test being least preferred (p<0.001). Preferences of IAR were heterogeneous with individuals who underwent colonoscopy or sigmoidoscopy screening preferring colonoscopy and the rest preferring mt-sDNA (p<0.001). Conclusions: While both GI and PCPs overwhelmingly preferred colonoscopy, preferences of IAR were heterogenous, with mt-sDNA being preferred on average other modalities. Offering choices in addition to colonoscopy could improve screening uptake. [Table: see text]