bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive analysis of the mutational status of early colon cancer: Real world data from the AIO ColoPredict registry study.
Authors: Gisder Doreen Maria , Wisser Sarah , Lugnier Celine , Christmann Jens , Anna-Lena Kraeft , Feder Inke Sabine , Tischoff Iris , Teschendorf Christian , Vera Heuer , Sargin Bülent , Hollerbach Stepahn , Lamberti Christof , Tannapfel Andrea , Reinacher-Schick Anke C.
Published: June 2023

e15535

Background: The comprehensive analysis of the mutational status of colon cancer (CC) may identify targetable alterations also in early stages. This may open up potential beneficial treatment choices, e.g. immunotherapy in microsatellite instable (MSI) tumors. So far, there is few data regarding the distribution of molecular alterations in CC in a real world setting in Germany. Methods: We analyzed clinical and molecular data from our Colopredict Plus (CPP) registry trial including CC patients (pts.) stage I-III. Samples were tested for MS status by immunohistochemistry and for gene mutations (MT) using a 71 gene panel comprised for CC. Molecular data was correlated with clinicopathologic parameters. Disease free Survival (DFS) was estimated by the Kaplan-Meier method. Results: Data from 2746 pts. was included. Female: 1476/2746 (53,8 %), median age: 72 yrs (range: 22-100 yrs), right sided tumor: 1607/2746 (58,5 %), stage distribution I/II/III/NA: 414 (15,1 %)/1198 (43,6 %)/1076 (39,2 %)/58 (2,1 %). MSI/MSS: 544(19,8%)/2202/ (80,2%). A KRAS mutation was observed in 846/2746 (30,8 %). The most frequent hotspot MT were codon 12 KRAS MT with p.G12D (27%), p.G12V (19%), p.G12A (6%), and p.G12C (6%) followed by codon 13 MT with p.G13D (18%). The subtypes p.G12D, p.G12V, and p.Q61K were significantly more frequent in the right colon. BRAF MT was seen in 560/2746 (20,4%). Observed rare MT were: POLE (76/2746 (2,8 %), PTEN 188/2746 (6,8 %), and EGFR (21/2746; 0,8%). MSI CC were more frequent in the right colon and associated with BRAF MT (346/560; 61,8 %), and also MT in BRCA1 (35/53; 66 %), BRCA2 (119/171; 69,6 %), POLE (45/76 (59,2 %), PTEN 107/188 (56,9 %), and EGFR (18/21, 85,7%). In contrast, TP53 MT (1223/2746 (44,5 %)) were associated with MSS (1090/2746 (49,5 %)). 3 yrs DFS in MSI BRAF WT vs. MSS BRAF MT pts. was 0,75 (0,67 – 0,81 vs 0,52 (0,36 – 0,65) (p =0,11). DFS did not differ in specific KRAS MT variants. Conclusions: We here show a comprehensive analysis of genetic alterations in early CC in a prospective real world cohort. As expected, MSI was correlated with female sex, right sided primary tumor and BRAF MT. Interestingly, we also found a strong correlation of BRCA1 MT, BRCA2 MT, EGFR MT, POLE MT, and PTEN MT with presence of MSI while MSS was associated with TP53 MT. Broad molecular characterization of early CC may help individualize treatment strategies in the future.
Tumor immune environment in multiple primary malignancies involving colorectal cancers: Comparison with single primary colorectal cancers.
Authors: Chen Junyi
Published: June 2023

e15536

Background: Multiple primary malignancies (MPM) are characterized by two or more primary tumors in an individual patient, excluding relapse or subordinate relationship. Because the therapeutic options usually become limited, the diagnosis of MPM cause a lot of troubles to both clinicians and patients. A comprehensive investigation in comparing the tumor immune environment in MPM involving colorectal cancers (CRC) with single primary CRC will provide clues for the etiology and the management of MPM. Methods: Three patients with MPM involving CRC and twenty four patients with single primary CRC from our hospital were enrolled in the study. FFPE samples from colorectal lesions were analyzed for the tumor infiltrating lymphocytes [PD-L1+, PD-1+, CD3+, CD4+, CD8+, CD20+, FoxP3+, CD56+, CD163+, CD68+] by multiplex immunofluorescence technique. The tumor-enriched segments and stroma areas annotated by pathologists on images. Then artificial intelligence (AI) employing algorithms of image processing, machine learning, and deep learning techniques distinguished the core and peritumor areas, and calculated the density (counts per mm2) of each marker in two regions. A nonparametric approach (Kruskal–Wallis) was used to compare the density of immune cells between MPM involving CRC and single primary CRC groups. Results: The density of CD4+, CD56dim, FoxP3+ cells in patients with single primary CRC were significantly higher than those in MPM both in the stroma and tumor-enriched segments (all, p < 0.05). In the tumor-enriched segments, the density of PD-1+ in patients with single primary CRC was also significantly more than that in MPM. Moreover, the density of PD-1+CD8+ cells in patients with single primary CRC showed a trend of higher density than those in MPM patients in the stroma area (p = 0.06). However, the density of PD-1+ and PD-1+CD8+ cells did not show significant differences related to cancer types (MPM and single primary CRC) in the stroma. Other indicators such as CD3+, CD20+, CD8+, CD68+CD163+, CD68+CD163-, CD56bright and PD-L1+, had no significant difference related to cancer types (MPM and single primary CRC) regardless of the area (tumor-enriched segments and stroma area). Conclusions: We identified that the tumor infiltrating lymphocytes such as CD4+ cells infiltrated more in single primary CRC than those in MPM involving CRC, suggesting that MPM involving CRC may unresponsive to immunotherapy monotherapy. With preclinical studies suggesting potential for synergistic effects, combining immunotherapies may be a promising approach to treat MPM, which requires a further validation with a larger sample size.
Single cell transcriptomics to identify immunological ACKR1+ DCs and their effect on clinical outcomes in left-sided CRC.
Authors: Wang Qian , Fan Tongqiang , Wang Tao , Xiao Shanshan
Published: June 2023

e15550

Background: Myeloid cells play critical roles in the growth and metastasis of malignant tumors with both protumor and antitumor capabilities. Plenty of studies have reported they participated in modulating tumor inflammation and angiogenesis, and therapeutic strategies targeting myeloid cells are ongoing in pre-clinical and clinical trials. The functions of myeloid cells and their subtypes in left-sided and right-side CRC remain unclear. Methods: A published scRNA-seq dataset (Pelka et al., 2021) with 21 samples from left-sided CRC and 79 from right-sided CRC (colorectal cancer) was obtained. Seurat (Stuart et al., 2019) was used to perform dimensionality reduction and differential expression analysis, and the cell subtypes in the myeloid cells were identified to study the associations between clinical outcomes and different tumor tissue sites of CRC. We also obtained an immunotherapy dataset from TISMO to identify associations between cell subtypes and immunotherapy outcomes. Results: Systematic comparisons of myeloid cells (n = 39,167) from left-sided and right-sided CRC revealed that highly expressed genes from right-sided CRC showed protumor capability and those from left-sided CRC showed antitumor activity. Specifically, left-sided CRC harbored a significant (p = 0.018) higher proportion of ACKR1+ DCs compared to right-sided CRC. ACKR1+ DCs might be immunological as its marker genes were significantly positively correlated with CD8+T cells and highly enriched in APC(antigen processing presentation)-related pathways. TCGA survival analysis revealed that the higher expression of the marker genes in ACKR1+ DC was associated with better overall survival (OS, p = 0.0088). Furthermore, immunotherapy biopsy showed ACKR1+ DCs subtype significantly enriched in immunotherapy responsive group compared to non-responsive group in colon cancer (p = 0.019), melanoma (p = 0.0058) and renal adenocarcinoma (p = 3.3e-06) among the obtained TISMO dataset. Conclusions: We identified an immunological ACKR1+ DCs subtype, which was highly enriched in left-sided CRC and was correlated with better clinical outcomes and immunotherapy responses. Those findings might provide potential therapeutic target and help better understand the mechanism of treatment strategies in CRC.
Survival trends for left and right sided colon cancer using the population-based SEER database: A 45-year analysis from 1975 to 2019.
Authors: Ulanja Mark Bilinyi , Asafo-Agyei Kwabena Oppong , Buetler Bryce D , Antwi-Amoabeng Daniel , Ulanja Reginald N. , Neelam Vijay , Mabrouk Tarig , Governor Samuel B , Amankwah Millicent , Rahman Ganiyu A. , Djankpa Francis T. , Alese Olatunji B.
Published: June 2023

e15560

Background: Survival differences between left sided (LCC) and right sided colon cancer (RCC) have been previously reported with mixed results. Many used short study periods and did not account for "other cause of mortality" (OCM). The differences in survival may exist irrespective of modern therapeutic agents, with implications for future clinical trial designs. Methods: We sought to assess the trends in the cause- specific and overall survival of colon cancer based on sidedness, using competing risk analysis. A SEER database from 1975 to 2019 was used.Time interval chosen based on clinical adoption of modern chemotherapy (1975-1989 = period A, 1990-2004 = B, 2005-2019 = C). Cox model was used for overall survival (OS), and Fine-Gray competing risk analysis for cause-specific survival (CSS). Adenocarcinoma were included, and primary rectal cancers excluded. Results: Of the 227,637 colon cancer patients, 50.1% were female and 46.2% RCC. Racial distribution of LCC vs RCC; Black-48.5% vs 51.5%, White-53.1% vs 46.9%, API/AN-63.7% vs 36.3%; p < 0.001. Age ≥ 65 were more likely to have RCC vs LCC (51.4% vs 48.6%), LCC common for age 18-49 (64.6% vs 35.4%), 50-64 (62.3% vs 37.7%), p < 0.00l. Females more likely to have RCC (50.4%vs 41.9%; p < 0.001), and males to have LCC (58.1% vs 49.6%;p < 0.001). Median CSS for LCC and RCC was 19.3 and 16.7 years respectively for 1975-1989 but median CSS for period B and C did not reach during study period. Median OS increased over time for both LCC (A = 5.5 yrs.; B = 7.6yrs and C = 10.5 yrs.) and RCC (4.3, 5.8 and 7.5yrs respectively). CSS was better for LCC than RCC for period C (aHR 0.89; 0.86-0.92; p < 0.001). LCC consistently showed superior OS for all study periods. Stage stratification showed worse CSS for localized and regional LCC in the earlier study periods, but the risk attenuated over time. However, left sided distant disease had superior CSS for all periods. Overall survival was better for LCC irrespective of stage, with gradual improvement over time(table 1). Conclusions: Over the past four decades, LCC has shown superior survival over right sided tumors. Furthermore, prognosis between LCC and RCC became more divergent in favor of LCC with the adoption of modern chemotherapy. Clinical trials for colon cancer should consider sidedness when recruiting patients for intervention. [Table: see text]
Results of a retrospective multicenter study comparing the effectiveness of regorafenib and the rechallenge of chemotherapy in patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Kuzmina Evgenia , Fedyanin Mikhail , Reshetov Igor , Parts Sergey , Pokataev Ilya , Polyanskiy Maxim , Antonova Tatiana , Pikulin Dmirii , Arseneva Evgenia , Anikina Marina , Golubev Pavel , Syskova Anna , Galkin Vsevolod
Published: June 2023

e15561

Background: Regorafenib is considered the standard third-line therapy of mCRC. However, the modest efficacy and significant toxicity of regorafenib urges the search for new therapeutic approaches. In various countries, the re-challenge of the previously effective treatment regimens is being considered. We compared the effectiveness of various variants of systemic therapy in the third and subsequent lines of the treatment. Methods: We analyzed the prospective database of pts with mCRC from two clinics of the Russian Federation. The statistical hypothesis implied the equivalence of the 6-month overall survival on the repeated chemotherapy (CT) and targeted therapy with the third line regorafenib therapy, provided the equivalence boundaries from 0.8 to 1.25. With α = 0.05, the study power is 80% with 178 patients, 89 people in each group. We conducted statistical analysis with the SPSS statistical software package (v. 20, IBM). Results: In the database, we identified 215 patients with morphologically confirmed metastatic colon cancer who received two or more lines of antitumor drug therapy from 2010 to 2021. Of them, we selected 132 patients with a history of regorafenib therapy, and 83 patients with the re-challenge of CT as the third line of the therapy. Overall survival (OS) in the re-challenge and regorafenib groups did not differ (hazard ratio [HR] 1.01 with 95%CI 0.7-1.45; p = 0.9) and the 6-month OS was 74 and 70%, respectively. Progression-free survival was significantly higher in the re-challenge group (HR 1.94 with 95%CI 1.3-2.7; p < 0.001); In the multifactorial analysis, the re-challenge of previous treatment regimens kept its independent positive effect on progression-free survival (HR 1.9 with 95%CI 1.3-2.8; p = 0.0001) also as index T < 3 (HR 0.7, 95CI 0.55-0,94); ECOG ≥1 a (HR 1.5 with 95%CI 1.16-2.05; p < 0.01) affected PFS negatively. The reduction of the regorafenib dose did not affect PFS (HR 0.9 with 95% CI from 0.9 to 1.0; p = 0.1), its starting dose (HR 0.9 with 95 CI from 0.9 to 1.0; p = 0.2), and a break in the regorafenib treatment (HR 0.9 with 95% CI from 0.5 to 1.8; p = 0.9). Conclusions: Regorafenib and the re-challenge of previously effective CT in the third-line of mCRP therapy show the similar 6-mon. OS. However, progression-free survival is significantly higher in the re-challenge group in third line therapy.
A phase IV study to evaluate the safety of fruquintinib in Chinese real-world clinical practice.
Authors: Li Jin , Wang Zhi-Qiang , Zhong Haijun , He Yifu , Zhang Chen , Niu Zuoxing , Yang Shujun , Zhang Tao , Zhu Liangjun , Shu Yongqian , Peng Jianjun , Song Yan , Li Jian , Yuan Ying , Zhang Haibo , Yu Gengsheng , Hua yun-Qi , Xiao Jianjun , Shi Michael , Su Weiguo
Published: June 2023

e15568

Background: Fruquintinib is a highly selective, potent, oral tyrosine kinase inhibitor of VEGFR-1, -2, and -3, which was approved in China for 3L mCRC patients based on results of FRESCO study (NCT02314819). In addition, FRESCO-2 (NCT04322539) demonstrated a consistent efficacy and safety profile of Fruquintinib in more heavily treated mCRC worldwide patients. This Phase IV study aims to evaluate the safety of Fruquintinib in real-world clinical practice in China. Methods: This is a prospective, multicenter, phase IV study, to evaluate a real-world safety of Fruquintinib in China. Patients who are within the first cycle of Fruquintinib treatment or plan to use Fruquintinib within 1 week can be enrolled into this study. Three visits are scheduled, including the day of consent, 1 month after consent, and 6 months after consent or 30 days after the last dose (whichever occurs first). The primary endpoint is the collected AE. Results: From April 2019 to Feb 2022, a total of 3005 patients from 96 study sites received at least one dose of fruquintinib and were enrolled in the safety analysis set (SS). The median age of the patients was 60, of which 1053 patients (35.0%) were ≥65.In SS, a total of 1923 patients (64.0%) started Fruquintinib at 5 mg/day. The median relative dose intensity was 85.3%; the median exposure time was 2.7months. In SS, 2291 patients (76.2%) reported TEAEs; 1901 patients (63.3%) reported investigator assessed fruquintinib-related TEAEs.718 patients (23.9%) reported ≥Grade3 TEAEs; 418 patients (13.9%) reported investigator assessed fruquintinib-related ≥Grade3 TEAEs. 330 patients (11.0%) reported SAE; 86 patients (2.9%) reported investigator assessed fruquintinib-related SAE. 169 patients (5.6 %) reported TEAEs leading to death;8 patients (0.3%) reported investigator assessed fruquintinib-related TEAEs leading to death. The most frequent fruquintinib-related TEAEs(＞10%）include palmar-plantar erythrodysesthesia syndrome (PPES,19.4%)，hypertension (15.6%) & fatigue (10.1%); the most frequent Fruquintinib-related≥Grade 3 TEAE (≥1%）include hypertension (6.4%) & PPES (2.2%); The most frequent fruquintinib-related TEAE (≥5%) leading to dose modification was PPES (5.4%). Conclusions: The results are consistent with the fruquintinib safety profile observed in existing clinical studies. No new or significant safety signals were identified. Clinical trial information: NCT04005066 .
Chemotherapy and radiofrequency hyperthermia (oncothermia) in the treatment of metastatic colorectal cancer.
Authors: Deniz Gulhan Ipek , Can Ayten , Tansan Sualp
Published: June 2023

e15569

Background: Colorectal cancer (CRC) is the second leading cause of death in adults. Standard treatment for metastatic disease includes chemotherapy and biological agents. Although more than 50% of patients respond to multi agent chemotherapy, resistance to treatment is a significant problem and more than 85 % of patients die within five years. Radiofrequency hyperthermia (Oncothermia- OT) is a non-invasive treatment modality which utilizes 13 MHz external radiofrequency waves to selectively heat cancer cells to 45 C, contributing to apoptosis, and aggregation of DNA repair enzymes, potentially overcoming resistance and improving chemotherapy efficacy. It has been used alone or in combination with chemotherapy. Since most metastatic CRC patients have disease limited to the abdominal cavity and liver, Oncothermia can be applied with a single electrode covering the entire abdominal cavity, immediately following chemotherapy without additional side effects. Methods: We treated 25 consecutive CRC patients with disease limited to liver and/or abdominal cavity with chemotherapy and biological agents and concomitant weekly OT (Oncotherm-EHY 3010) for one hour to the whole abdomen. Chemotherapy was FOLFIRI in 2, FOLFOX in 6, FOLFIRINOX in 17. Bevacizumab was used with chemotherapy in 22 and cetuximab in 1 patient. Patients were followed by periodic CT/MRI/PET-CT. Treatment duration ranged from 4 to 60 months. Results: No unexpected or grade III-IV toxicity was observed. Complete response was observed in 3 patients, partial response in 21 patients and stable disease in one patient for an objective response rate of 96%. Median follow up is 20.1 months (range 4-82+ months). 16 patients are alive, 3 with no disease and 13 on treatment. 9 patients have died. Conclusions: Although this is a single center retrospective observation, the combination of chemotherapy with Oncothermia appears tolerable and feasible in metastatic CRC. Despite the limitations of this observation, activity of this multi-modality treatment appears promising. Prospective randomized trials are needed to confirm these findings.
Treatment modalities of regorafenib and survival in metastatic colorectal (mCRC) patients: A real-world multicenter retrospective study.
Authors: Qu Wang , Liu Zimin , Zhu Liangjun , Chen Xiaobing , Liu Bo , Zhao Yun-Bo , Yan Hao , Qu Xiujuan , Li Shengmian , Zang Ai-min , Jiang Zhichao , Sun Yongkun , Zhou Ai-Ping
Published: June 2023

e15571

Background: Regorafenib has been widely used as the later-line treatment for mCRC. This study aimed to describe the treatment modalities, as well as the efficacy and safety of regorafenib in a real-world setting. Methods: We conducted a retrospective study of patients (Pts) with refractory mCRC receiving at least one cycle of regorafenib as the third or higher line treatment from August 2017 to June 2020 in China. Demographic characteristics, treatment modality and survival were collected. The primary endpoint was overall survival. Uni- and multivariate analysis were conducted by Kaplan-Miere analysis and Cox regression model. Results: A total of 768 Pts from 10 centers were screened and 621 Pts were finally enrolled with a median age of 61 (18-84) years. 376 Pts received regorafenib monotherapy and 245 Pts accepted combination therapy. With a median follow-up time of 28.4 months, the median progression-free survival (mPFS) was 4.3 months (95%CI: 3.8-5.2) and the median overall survival (mOS) was 11.6 months (95% CI: 10.5-12.6). The mOS of Pts received regorafenib monotherapy (R, n = 376), regorafenib plus PD-1 inhibitor (R+I, n = 161), regorafenib plus chemotherapy (R+C, n = 53) and regorafenib plus chemotherapy, PD-1 inhibitor (R+C+I, n = 31) were 10.0, 13.2, 13.5 and 19.3 months, respectively (p = 0.0017). While the median PFS were 3.8, 5.4, 4.6 and 4.8 months, respectively (p = 0.4944). In multivariate analysis, treatment with R+I (HR = 0.712, 95%CI 0.521-0.973; p = 0.0330) and ECOG PS (HR = 0.400, 95%CI 0.232-0,690; p = 0.0010) were the only significant factors for superior mOS. Univariate analysis in subgroups demonstrated longer OS as well as PFS in KRAS mutated or antiangiogenesis therapy naïve Pts in R+I group than those in R group. Moreover, there was a tendency of shorter OS in Pts received 80mg as the final tolerated dose in R+I group compared to 160mg, while Pts received 120mg presented comparable survival. The incidence of all grade treatment-related adverse events was higher in R+I (87.9%) vs R (66.3%) group. Conclusions: The combination of regorafenib and PD-1 inhibitor was commonly adopted as the later-line treatment in mCRC patients in real-world practice and seemed to have a prolonged overall survival than regorafenib alone. Further confirmatory studies are warranted. Clinical trial information: NCT04835324 .
The multi-omics signature to predict sensitive to anti-epidermal growth factor receptor therapy in RAS wild-type colorectal cancer liver metastases.
Authors: Chang Wenju , Liu Yu , Zhou Shizhao , Chen Yuan , Zeng Mengsu , Wang Liansheng , Xu Jianmin
Published: June 2023

e15578

Background: There are nearly half patients with Ras wild-type metastatic colorectal cancer (mCRC) do not response to Anti-EGFR therapy. Identification of patients who are sensitive to anti-EGFR therapy may increase the response rate and reduce the adverse effect. In this study, we aimed to develop and validate a multi-omics deep learning model to predict cetuximab efficacy in RAS wild type mCRC patients. Methods: In this study, we retrospectively analyzed 213 Ras wild type mCRC patients. The training and testing cohorts comprised patients in Arm A (FOLFOX + cetuximab) of the CHINESE study (NCT01564810) and patients in the CHINESE follow-up study (PMID: 30305811). The external and negative validation cohorts were derived from an independent cohort and Arm B (FOLFOX) of the CHINESE study, respectively. Based on the deep learning framework Pytorch, we first built the radiomic and genetic signature. Next, we passed the CT images and gene data into the trained ResNet18 and Random Forest and then we sum the output probabilities of two models with a weight of 3:7 to obtain the classification probability of the fusion model. Results: The signature successfully predict sensitivity to anti-EGFR therapy (The area under the curve (AUC) of the radiomic signature: 0.75; the genetic signature: 0.81; the fusion signature: 0.86) but failed with chemotherapy (The fusion signature: 0.54). In cetuximab-containing sets, the fusion signature outperformed existing biomarkers for detection of treatment sensitivity (OR = 17.9, 95% CI 3.22–154.31, P = 0.003) and was strongly associated with progression free survival (mPFS: 12.0 vs. 15.0 months, HR: 0.44, 95% CI 0.20–0.99, P = 0.047). Conclusions: The multi-omics signature can serve as an intermediate surrogate marker of anti-EGFR treatment sensitivity and survival. The signature outperformed known biomarkers in providing an early prediction of treatment sensitivity and could be used to RAS wild type mCRC treatment decisions.
A phase II clinical trial of prior regimen rechallenge in third- or later-line treatment for patients with metastatic colorectal cancer.
Authors: Wang Chenchen , Guo Weijian , Huang Mingzhu , Li Wenhua
Published: June 2023

e15583

Background: Current choices of systemic treatment for patients with metastatic colorectal cancer remained limited, with some patients facing drugless conditions after failure of standard treatment. For those who have responded to the front-line treatment, there is a lack of data from prospective studies, on whether reapplication of former regimens in the later line can still bring clinical benefits. We conducted an exploratory study to evaluate the efficacy and safety of prior regimen rechallenge in the third or later-line treatment in patients with metastatic colorectal cancer (mCRC). Methods: This is a single-arm prospective phase II study (ClinicalTrials.gov Identifier: NCT03485027). The key inclusion criteria were:(1) histologically confirmed mCRC; (2) treatment failure to at least two lines of systemic chemotherapy; progression free survival (PFS) of the rechallenged regimen should be at least four months in the prior setting without unrecoverable toxicity; (3) the time interval between the re-applied chemotherapy regimen and its previous administration was at least 6 months. Eligible patients received the reapplication regimens, including XELOX, FOLFOX, FOLFIRI, Irinotecan monotherapy with or without targeted drug, which was formerly used. Evaluation was repeated every 6 weeks and treatment continues until the disease progression or intolerable adverse effects. The primary end point is PFS. The secondary endpoint is overall survival (OS), objective response rate (ORR), disease control rate (DCR) and treatment safety. Results: From Jan 24, 2018 to Dec 24, 2022, a total of 53 patients were recruited, and 51 patients who had received at least one cycle of rechallenged medication were included in this analysis. The median age was 59 (range 36-82) years old. Among these patients, 38 were administrated with the combination of targeted and chemotherapy as the rechallenge regimen (24 with bevacizumab plus chemotherapy and 14 with cetuximab plus chemotherapy), and 13 with chemotherapy alone (7 with oxaliplatin-based chemotherapy and 6 with irinotecan-based chemotherapy). A total of 41 patients had received the efficacy evaluation after treatment. One patient achieved partial response (tumor change from baseline -38.4%), 23 patients with stable disease and 17 patients with progressive disease. The ORR and DCR were 2.4% and 58.5%, respectively. At the last follow-up date on Jan 31, 2023, the median PFS was 4.0 months (95% CI, 2.62–5.38). The data of OS was still immature. Grade 3 or 4 adverse events were reported in 6 patients (11.76%). The detailed grade 3 or 4 adverse events were neutropenia in 4 patients, oxaliplatin related acute anaphylaxis in 2 patients, diarrhea in 2 patients. Conclusions: For the patients with heavily treated mCRC, the re-application of chemotherapy with front-line treatment regimen has shown a decent effectiveness with acceptable safety. Clinical trial information: NCT03485027 .
Efficacy and safety of encorafenib-based regimens in colorectal cancer: A systematic review of clinical trials.
Authors: Aiman Wajeeha , Jumean Samer , Garcia Jose , Asfeen Ummul , Alkhlaifat Osama , Qirem Murad , Rayad Mohammad Nabil , Ahmad Amaar , DaCosta Theodore , Guron Gunwant K. , Shaaban Hamid Salim
Published: June 2023

e15600

Background: BRAF gene mutation is present in 10% of the world’s 3rd common cancer, i.e., colorectal cancer (CRC). Constitutive activation of the mitogen-activated protein kinase pathway (MAPKP) results from this mutation, abnormal activation of MAPKP, inhibiting apoptosis and enhancing proliferative activity. In this systematic review, we will assess the efficacy of encorafenib (a BRAF inhibitor) based regimens in CRC. Methods: We followed PRISMA guidelines to conduct this systematic review. A literature search was performed on PubMed, Embase, and Clinicaltrials.gov with mesh terms, ‘’Colorectal Neoplasms’’ and “Proto-Oncogene Proteins B-raf” from the inception of data till 01/05/2023. We screened 4572 articles and included 1 randomized clinical trial (RCT, N = 665), and 4 non-randomized trials (nRCTs, N = 175), measuring the efficacy of encorafenib (E) based regimens in BRAF V600-mutated CRC. Results: In 4 clinical trials (N = 840), 246 patients treated with a double regimen and 373 treated with a triple regimen of E. In 2 clinical trials (N = 319), triple therapy of E + C + Binimetinib showed an overall response rate (ORR) of 47.8% and 26% in the untreated metastatic CRC (mCRC) and phase III randomized trial triple regimen arm, respectively. A recent trial on triple therapy of E + C + nivolumab (N) showed an ORR of 45% with overall survival (OS) and progression-free survival (PFS) of 11.4 and 7.3 months, respectively. In 1 randomized trial (N = 665), ORR improved from 2% in the control arm to 26% and 20% in triple and double regimens, respectively, which was mainly partial response (PR) with complete response (CR) of 4-5% in both groups. The OS was 9 and 8.4 months with a hazard ratio (HR) for death vs. control of 0.52; (95% confidence interval [CI], 0.39 to 0.70; P < 0.001) and 0.60; (95% CI, 0.45 to 0.79; P < 0.001) in the triple and dual regimen, respectively. In 1 trial of dose escalation study, alpelisib (A) was added to E + C and the addition of this third drug showed minimal changes in the ORR from 18 to 19%, and PFS improved from 3.7 to 4.2 months. (Table 1). Conclusions: A combination of BRAF inhibitors with anti-EGFR monoclonal antibodies showed a clinically significant increase in antitumor activity in BRAF-mutated mCRC compared to standard therapy. The addition of MEK/PI3K inhibitor as a third drug to E + C also showed some improvement in ORR and PFS. Triple therapy with E + C + N was also effective and tolerated well by the microsatellite stable (MSS) BRAF mutated mCRC population. Randomized trials are needed. [Table: see text]
First clinical study reporting safety and outcomes of high dose oxaliplatin use in PIPAC for colorectal peritoneal carcinomatosis.
Authors: Somashekhar S.P. , Rajgopal Ashwin K. , Rakshit Susmita , Fernandes Aaron marian , Patil Darshan , Kumar Rohit
Published: June 2023

e15606

Background: PIPAC in inoperable colorectal peritoneal carcinomatosis has showed better oncological outcomes at existing doses of 92mg/m2. However the maximum dose that can be used and its clinical outcomes is not defined yet. Methods: PIPAC was done at dose 120 mg /m2 oxaliplatin which was established from a phase 2 study. The patient demographics, perioperative findings, adverse events, and outcomes were prospectively recorded. Response rate was graded as Peritoneal Regression Grading Score (PRGS). QoL of the patients was studied according to the EORTC QLQ - C30 score. Results: 42 PIPAC administrations were performed in 15 patients. The median hospital stay was 1.5 day (1-3 day). CTCAE grade 3 was observed in 5 patients, for abdominal pain and nausea, grade 3 fatigue in 4 patients. Transient increase in C- reactive protein was seen in 8 patients, haematological, renal and hepatic functions were not impaired in any patients except for mild transient elevation in AST and ALT levels in 7 patients. 12 patients completed 3 cycles of PIPAC. Of the 15 patients, 3 had complete response (PRGS 1) and 8 had major (PRGS 2), 3 had minor response (PRGS 3). There was improvement in functional scale, symptom scale and overall global health status for all patients. Conclusions: PIPAC can be performed safely at dose of oxaliplatin 120mg/m2. There is better objective & pathological response with this dose with no major complications or side effects to the patients. There is also improvement in quality of life. This dose should be new standard of care for further studies.
Characterization of visits to the emergency room by patients with colorectal cancer in the year prior to their diagnosis: A retrospective study.
Authors: Massarweh Amir , Brenner Baruch , Ofer Jonathan
Published: June 2023

e15609

Background: Colorectal cancer (CRC) is one of the leading causes of cancer death globally, with more than 0.9 million deaths annually. Despite screening programs, many of the CRC patients (pts) are diagnosed at an advanced stage, resulting in an overall 5-year survival rate of only about 60%. Enhancing the detection of CRC in pts referred to the Emergency Room (ER) could potentially improve early detection and survival outcomes. While the prevalence of initial cancer diagnoses obtained through ER admission is documented, the proportion of individuals diagnosed with CRC who visited the ER during the year proceeding their diagnosis remains unknown. This study aimed to examine the percentage of CRC pts treated at Rabin Medical Center (RMC) who visited the ER in the year prior to diagnosis and to characterize these visits. Methods: A retrospective cohort study was conducted to identify pts diagnosed and treated at RMC for histologically confirmed CRC between 2012-2022 and to characterize their ER visits in the year prior to diagnosis. Each visit was recorded by date and the number of months before diagnosis. ER visits initiated for a recent diagnosis of CRC, i.e., occurring one month before diagnosis, were excluded. Demographic and clinical information (age at ER visit, gender, stage at diagnosis, number of visits, and interval between the first visit and diagnosis) was collected and analyzed. Results: Of the 2,240 pts treated for CRC at RMC between 2012-2022, 476 (21.2%) visited an ER, at RMC (13.3%) or elsewhere (7.9%), in the year prior to diagnosis. The median age at the first visit was 72 years (range: 25-96) and 55.7% were males. Pts were diagnosed with localized, locally advanced, and metastatic disease in 134 (45.0%), 70 (23.5%), and 63 (21.1%) cases, respectively, while stage was not yet established in 31 (10.4%). Quantitative and temporal characteristics of the ER visits are presented (Table 1). Pts had on average 1.6 visits (range: 1-11) in the year prior to diagnosis; 113 (37.9%) had 2 or more visits during that year. The median interval between the first ER visit and the CRC diagnosis was 4 months (range: 2-12); an interval of 5 months or longer was observed in 127 (42.6%) pts. Conclusions: To our knowledge, this is the first report on ER visits of CRC pts in the year prior to their diagnosis. The high percentage of pts visiting the ER highlights the importance of developing screening tools at the ER level to improve early detection and survival outcomes. This is further emphasized by prevalence of repeat ER visits and long interval between the first ER visit and the CRC diagnosis in many cases. [Table: see text]
Transcatheter-directed Y-90 radioembolization compared with chemoembolization for the treatment of hepatic metastases from colon cancer.
Authors: Young Peter , Miles Brittany , Dang Brittany , Mackey James David
Published: June 2023

e15620

Background: Arterially directed embolic therapy has been a mainstay in the management of hepatic malignancy of both primary and metastatic origin. The benefits of transcatheter-directed Yttrium-90 radioembolization (TARE) and chemoembolization (TACE) in conjunction with systemic therapy are well documented, though only TARE is currently recommended for the management of hepatic metastases from colon cancer. We evaluated patients who underwent TARE or TACE to assess survival rates at 2 years post-procedure. Methods: The TriNetX Diamond network was used for this study. TriNetX provides access to anonymized medical record information on more than 213 million patients in 92 large healthcare organizations. Two cohorts of patients were created utilizing International Classification of Disease-10 (ICD-10) codes. All patients were required to have colon cancer (C18), liver metastases (C78.7), and liver-directed treatment (CPT code 37243). One cohort received chemoembolization (CPT 96420) while the other received Yttrium-90 microspheres (CPT 79445). The cohorts were balanced for age, race, gender, and ethnicity, resulting in 336 patients in each arm. They were then evaluated for risk of death at two years. Results: Patients who received Y-90 had a risk ratio for death of 1.23 compared to patients treated with chemoembolization. Figure 1. Conclusions: Patients who underwent TARE were at a significantly higher risk of mortality at 2 years post-procedure compared to those who underwent TACE. As only Y-90 radioembolization is currently recommended under NCCN guidelines for the treatment of hepatic metastatic lesions from colon cancer, we hope to further discussion among specialists to determine whether TACE may provide an alternative treatment option. [Table: see text]
Sex difference in tolerability of adjuvant oxaliplatin-based chemotherapy for colorectal cancer and changes in diagnostic components of sarcopenia: A prospective study.
Authors: Nozawa Hiroaki , Abe Shinya , Abe Kentaro , Yokota Yumi , Yakabe Mitsutaka , Akishita Masahiro , Ishihara Soichiro
Published: June 2023

e15625

Background: We previously reported that based on CT images at the 3rd lumbar vertebra, female patients with colorectal cancer (CRC) were more likely to be sarcopenic than male patients after curative resection, and predisposed to develop early dose limiting toxicities (DLTs) in adjuvant CAPOX therapy. Although oxaliplatin-based adjuvant chemotherapy for CRC is prevalently used worldwide, it is largely unknown how the treatment affects patients in terms of sarcopenia. Therefore we conducted a prospectively study on the impact of adjuvant chemotherapy on multifactorial components assessed for sarcopenia. Methods: We examined stage II-III CRC patients who received adjuvant CAPOX after curative surgery after March 2022. Informed consent was obtained from all participants. During this systemic therapy, we assessed nutritional status using Mini-Nutritional Assessment (MNA, an 18-item questionnaire consisting of psychological well-being, diet quality, physical activity and anthropometric metrics; score range:0-30), and examined gait speed and grip strength, as well as whole body skeletal muscle mass, fat mass, and bone mineral using a body composition analyzer. The changes in these metrics were analyzed in association with dose reduction/adverse events of CAPOX. All continuous variables were tested by Wilcoxon rank-sum test. Results: Eighteen men and 13 women (mean age: 61 years old) were included in this study. Seven (39%) male and seven (54%) female patients required dose reduction within the four treatment cycles (p = 0.65). The median MNA, gait speed, grip, muscle mass, fat mass and bone mineral at the first and fourth cycles of CAPOX in men were 20.4 and 24.0, 1.10 and 1.23 m/sec, 30.9 and 31.2 kg, 27.3 and 28.0 kg, 11.8 and 11.9 kg, and 2.8 and 2.9 kg, respectively. The median of these metrics at the first and fourth cycles of CAPOX in women were 21.4 and 22.4, 1.32 and 1.33 m/sec, 22.0 and 22.4 kg, 21.95 and 22.12 kg, 13.43 and 14.62 kg, and 2.34 and 2.31 kg, respectively. The relative values (medians) of the metrics at the fourth cycle to those at the first cycle of CAPOX (men vs women) were as follows; MNA:1.131 vs 1.045 (p = 0.057), gait speed:1.075 vs 0.950 (p = 0.17), grip:1.018 vs 1.044 (p = 0.81), muscle mass:1.028 vs 1.011 (p = 0.036), fat mass:1.029 vs 1.080 (p = 0.47), and bone mineral:1.030 vs 0.991 (p = 0.015). Conclusions: It is suggested that adjuvant CAPOX has negative impact on postoperative recovery of psychological and physical components in female patients.
Immune checkpoint inhibition in locally advanced rectal adenocarcinoma at Mayo Clinic.
Authors: Imperial Robin John Lester , Alomari Mohammad , Elawady Mohamed , Jones Jeremy Clifton , DeLeon Michelle
Published: June 2023

e15626

Background: Studies have shown the effectiveness of immune checkpoint inhibition (ICI) in patients with tumors demonstrating microsatellite instability (MSI-H) and an associated defect in DNA mismatch repair (dMMR). In particular, KEYNOTE-177 demonstrated significant survival benefit for patients with unresectable or metastatic colorectal cancer with MSI-H or dMMR. Recently published case reports and series have demonstrated similar outcomes for patients with locally advanced and resectable rectal cancer. We report on the experience of patients with locally advanced, resectable rectal adenocarcinoma treated across the Mayo Clinic Health System. Methods: We conducted a retrospective analysis of patients treated at Mayo Clinic since 2015 A search of the Mayo Clinic database was done to include parameters for confirmed rectal adenocarcinoma, dMMR in pathology reports. Patients receiving ICI treatment including pembrolizumab, nivolumab/ipilimumab and durvalumab in any combination with chemotherapy and/or radiation were included. Patients with metastatic disease at the time of surgical intervention or ICI were excluded. Clinical data was assimilated. Results: Twenty-one patients met criteria for inclusion in our analysis. Fifteen patients had de novo disease. Six patients had local recurrence and had been treated previously with chemotherapy, radiation (RT) and surgery. None of the patients included had prior ICI therapy. Fifteen patients had Lynch syndrome. The median age of diagnosis was 41.5 years. Seven patients underwent surgical intervention. of the seven patients received surgery upfront followed by immunotherapy. The remaining six had neoadjuvant immunotherapy alone or in combination with chemotherapy and/or radiation. Prior to surgery, all patients demonstrated radiographic partial response (rPR). 67% of these demonstrated a pathologic complete response (pCR) while 33% had residual disease. The patient who received surgery upfront and adjuvant ICI continues to have radiographic stable disease after 1 year of treatment. For patients who did not have surgery, 50% had radiographic “complete or near complete” response (rCR), 43% had rPR and 7% had radiographic stable disease. Ten patients received RT and ICI with 70% demonstrating rCR and 30% rPR. Overall, the objective response rate was 90 Response to treatment was observed upwards of 75 months. Only 1 person in the study had progression of disease that occurred after 14 months of therapy. Conclusions: Similar to KEYNOTE-177, patients with locally advanced MSI-H/dMMR rectal cancer have significant and durable response to immunotherapy alone or in combination with chemotherapy, radiation and surgery. Further large prospective trials are needed to validate these findings and determine a standardized approach.
Early colorectal cancer detection with a spectroscopic liquid biopsy.
Authors: Cameron James Munro , Antoniou Georgios , Brennan Paul , Conn Justin , Gray Ewan , King Sharon , McHardy Rose , Moug Susan , Nobes Jennifer , Palmer David , Sala Alexandra , Smith Benjamin , Strachan Judith , Mowat Craig , Baker Matthew
Published: June 2023

e15627

Background: Earlier diagnosis and treatment of colorectal cancer (CRC) maximizes the opportunity to combat or control disease progression. The average 5-year survival rate after diagnosis decreases from 91% in early-stage CRC, to as low as 15% for stage IV CRC. Furthermore, rapid detection and removal of pre-cancerous adenomas – e.g., advanced adenomas (AA) – can significantly improve survival rates of affected patients. However, current stool-based tests have inadequate AA sensitivities, such as FIT (24%) and FIT-DNA (42%). Liquid biopsies have great potential to supplement FIT tests and improve diagnostic pathways, but current blood tests based on tumor-derived biomarkers also have limited sensitivity for AA detection. Methods: The Dxcover® Cancer Liquid Biopsy is based on Fourier-transform infrared (FTIR) spectroscopy applied to serum from a standard blood sample. The spectral data are collected and analyzed using pattern recognition and machine learning algorithms to detect disease-specific signatures. We initially examined test performance for the detection of multiple cancer types. Additionally, we have analyzed a retrospective cohort of samples comprising 100 CRC, 99 AA removed by surgical resection and 97 colonoscopy screening controls. Results: The CRC classifier from the discovery multi-cancer dataset resulted in 74% sensitivity with 91% specificity when differentiating CRC and non-cancer, which surpasses the targets set by the Centers for Medicare & Medicaid Services (CMS) for coverage of CRC tests. Receiver operating characteristic (ROC) analysis reported an area under the curve (AUC) value of 0.91. The machine learning algorithms can be fine-tuned to maximize either sensitivity or specificity depending on the requirements of different patient pathways. When tuned for higher sensitivity, the model produced 97% sensitivity (49% specificity), and when tailored for greater specificity (97%) the sensitivity was 47%. We have now progressed these findings to examine the ability of the technology to differentiate patients with CRC, AA and colonoscopy controls. Furthermore, we assess whether combining spectral data with additional clinical information, such as biomarker data and patient demographics, can enhance test performance. Conclusions: A rapid blood test that is sensitive to AA and early-stage CRC could improve patient prognosis and reduce cancer burden. With further development, this liquid biopsy could have a profound impact on the earlier detection of CRC.
Adjuvant chemotherapy in ypStage III locally advanced rectal cancer after neoadjuvant treatment with an oxaliplatin-based regimen.
Authors: Cai Runkai , Zhang Jianwei , Cai Yue , Wu Zehua , Hu Huabin , Xie Xiaoyu , Deng Yanhong , Cheng Yi , Zhang Yuting
Published: June 2023

e15628

Background: Fluorouracil -based neoadjuvant chemoradiotherapy(CRT) followed by total mesorectal excision and adjuvant chemotherapy is the standard treatment for locally advanced rectal cancer (LARC). Adjvuant FOLFOX improved survival benefit compared with fluorouracil in patients with ypStage II andIII after CRT. However, induction or consolidation chemotherapy with FOLFOX before surgery had been the new standard for LARC. Whether adjuvant chemotherapy with FOLFOX still improves survival outcomes in ypStage III patients previously exposed to oxaliplatin-based treatment was unknwon. Methods: Patients with LARC receiving oxaliplatin-based neoadjuvant treatment from January 2015 to December 2019 were retrospective analyzed. The inclusion criteria included neoadjuvant FOLFOX chemotherapy alone or induction chemotherpay, concurrent FOLFOX and consolidation chemotherapy before CRT. The duration of neoadjuvant oxaliplatin exposure time was less than 4 months. The efficacy of adjvuant FOLFOX chemotherapy was analyzed among these ypStage III patients according to adjuvant chemotherapy cycles after surgery. Results: A total of 227 patients with ypStage III were enrolled, with the 3-year DFS rate of 46.1% (95%Cl 37.3%-54.9%).Among these patients, 193 patients received adjuvant FOLFOX chemotherapy, including 7 patients had ≤ 2 cycles of adjuvant treatment. And 34 patients had observation after surgery. The 3-year DFS rates bewteen FOXFOL adjvuant chemotherapy group and observation group were 44.7% vs. 56.5%, respectively (HR, 1.190, 95%Cl 0.6246-2.267, P = 0.597). Forty-one patients had ≤ 2 cycles of adjuvant treatment. The 3-year DFS was 43.6% vs. 60.4% (P = 0.597) between pateints receiving over 2 cycles of adjvuant chemotherapy and ≤ 2 cycles of treatment. Conclusions: Among ypStage III LARC pateints after neoadjuvant treatment with Oxaliplatin-Based regimen, adjuvant chemotherapy with FOLFOX failed to improved surival benefit. More enhanced regimen might be necessary for these oxalipatin-resistant patients.