bluuebunny/crossref_metadata_2025 huggingface dataset:
Regorafenib plus tislelizumab for patients with metastatic colorectal cancer: A real-world study.
Authors: Gao Xiang , Chen Xiaoping , Zhao Yutian , Mao Yong
Published: June 2023

e15589

Background: Regorafenib improves progression-free survival (PFS) and overall survival (OS) in patients with refractory metastatic colorectal cancer (mCRC). As a multikinase inhibitor, regorafenib could regulate the immune microenvironment. We aimed to evaluate the efficacy and safety of regorafenib plus tislelizumab in patients with mCRC in a real-world setting. Methods: We retrospectively analyzed the efficacy and safety of patients with mCRC who received at least one cycle of regorafenib plus tislelizumab between Mar 10, 2021 and Dec 18, 2022 in the Affiliated Hospital of Jiangnan University. 33 patients were received regorafenib (80mg, po, qd, d1-21) every 4 weeks and tislelizumab (200mg, iv) every 3 weeks, until disease progression, intolerable toxicities, or physician/patient withdrawal. The safety and efficacy were assessed by investigators per CTCAE v5.0 and RECIST v1.1, respectively. Results: A total of 33 mCRC patients (19 male vs. 14 female, 5 second-line recipients vs. 20 third-line recipients vs. 7 fourth-line recipients vs. 1 unknown, average age of 62.6 years) were enrolled. Most patients had left-sided cancer (63.6%), liver metastases and lung metastases both occurred in 19 patients (57.6%). With a median follow-up of 6.77 months (range 0- 21.6), the objective response rate (ORR) and disease control rate (DCR) were 15.2% and 100%, with a median PFS of 12.97 months (95% CI, 9.07-NA). The median OS was 19.83 months (95%CI, 7.66-32.01). There was no significant difference in OS between patients with and without liver metastases, the mOS was 19.8 months (95%CI, 9.53-NA) vs. not reached (NR); P = 0.368. The incidence of grade 3/4 adverse events was 24.2%, the most common TRAEs of grade ≥3 were anemia (9.1%) and hyperbilirubinemia (9.1%). No new safety signals were identified. Conclusions: The combination of regorafenib and tislelizumab had a manageable safety profile and promising efficacy in mCRC patients. And this combined therapy needs further prospective studies to verify the outcomes.
Long-term survivors (LTSs) population of metastatic colorectal cancer (mCRC): A Northern Italian comprehensive cancer center experience.
Authors: Damato Angela , Rotolo Martina , Borghi Eleonora , Caputo Francesco , Iachetta Francesco , Panebianco Michele , Fanello Silvia , Lombardi Mattia , Gervasi Erika , Larocca Mario , Pinto Carmine
Published: June 2023

e15590

Background: mCRC patients (pts) have a median survival of 13-24 months with a 5-year survival rate of about 1%. LTSs are defined as pts with survival greater than or equal to 36 months after diagnosis of mCRC. Mutational status, new treatments, and surgery resection advances led to improved survival outcomes. Methods: This is a single-center retrospective analysis of 106 consecutive CRC pts with synchronous or metachronous metastases diagnosed from the AUSL-IRCCS of Reggio Emilia Comprehensive Cancer Center between January 1st, 2017, and November 30, 2019. Clinical and pathological characteristics of pts were obtained from clinical records. Long-term survivors were defined as pts with survival > 36 months. Results: Out of 106 mCRC, 33 (31.1%) were LTSs with a median survival of 53 months (range, 36-129 months). At the data cut-off of November 30, 2022, 24 (72.7%) were still alive. Among all, 18 (54.5%) were men, the median age was 65 years (47-83), and 14 (42.4%) had a right tumor primary site. Synchronous metastases were found in 20 (60.6%), while 13 (39.4%) developed metachronous metastases; the most frequent site of metastases was the liver (63.6%), peritoneum and lymph nodes (21.2%), respectively. Surgical resections and systemic treatment regimens based on fluorouracil, oxaliplatin, and/or irinotecan, cetuximab, bevacizumab, TAS-102, regorafenib, and others are listed in Table 1. Regarding biological status, 28 (84.8%) had an MSS, 18 (54.5%) RAS wild type, and 3 (9.1%) BRAF V600E mutated of which 2 (66.7%) underwent surgical resection of primary tumor and metastases, receiving up to 2 lines of systemic treatments. Conclusions: This study confirms that long-term survivors of mCRC pts are the results of intrinsic tumor biology, appropriate treatment timing including surgery, and the available pharmacological opportunities beyond chemotherapy. Further analysis including the role of liquid biopsy is under investigation to identify prognostic and predictive biomarkers in order to improve survival outcomes. [Table: see text]
Therapeutic potential of dual CDK12 and 13 inhibition in colorectal cancer.
Authors: Altunel Erdem , Zokaasadi Mohammad , Somarelli Jason A. , McCall Shannon J. , Gultawatvichai Patan , Whalen Giles Francis , Pitarresi Jason , Hsu David S.
Published: June 2023

e15601

Background: To date, studies on cyclin-dependent kinase inhibitors in colorectal cancer (CRC), such as targeting CDK4/6 with Palbociclib, have shown little to no clinical benefit. However, tumor profiling of CRC has shown that mutations and amplifications in CDK 12 and 13 are prevalent in 5 to 10% of CRC patients, suggesting that CDK12/13 inhibition may be a potential target for patients with CRC. Methods: To study the effects of inhibiting CDK12 and 13 in CRC, a total of 11 patient-derived organoids (PDO) were first established from patients undergoing biopsy or resection of their primary or metastatic CRC. In vitro drug sensitivity assays were performed by treating each PDO with THZ531, a selective dual CDK12/13 inhibitor; 5-flurouracil, oxaliplatin and SN38 as a standard of care; or Palbociclib (CDK 4/6 inhibitor) at seven different drug concentrations (0.0064 μM - 100 μM) with five replicates at each concentration. Viability was assessed 72 hours following the addition of each drug using CellTiter-Glo (Promega) and IC50s were calculated. Results: Targeting CDK12/13 with THZ531 demonstrated dose dependent activity in the majority of CRC PDOs, with IC50 values ranging from 0.06 μM to 4.2 μM. In comparison, targeting CDK4/6 with Palbociclib was ineffective, with IC50 values ranging from 2.5 μM to 17 μM (p = 0.0003, 95% CI 3.7 to 10.4). Inhibition of CDK12/13 was also more effective than standard of care chemotherapy with either 5- FU or oxaliplatin (mean IC50 values were 4.2 μM and 21.4 μM for 5-fluorouracil and oxaliplatin, p < 0.05) and was comparable to irinotecan (mean IC50 was 0.07 μM for SN38). Finally, no significant correlation was found between sensitivity to THZ531 and microsatellite status, mutations in RAS and BRAF, or grade of the original patient tumor. Conclusions: We identify dual CDK12/13 inhibition as a promising therapy to treat CRC. Further studies will focus on characterizing mechanisms of action, evaluating efficacy and toxicity in vivo, and determining biomarkers of response based on actionable genomic alterations.
Colorectal Cancer Clinical Trial Summit: Devising solutions and interventions.
Authors: Newcomer Kim , Goodman Andrea , Fenstermacher David
Published: June 2023

e15603

Background: Only 5% of adult cancer patients enroll in cancer clinical trials; however, approximately 70% are willing to participate. The numerous gaps between patient willingness and trial participation rates suggest that enrollment in clinical trials can be challenging. The Colorectal Cancer Alliance Clinical Trial Think Tank Summit brought together multidisciplinary voices to propose solutions and tailor interventions to increase participation in colorectal cancer (CRC) clinical trials and save lives. Methods: An expert advisory committee supported the planning of the Summit by collating existing knowledge and best practices from across the field. The Alliance collected patient perspectives through interviews and aligned around three critical themes for change in CRC clinical trials. The Summit created a forum for thoughtful and strategic discussions with expert speakers and sessions to explore thematic solutions. Results: The advisory committee’s research activities and discussion identified strategic solutions across the following themes: 1. Marketing & Messaging Trust in Clinical Trials; 2. Fostering Readiness for Community-Based Cancer Research, and 3. Clinical Trial Patient Navigation. There was consensus that cancer patients and the public need to be educated on the importance of clinical trial access and dispel myths about clinical trials. Messaging must be culturally competent, creating quality standards for trial awareness and participation for utilization in a marketing campaign.  Summit participants discussed barriers to clinical trial enrollment at the institutional, structural, provider, and patient levels. Collaborations with industry sponsors and partnering with community oncology programs are necessary for designing and conducting research serving the understudied and underserved.   Participants identified that navigators are crucial for decentralized clinical trials and are a key element for improving clinical trial efficiency and the patient experience. Developing and launching a centralized clinical trial navigator pilot program is necessary to ensure that navigators are knowledgeable about recruiting CRC clinical trials nationally. Conclusions: Clinical trials are essential to advancing new treatments. To extend clinical research into the community, standardized messaging is needed that dispels myths about clinical trials and highlights positive trial outcomes. By improving our overall messaging, collaboration, education, and access to resources, we can accelerate CRC clinical trial participation to improve outcomes and research answers.
A phase Ib adaptive study of dasatinib for the prevention of oxaliplatin-induced neuropathy in patients with gastrointestinal (GI) cancers receiving FOLFOX chemotherapy with or without bevacizumab.
Authors: Noonan Anne M. , Farid Saira , Schnell Patrick , Trunzo Danielle , Malalur Pannaga G. , Jin Ning , Manne Ashish , Abushahin Laith I. , Rahman Shafia , Hays John L. , Elkhatib Rifat T. , Mittra Arjun , Roychowdhury Sameek , Lustberg Maryam B. , Sparreboom Alex , Hu Shuiying
Published: June 2023

e15613

Background: Neurotoxicity is one of the most significant and disabling side effects of oxaliplatin (OX) and frequently limits the amount of OX that can be used. OX uptake by organic cation transporter 2 (OCT2) into mouse and rat dorsal root ganglia is a prerequisite for OX-induced peripheral neuropathy (OIPN). Preclinical data in rat and mouse models from our group showed that by inhibiting YES1, pre-treatment with dasatinib (D) inactivated OCT2 and prevented acute and chronic OIPN. A phase I trial is ongoing investigating addition of D prior to OX to prevent OIPN. Methods: This is a Bayesian Phase 1b dose-finding study with adaptive dose selection using efficacy-toxicity trade-offs in patients (pts) with GI cancers who are candidates for mFOLFOX6 ± bevacizumab [NCT04164069]. Pts received chemotherapy on day 1 and 15 schedule, every 28 days. D was administered at one of 2 dose levels – 100mg or 140mg PO, given 24 hours and 30 mins prior to OX on C1D14, C1D15 respectively and repeated on C1D28 and C2D1. During cycle 1, pharmacokinetic and pharmacodynamic data was obtained at baseline, during, and up to 24 hours after D or OX administration. Recommended Phase 2 dose (RP2D) was defined as the lowest intermittent dose of D that increases serum biomarkers of OCT2, including methylnicotinamide (NMN) and creatinine, by ≥2-fold without influencing the clearance of oxaliplatin by ≥20%, toxicity profile was evaluated based on CTCAE v. 5.0. Results: 11 pts were screened. 5 pts enrolled in cohort 1 (D 100 mg) and 2 in cohort 2 (D 140 mg). In this preliminary analysis, 5 patients were evaluated for efficacy biomarkers and 4 pts were evaluated for both efficacy biomarkers and toxicity. There were no DLTs observed in either cohort. 3/5 pts had ≥2-fold increase in AUC of NMN, and 4/5 pts had ≥2-fold increase in AUC of creatinine. 4/5 pts had ≤20% change in the clearance of OX. Conclusions: Addition of D 140 mg to traditional FOLFOX regimen was safe and resulted in increasing levels of biomarkers as indication of inhibition of OCT2 in comparison to baseline for the majority of pts enrolled. Enrollment and analysis are ongoing at D 140mg dose to confirm the RP2D to prevent OPIN in a future randomized phase II study. Clinical trial information: NCT04164069 . [Table: see text]
Frequency of fluoropyrimidine-related toxicity in patients with colon cancer from a Mexican oncology center.
Authors: Alvarado Villarreal Francisco J , Garza-Rodriguez Maria Lourdes , Garibay-Villegas Azael Elian , Treviño-Martínez Nicole , Alcorta-Nuñez Fernando , Burciaga Flores Carlos Horacio , Vidal-Gutiérrez Oscar , Burguete-Torres Alan , Pérez-Ibave Diana Cristina
Published: June 2023

e15616

Background: Fluoropyrimidines are chemotherapeutic agents used in various types of cancer such as colorectal, breast, gastric, etc. Approximately 30% of patients treated with fluoropyrimidines present severe toxicity, which can lead to death in around 1% of them. Reduced activity of the enzyme dihydropyrimidine dehydrogenase (DPD) can cause severe fluoropyrimidine-related toxicity. The objective of this study was to identify the frequency of fluoropyrimidine-related toxicity in patients treated at an oncology center from Northeast Mexico. Methods: Retrospective and observational study of patients treated at the Centro Universitario contra el Cáncer (CUCC) in Monterrey, Mexico. Patients older than 18 years with a diagnosis of colon cancer who were treated during 2021 with the diagnosis of colon and considered candidates for fluoropyrimidine-based chemotherapy (5-FU, capecitabine) were included. Pregnant patients were excluded. None of them had a DPYD testing performed. Results: We analyzed 88 patients, of whom 51 (58%) were men, 6 (7%) in stage I, 16 (18%) in stage II, 31 (35%) in stage III, and 35 (40%) in stage IV. The mean age was 59 years, 15 (17%) of them had a PS>2, overall, 94% of patients received fluoropyrimidine-based CT, presenting up to 47 (57%) of toxicities, 26 (32%) in G1, 11 (13%) in G2, and 10 (12%) in G3; no G > 4 toxicities were documented. There were 7 patients (9%) that required CT discontinuation due to toxicity at some point during their treatment (see Table 1). In the subgroup of patients in stage IV, 8 (24%) had PS>2, and 6 (18%) of them had some mutational panel. Conclusions: This is one of the few descriptive studies of toxicities in a population from northeastern Mexico undergoing treatment with fluoropyrimidine-based CT, in which up to 9% of the patients discontinue treatment due to toxicity. Our findings evidence a high percentage of patients with fluoropyrimidine-related toxicity. DPYD testing has not been widely adopted in most oncology centers in Mexico, mostly because of the limited access to genome sequencing. Genetic studies in this population could identify poor metabolizers patients with a high risk of toxicity before starting treatment. [Table: see text]
Association of treatment regimens with quality of life and overall survival in patients with metastatic colorectal cancer in Peru.
Authors: Namuche Fernando , Leon Jorge
Published: June 2023

e15617

Background: Colorectal cancer is a significant public health concern in Peru. Metastatic colorectal cancer patients have limited treatment options, and the prognosis is generally poor. In recent years, treatment regimens for metastatic colorectal cancer have evolved significantly, with the emergence of targeted therapies and immunotherapy. However, little is known about the impact of these treatment regimens on quality of life and overall survival in the Peruvian population. The objective of this study is to investigate the association between treatment regimens and quality of life and overall survival (OS) in Peruvian metastatic colorectal cancer patients. Methods: This retrospective study included patients diagnosed with metastatic colorectal cancer between 2010 and 2020 at the AUNA clinic. Patients were included if they received chemotherapy as first-line treatment and were followed up for at least 6 months. Quality of life was assessed using the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) questionnaire, which includes subscales for physical, social/family, emotional, and functional well-being, as well as colorectal cancer-specific concerns. Treatment regimens considered were: FOLFOX, FOLFIRI and others. Univariate and multivariate analyses were performed to identify factors associated with quality of life and overall survival. Results: A total of 193 patients were included in the study, and the median follow-up time was 14 months. The majority of patients were male (60.6%) and the median age was 57 years. The most common first-line chemotherapy regimens were FOLFOX (52.7%), FOLFIRI (23.5%), and capecitabine plus oxaliplatin (16.4%). The median overall survival was 14 months, and the 1-year overall survival rate was 52.8%. Patients treated with FOLFOX had significantly better quality of life scores than those treated with FOLFIRI or capecitabine plus oxaliplatin (p = 0.012). The difference in quality of life scores was most pronounced in the emotional and social/family well-being subscales. However, there was no significant difference in overall survival among the different treatment regimens (p = 0.344). Multivariate analysis showed that the presence of liver metastases and higher FACT-C scores were independent predictors of OS. Conclusions: Our study has shown that the choice of treatment regimen in Peruvian metastatic colorectal cancer patients can have a significant impact on their quality of life. Patients treated with FOLFOX as first line had better quality of life scores than those treated with FOLFIRI or capecitabine plus oxaliplatin, particularly in emotional and social/family well-being subscales. However, there was no significant difference in OS among the different treatment regimens. The presence of liver metastases and higher quality of life scores were found to be independent predictors of overall survival.
Using deep learning to recognize local advanced rectal cancer in CT images.
Authors: Lin ChunYu
Published: June 2023

e15624

Background: Colorectal cancer was the most prevalent malignant disease in developed country and cause 45% mortality rate. Rectal cancer accounted 40% of this disease and is difficult to treat due to its anatomical position. Preoperative neoadjuvant radio-chemotherapy for local advanced rectal cancer can increase circumferential resection margin (CRM) which lead to lower local recurrence rate. MRI was suggested as staging methods for CRM status and nodal evaluation. However, MRI resources were much less than CT scans. CT scans was prevalent and can provide substantial agreement in CRM evaluation under experienced specialist. This study tries to use deep learning to detect local advanced rectal cancer in CT images at initiation of treatment as advisement for neoadjuvant chemoradiotherapy. Methods: From 2010.10.1~2021.12.31, rectal cancer patients with cT3-4 lesion was included. Collect high quality CT images with DICOM files in tumor segment. cT1-2, low rectal lesions, non-CRC cases were not included. Non-contrast and artificial defect images were also excluded. CT images were labeled as” diseased “ when CRM were threatened ( < 2mm). All images were labeled according to judgment of 2 specialist. The data were separated into 2 parts. One for AI model training and testing, another for external validation. The training testing dataset was achieved by deep learning neuro network and evaluating model accuracy performance. Then the model was applied into external validation dataset for real-world testing, evaluating coherent rate between AI and the Dr. decision. Furthermore, to see the cancer survival outcomes according to AI model prediction results. Results: From 2010.10.1~2022.12.31, 1256 rectal cancer cases images were included. 706 cases (889 CT series, 5958 images) with cT3-4 lesions and high quality DICOM files were eligible. 620 cases (803 series, 5318 images) with cT3-4 lesions were classified in training validation set. 1907 (35.9%) images were diseased, 3411 (64.1%) images were normal. 86 clinical stage 2-3 cases (640 images) directly underwent resection during 2014.12.1-2017.5.31 were classified as external validation group. For recognizing CRM+ local advanced rectal cancer by EfficientNetB0, the algorithm achieved an area under the receiver operating characteristic curve (AUC): 0.91 (86.1% accuracy). For External validation set, the sensitivity for AI to detect CRM+ by Dr was 80%; 88% (by images; by cases), the specificity was 68%; 66% (by images; by cases). The survival curve (local recurrence rate, DFS, OS) was also superior in AI- group than AI+ group which was comparable with the results of Dr. Conclusions: Deep Learning can detect local advanced rectal cancer in CT images and prediction results also implicate poor disease outcome.
Effect of neoadjuvant chemotherapy on overall survival in stage II and stage III colon cancer: A propensity-score matched analysis of the National Cancer Database.
Authors: Horesh Nir , Emile Sameh Hany , Freund Michael , Garoufalia Zoe , Gefen Rachel , Zhou Peige , Nagarajan Arun , Wexner Steven D
Published: June 2023

e15632

Background: Neoadjuvant chemotherapy (NAC) is currently indicated for patients with advanced colon cancer. However, there are little data regarding the impact of NAC on short-term outcomes and overall survival (OS). This study aimed to determine the role of NAC in patients with advanced colon cancer. Methods: A retrospective analysis of all patients with stage II-III colonic adenocarcinoma in the US National Cancer Database (NCDB) between 2006 and 2019. Propensity score matching was used to adjust for possible confounders. The cohort was divided into two equally matched groups: patients who received NAC and controls. The primary outcome was 5-year OS. Results: 902 (1.6% of the original cohort) patients with clinical stage II-III colonic adenocarcinoma were treated with NAC. Before matching, patients treated with NAC were significantly younger (61 vs 76 years; p < 0.001) and more often male (54.5% vs. 46.5%; p < 0.001) and had more private insurance (46.9% vs 22.6%; p < 0.001) and a lower Charlson comorbidity index score (p < 0.001). In addition, patients treated with NAC had more left-sided tumors (41.7% vs 30.1%; p < 0.001) and underwent more resections of a contiguous organ with colonic resection (27.1% vs 7.6%; p < 0.001). After matching, 620 patients were included in each group. The mean OS of patients in the NAC group was comparable to the control group (105.2 months, 95%CI: 98.1-112.2 vs 105 months, 95%CI: 98.2-111.7; p = 0.627). Stratifying OS based on clinical stage demonstrated that mean OS was significantly longer in patients with stage III (100.8 months, 95%CI 92.6-109.1 vs 88.4 months, 95%CI 79.7-97.1; p = 0.01), while the opposite effect was noted in stage II patients (106.1 months, 95%CI 96-116.3 vs 119.8 months, 95%CI 110.5-129.2; p = 0.04). Cox regression survival analysis showed that NAC was significantly associated with a lower risk of mortality (HR 0.72, 95%CI 0.64-0.8; p < 0.001). Conclusions: Preoperative neoadjuvant chemotherapy is associated with improved OS in patients with Stage III colon cancer, but not in patients with stage II disease.
Retrospective study of combined pelvic organ resection in the treatment of primary and recurrent pelvic malignant tumors.
Authors: Zhenyu Li , Zhao Yuzhou , Li Changzheng
Published: June 2023

e15635

Background: For locally advanced or recurrent pelvic malignancies, combined pelvic organ resection has been used to treat rectal, bladder, gynecological and other related malignancies. As an interdisciplinary and high-risk operation, the perioperative safety and future information are often very limited. We retrospectively analyzed the efficacy of PE surgery in our institution. Methods: In this retrospective study, 59 patients with pelvic malignant tumors received PE surgery from July 2015 to July 2021. They were divided into two groups according to the location of the disease: rectal tumor group (n = 40) and cervical cancer group (n = 19). The baseline data, gene detection reports, pathological reports, perioperative conditions and prognosis were analyzed. The two groups were compared by independent sample t-test; Comparison between groups χ2 test, the survival curve was drawn by Kaplan-Meier method and compared by log rank test. Results: Among these 59 patients treated with PE, the rectal tumor group and the cervical cancer group did not differ significantly in terms of demographics, operative time, hospital stay, intraoperative blood loss, and rates of use of preoperative and intraoperative radiotherapy. Compared with the two groups, the overall incidence of postoperative complications was 37% in the group with rectal tumours and 26% in the group with perineal wound infection being the most common, cervical cancer 46% and urinary tract infection being the most common. Comparing the postoperative survival OS between patients in the rectal tumor group and those in the cervical cancer group, the former was better, with 5-year overall survival rates of 37% in the rectal tumor group and 28% in the cervical cancer group. Within the group of rectal tumours, however, there are differences in survival between patients with primary (LARC) and recurrent (lrrc) rectal tumours; Patients with LARC have shown a significant survival benefit postoperatively, with 5-year overall survival rates of 40% for patients with LARC and 27% for patients with lrrc. OS was significantly better in patients with well differentiated tumors, N0 stage, and high microsatellite instability (MSI). On the basis of univariate analysis, poorly differentiated tumor, regional lymph node dissemination, MSI, and no chemotherapy received perioperatively were significant predictors of poor survival (P < 0.05). Conclusions: PE is currently an effective treatment for pelvic malignancies with aggressive radical resection of lesions, which can effectively improve their cure rate, improve quality of life, and careful patient selection can optimize outcomes.
Screening the key pathogenic mutations in Chinese patients with colorectal cancers using liquid and tissue biopsy.
Authors: Wu He , Peng Huixin
Published: June 2023

e15637

Background: Colorectal cancer (CRC) is the third most common cancer worldwide. Over the past decades, significant progress has been made in the clinical treatment of CRC. Targeted therapy is an optional approach that has successfully prolonged overall survival for CRC patients. It is necessary to determine the personalized targets for guiding the usage of specific drugs, which requires biopsy to obtain pathological samples for analysis. Both tissue biopsy and liquid biopsy are commonly used in clinical diagnosis, while each has its own advantages and limitations. The mutation detection rate of tissue biopsy is usually higher, and more genes can be detected, but most tissue biopsies require surgery to obtain samples and may be biased due to the intra-tumor heterogeneity. Liquid biopsy is less harmful to patients, but the detection sensitivity is much lower than tissue biopsy. Methods: In this study, 353 paraffin tissue section samples were used as tissue biopsy samples and 112 blood samples were used as liquid biopsy samples. All samples are from Chinese patients and are collected from December 2021 to August 2022. Whole-genome sequencing was performed, and several processes have been conducted to eliminate noise, duplicates and reads with low depth, therefore the gene mutations detected in the samples were considerably reliable. We selected APC, TP53, KRAS, PIK3CA and BRAF as the key pathogenic genes for CRC, analyzed the mutation detection results in tissue and blood samples. The detection difference between two types of biopsies was assessed using Pearson's Chi-squared test. Results: Among all samples, 21 (5.95%) tissue biopsy samples and 37 (33.04%) liquid biopsy samples did not contain any key pathogenic genes. For all biopsy samples, the detection rates for APC in tissue biopsy samples (n = 236, 66.86%) and liquid biopsy samples (n = 49, 43.75%) demonstrate significant difference (p = 2.02e-05). The differential detection rates were also observed in TP53 (n = 223 vs. n = 51, 63.17% vs. 45.54%, p = 0.0014) and KRAS (n = 183 vs. n = 39, 51.84% vs. 34.82%, p = 0.0024). There is no significant difference in detection rates of PIK3CA (n = 77 vs. n = 15, 21.81% vs. 13.39%, p = 0.0699) and BRAF. Only 25 (7.08%) tissue biopsy samples and 8 (7.14%) liquid biopsy samples were found to detect BRAF (p = 1). Conclusions: Generally, there is no doubt that the overall detection sensitivity of tissue biopsy is higher than that of liquid biopsy for CRC, and our analysis provided the statistical support. But for some relatively rare disease-causing genes, there is not much difference between the two biopsy methods. For patients, tissue biopsies can be more painful than liquid biopsies, so how to improve the detection of liquid biopsy in CRC is still a subject that requires efforts.
Proteome analysis of patients with early onset colorectal cancer in Ireland.
Authors: O Reilly Mary , Kristic Aleksandar , Murphy Catherine , Linehan Anna , Wynne Kieran , Sheahan Kieran , Winter Des C , McDermott Ray , Kolch Walter
Published: June 2023

e15639

Background: Early onset colorectal cancer (EOCRC) is defined as colorectal cancer (CRC) in those under the age of 50. The incidence of EOCRC is rising at an alarming rate. Unlike in the USA, screening for CRC in Ireland begins at 60 years of age. It has been hypothesized that the signatures of CRC in younger populations could differ from that in elderly patients. Deep characterization of the tissue using omics profiling, including proteomics, could provide the answer to this question. Moreover, omics profiling could identify new biomarkers for patient stratification and earlier diagnosis. Methods: Forty micrograms of healthy and matched frozen tumors were taken from 8 patients with locally advanced EOCRC for whole proteome analysis. The samples were digested with trypsin and mass spectrometry was performed using data dependent analysis parallel accumulation serial fragmentation (DDA-PASEF). The raw data was searched against the Homo sapiens subset of the Uniprot Swissprot database (reviewed) with the proteomics pipeline software Fragpipe (Version 19.1) Statistical analysis was performed using Perseus software. Results: When we compared proteomes of 8 tumor tissues versus matched normal tissues, out of 5,717 protein IDs, there were more than 1,300 differentially expressed proteins. Our pathway enrichment analysis, using differentially expressed proteins, has identified a number of molecular functions altered in EOCRC samples. The most enriched signaling pathways were associated with FAT10 signaling, neutrophil extracellular trap (NET) signaling and oxidative stress response. The upstream regulator analysis (URA) has identified LASP1 and LONP1 proteins. LASP1 is known to promote CRC progression via the Hippo signaling pathway, while LONP1 is known to play a role in mitochondrial functions, metabolism, and epithelial–mesenchymal transition (EMT) in CRC cells. Importantly, the NET signaling activation in all samples suggests unfavorable immunomodulation that could stimulate cell proliferation and invasiveness. The observed activation of oxidative stress signaling components is in line with the inflammatory nature of CRC, which could signify potential response to immune checkpoint inhibitors. Conclusions: Our findings in a small cohort of patients indicate that proteomics can provide a deeper insight into aberrant signalling in EOCRC. We have identified novel vulnerabilities that might be used as therapeutic targets as well as patient stratification biomarkers. Additional proteome studies with corresponding genomic and transcriptomic analysis are needed to fully understand the potential of this approach.
Circulating levels of the pro-inflammatory monomeric isoform of C-reactive protein (mCRP) correlate with inflammatory markers in patients with stage II-III colon cancer.
Authors: Fuglestad Anniken Joerlo , Bousquet Paula Anna , Køstner Anne Helene , Meltzer Sebastian , Ree Anne Hansen , Fernandez-Botran Rafael , Kersten Christian
Published: June 2023

e15641

Background: Tumor-promoting inflammation is an established hallmark of cancer. C-reactive protein (CRP) is one of the most studied negative prognostic markers of the systemic inflammatory response (SIR) and known to be implicated in detrimental immune responses. Circulating CRP, as measured in routine practice, is a pentameric structure (pCRP). However, when pCRP binds to activated membranes, the protein dissociates into subunits termed monomeric CRP (mCRP). Pro-inflammatory characteristics of mCRP have been reported to be stronger than for pCRP. While a role for mCRP in cancer has been proposed, the circulating level of mCRP has never been investigated in cancer patients. Our aim was to detect and quantify plasma mCRP of patients diagnosed with stage II-III colon cancer (CC) and investigate possible correlations with other inflammatory markers. Methods: 40 patients treated for stage II-III CC between 2012 and 2015 at Sorlandet Hospital, Norway, were included in the study. 20 patients had pCRP level < 10 mg/L and 20 patients had pCRP > 10 mg/L, the latter interpreted as presence of SIR. Levels of pCRP and albumin were captured at the time of diagnosis. Pre-operative mCRP and the cytokines IL-6, IL-8 and TNFa were all measured using EDTA plasma samples. Pre-operative mCRP levels were measured by a specific ELISA employing reagents kindly provided by Drs. L. Potempa and I. Rajab (Roosevelt University, Schaumburg, IL). Results: Of the 40 patients, 47.5% were female, 57.5% had right-sided primary tumor and 50.0% were stage III. Median values (min-max) were for mCRP 2.55 ng/mL (0.00-10.9), pCRP 9.95 mg/L (0.50-136), IL-6 5.10 pg/mL (2.60-25.1), IL-8 4.95 pg/mL (0.40-32.4), TNFa 5.90 pg/mL (3.10-29.5) and albumin 40 g/L (29.0-46.0). Conclusions: To the authors’ knowledge, this is the first time mCRP has been reported in systemic circulation of cancer patients. Our study shows plasma mCRP to be quantifiable in CC patients, albeit at very low levels. This may be due to its reduced aqueous solubility and supports the notion of mCRP as a circulating particle-bound or tissue-associated isoform. However, despite low circulating mCRP levels and a small number of patients, mCRP still correlated with other well-known SIR markers with proven negative prognostic value in cancer patients, supporting its potential role as a pro-inflammatory player in CC. Further studies correlating SIR with circulating and tissue-bound mCRP are currently being performed. [Table: see text]
Circulating tumor DNA guided therapeutic strategies for colorectal cancer patients with multiple small pulmonary-limited nodules: An open-label, prospective, phase II cohort study.
Authors: Chang Jinjia , Li Wenhua , Jian Qijie , Pang Fei , Li Feng , Wang Kai , Peng Junjie
Published: June 2023

e15645

Background: The clinical diagnosis and treatment of small pulmonary nodules (suspected to be lung metastases) in advanced colorectal cancer (CRC) patients remain controversy. Previous studies have shown that tumor-informed circulating tumor DNA (ctDNA) testing with blood sample can sensitively detect recurrence or metastasis of CRC patients. This study was designed to explore the clinical value of tumor-informed ctDNA test in metastatic CRC patients with small pulmonary-limited nodules. We aimed to identify the low-risk patients for de-escalation therapy, as well as high-risk patients with no evidence of disease (NED) for escalation therapy. Methods: This is an ongoing, open-label, prospective and phase II cohort study (NCT 05495672). According to the longest diameter of the pulmonary nodule, patients were divided into two cohorts: Cohort 1(0-1cm) and Cohort 2 (1-2cm). Tumor-informed ctDNA test (OriMIRACLE S) would be performed every three months until progression or 2 years. The treatment strategy of each patient is decided by a multidisciplinary team depending on ctDNA and lung CT scan results. In general, negative minimal residual disease (MRD) patients will receive only regular follow-up. Patients with positive MRD will receive intensive examination and local treatments for pulmonary nodules such as surgery, radio frequency ablation or stereotactic body radiotherapy combined with or without systemic therapeutic treatment, aiming to achieve NED or cure. Results: From June 2022 to December 2022, a total of 26 patients were screened in the group, one patient was eliminated (with extrapulmonary metastasis), and a total of 25 patients were successfully enrolled. At present, 1 patient died (by acute intestinal perforation), 4 patients were excluded from the group (with the emergence of extrapulmonary metastasis), and a total of 20 patients were in the group. The positive rate of MRD in baseline were 4/11(36.4%) for Cohort 1 and 10/14 (71.4%) for Cohort 2, respectively. Notably, in Cohort 1, 3 of 4 patients with positive MRD at baseline were examined extrapulmonary metastasis during the follow-up examination. Conclusions: Our preliminary results suggested that the positive rate of MRD were higher in Cohort 2 than Cohort 1. Patients with pulmonary nodule less than 1 cm tended to develop extrapulmonary metastasis if baseline MRD was positive. In such circumstances, more intensive follow-up examination is suggested to prevent early disease progression. Clinical trial information: NCT05495672 .
Efficacy and safety of camrelizumab and apatinib combined with neoadjuvant concurrent chemoradiation for MSS locally advanced rectal cancer.
Authors: Jiang Tao , Wang Dongsheng , Cheng Jingjing , Wei Xiaojuan , Fu Jialei , Cao Lianjing , Lei Peijie , Zhang Xianxiang , Gao Yuan , Hu Jilin , Zhang Hongjun , Cao Bin , He Baoguo , Mao Qingdong , Qi Peng , Wang Jigang , Zhou Xiaoming , Tan Junying , Lu Haijun
Published: June 2023

e15647

Background: Long-term neoadjuvant concurrent chemoradiotherapy (CRT) is the standard therapy for local advanced rectal cancer (LARC).However, the pCR rate is only about 15 %. Immune checkpoint inhibitors (ICIs) and antiangiogenic agents have shown activity in advanced rectal cancer, but their efficacy in the neoadjuvant setting is unclear. In this exploratory trial, we evaluate the efficacy and safety of a combination of ICI (Camrelizumab), anti-angiogenesis (Apatinib) and CRT for neoadjuvant treatment of microsatellite-stable (MSS) LARC. Methods: Patients in experimental group received Camrelizumab injection combined with Apatinib tablets and concurrent CRT. Radiotherapy dose: 5040cGy/28f/180cGy; Capecitabine 825 mg/m2 bid on the radiotherapy day; Apatinib 250mg qd d1-d60; Camrelizumab 200 mg q3w, d22, d43, d64. Surgery with total mesorectal excision was performed 7-9 weeks after the end of CRT. The primary endpoint was pCR rate and the secondary endpoints included major pathological response (MPR) rate, R0 resection rate, 2-year DFS rate, 3-year OS rate and safety. Results: From July/2022 to October/2022, a total of 11 patients were recruited and assessed, 90.91% (10/11) of which is at high-risk (cT3 with any MRF involved, any cT4a/b, lateral node +, HLARC). Out of the 11 patients evaluable for pathological response, 4 (36.36%) patients achieved a pCR (AJCC grade 0) and 7 (63.64%) obtained a MPR(AJCC grade 0+1)(table). All patients achieved R0 resection and downstaging. Treatment-related severe adverse events were observed in 3 patients (grade 3-4 transaminase elevations); all fully recovered and received radical surgery. No treatment-related deaths were observed. Conclusions: A promising pCR rate of 36.36%, with mild toxicities, was shown in MSS LARC patients treated with neoadjuvant Camrelizumab combined with Apatinib and long-term CRT plus radical surgery, suggesting the candidate therapy for the future non-surgical approach. Clinical trial information: ChiCTR2100053040 . [Table: see text]
Implementation of 3 month therapy for stage III colon cancer in a large community practice.
Authors: Shklar Victoria , Barnes Martin Christopher , Chaudhary Hira , Ukrani Janta , Staszewski Harry
Published: June 2023

e15653

Background: Standard adjuvant chemotherapy for Stage III colon cancer comprises FOLFOX (5 FU/oxaliplatin(OX)/leucovorin) or CAPOX (capecitabine (CAP), OX) for six months. Toxicity from OX impacts quality of life and persists beyond treatment. In March 2018, the NEJM published the IDEA study demonstrating that 3 month FOLFOX or CAPOX was non-inferior to 6 month with less toxicity, specifically in low risk (LR) populations ( < T4 and/or < N2). National guidelines then incorporated 3 month options. We profiled adoption of these regimens at NY Cancer & Blood Specialists after updated guidelines were published. By examining guideline compliance we hope to improve the treatment of patients with Stage III. Methods: We retrospectively reviewed all 234 electronic charts of patients presenting for management of Stage III after the NEJM publication. Substage, duration of therapy, and reasons for delay or discontinuation were analyzed. Results: 234 patients underwent surgery and presented for consideration of adjuvant therapy. 32 (14%) had stage IIIA, 164 (70%) had IIIB, and 32 (14%) had IIIC. 96 (41%) had high risk (HR) disease, 11/96 (11%) patients were recommended 3 months of therapy and 81/96 (84%) were recommended 6 months. 138 patients (59%) were LR, of which 48/138 (35%) were recommended 3 months of therapy and 81/138 (59%) were recommended 6 months. Thus, 59/234 (25%) patients were recommended to proceed with only 3 months of therapy (see table). 215/234 patients (92%) received adjuvant therapy (2 died prior to treatment start, 8 were not treated due to age or poor performance status, 1 had financial issues, 6 refused, 2 were lost to follow-up). 57 patients received or were planned for CAPOX, 114 for FOLFOX, 41 for CAP, and 9 for 5-FU. Treatment started a mean of 7 weeks post-op. 108/215 patients (50%) required dose interruptions, while 85 (40%) required dose reductions and 14 (7%) switched regimens. 164 patients (76%) completed the full duration with some therapy. 41 patients had a recurrence/progression (34 actually received adjuvant therapy). Conclusions: Among 234 patients with stage III colon cancer intended for adjuvant therapy in a large community practice, 25% were planned for or treated with 3 months vs 6. Of those that initiated therapy, 76% completed treatment. The results of the IDEA trial have influenced decision making for community oncologists. While only a quarter implemented shorter durations of treatment, we expect that this rate will increase as improved patient outcomes are demonstrated. [Table: see text]
Preoperative radiotherapy for select T4 primary and locally recurrent colon cancers: Experience from an Australian quaternary centre.
Authors: Agas Ryan Anthony Francisco , Gosavi Rathin Ryan , Fahey Michael T , Ngan Samuel Y
Published: June 2023

e15656

Background: We report our experience with preoperative radiotherapy for select T4 primary or locally recurrent colon cancers in a single, quaternary institution. Methods: A total of 89 patients with T4 primary (n = 40) and locally recurrent (n = 49) adenocarcinoma of the colon ( > 15 cm from the anal verge) underwent preoperative-intent radiotherapy in our centre from 2005 to 2020. Majority of the tumours arose from the sigmoid, 79% (n = 29) for the T4 primary group and 68% (n = 32) for the locally recurrent group. The most common tumour sites prior to preoperative radiotherapy in the locally recurrent group were the lateral pelvic brim (n = 24; left = 16; right = 8), and the proximal presacral area (n = 13). Of the evaluable patients, 95.8% (23/24) of the T4 primary group and 91.3% (21/23) of the locally recurrent group were MMR-proficient. Preoperative radiotherapy prescription was 45-50.4 Gy given in 1.8-2 Gy per fraction. Concurrent 5-FU based chemotherapy was given in 95% (n = 38) of the T4 primary group and 95.9% (n = 47) locally recurrent group. Median follow-up time was 48.9 months (range, 31.5- 80.7) for the T4 primary group and 43.1 months (range, 24.2- 74.1) for the locally recurrent group. Results: In the T4 primary group, downstaging of the pre-treatment clinical stage was documented in 57.5% (n = 23) and curative-intent surgery was possible in 90% (n = 36), 80.5% (n = 29) of which were R0 resections. On the other hand, curative-intent surgery was possible in 79.6% (n = 39) of the locally recurrent group, 64% (n = 25) of which were R0 resections. Of the patients who underwent surgery, 22% (n = 8) in the T4 primary group and 41% (n = 16) in the locally recurrent group avoided a multi-visceral resection. A pathologic complete response was achieved in 8.3% (n = 3) in the T4 primary group and in 10.3% (n = 4) in the locally recurrent group. For the T4 primary group, 13% had local failures (Hazard rate 3%, 95% CI 1-6%), 38% had any disease progression (Hazard Rate 9%; 95% CI 5-14), and 45% died (Hazard Rate 8%; 95% CI 5-13) during the follow-up period. For the locally recurrent group, 35% had local failures (Hazard Rate 13%, 95 CI 9-19), 61% had any disease progression (Hazard Rate 20%, 95% CI 14-29), and 60% died (13%, 95% CI 9-19) the follow-up period. Grade 1-2 anastomotic leak occurred in a total of 6 (8%) patients, 3 in each group. Readmission after surgery was needed in a total of 17 (22.6%) patients, 4 in the T4 primary group and 13 in the locally recurrent group. There was no 30-day mortality in the entire cohort. Conclusions: Curative-intent resection may be achieved after preoperative radiotherapy for select T4 primary and locally recurrent colon cancer, which may translate in encouraging clinical outcomes for an advanced cohort of patients. Careful patient selection is required to identify which colon cancer patients may benefit with preoperative radiotherapy.
Development and validation of a clinical prognostic model for BRAF V600E mutated colorectal cancer patients based on pathological stage, microsatellite status, and primary tumor site.
Authors: Ou Kai , Yang Lin
Published: June 2023

e15660

Background: Colorectal cancer patients with BRAF V600E mutations may be a heterogeneous population with different outcomes. Clinical and molecular pathologic factors related to the prognosis of colorectal cancer need further investigation. Methods: The clinical and pathological information of 206 patients with BRAF V600E mutated colorectal cancer diagnosed in Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College from 2014 to 2021 was retrospectively collected. LASSO regression, COX regression and Nomograms were used to develop clinical prognostic models. The differentiation was measured by C-statistic and decision curve analysis, and the predicted variability was evaluated by calibration curve. The prognostic model was externally validated with validation set data from 164 patients pooled from 5 studies. Results: Our clinical prognostic model included three variables: pathological stage, microsatellite status, and primary tumor site. In internal validation, the model had a concordant index of 0.785 (95%CI [0.732-0.839]) and a concordant index of 0.754 (95%CI [0.698-0.810]) using pathological staging. External validation confirmed the robustness of the model with a consistency index of 0.670 (95%CI ([0.617-0.724]) and a consistency index of 0.584 (95%CI [0.546-0.622]) using pathological staging. The application of decision curve analysis in both the training set and the validation set showed that our three-factor clinical prediction model was superior to the pathological staging. The calibration graph drawn based on the prediction and the actual situation is close to the 45° diagonal. Conclusions: By adding microsatellite status and primary tumor site on the basis of pathological stage, we improved the discriminability and prediction accuracy of the model, and successfully established a prognosis model for patients with BRAF V600E mutation of colorectal cancer.