bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and effectiveness of subtotal pelvic peritonectomy for patients with colorectal cancer with limited peritoneal metastasis in pelvic cavity.
Authors: Liao Leen , Tang Jinghua , Xiao Binyi , Jiang Wu , Han Kai , Kong Ling-Heng , Yu Jiehai , Pan Zhi-Zhong , Ding Pei-Rong 
Published: June 2023

e15587 Background: Cytoreductive surgery with extensive visceral resection and peritonectomy has shown long-term survival benefits for colorectal cancer (CRC) patients with peritoneal metastasis. However, the extent of peritonectomy remains controversial for limited peritoneal metastasis. This study modified the selective pelvic peritonectomy (SPP) to subtotal pelvic peritonectomy (STPP) for patients with limited peritoneal metastasis in pelvic cavity, and aimed to assess the outcome of STPP. Methods: CRC patients with limited peritoneal metastases in pelvic cavity and underwent R0 resection were included from a prospectively collected database. Grade III/IV morbidity rate, disease free survival (DFS) and overall survival (OS) were analyzed. Results: A total of 51 patients were included (22 in the STPP group and 29 in the SPP group). An average of 60 minutes increased in operative time in the STPP group, but no perioperative mortality occurred. Grade III/IV complication rates did not differ between two groups. At a median follow-up of 38.1 months, the 3-year-DFS was 63.0% in the STPP group and 29.3% in the SPP group ( P = 0.006). The 3-year-OS was 82.6% and 55.6% for the STPP and SPP groups, respectively ( P = 0.033). Moreover, STPP was independently associated with improved DFS. Eight (38.1%) cases with remaining ovaries developed ovarian metastasis, of whom 6 (75%) underwent a second operation. Conclusions: Subtotal pelvic peritonectomy is associated with promising long-term outcome in CRC patients with limited peritoneal metastasis in the pelvic cavity. Prophylactic bilateral oophorectomy should be strongly considered during this procedure.
Proteomic profiling of FOLFOX-resistant colorectal cancer cells.
Authors: Tam Shing Yau , Islam Khan Md Zahirul , Yip Jerica Hiu Yui , Yan Hong Yiu , Tam Tsz Yan , Law Helen Ka Wai 
Published: June 2023

e15588 Background: Chemoresistance is a major cause of colorectal cancer (CRC) mortality. Although multidrug regimen has been established as the backbone of CRC chemotherapy for better treatment efficacy, chemoresistance is common among late-stage CRC. Proteomic profiling of both the chemoresistant and wild-type CRC cells may provide hints for the mechanisms of chemoresistance and suggest targets for improving chemotherapy efficacy. Methods: Human CRC cell lines (DLD-1 and HCT-116) were treated with progressively increased dosage of FOLFOX (5-flurouracil (5-FU), folinic acid (LEU) and oxaliplatin (OXA)) to develop chemoresistance as DLD-1-R and HCT-116-R respectively. After confirmation of the successful development of chemoresistance by Cell Counting Kit-8 test (CCK-8), the comparison of cell samples between chemoresistant and wild-type cell lines were conducted by proteomic profiling using quantitative mass spectrometry (MS)-based techniques. MS and MS/ MS peptides spectra were analysed by Progenesis QI for proteomics software compared with Swiss-Prot dataset. Differentially expressed proteins (DEP) are defined as -1 > log2FC > 1, p < 0.05. Gene-list enrichment by Enrichr (https://maayanlab.cloud/Enrichr/) was employed for identifying the hallmark gene sets of the significantly enriched molecular processes and pathways of each group. All experiments were performed with at least 3 replications. Results: The development of FOLFOX-resistance took one year. The highest drug concentrations achieved were 0.5mM 5-FU, 50µM LEU, and 50µM OXA for DLD-1-R, and 5µM 5-FU, 0.5µM LEU, and 0.5µM OXA for HCT-116-R. The chemoresistance was found to be 14.73 (DLD-1-R) and 1.61 (HCT-116-R) times of the wild-type DLD-1 and HCT-116 respectively from CCK-8 tests. A total of 345 DEP with 154 up-regulated and 191 down-regulated proteins were found in DLD-1-R. While a total of 95 DEP with 66 up-regulated and 29 down-regulated proteins were found in HCT-116-R. Gene ontology molecular process (2021) analyses found that cadherin binding were significantly enriched in both DLD-1-R and HCT-116-R (Adjusted p-value < 0.05). KEGG pathway (2021) analysis found that oxidative phosphorylation, regulation of actin cytoskeleton and HIF-1 signalling pathway are among the significantly enriched pathways in DLD-1-R (Adjusted p value < 0.05). There was no significantly enriched pathway found in HCT-116-R in the same analysis. Conclusions: Our study has successfully established CRC cells with chemoresistance to the FOLFOX regimen. Proteomic profiling has found the cadherin binding as the significantly altered molecular process along with several important signalling pathways in chemoresistant CRC cells. These findings could suggest new directions in the development of anti-chemoresistance strategies of CRC.
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.&nbsp; 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. &nbsp; 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.