bluuebunny/crossref_metadata_2025_split huggingface dataset:
Short-course radiotherapy in rectal cancer: A single-center experience in Argentina.
Authors: Tissera Natalia Soledad , Freile Berenice , Luca Romina , Pedraza Ivana Inés , Esteso Federico , Enrico Diego Hernán , Waisberg Federico , Galli Mariana , Chacon Carolina , Sanchez Loria Fernando , Huertas Eduardo , Chacon Matias Rodrigo , O'Connor Juan Manuel 
Published: January 2023

146 Background: Short-course radiotherapy (SCRT) is an option in the neoadjuvant setting of resectable stage II-III rectal cancer, as well as in stage IV disease for local control without delay to initiate systemic treatment. Short-course radiotherapy is reported to be a comparable strategy for locally advanced rectal cancer. Limited data exist regarding the use of short-course radiation therapy when used as part of a non-surgical watch and wait approach. Methods: This is a retrospective analysis of all patients that underwent SCRT for rectal cancer at the Alexander Fleming Institute from 3/2014 to 6/2022. Results: 44 patients were treated with SCRT, 29 (66%) were male, with a median age of 59 years (46-73). Most of the patients had stage IV disease (26, 59,1%) followed by clinical stage II-III (18, 40,9%). 30 (68%) were localized in the middle with 14 (32%) in the lower rectum, by MRI imaging. In locally advanced disease 5/18 had T4 disease and 7/18 had N≥2. 14/18 patients (89%) underwent SCRT followed by consolidation chemotherapy (ChT) and 4 (11%) had induction ChT followed by SCRT. In metastatic disease 14/26 patients (53.84%) underwent SCRT followed by consolidation ChT, 10 (38.46%) had induction ChT followed by SCRT, and 2 (7.7%) received only SCRT. 29 (65.9%) of patients underwent surgery. 17/29(58.6%) had metastatic disease and 12/29 (41.4%) had locally advanced disease. Pathological response rates in operated patients were 2 (6.9%). 8 (18.2%) cases had a clinical complete response (cCR) (n=6 stage II-III and n=2 stage IV). Five (27.7% of the locally advanced group) patients with cCR underwent watch and wait with 1 local recurrence after 14 months. The remainder is disease free with a median follow-up time of 20 months (IC 95%: 15.14-24.85). Those that underwent SCRT following chemotherapy were more likely to have AEs compared to those that had chemotherapy following SCRT (11/30, 36.7% vs 25%, p=0.02). Conclusions: Our work shows that in a subgroup of patients diagnosed with LARC treated with SCRT followed by Chemotherapy, surgical treatment could be deferred after achieving a complete clinical response. The shorter time involved by SCRT allowed for less treatments with similar toxicity to long-course treatment regimens. SCRT is a reasonable option for local disease control in stage IV disease.
Efficacy and safety of neoadjuvant immune checkpoint inhibitors in patients with localized mismatch repair deficient colorectal cancer: A systematic review.
Authors: Grewal Udhayvir Singh , Vora Kruti Bhagirath , Parikh Aparna Raj , Mahipal Amit , Chakrabarti Sakti 
Published: January 2023

149 Background: Clinical data demonstrating remarkable anti-tumor activity of immune checkpoint inhibitors (ICI) in patients with mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) and preclinical data suggesting enhanced efficacy of ICIs in the neoadjuvant setting than in the adjuvant setting led to numerous studies with neoadjuvant ICI in various tumor types including in dMMR CRC. We performed a systematic literature review of the published studies reporting the efficacy and safety of neoadjuvant ICIs in patients with localized dMMR CRC. Methods: Medline and Embase were searched for eligible case reports, case series, and clinical trial reports. Eligibility criteria included: 1. patients aged 18 years or older, 2. localized dMMR CRC, and 3. received neoadjuvant therapy primarily with ICI. Patients receiving radiation or chemotherapy along with ICI were excluded. The systematic review was conducted according to the PRISMA harms guidelines. Results: The database search yielded 143 citations which were reviewed by 3 authors (UG, KV, and SC), and 14 citations fulfilled all criteria for inclusion. The analysis included 173 patients with colon cancer (CC) and 19 with rectal cancer (RC). Among the patients with CC, 41 (24 %) received single-agent programmed death 1 (PD-1) blocker, and 132 (76 %) received dual blockade with an anti-PD-1 agent plus an anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) agent. Resection was performed in 171/173 (99%) patients, and 117/171 (69%) achieved complete pathological response (pCR). After median follow-up ranging between 8 and 15 months, none of the patients experienced cancer relapse. Among patients with RC, 16/19 (84%) received a PD-1 blocker, and 3 (16%) received dual PD-1 plus CTLA-4 blocker. Complete clinical response (cCR) was reported in 14/19 (74%) patients, and of the 5 patients who underwent surgery, 4 (80%) achieved pCR. All patients remained progression-free after median follow-up ranging from 6 to 12 months. Cancer progression or death on neoadjuvant ICI was not reported in any studies with CC or RC patients, and only two studies reported grade 3+ toxicity in 3% of CC patients. Conclusions: Neoadjuvant therapy with ICIs results in a remarkably high rate of clinical and pathological tumor regression with negligible safety concerns in patients with dMMR localized CRC. Well-designed clinical trials with long-term follow-up are needed to evaluate the organ-sparing potential of neoadjuvant ICI therapy in patients with dMMR CRC.
Impact of COVID-19 pandemic on diagnosis, staging, and outcomes of patients with early-onset colorectal cancer.
Authors: Martinez-Perez Daniel , Viñal David , García Cuesta Jose Ángel , Rueda-Lara Antonio , Ruiz-Gutierrez Iciar , Jiménez-Bou Diego , Peña-Lopez Jesus , Martin-Montalvo Gema , Alameda-Guijarro Maria , Gutiérrez-Sainz Laura , Barbachano Antonio , Rodriguez-Cobos Javier , Bustamante-Madrid Pilar , Larriba Maria Jesús , Fernandez-Barral Asuncion , Burgos Aurora , Prieto-Nieto Maria Isabel , Pastrian Laura Guerra , Gonzalez-Sancho Jose Manuel , Rodriguez Salas Nuria 
Published: January 2023

15 Background: Although we seem to be recovering from COVID-19, we are now facing the long-term consequence of the pandemic on vulnerable subgroup of patients such as patients with early-onset colorectal cancer (EOCRC). We aim to study how the COVID-19 pandemic affected the diagnosis and clinic-pathological characteristics, treatment and outcomes of patients with EOCRC. Methods: This is an observational retrospective study including patients with EOCRC diagnosed between September 2016 and August 2021 at Hospital Universitario La Paz, Madrid, Spain. Two cohorts were stablished: before and after March 14, 2020, the day of the first lockdown in Spain. Results: A total of 1409 patients with CRC were included. Of those, 5,2% were EOCRC (n=75). Fifty-five (73%) and 20 (27%) were diagnosed pre, and post pandemic. The rate of EOCRC diagnosis per month was 1,8 and 1,1 in the pre and postpandemic group, respectively. Fifty percent of patients in the postpandemic group were diagnosed with metastatic disease, while only 29% had stage IV at diagnosis in the prepandemic subgroup (P = 0,09). High tumor budding, surgical margins affected, lymphovascular, and perineural invasion were also pathological features more observed in the postpandemic subgroup, although results are not statistically significant. The differences between both groups are depicted. After a median follow-up of 23 months (33 and 14 months in the pre and postpandemic group, respectively), 11 patients have died (15%). Median overall survival (OS) was not reached in either group. At 12 months, 94% and 89% of patients were alive in the pre and postpandemic group, respectively. Conclusions: COVID-19 has influenced the diagnosis and staging of patients with EOCRC. Long-term follow-up is needed to assess the survival in this population. The role of primary care in the diagnosis and early referral of these patients is, more than ever, crucial. [Table: see text]
Efficacy and safety of fruquintinib plus mFOLFOX6/FOLFIRI as first-line therapy in advanced metastatic colorectal cancer (mCRC).
Authors: Zhou Fuxiang , Wen-bo Wang , Xia Ling , Dai Jing , Wu Han , Yang Lei , Xiong Zhiguo , Gong Jun 
Published: January 2023

152 Background: Fruquintinib is a highly selective, and potent oral inhibitor of VEGF receptor 1, 2, 3 and has been recommended as a third-line treatment for mCRC patients (pts) in China because of its low toxicity, favorable ORR and survival benefit. FOLFOX/FOLFIRI is the preferred chemotherapy regimens of first-line for mCRC pts according to the NCCN guideline. Our study aimed to investigate the efficacy and safety of fruquintinib plus mFOLFOX6/FOLFIRI as first-line therapy in advanced mCRC pts. Methods: In this prospective, open-label, multi-center, single-arm phase 2 study (NCT05004441), pts who are diagnosed with unresectable mCRC, without prior systemic threated are recruited. RAS/BRAF status should be detected to exclude BRAF mutations before enrollment. Pts receive fruquintinib (3mg, QD, PO, Q4W) in combination with mFOLFOX6/FOLFIRI (Q2W) for up to 8 cycles. Pts with SD or above are followed by maintenance therapy (fruquintinib 3mg, QD, PO, Q4W, capecitabine 850mg/m2, BID, PO, D1-7, D15-21, Q4W) until disease progression or intolerable toxicity. The primary endpoint is objective response rate (ORR), and secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Results: Based on a data cutoff of September 2, 2022, 19 pts have been enrolled and treated, of which 13 pts have efficacy evaluation data. Media age is 60 (range: 50-73) years and 62% pts are male. 7 (54%) pts harboring RAS mutations while the remaining pts are wild-type (wt). 54% treated with mFOLFOX6. At a median follow-up of 5.9mo, all 13 pts are still on treatment. In best overall response assessment, the ORR is 77%, with 10 (77%) partial response (PR). Stable disease (SD) is 3 (23%) with a DCR of 100%. Median PFS has not yet reached. Safety profile exhibited that the regimen is tolerable and mainly grade 1/2. Grade 3 treatment-related adverse events (TRAEs) are neutrophil count decreased (23%), GGT increased (15%), leukopenia, AST increased and hypertension accounted for 1% respectively. No pts have serious adverse events. Conclusions: Combination treatment with fruquintinib plus mFOLFOX6/FOLFIRI as the first-line therapy followed by fruquintinib plus capecitabine maintenance in advanced mCRC pts shows promising efficacy and manageable safety profile. Longer follow up data with PFS, and OS will be presented. Clinical trial information: NCT05004441 .
Phase Ib study of dabrafenib, trametinib, irinotecan and cetuximab in BRAF V600E-mutated metastatic colorectal cancer.
Authors: Chen Yungchang , Li Xiaoqian , Yuxin Man , Hu Hai , Wang Liyang , Zhang Zhixuan , Chen Ping , Liu Yang , Lu Jin , Lin Tongyu 
Published: January 2023

156 Background: The low efficacy of single-agent BRAF inhibitor in metastatic colorectal cancer (mCRC) is usually due to EGFR feedback upregulation caused by BRAF blockade. Therefore, multi-drug combination therapy with BRAF inhibitor has been tried. Here, we reported the preliminary results of quadruple therapy with dabrafenib, a selective BRAF inhibitor, trametinib, a selective MEK inhibitor, irinotecan and cetuximab in patients with BRAF V600E-mutated mCRC. Methods: This was an ongoing phase Ib study, patients with mCRC who relapse or refractory to standard treatments were enrolled. Patients were treated with dabrafenib (150mg/150mg doses orally twice daily), trametinib (2mg orally once daily), irinotecan (80mg/m2 weekly) and cetuximab (400mg/m2 in first dose and 250mg/m2 weekly). Treatment was continued until disease progression, development of unacceptable toxicity, or drawal of consent. The primary end-point was disease control rate (DCR), and the secondary end-points included progression-free survival (PFS) and duration of disease remission (DOR). This trial is registered with Chinese ClinicalTrials.gov, number ChiCTR2200063316. Results: From July 2018 to January 2021, 10 patients were enrolled. The median age was 53.5 (age 25-65), nine with colon cancer and one with rectal cancer. The most common adverse events (AEs) (50% or more) were fatigue, fever, rash, vomit, leukopenia, anemia, ALT elevation, and AST elevation. Four patients suffered rash which was the most common severe AE (SAE). Two patients presented with grade 3/4 anemia. Only one patient suffered grade 3/4 AEs with nausea and vomit. The DCR was 90% (9/10). After a median follow-up of 19.7 months, the median PFS was 7.5 months (range 1.8-32.4 months). The median DOR was 5.2 months (range 0-27.7 months). Conclusions: Dabrafenib, trametinib, irinotecan and cetuximab has tolerable toxicity and promising antitumor activity in BRAF V600E-mutated mCRC. This regimen warrants a further phase II clinical trial. Clinical trial information: ChiCTR2200063316 . [Table: see text]
A systematic review to assess the efficacy of HER2-targeted treatment regimens in HER2-positive metastatic colorectal cancer (mCRC).
Authors: Bakhtiar Muhammad , Gholami Sepideh , Saeed Anwaar 
Published: January 2023

166 Background: Recently, there has been a breakthrough in the treatment and disease control of HER-2 positive mCRC using Trastuzumab (TRA) +Tyrosine Kinase inhibitor (TKI) regimens and regimens with trastuzumab based antibody drug conjugates (ADCs). Methods: A total of 14 randomized controlled trials and single arm clinical trials were collected from PubMed, Cochrane library, and Embase. 7 trials were excluded for being duplicate, irrelevant or because of lack of response from the trial researchers. Data from the remaining 7 articles was extracted either from the full publication or from researchers for undergoing studies. Trials using similar drug combinations were added up and results were reported cumulatively. Results: The data demonstrate an ORR of 30% or greater with the ADC, TRA deruxtecan or TRA+Tucatinib regimen with the Tucatinib combination being the most efficacious (38.10%), followed closely by the Deruxtecan ADC (36.99%). Promising disease control rate (DCR) was observed with all the combinations with TRA-Ematasin + Pertuzumab leading the charts (77.40%). TRA-Lapatinib provided the longest PFS (16.75 months) followed by TRA-Tucatinib (8.2 months) (Table). Most common treatment related adverse events (AEs) were fatigue, nausea, vomiting, diarrhea and dermatitis. More nausea/vomiting reported with TRA-deruxtecan (64.4%), while more diarrhea reported with TRA-lapatinib (81%) and TRA-tucatinib (52.3%). Dermatitis was reported mostly with TRA-lapatinib (44%) and TRA-tucatinib (17.4%). Conclusions: Our analysis shows that combination treatment with TRA-Deruxtecan and TRA-tucatinib are associated with the highest ORR and DCR in HER2+ mCRC. Long term data are needed to define clinical efficacious based on survival endpoints.[Table: see text]
Impact of Lynch syndrome, BRAFV600E, and RAS mutations on outcomes in MSI/dMMR metastatic colorectal cancer (mCRC) treated with immune checkpoint inhibitors (ICI): Analysis of combined international cohorts.
Authors: Colle Raphael , Lonardi Sara , Cachanado Marine , Overman Michael J. , Elez Elena , Fakih Marwan , Corti Francesca , Jayachandran Priya , Svrcek Magali , Dardenne Antoine , Duval Alex , Cohen Romain , Pietrantonio Filippo , Andre Thierry 
Published: January 2023

171 Background: ICI have demonstrated efficacy in patients (pts) with MSI/dMMR mCRC . Lynch (LS) vs sporadic (Sp) status, BRAFV600E and RAS mutations (mt) are known factors of clinical and molecular heterogeneity in this population. We aimed to evaluate the prognostic value of these parameters in ICI-treated MSI mCRC pts. Methods: Pts are drawn from international cohorts (France, Italy, Spain, and USA). Pts were considered to have cancer linked to LS only in case of determined germline mutation and Sp in case of loss of MLH1/PMS2 protein expression associated with BRAF V600E mutation and/or hypermethylation of MLH1 promoter, or in case of biallelic somatic mutations of MMR genes. Survival analyses: progression-free survival (PFS) per iRECIST criteria and overall survival (OS) were adjusted on prognostic modifiers, selected on unadjusted analysis (p < 0.2) in case of limited number of events. Results: On the 466 pts included, 112 (24%) received ICI in first line, 305 (65%) received anti-PD1 alone, 161 (35%) anti-PD1 plus anti-CTLA4, 129 (29%) had BRAFV600Emt and 153 (34%) RASmt. Median follow-up was 24.0 months. In adjusted analysis of the whole population (n=466; 186 PFS events and 143 OS events), no association with PFS and OS was observed for BRAFV600E mt (PFS HR 1.20 [0.80 to 1.79], p=0.372; OS HR 1.06 [0.66 to 1.70], p= 0.811) and RASmt (PFS HR 0.93 [0.64 to 1.36], p= 0.712; OS HR 0.75 [0.48 to 1.17] p= 0.202). Adjusting factors were age, ECOG status, number of prior chemotherapies, treatment type (bi vs monotherapy), sidness (right vs left + rectum), primary tumor surgery. Concerning the population with determined Lynch status (n= 242; 83 PFS events and 54 OS events), PFS results are displayed. The analysis of impact of LS was not adjusted on BRAFV600E mutational status due to collinearity. In adjusted analysis, LS improved PFS compared with Sp (HR = 0.49, 95%CI (0.25 to 0.96), p = 0.036). Adjusted HR for OS was 0.56 without reaching significance 95%CI (0.25 to 1.22), p = 0.143. Conclusions: In this analysis of ICI-treated MSI/dMMR mCRC pts, RAS/BRAFV600E mutations are not associated with survival while Lynch syndrome pts demonstrated improved PFS. [Table: see text]
Metabolomic differences in young-onset versus average-onset colorectal adenocarcinoma.
Authors: Jayakrishnan Thejus , Farha Nicole , Mariam Arshiya , Rotroff Daniel Miller , Aucejo Federico , Barot Shimoli V , Conces Madison , Nair Kanika G. , Krishnamurthi Smitha S. , Schmit Stephanie , Liska David , Khorana Alok A. , Kamath Suneel Deepak 
Published: January 2023

174 Background: Novel deleterious effects of environmental exposures may play a role in the rising incidence of young-onset colorectal cancer (yoCRC). We used metabolomics to assess differences between yoCRC and average-onset CRC (aoCRC), in comparison to healthy controls, which may suggest certain exposure risks. Methods: Patients with stage I-IV CRC and healthy controls were identified from prospective biobanks and categorized based on age<50 years (yoCRC or young controls) or age>60 years (aoCRC or older controls). Serum metabolites were profiled using GC-TOF mass spectrometry. Differential abundance of metabolites was investigated using unadjusted logistic regression. Metabolic pathway analysis was performed using Metaboanalyst 5.0. All p-values were adjusted for multiple testing (false-discovery rate, FDR p<0.20 considered significant). Results: The study population comprised 170 CRC patients (66 yoCRC and 104 aoCRC) and 49 healthy controls (34 young and 15 old). Association analyses revealed four differentially abundant metabolites: citrate (FDR p=0.04), cholesterol (0.14), and two unidentified metabolites (UM). Metabolic pathways significantly altered in yoCRC vs. aoCRC included: carbohydrate metabolism (citrate cycle, FDR p=0.11), carbohydrate biosynthesis (glyoxylate and dicarboxylate metabolism, FDR p=0.03), amino-acid metabolism (alanine, aspartate, and glutamate metabolism, FDR p=0.04, arginine biosynthesis, FDR p=0.04, and amino-acid t-RNA biosynthesis, FDR p=0.04). There were no significant metabolomic differences between young and older controls. Conclusions: We identified significant differences in the citrate cycle - a core pathway of cellular metabolism and associated with colorectal cancer. Metabolomic differences in pathways of carcinogenic significance (aspartate) and environmental exposures (arginine and dietary red meat) were also noted, suggesting potential relationships with younger age of CRC onset. The study provides future directions for more precise analyses with a larger sample size for healthy controls and adjusting for confounders. [Table: see text]
Molecular characterization of metastatic colorectal cancer (mCRC) in patients (pts) treated with cetuximab and pembrolizumab.
Authors: Fountzilas Christos , Rosario Spencer , Withers Henry G. , Mukherjee Sarbajit , Bajor David L , Saltzman Joel N. , Wang Chong , Attwood Kristopher , Knudsen Erik S. , Witkiewicz Agnieszka K , Iyer Renuka V. , Boland Patrick M 
Published: January 2023

178 Background: Anti-EGFR therapy has the potential to increase a localized anti-tumor immune response. We recently published the results of a phase Ib/II trial of the anti-EGFR antibody cetuximab in combination with the anti-PD1 antibody pembrolizumab in pts with advanced, RASwt CRC (PMID: 34645646). Despite its partial local immunologic efficacy, this combination of cetuximab and pembrolizumab was inactive. Here we present the results of comprehensive molecular characterization of pts with tumors amenable to DNA and RNA sequencing. Methods: Forty-two pts with RASwt mCRC were treated with cetuximab plus pembrolizumab. Archival or fresh tumor samples were obtained at baseline and, in select patients, on-treatment. Tumor samples underwent targeted DNA sequencing and whole transcriptome sequencing. Gene set enrichment analysis (GSEA), metabolic dysregulation assessment, and immune deconvolution were performed. Genomic data were linked to clinical outcomes. Results: Eighteen pts had tissue available for dual DNA/RNA extraction and sequencing. Of these, 10 had available matched on-treatment tumor samples. The most common mutations detected in protein coding regions were TP53 (14 pts), ERBB4 (5 pts), CDKN2A and APC (6 pts each). There were no statistically significant differences in progression-free survival (PFS) in pts with and without resistance-associated mutations (i.e., RAS, MET, ERBB4). Further, there was no significant difference associated with the consensus molecular subtype (CMS). However, when we compared patients with stable/increased tumor change percentage to those with decreased tumor change percentage, we found downstream transcriptional differences associated with altered metabolism, and in particular lipid and amino acid metabolism. Conclusions: We identified a significant number of patients with mutations predicting resistance to either or both cetuximab and pembrolizumab; however, none were associated with survival. However, we did identify metabolic pathways of interest, which may be associated with response to therapy. It is important to note, our analysis is limited by the small number of specimens (Trial registration NCT02713373). Clinical trial information: NCT02713373 .