bluuebunny/crossref_metadata_2025 huggingface dataset:
Application and evaluation of fecal SDC2 gene methylation in the diagnosis and treatment of colorectal cancer.
Authors: Xie Rongjia , Liu Zhuqing , Xu Qing
Published: June 2024

e15541

Background: SDC2 gene encodes the transmembrane proteoglycan molecule Syndecan-2. Syndecan-2 protein affects the proliferation, migration and invasion of colorectal cancer cells by regulating cell adhesion, tissue differentiation and angiogenesis. The aim of this study is to verify the sensitivity and specificity of fecal SDC2 gene methylation in the detection of colorectal cancer, find the dominant population who can benefit from this detection, expand its clinical application scenarios, and explore its role in the evaluation of the efficacy and prognosis of patients with advanced colorectal cancer. Methods: A total of 72 patients diagnosed with colorectal cancer were included in the study. The methylation level of SDC2 gene in feces of patients was detected by fluorescence PCR. We evaluated sensitivity and specificity and assessed associations between fecal SDC2 methylation levels, fecal occult blood tests, characteristics of the lesions on colonoscopy, and clinical practice. The critical value of reaction solution A was 10.0, and the critical value of reaction solution B was 10.5. When the Ct value of any tube of reaction solution A or B was less than the critical value, it was judged as "positive". Results: Data from 72 patients were evaluated, with a sensitivity of 89.1% (41/46 95%CI 0.798 to 0.985) for patients with untreated colorectal cancer. The sensitivity of SDC2 methylation detection was 46.2% (12/26 95%CI 0.256-0.667) in patients with partial response or stable disease after palliative treatment. The difference in the detection rate of SDC2 methylation between the two groups was statistically significant (P < 0.001). Among the 46 untreated patients with colorectal cancer, 32 patients with positive SDC2 gene methylation received radical surgery, and 30 of them (93.75%) turned to SDC2 gene methylation negative after surgery. Patients who achieved clinical benefit (CR+PR+SD) found reduced SDC2 gene methylation levels in the stool.There was no significant difference in the methylation level of SDC2 gene between colorectal cancer patients with different fecal occult blood test results (-, +, ++, +++) (P = 0.564)、different lesions (ascending colon, transverse colon , descending colon , sigmoid colon, and rectal) (P = 0.179)、different stages (stage I, II, III, IV) (P = 0.828)、different types (infiltrative, ulcerative, protruding) (P = 0.629), and different sizes of lesions (≤ 5cm, 6-9cm, ≥10cm) (P = 0.644). Conclusions: The high sensitivity of fecal SDC2 gene methylation in detecting untreated CRC patients may help make colonoscopy a screening method only for those at high risk of developing CRC. It may help to evaluate the efficacy of radical surgery, predict the recurrence of colorectal cancer and monitor the efficacy of palliative treatments for colorectal cancer. This work was supported by Shanghai Shenkang Project (No.SHDC2022CRT009).
The effect of HER2-targeted inhibitors as second-line or later-line regimens in the treatment of HER2-positive advanced colorectal cancer: A systematic review and meta-analysis.
Authors: Zhang Qianyuan , Liu Haiyu , Zhang Suyun , Chen Jinghan , Luo Qiong , Xu Qian , Chen Xiangqi , Yang Sheng
Published: June 2024

e15542

Background: To systematically evaluate and meta-analyze the efficacy and safety of Human Epidermal Growth Factor Receptor-2 Inhibitor (HER2 Inhibitor) as a second-line or later-line antitumor regimen in the treatment of HER2-positive advanced colorectal cancer and provides a new method to treat metastatic colorectal cancer who failed with first-line treatment. Methods: Literature focusing on the use of HER2-targeted inhibitors in the treatment of HER2-positive mCRC was downloaded from Pubmed, Web of Science, EMBASE and Google Scholar databases from January 1, 2019 to October 31, 2022, and the final included articles were determined by screening and relevant data were extracted, including Objective Response Rate (ORR), disease control rate (DCR), Progression-Free-Survival (PFS), Overall Survival (OS), and Serious Adverse Events (SAEs) (Grade 3/4 adverse events). Binary variables were compared using 95% confidence intervals (CI) and odds ratios (OR); for continuous variables, heterogeneity was checked using Cochran's Q Test (p values and I²) and Weighted mean difference (WMD) and 95% CI. P < 0.05 or I² > 50% denote statistical significance, and results were combined using a random-effects model. The efficacy and safety of adding HER2-targeted inhibitors in treating HER2-positive mCRC were further discussed using the above methods. Results: The systematic review and meta-analysis included 17 studies with a total of 267 patients, with an overall DCR of 57% (95% CI: 43%-70%), an ORR of 29% (95% CI: 21%-37%), a median OS of 13.11 months (95% CI: 10.57-15.64), a median PFS of 4.40 months (95% CI: 3.64-5.15), and SAEs of 20% (95% CI: 0.11-0.29). The efficacy of the second-line and later-line treatment was significantly better than that of the well-known EPIC study, ML18147 study, CONCUR study and FRESCO-2 study. Conclusions: Systematic review and meta-analysis show that HER2-targeted inhibitors as second-line or later-line regimens demonstrate ideal antitumor efficacy and safety in HER2-positive mCRC, which is better than the standard regimen without anti-HER2 therapy. Specifically, the new ADC drug (A antibody-drug Conjugate, ADC) should be able to improve the treatment effect of these patients more effectively. Therefore, HER2-targeted inhibitors can effectively improve the efficacy of second-line and later-line therapy for HER2-positive mCRC. Furthermore, it is still worth exploring its therapeutic effects application as first-line therapy, which is expected to offer new strategies for the clinical diagnosis and treatment of HER2-positive advanced colorectal cancer.
Predictors of survival outcome of TAS102 combined with bevacizumab compared to TAS102 alone in Saudi patients with metastatic colorectal cancer beyond second line of systemic therapy.
Authors: Elsamany Shereef Ahmed , Alghanmi Hosam , Tashkandi Emad M , Al-Shehri Ahmed Saleh , Hassanin Fayza , Abdulaziz Nashwa A. , Alhowari Mai , Mahrous Mervat , Alghamdi Mohammed Abdullah
Published: June 2024

e15545

Background: Significant proportion of metastatic colorectal cancer (mCRC) patients receive systemic therapy beyond second line. This study aims to assess predictors of survival outcome in patients treated with TAS 102/bevacizumab compared to TAS102 alone beyond 2nd line. Methods: In this retrospective study, we assessed patients with mCRC treated with TAS102/bevacizumab or TAS102 alone beyond second line in 4 institutes in Saudi Arabia from January 2020 to December 2022. We checked progression-free survival (PFS) and overall survival (OS) of the study group and we assessed different parameters that may affect the survival outcomes. Results: We included 68 patients in this analysis (39 treated with TAS102/bevacizumab, 29 with TAS102 alone) with a median follow up of 20 months. Noteworthy, 39.7% of patients received treatment in third line (56.4% vs. 17.2%, respectively, p = 0.001) and 48.5% developed neutropenia with first cycle (51.3% vs. 44.8%, p = 0.59). Time from stage IV diagnosis to study treatment (TTAS102) was > 18 months in 56.4% vs. 44.8 %, respectively, p = 0.34. The two treatment arms were balanced for other parameters including site of primary tumour, tumour stage at diagnosis. Median PFS was significantly higher with TAS102/Bevacizumab compared to TAS102 alone (5 vs 3 months, HR = 0.59, 95% CI 0.35-0.98, p = 0.043). Similarly, median OS was significantly improved with TAS102/bevacizumab (15 vs 8 months, HR = 0.55, 95% CI: 0.30-0.98. p = 0.034). After adjustment of line of study treatment, TTAS102 and number of metastatic sites, PFS and OS were significantly improved with TAS102/bevacizumab compared to TAS102 alone (PFS: HR = 0.48, 95% CI: 0.26-0.89, p = 0.021), (OS: HR = 0.54, 95% CI: 0.26-0.91, p = 0.034). Survival outcomes were higher with TAS102/bevacizumab compared to TAS102 in patients with TTAS102 > 18 months (PFS: 5 vs. 3 months, HR = 0.27, 95% CI: 0.12-0.62, p = 0.002), (OS: 22 vs. 6 months, HR = 0.28, 95% CI: 0.11-0.68, p = 0.005) and in patients with neutropenia with first cycle (PFS: 6 vs 3 months, HR = 0.45, 95% CI: 0.21-0.98, p = 0.043), (OS: 26 vs 8 months, HR = 0.33, 95% CI: 0.13-0.81, p = 0. 0.016). No difference in survival outcomes in patients with TTAS102≤ 18 months and those with no neutropenia with first cycle. Conclusions: TAS102 with bevacizumab is associated with improved PFS and OS beyond 2nd line compared to TAS 102 alone especially in patients with longer TTAS102 and first cycle neutropenia.
Quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) analysis of fruquintinib + best supportive care (BSC) compared with placebo + BSC in metastatic colorectal cancer (mCRC): Results from the FRESCO-2 trial.
Authors: Stintzing Sebastian , Tabernero Josep , Satoh Taroh , Dasari Arvind , Lonardi Sara , Eng Cathy , Garcia-Carbonero Rocio , Elez Elena , Yoshino Takayuki , Sobrero Alberto F. , Yao James C. , Kasper Stefan , Arnold Dirk , Basic Edin , Granold Matthias , Petschulies Marco , Wu Liwen , Chen Lucy F. , Yang Zhao , Van Cutsem Eric
Published: June 2024

e15554

Background: As mCRC and its treatment can adversely impact quality of life (QoL), maintaining QoL is an important treatment goal in addition to improving survival outcomes, particularly as patients progress through lines of therapy. In the global, randomized, double-blind, phase 3 FRESCO-2 trial (NCT04322539), fruquintinib (F) + BSC vs placebo (P) + BSC demonstrated significantly improved overall survival (OS) (median 7.4 months vs 4.8 months; HR 0.66, 95% confidence interval [CI] 0.55–0.80) and progression-free survival, with a manageable safety profile and without deterioration of QoL in heavily pretreated patients with refractory mCRC. The objective of this post-hoc Q-TWiST analysis was to assess the quality-adjusted survival benefit of F + BSC in the context of the FRESCO-2 trial. Methods: The Q-TWiST analysis was applied to all 691 randomized patients from FRESCO-2 (F + BSC n = 461 vs P + BSC n = 230). Survival time of each patient was partitioned into 3 health states: time spent with treatment-emergent adverse events of CTCAE grade 3 or 4 before disease progression (TOX), time before disease progression without toxicity (TWiST), and time between disease progression and death or censoring (REL). Assuming utility coefficients of 1 for TWIST and 0.5 for TOX and REL, Q-TWiST was calculated as the utility-weighted sum of the time spent in each health state. The mean time spent in each of the 3 health states was calculated for each treatment group using Kaplan-Meier analysis, and a 95% CI for the difference between treatment was calculated using the nonparametric bootstrap method. Results: Q-TWiST was 6.25 months for F + BSC and 4.21 months for P + BSC, a difference of 2.04 (95% CI 1.51–2.57) months longer with F + BSC vs P + BSC. This difference in Q-TWiST was mainly driven by the difference in the TWiST component (2.14 months [95% CI 1.78–2.49]; F + BSC 4.06 months vs P + BSC 1.92 months). The relative Q-TWiST gain, calculated as the difference in Q-TWiST divided by the mean OS time of the P + BSC group, was 31.4% in favor of F + BSC. Conclusions: In the FRESCO-2 trial, F + BSC demonstrated a clinically meaningful quality-adjusted survival benefit compared with P + BSC in heavily pretreated patients with refractory mCRC. Clinical trial information: NCT04322539 .
Regorafenib Plus for third-line treatment in metastatic colorectal cancer: A real-world study.
Authors: Yisilamu Patiguli , Yao Jiannan , Ge Yang
Published: June 2024

e15562

Background: Regorafenib, approved as a monotherapy for refractory metastatic colorectal cancer (mCRC), is recognized for its potential immunomodulatory effects and ability to reverse chemotherapeutic resistance. In response to this, a combination regimen known as regorafenib Plus has been customized for specific patients. This study aims to evaluate the effectiveness and safety of regorafenib as a standalone treatment and in combination with other therapies (including concurrent/sequential chemotherapy, immunotherapy, transarterial chemoembolization [TACE]) in the real-world setting. The goal is to present viable treatment options for patients with mCRC. Methods: In this retrospective study, patients with chemo-refractory metastatic colorectal cancer (mCRC) who underwent regorafenib treatment at Beijing Chaoyang Hospital between January 2018 and October 2023 were stratified into two cohorts: monotherapy (Rego Mono) and concurrent/sequential combination therapy (Rego Plus). Index date was the initiation of regorafenib therapy in a sequence and median follow-up was 19.1 months. The clinical outcomes included progression-free survival (PFS), overall survival (OS), and 1/2-year OS rates. Results: A total of 67 pts were included (n = 39 Rego Mono; n = 28 Rego Plus). Baseline characteristics were comparable between cohorts. The median progression-free survival (PFS) was significantly extended in the Rego Plus group compared to Rego Mono (8.0 vs. 3.6 months, P = 0.000), and overall survival (OS) was also notably prolonged (24.4 vs. 19.1 months, P = 0.046). The 1/2-year OS rates were also improved by Rego Plus (63% vs 37.1%, 25.5% vs 11.4%). However, there were no statistical differences in PFS between concurrent and sequential combination therapies (8.4 vs 8.0 mont). Notably, under sequential therapy, after 3.7 months of PFS with regorafenib alone, an additional 4.7 months of PFS was observed when combined therapy was introduced. Regarding safety, Rego Plus was associated with an increased rate of adverse events (AEs) without an escalation in severity. Common AEs included rash, hand-foot syndrome, hypertension, and diarrhea. Conclusions: Rego Plus significantly prolonged PFS and OS in patients with chemo-refractory mCRC. Particularly when tumor stabilization is evident during monotherapy, the introduction of Rego Plus can offer a comparable or even longer PFS benefit, nearly doubling the PFS. Despite an elevated rate of AEs, the severity of these events did not increase, suggesting good tolerability. This approach has the potential to enhance the effectiveness of existing third-line therapies for mCRC, ultimately contributing to an improved prognosis for patients.
Chemotherapy plus EGFR antibody as conversion treatment in RAS wild type, right-sided metastatic colon cancer: A systematic review and meta-analysis.
Authors: Wang Jian , Wang Xiangling , Xia Pingtian , Wang Yanlei , Sun Dong , Guo Sen , Dai Yong , Hao Jing
Published: June 2024

e15568

Background: The optimal conversion strategy for right-sided RAS wild type (WT) metastatic colorectal cancer (mCRC) remains a contentious issue, especially regarding the role of EGFR antibodies. EGFR antibody treatment might be an attractive option in patients with contraindications to bevacizumab or in hyperselected patients with microsatellite stable subtypes and without RAS/BRAF/HER2 alterations, potentially allowing a shorter time to conversion surgery. Methods: We performed a systematic search of PubMed/MEDLINE and EMBASE for randomized trials reporting the overall response rate (ORR) and resection rate following chemotherapy (CT) plus anti-EGFR agents (cetuximab or panitumumab) for right-sided mCRC. Studies were selected regardless of whether the resection rate was a study endpoint or not. We used a random-effects model with generic inverse variance to compute pooled ORR and resection rates and to compare CT regimens combined with anti-EGFR or anti-VEGF agents. Results: Ten randomized trials with a total of 4465 mCRC patients were included; seven trials reported the resection rate as a secondary endpoint. 828/4465 (18.5%) patients were right-sided, of whom 419/828 (50.6%) patients received CT doublet or triplet plus anti-EGFR, 263/828 (31.8%) treated with CT plus bevacizumab, and 146/828 (17.6%) patients with CT alone. The ORR was significantly higher in the anti-EGFR group compared to CT alone (50.89% vs 31.03%, OR: 2.23 [95% CI: 1.50-3.32], p < 0.01). No significant difference in ORR was observed between the CT plus anti-EGFR and CT plus bevacizumab groups (50.89% vs 53.32%, OR: 0.89 [95% CI: 0.65-1.21], p = 0.44). Resection rates were 8.08% for CT plus anti-EGFR, 4.79% for CT plus bevacizumab, and 12.24% for CT alone, with no significant differences among the three arms (χ2= 2.15, p = 0.34). Subgroup analysis of RAS/BRAF WT patients with right-sided tumors from the PARADIGM and PEAK trials showed no difference in progression-free survival (PFS) between the CT plus anti-EGFR or bevacizumab groups (11.01m vs 11.60m, HR = 1.04 [95% CI: 0.58-1.50]), but there was a trend toward improved overall survival (OS) with anti-EGFR treatment (30.66m vs 28.67m, HR = 0.81 [95% CI: 0.45-1.17]). Conclusions: The data indicate that augmenting chemotherapy with anti-EGFR could be a viable conversion therapy for patients with RAS/BRAF WT right-sided mCRC, underscoring its potential utility in this subset of patients.
Outcomes of patients with peritoneal carcinomatosis treated with HIPEC and chemotherapy or HIPEC alone: A single center community experience.
Authors: Huber Benjamin Michael
Published: June 2024

e15578

Background: Peritoneal carcinomatosis is a common presentation of intraperitoneal malignancies. The optimal management of peritoneal carcinomatosis is currently unknown but can contain a combination of HIPEC and chemotherapy. Optimal timing and order of these interventions is controversial. HIPEC surgery alone can provide a cure rate of approximately 16% with macroscopically complete resection. The PRODIGE 7 trial demonstrated no difference in overall survival between HIPEC plus cytoreduction versus cytoreduction alone with six months of systemic chemotherapy. Which patients should receive HIPEC, chemotherapy and HIPEC or chemotherapy alone remains unknown. Methods: This is a single center, retrospective chart review assessing all patients age 18 and above who received HIPEC surgery with and without the administration of chemotherapy at Ascension Saint John Hospital. Results: We found that there was no significant difference in overall survival and progression free survival between the HIPEC and HIPEC with chemotherapy group with a OS of 57.2 months and 52.5 months; and PFS of 33.6 and 34.4 months respectively. We found that patients with a PCI score between 0 and 13, overall survival favored the HIPEC alone group versus the HIPEC with chemotherapy with a p value of 0.043. There was no difference in progression free survival and overall survival in all other groups when stratified by PCI. When stratified by disease subtype, we no differences between PFS and OS for both appendiceal and colon cancer. Conclusions: The primary objective of this study was to investigate the difference in overall survival and progression free survival among patients with peritoneal carcinomatosis when treated with either HIPEC with systemic chemotherapy versus HIPEC alone. This analysis among 100 patients showed no statistically significant differences in OS or PFS for patients receiving a combination of HIPEC with systemic chemotherapy versus HIPEC alone. The only exception to this was with respect to OS in patients with a PCI score between 0-13. In this group, 0 patients in the HIPEC along group experienced disease progression where 5 progressed in the HIPEC and chemotherapy group. Our data suggests that HIPEC alone may be a reasonable treatment approach for patients with a low PCI score. Important conclusions can be drawn from the data when compared to historical trials. The PROTEGE 7 study found that the median overall survival was approximately 41.7 months for the HIPEC and cytoreductive surgery group and 41.2 months versus cytoreductive surgery alone. The overall survival for the HIPEC alone group was 57.2 months and 52.5 months for the HIPEC plus chemotherapy group. This data suggests that the combination of HIPEC and chemotherapy is a reasonable approach to patients with peritoneal carcinomatosis.
The impact of socioeconomic status on gastrointestinal cancer care delivery in southeast Texas.
Authors: Abdelhakeem Ahmed , Anwar Junaid , Thompson Jacob , Terro Telice , Henry Sara , Blevins Samantha , Vasefi Maryam
Published: June 2024

e15579

Background: Gastrointestinal (GI) cancers are a leading cause of cancer deaths in the US with an estimated 1,038,410 new cases and a 30.4% mortality rate in 2023. Disparities in cancer care are well documented and result from several variables, including socioeconomic status (SES), behavioral, and biological factors. We conducted a retrospective population-based cohort study aimed to investigate the relationship between various socioeconomic factors and delays in cancer treatment initiation, emphasizing the impact of gender, race, age, and geographical distance on the time to treatment initiation (TTI). Methods: We identified patients with colorectal, hepatobiliary, small intestinal, and gastroesophageal cancers, who received their cancer diagnosis and initiated treatment at Baptist Hospitals of Southeast Texas in Beaumont, Texas between January 2012, and December 2017. SES data, including age, sex, race, geographical distribution, insurance status, cancer staging, and treatment were collected. Logistic regression was performed to determine risk association by calculating odds ratios with 95% confidence intervals, as well as p-values to determine significance. The primary outcomes of interest were the overall survival (OS) rate, and TTI defined as the time interval between the confirmed cancer diagnosis and initiating the first treatment modality. Results: A total of 517 GI cancer patients were included in this study, with 359 comprising a cohort of patients with colorectal cancer. The majority of patients included were ; caucasians(%) males (%).. African American patients were significantly more likely to receive delayed treatment, Odds Ratio (OR): 5.89, 95% confidence interval (CI) 4.02-8.62, especially compared to the odds for similar Caucasian patients (OR: 0.16, CI: 0.11-0.23). When compared to younger counterparts, patients above the age of 80 were found to have poorer odds of prolonged survival (OR: 2.91, CI: 1.80-4.72). Patients who lived 30 miles away or further from our hospital had longer TTI compared to those living within 30 miles radius (OR: 1.85, CI: 1.19-2.87), a risk which remained significant within the colorectal cancer cohort (OR: 2.20, CI: 1.29-3.74). Patients with Medicare insurance showed longer TTI (OR: 1.50, CI: 1.01-2.23), and decreased OS (OR: 1.79, CI: 1.05-3.06)). No statistically significant difference was observed based on gender. Conclusions: Age, geographical location, and racial SES variables contribute to the disparities in GI cancer care in our community. Addressing these disparities and implementing targeted interventions to mitigate the impact of socioeconomic barriers is imperative to ensure equitable access to timely and effective cancer care, ultimately leading to improved patient outcomes and cancer survival rates.
Circulating tumor DNA (ctDNA) kinetics in colorectal cancer (CRC) treated with curative intent in the VICTORI study with an ultrasensitive MRD assay.
Authors: Solar Vasconcelos Joao Paulo , Titmuss Emma , Navarro Fabio , Abbott Charles , Chia Brendan , Topham James T. , Ladua Gale , Krishnan Tharani , Hegebarth Daniela , Lim Howard J , Gill Karamjit , Gill Sharlene , Brown Carl J. , Ghuman Amandeep (Anu) , Meneghetti Adam , Renouf Daniel John , Schaeffer David F. , Chen Richard , Boyle Sean Michael , Loree Jonathan M.
Published: June 2024

e15625

Background: Detection of molecular residual disease (MRD) with ctDNA is highly prognostic for recurrence in CRC. However, many cancers still recur without detectable ctDNA and increased lead time before clinical recurrence may create a window of opportunity to intervene. Here we apply an ultra-sensitive assay, NeXT Personal, to profile patients in the VICTORI study, a prospective cohort of patients with CRC managed with curative-intent treatment. Methods: To date, the first 33 patients with CRC have undergone panel creation. NeXT Personal was employed to construct personalized liquid biopsy panels for each patient with up to ~1,800 single nucleotide variants (SNV) identified via whole-genome sequencing. For each patient, plasma is collected before curative intervention (baseline), every 2 weeks for 2 months (MRD window), and every 3 months for up to 3 years (surveillance). VICTORI will enroll > 175 patients and include a health economics analysis. Results: Of 33 patients enrolled to date, 25 (76%) are stage I-III and 8 are stage IV treated with curative interventions. 18 colon cancers and 15 rectal cancers are included. Pre-operative baseline sensitivity was 90.6% (29/32; 1 patient excluded as pCR at the time of baseline blood draw). Of the MRD- patients at baseline, 2 had prior neoadjuvant treatment and 1 was stage 1. Preliminary results (median 7.2 month follow-up; 5 recurrences) show 80% (4/5) of recurrences are MRD+ at the 4-week landmark and 50% (2/4; 1 missing sample) were MRD+ at the 2-week landmark. In 75% (3/4) stage II-III recurrences, the first MRD+ detection was in the ultra-low range of < 100 PPM ( < 0.01% tumor fraction). MRD detection at week 4 and 8 trended towards poorer recurrence-free survival (RFS) with similar separation of patients (log rank p = 0.062 and p = 0.011, respectively). Conclusions: Preliminary results from our prospective study demonstrate strong rates of ctDNA detection at week 4 landmark analysis, potentially due to detection of very low levels of ctDNA with an ultra-sensitive MRD assay. The majority of the first detections for MRD were in the ultra-low ctDNA range, indicating the importance of high sensitivity MRD testing. [Table: see text]
A GWAS in Swedish colorectal cancer families with gastric and prostate cancer.
Authors: Samola Winnberg Johanna , Vermani Litika , Liu Wen , Soller Veronika , Thutkawkorapin Jessada , Lindblad Mats , Lindblom Annika
Published: June 2024

e15644

Background: We have previously suggested a syndrome with increased risk for colorectal- and other cancers, primarily gastric- and prostate cancer. The data favoured this syndrome inherited as a complex disease. Therefore, we conducted a Genome Wide Association Study (GWAS) on colorectal cancer patients, who’s relatives had prostate-, and/or gastric cancer. Methods: The GWAS analysis consisted of 685 cases of colorectal cancer and 4780 healthy controls from Sweden. A sliding window haplotype analysis was conducted using a logistic regression model.Thereafter, we performed sequencing to find candidate variants, finally to be tested in a nested case-control study. Results: Candidate loci/genes on ten chromosomal regions were suggested with odds ratios (ORs) between 1.71-3.62 and p-values < 5x10-8 in the analysis. The regions suggested were 1q32.2, 3q29, 4q35.1, 4p15.31, 4q26, 8p23.1, 13q33.3, 13q13.3, 16q23.3 and 22q11.21. All regions, except one on 1q32.2, had protein coding genes, many already shown to be involved in cancer, such as ZDHHC19, SYNPO2, PCYT1A, MYO16, TXNRD2, COMT, and CDH13. Sequencing of 122 colorectal cancer patients with gastric- and prostate cancer in their families identified 10 candidate variants from six of the loci in the haplotype regions to finally be tested in a nested case-control study of similar colorectal cancer cases and controls. Conclusions: There was some support for an increased risk of colorectal-, gastric-, and/or prostate cancer in all the six loci tested. [Table: see text]
Effect of combinatorial immune checkpoint blockade on myocardial expression of NLRP-3 and secretion of H-FABP, NT-Pro-BNP, interleukin-1β, and interleukin-6: Biochemical implications in cardio-immuno-oncology.
Authors: Paccone Andrea , Quagliariello Vincenzo , Passariello Margherita , Iovine Martina , Bisceglia Irma , Ascierto Paolo Antonio , Inno Alessandro , Maurea Fabrizio , Giacobbe Ilaria , Berretta Massimiliano , Giordano Vienna , Izzo Francesca , Barbato Matteo , Arianna Raffaele , De Lorenzo Claudia , Maurea Nicola
Published: June 2024

e24016

Background: Immune checkpoint blockade in monotherapy or combinatorial regimens with chemotherapy or radiotherapy have become an integral part of oncology in recent years. Monoclonal antibodies against CTLA-4 or PD-1 or PDL-1 are the most studied ICIs in randomized clinical trials, however, more recently, an anti-LAG3 (Lymphocyte activation gene-3) antibody, Relatlimab, has been approved by FDA in combination with Nivolumab for metastatic melanoma therapy. Moreover, Atezolizumab is actually under study in association with Ipilimumab for therapy of metastatic lung cancer. Myocarditis, vasculitis and endothelitis are rarely observed in these patients on monotherapy, however new combination therapies could expose patients to more adverse cardiovascular events. Methods: human cardiomyocytes, human peripheral blood lymphocytes (hPBMCs) and combinatorial ICIs (PD-L1 and CTLA-4 or PD-1 and LAG-3 blocking agents, at 100 nM) for 48 h. After treatments, cardiac cell lysis and secretion of biomarkers of cardiotoxicity (H-FABP, troponin-T, BNP, NT-Pro-BNP), NLRP3-inflammasome and Interleukin 1 and 6 were determined through colorimetric and enzymatic assays. Mitochondrial functions were studied in cardiomyocyte cell lysates through quantification of intracellular Ca++, ATP content and NADH:ubiquinone oxidoreductase core subunit S1 (Ndufs1) levels. Histone deacetylases type 4 (HDAC-4) protein levels were also determined in cardiomyocyte cell lysates to study potential epigenetic changes induced by immunotherapy regimens. Results: Both combinations of immune checkpoint inhibitors exert more potent cardiotoxic side effects compared to monotherapies against human cardiac cells co-cultured with human lymphocytes. LDH release from cardiac cells was 43% higher in PD-L1/CTLA-4 blocking agents, and 35.7% higher in PD-1/LAG-3 blocking agents compared to monotherapies. HDAC4 and intracellular Ca++ levels were increased, instead ATP content and Ndufs1 were reduced in myocardial cell lysates (p < 0.001 vs untreated cells). Troponin-T, BNP, NT-Pro-BNP and H-FABP, were also strongly increased in combination therapy compared to monotherapy regimen. NLRP3 expression, IL-6 and IL-1β levels were also increased by PDL-1/CTLA-4 and PD-1/LAG-3 combined blocking agents compared to untreated cells and monotherapies. Conclusions: Data of the present study, although in vitro, indicate that combinatorial immune checkpoint blockade, induce a pro- inflammatory phenotype, thus indicating that these therapies should be closely monitored by the multidisciplinary team consisting of oncologists, cardiologists and immunologists.
Investigation of cardiotoxicity with concomitant use of anthracyclines and checkpoint inhibitors.
Authors: Mazloom Anita , Asturias Jose Alejandro , Manan Haris , Prodduturvar Pranitha
Published: June 2024

e24022

Background: Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment and currently are the standard of care for early stage triple negative breast cancer in combination with anthracyclines (AC). It is known that both ICI and AC carry risk of cardiotoxicity. Studies have also shown that there is increased risk of cardiotoxicity with dual ICI. However no studies have evaluated the risk with concomitant use of ICI and AC. Here we investigated if there is increased cardiotoxicity risk with this combination regimen in a retrospective study. Methods: We did a retrospective analysis of patients with stage II and stage III triple negative breast cancer treated with combined AC and ICI at University of South Alabama Mitchell Cancer Institute Mobile, AL from January 2020 until June 2023. Data included demographics, cardiovascular (CV) risk factors and treatment. CV risk factors were detailed from 2022 ASCO guidelines. Echocardiograms were used to evaluate left ventricular ejection (LVEF). Therapy related cardiovascular toxicity was defined by ESC guidelines 2022 as any new decrease in LVEF to < 40% or any decrease in LVEF < 50% and 10 percentage points decrease from baseline. Adverse events (AE) and risk analysis were calculated. Results: Of the total 49 patients, all were female with a mean age of 53 years old (30-82). 55% of patients had less than 2 CV risk factors (n = 27) and 45% had more than 2 (n = 22). 84% completed all 4 cycles of neoadjuvant AC course without dose adjustment. The median number of cycles of Pembrolizumab was 12 with a range of 7 to 17 cycles including adjuvant Pembrolizumab. All patients had a baseline echo with LVEF > 55%. Two patients (0.04%) developed cardiotoxicity. One patient had LVEF that decreased to EF 45-50% while on surveillance. Another patient developed myocarditis during treatment with EF 25-30% and died from cardiogenic shock. Both patients had 2 CV risk factors and were African American. Only 24% (n = 12) had surveillance echocardiograms completed one year post treatment. Conclusions: Our study results showed that cardiotoxicity risk was lower compared to that in the Keynote-522 trial. The outcomes are limited as a majority (76%) of the patients did not have surveillance echos completed. While the risk of cardiotoxicity with ICI and AC have been studied independently, there have been mouse models that showed that AC therapy may make heart vulnerable to toxicity from ICI therapy. To our knowledge, this is the first study to evaluate cardiotoxicity in patients who received concomitant AC and ICI treatment. Our study highlights the importance of prospective studies and long term follow up to monitor cardiotoxicity in these patients as early detection is key to prevent future morbidity. [Table: see text]
Cardiovascular toxicity of fluoropyrimidines: Experience from a quaternary referral center.
Authors: Chedid El Helou Michel , Laderian Bahar , El Hajjar Abdel Hadi , Mushtaq Ali , Sadler Diego , Moudgil Rohit , Griffin Brian , Collier Patrick
Published: June 2024

e24028

Background: Fluoropyrimidines, including 5-fluorouracil (5-FU) and capecitabine, are widely used chemotherapeutic agents. Their use has been linked to various forms of cardiovascular (CV) toxicity. We sought to analyze the rate of CV events and associated factors in patients receiving fluoropyrimidines at our institution. Methods: We included all patients who received intravenous 5-FU or oral capecitabine at the Cleveland Clinic since 2000. Diagnosis data was obtained based on ICD-10 Codes. CV events included chest pain/angina, myocardial infarction, chronic ischemic heart disease, arrhythmias, conduction disorders, cardiac arrest, cardiomyopathy, and heart failure. CV events were accounted for if they occurred during treatment or within 30 days following the latest administration of the agent. Logistic regression was performed to identify predictors of CV events. Results: A total of 17,236 patients were included, of which 9,386 (54.5) received 5-FU and 7,850 (45.5) received capecitabine. Median age at treatment was 63. The most frequent malignancies were gastrointestinal (70%) and breast cancer (12.3%). A total of 2,283 patients (13.2%) experienced at least one CV event either during treatment or within 30 days following drug administration. The most frequent CV events were chest pain/angina (35.7% of all events). On multivariable logistic regression, factors associated with increased risk of CV events were black race, smoking history, hypertension, and obesity (Table). A prior history of CV disease was also associated with increased risk of CV events (OR 1.22; 95% CI [1.09 - 1.33]). Finally, intravenous 5-FU was linked to higher odds of CV events compared to oral capecitabine (OR 1.48; 95% CI [1.34 - 1.63]). Conclusions: This large-scale cohort study provides pivotal insights into the cardiovascular risks associated with fluoropyrimidine therapy. Besides traditional risk factors, black patients were more likely to suffer from CV events. Additionally, capecitabine may offer better CV outcomes compared to 5-FU. These findings underscore the need for refined risk assessment and enhanced cardiovascular monitoring in patients treated with fluoropyrimidines. [Table: see text]
End of life treatment in gynecological cancers in an integrated care model: A single institution experience from Oman.
Authors: Zribi Aref , Faisal Abdellatif Ahmed Amnah , Al-Sayegh Hasan , A Burney Ikram
Published: June 2024

e24036

Background: The use of chemotherapy closer to the end of life (EOL) and the optimal time of initiating palliative care interventions are subjects of ongoing debate. In a traditional care model (TCM), the institution of EOL care is a complex decision-making process, that involves patient, family members, and the oncologist, and involves transfer of patients from one to the other service. Integrated care model (ICM) is a newer concept, is designed around the needs of the patients, and may have the potential to improve quality of life and reduce the cost of healthcare towards EOL. At our center, we work in ICM in organ-based clinical programs and report the use of systemic treatment in patients with gynecological cancers (GC) nearing EOL. Methods: We analyzed retrospectively the use of chemotherapy and other systemic cancer-directed therapies in patients with GC, who died between Sept 2021 and December 2023 at a single institution. Information on the cancer-type, intention of treatment, and the time between last treatment and death was obtained from electronic patient records (EPR). Results: Over the study period, a total of 22 patients passed away. All patients received palliative care as part of the integrated care. All patients had been declared ‘not for resuscitation’ before death. Twelve patients had ovarian cancer, 5 had endometrial cancer, 4 had cancer of cervix, and one had vulvar cancer. The median age at diagnosis was 53 years (29-80). The systemic treatment was 1st line in 5 patients (23%), 2nd line in 8 patients (36%), and 3rd or more line in 6 patients (27%) respectively. Three patients (14%) did not receive any cancer-directed treatment (aged 80, 71 and 61). The ultimate line of treatment was cytotoxic chemotherapy for all patients, except for one who received Olaparib, and one who received trastuzumab with chemotherapy. There was no treatment-related mortality. The median time from last treatment to death was 55 days. Of the 19 patients who received treatment, 6 patients (32%) received treatment in the last 30 days, 5 between 30 and 60 days (26%), 5 between 60 and 90 days (26%), and 3 more than 90 days before death. Four patients died at home. Age at diagnosis (51 vs 55 years), age at death (51.5 vs 57.5 years), or time from diagnosis to death (11.5 vs 22 months), did not predict whether patients received treatment within the 30 days of death or earlier. Conclusions: All patients received palliative care as part of integrated cancer care. The ICM may have led to lower use of cancer treatment near EOL. The data may provide a benchmark for the region.
Adoption of the International Cognition and Cancer Task Force recommendations for harmonizing studies of cancer-related cognitive impairment: A systematic review of published literature.
Authors: Ferguson Robert J. , Patel Janvi V. , Orosco Naomi Massoud , Sinagra Chloe
Published: June 2024

e24043

Background: This abstract presents a review of published research literature to determine research investigators’ rate of adoption of the International Cognition and Cancer Task Force (ICCTF) recommended criteria for defining cancer-related cognitive impairment (CRCI). Published in 2011, the ICCTF recommendations were intended to identify psychometric standards that would facilitate harmonization of neuropsychological test data across studies for improved accuracy of estimating prevalence of CRCI in cancer populations. The ICCTF recommended standards could help decipher variability or stability of CRCI prevalence across various cancer groups, such as individuals within a diagnostic classification (e.g., lung or breast cancer) or type of cancer treatment (e.g., chemotherapy, immunotherapy, or radiation therapy). However, since publication in 2011, the use of the ICCTF recommendations in CRCI research has not been examined. Methods: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we restricted study selection to only published studies that examined CRCI using standardized neuropsychological tests (vs. self-report measures). We then identified studies that used the ICCFT recommendations based on the ICCTF psychometric definition of cognitive impairment: In a standard battery of neuropsychological tests, one neuropsychological test score >2 standard deviations (sd) below the mean of a healthy control sample, or 2 neuropsychological test scores of >1.5 sd’s below the control mean, is considered a case of cognitive impairment. Results: We screened 146 CRCI studies published since 2011, with 93 manuscripts that utilized neuropsychological tests to evaluate CRCI. Of those, 35 (37.6%) incorporated the ICCTF recommendations in their methodology and data analysis. Between 2011 and 2022, there was a gradual adoption of ICCTF recommended standard of defining CRCI, ranging from 0% of published studies in 2011 to 56.2% in 2022, but a decline to 40% in 2023. With respect to cancer populations, ICCTF guidelines were most often used in studies of individuals with breast cancer (n = 17;18%). Conclusions: This review demonstrates increased use of the ICCTF recommended definition of CRCI in empirical investigations since their 2011 introduction but a decline in 2023. Use of the ICCTF recommendations can improve accuracy of estimating CRCI prevalence across different cancer disease populations and/or groups of individuals undergoing different cancer therapies. Greater adoption of the ICCTF definition of CRCI is encouraged especially considering a 2023 drop in its use. Broadening the study of CRCI using ICCTF recommendations among cancer populations beyond breast cancer is encouraged to better understand the breadth of impact CRCI across the spectrum of disease.
Head and neck cancer survivors’ perception of lymphedema care.
Authors: Kline-Quiroz Cristina , Murphy Barbara A. , Ridner Sheila H. , Smith Derek , Schlundt David G. , Bonnet Kemberlee
Published: June 2024

e24046

Background: Secondary lymphedema and fibrosis occurs in more than 90% of HNC survivors. Given the progressive nature of lymphedema, prompt identification and treatment are essential. Treatment of HNC related lymphedema is fraught by numerous barriers. Advanced pneumatic compression devices (APCD) may address critical barriers. We conducted a phase 3 randomized multi-site trial in HNC survivors with treatment naïve lymphedema comparing usual care to APCD. Here in we report a qualitative analysis of participants treatment experience. Methods: Semi-structured interviews were audio recorded and transcribed after participants completed the 6th-month visit (N = 14 usual care, N = 23 APCD). Questions addressed treatment experience, perceptions of care, barriers, and facilitators. A hierarchical coding system was developed and refined using the interview guide and preliminary review of the transcripts. Transcripts were coded by experienced qualitative researchers. The coded transcripts were analyzed using an iterative inductive-deductive approach and based on our theoretical framework. Results: Participants were 65% male, 35% female and identified as 92% white, 5% black, and 5% Hispanic. The average age was 62 with a range of 32-82. We identified two distinct and one common set of barriers and facilitators. For usual care, health system (care coordination, logistics) and therapist factors (perceived skills and demeanor) were important while device characteristics (fit, comfort) were important for the APCD. Cognitive affective factors (self-efficacy, knowledge, outcome expectations, frustration) were similar for both therapies and interacted with the device/system characteristics. Conclusions: We identified distinct treatment barriers and facilitators for usual lymphedema care and treatment with APCD. Barriers identified in this study highlight practice changing opportunities to address system issues and develop interventions to enhance care and quality of life. Utilization of both treatment strategies may allow tailoring of treatments thus optimizing outcomes. Clinical trial information: NCT04797390 .
Influence of intensity-modulated radiation therapy on long-term survival and late injury in patients with nasopharyngeal carcinoma after induction chemotherapy.
Authors: Gong Xiuyun , Jin Feng
Published: June 2024

e24048

Background: To retrospectively analyze the effect of nasopharyngeal primary tumor (GTVnx) target delineation after induction chemotherapy on the long-term survival and late injury of patients after intensity-modulated radiotherapy, so as to provide a reference for the optimal treatment of nasopharyngeal carcinoma. Methods: Retrospective analysis was performed on 52 patients with nasopharyngeal carcinoma who underwent target delineation and radiotherapy after induction chemotherapy in our department from December 2011 to October 2013. All patients underwent long-term survival follow-up and analysis of late injury. The survival rate was calculated by Kaplan-Meier method and log-rank test, Univariate prognostic analysis was performed. Cox model was used to conduct multivariate prognostic analysis. The late radiation toxicity was Evaluation by RTOG/EORTC. Results: From December 2011 to October 2013,52 patients were enrolled in the study group. The follow-up period was up to December 2020. Among them, 23 patients died and the mortality rate was 44.23%, the recurrence rate was 0.38%. Serious adverse reactions occurred in 7 cases (13.2%). The 1,3,5,8 year survival rates were as follows: OS was 94.2%, 82.7%, 65.4%, 49.6%, LRFS was 96.2%, 82.7%, 63.5%, 46.2%, the survival rates of DMFS were 94.2%, 78.8%, 59.6% and 44.2%. Conclusions: The 5 and 8-years OS, LRFS and DMFS of NPC after induction chemotherapy patients treated with IMRT was relatively high, Distant metastasis was the main cause of treatment failure, The main late injuries include grade Ⅰ / Ⅱ hearing impairment, dysphagia dental, caries, xerostomia, the grade Ⅲ and Ⅳ late radiation injury was lower.