bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of indole 3-propionic acid from microbiota on the immunity of CD8+ T cell to improve chemotherapy of colorectal cancer.
Authors: Xie Hongyu , Xu Haoyang , Wu Jinjie , Yang Jingyi , Zeng Wanyi , Jin Sanqing , He Zhen , Lan Ping
Published: June 2024

e15194

Background: Sensitivity of chemotherapy is a great challenge to improve the treatment efficacy in patients with colorectal cancer (CRC). Increasing study has revealed the role of microbiota in the modulation of chemotherapy sensitivity. However, the mechanism how microbiota regulates the efficacy of 5-fluorouracil (5-FU) is far from clear. Methods: We used germ-free mice and antibiotic-treated mice to demonstrate the impact of the gut microbiota on 5-FU sensitivity. Metabolomics analysis of serum from patients with CRC or mice experiments were applied to identify the key metabolite, indole 3-propionic acid (IPA). Specific pattern of microbiota with capability to produce IPA was revealed by metagenomics analysis of the mice feces. Single-cell RNA (scRNA) sequencing was subsequently used and antibody blockade experiments as well as T cell adoptive transfer experiment were conducted to confirm the role of CD8+ T cells in 5-FU treatment. AHR KO mice model was used to reveal how IPA regulate the immunity of CD8+ T cells. Engineering Escherichia coli strain BL21 with capability to produce IPA was constructed to modulate the chemotherapy sensitivity. Results: Decreased sensitivity of 5-FU chemotherapy was observed in both germ-free mice and antibiotic-treated mice models. Accumulation of serum IPA was found in mice with vancomycin intervention and verified in CRC patient with chemotherapy resistance. Additionally, metagenomic analysis of mice feces revealed that Clostridium sporogenes capable of producing IPA, are crucial for 5-FU chemotherapy sensitivity. Supplementation with IPA or Clostridium sporogenes could obviously improve the sensitivity of 5-FU chemotherapy. Subsequently scRNA sequencing analysis of tumor tissue revealed a higher infiltration of CD8+ T cells after IPA intervention. The role of IPA-induced CD8+ T cells in 5-FU treatment was confirmed by antibody blockade experiments and T cell adoptive transfer experiment. Further, improved therapeutic sensitivity by IPA and the infiltration of CD8+ T cells were vanished in AHR KO mice model. Biosynthesis of IPA by engineering bacteria was found to enhance the sensitivity of 5-FU chemotherapy. Conclusions: Indole 3-propionic acid from microbiota enhances the immunity of CD8+ T cell via activation of AHR signaling pathway, thus providing potential therapeutic strategies to improve the efficacy of chemotherapy in colorectal cancer.
Survival analysis and associated factors in metastatic early-onset colorectal cancer vs. metastatic average-onset colorectal cancer.
Authors: Jeri-Yabar Antoine , Vittini Liliana , Prado-Nuñez Sebastian , Dharmapuri Sirish
Published: June 2024

e15549

Background: Early-onset colorectal cancer (EO-CRC) is defined as colorectal cancer diagnosed before age 50 and its incidence has been increasing during the last decade. Average-onset colorectal cancer (AO-CRC) has presented a steady decline in incidence and related mortality over the past 20 years. There is controversy surrounding the disparities in outcomes and overall survival (OS) in EO-CRC vs. AO-CRC. Our study compared the OS and cause-specific survival (CSS) between metastatic EO-CRC (mEO-CRC) and metastatic AO-CRC (mAO-CRC) and identified associated factors. Methods: Data on patient characteristics, tumor characteristics, incidence and mortality were obtained from the SEER database from 2010 to 2020. We identified 23,278 individuals aged > 18 with confirmed diagnosis of all histologic subtypes of metastatic CRC (M1 on TNM stage) using ICD-O-3 site code C180, C182-9, C209 and histology codes: 8000, 8010, 8012, 8013, 8020-2, 8031-33, 8041, 8045, 8070-2, 8083, 8123-4, 8140, 8144-45, 8201, 8210-11, 8213, 8220-1, 8240, 8243-46, 8249, 8253, 8255, 8260-3, 8261-3, 8265, 8310, 8323, 8480-1, 8490, 8507, 8510, 8550, 8560, 8570, 8574, 8936, 8980. OS distributions and CCS were conducted using the Kaplan-Meier method and log-rank test was used to assess differences between mEO-CRC and mAO-CRC. Cox regression model used to assess associations between variables. Results: mEO-CRC constituted 17.79% of the cases, while 82.21% were mAO-CRC. Most patients with mEO-CRC were between 45-49 years old (47.66%), males (52.16%), white (72.57%), with histology of adenocarcinoma (87.30%). Left colon tumors were most prevalent in both groups (40.26%), but higher among mEO-CRC than in mAO-CRC (49.63% vs 38.23%, p < 0.001). mEO-CRC were more likely to receive chemotherapy (87.23% vs. 66.66%, p < 0.001) and radiotherapy (14.92% vs. 9.51%, p < 0.001), while surgery was similar in both groups (87.71% vs. 88.52%, p = 0.140). Patients with mEO-CRC had a higher OS (HR: 1.53, CI 95% 1.47-1.59, p < 0.001), as well as a higher CSS (HR: 1.33, 95% CI: 1.27-1.39, p < 0.001) when compared to mAO-CRC. mEO-CRC also had a significantly better median overall survival (30 months vs. 18 months p < 0.001). Factors associated with worse OS include mAO-CRC (p < 0.001), mucinous adenocarcinoma (p < 0.001), male sex (p 0.003) and no surgical intervention (p < 0.001). Conclusions: Patients with mEO-CRC had better OS and CSS when compared to patients with mAO-CRC and were more likely to receive cancer-directed therapy which could be explained by the mEO-CRC cohort having a higher performance status, less comorbidities, and better tolerance to cancer-related therapy. Factors associated with worse OS and CSS are mAO-CRC, mucinous adenocarcinoma, male sex and lack of surgical intervention. Furthermore, it is crucial to continue studying potential candidates who would benefit from early CRC screening.
Modified FOLFOXIRI plus bevacizumab as a salvage regimen for patients with refractory metastatic colorectal cancer.
Authors: Ou Yuxuan , Zhang Jianwei , Cai Yue , Hu Huabin , Xie Xiaoyu , Ling Jiayu , Deng Yanhong
Published: June 2024

e15559

Background: The triplet FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab showed improved outcomes for patients with metastatic colorectal cancer (mCRC) as first-line systemic treatment. However, those who progressed on standard therapies still faced the lack of optimal treatments in the third or later lines. There is a lack of data on applying triplet chemotherapy plus bevacizumab in later-line settings. We conducted a retrospective study to evaluate the efficacy and safety of modified FOLFOXIRI (mFOLFOXIRI) plus bevacizumab as a salvage regimen for patients with refractory metastatic colorectal cancer. Methods: Patients with refractory mCRC were retrospectively analyzed, who received mFOLFOXIRI plus bevacizumab in the third or later lines. The key inclusion criteria were:(1) 15-75 years old; (2) histologically confirmed mCRC; (3) treatment failure to at least two lines of treatments containing oxaliplatin, irinotecan, and 5-FU. Those with poor general condition (ECOG score > 2), or continuous grade 3-4 neuropathy and allergy to oxaliplatin were excluded. The mFOLFOXIRI regimen consists of oxaliplatin 85 mg/m² intravenous infusion for 2 hours; irinotecan 150 mg/m² intravenous infusion for 90 min; following intravenous infusion of leucovorin 400 mg/m² for 2 hours then 5-FU 2400 mg/m² for 46–48 hours continuous intravenous infusion, Q2W. Bevacizumab 5 mg/kg was administered by intravenous infusion Q2W. Results: 95 patients treated between January 2020 and December 2022 were retrospectively studied. The median age at diagnosis was 50.8 years (range 23-72 years). 50.5% of the patients had previously received at least four regimens. At the last follow-up date on December 31, 2023, the objective response rate (ORR) was 11.6% (1 complete response and 10 partial responses) and the disease control rate (DCR) was 68.4% (54 stable diseases). The median progression-free survival (PFS) was 6.2 months (95% CI, 5.4-7.0) and the median OS was 13.6 months (95% CI, 12.2-14.9). The most common adverse event was neutropenia (23.2%). Grade 3-4 adverse events were reported in 37 (38.9%) patients, including neutropenia (9.5%), oxaliplatin-related allergy (7.4%), thrombocytopenia (4.2%), thrombocytopenia (4.2%), diarrhea (4.2%), anemia (3.2%), nausea (3.2%), and neuropathy (2.1%). Conclusions: Modified FOLFOXIRI plus bevacizumab is effective as a salvage regimen in patients with refractory mCRC and with an acceptable safety profile.
FOLFOXIRI/bevacizumab (bev) versus doublets/bev as initial therapy of unresectable liver-only, right-sided and/or RAS or BRAF mutated (mut) metastatic colorectal cancer (mCRC): An individual patient data-based pooled analysis of randomized trials.
Authors: Antoniotti Carlotta , Marmorino Federica , Meinert Fabian Maximilian , Bergamo Francesca , Tonini Giuseppe , Rossini Daniele , Borelli Beatrice , De Rosa Antonio , Allegrini Giacomo , Stein Alexander , Moretto Roberto , Ronzoni Monica , Zaniboni Alberto , Germani Marco Maria , Sperotto Sara , Ongaro Elena , Ghelardi Filippo , Masi Gianluca , Schmoll Hans , Cremolini Chiara
Published: June 2024

e15563

Background: FOLFOXIRI/bev was associated with longer PFS and OS versus doublets/bev independently of the presence of liver-limited disease or not, and the secondary resection of metastatic lesions. Recently, in the CAIRO-5 study patients with liver-limited right-sided and/or RAS or BRAF mutated mCRC experienced no OS difference, but higher ORR, R0 resection rate, and longer PFS with the triplet/bev when compared with doublets/bev. Here we aim at providing an estimation of the efficacy and activity of FOLFOXIRI/bev over doublets/bev in patients with unresectable liver-only, right-sided and/or RAS or BRAF mut mCRC. Methods: We selected pts with liver-only, right-sided and/or RAS or BRAF mut mCRC, and treated with first-line doublets/bev or FOLFOXIRI/bev in four phase II or III randomized controlled trials (RCTs): TRIBE (NCT00719797), TRIBE2 (NCT02339116), CHARTA (NCT01321957), and STEAM (NCT01765582). Patients included in these RCTs were deemed initially unresectable according to a multidisciplinary evaluation and were not selected based on the potential conversion to resectability. We compared FOLFOXIRI/bev with doublets/bev in terms of PFS, OS, ORR, and R0 resection. Results: A total of 300 pts were eligible. The median age was 61 years and most of them had an ECOG performance status of 0 (83%) and synchronous metastases (91%). One hundred and thirty (43%) and 170 (57%) pts received doublets/bev and FOLFOXIRI/bev, respectively. Baseline characteristics were homogeneous between the two treatment groups. Pts receiving FOLFOXIRI/bev showed longer PFS (12.3 vs 10.3 months [mos] HR:0.75, p = 0.019) and a statistically not significant trend for better OS (29.1 vs 23.2 mos, HR:0.85, p = 0.253), than those treated with doublets/bev. FOLFOXIRI/bev was also associated with higher ORR (64% vs 53%, OR:1.54, p = 0.076) and no differences in R0 resection rate (27% vs 24%, OR:1.15, p = 0.696) was reported. No significant interaction was found between treatment effect and the achievement of R0 resection in terms of both PFS (Pinteraction:0.81) and OS (Pinteraction:0.53). Conclusions: As compared to doublets/bev, upfront FOLFOXIRI/bev provides a meaningful advantage to pts with initially unresectable, liver-only, right-sided and/or RAS or BRAF mut mCRC, in terms of activity and efficacy, thus corroborating the choice of this regimen as upfront treatment for these pts, regardless of the opportunity to achieve the R0 secondary resection of their liver metastatic lesions.
Bowel bag sparing in palliative radiotherapy (pRT) of rectal cancer (rCa): Tradeoff between organs at risk (OARs) and use of AI to reduce radiation oncologist (RO) workload.
Authors: Fredén Emil , Knutsson Johan , Yousif Rafat , Siegbahn Albert , Lind Pehr A.
Published: June 2024

e15615

Background: We retrospectively studied the potential to reduce bowel toxicity after pRT of rCa using a bowel dose (BD) minimization strategy; also its effect on dose to remaining normal tissues (NT) and pelvic bone marrow (PBM). Finally, we studied the use of AI to reduce the RO workload. Methods: 25 consecutive rCa patients (pts) previously treated with pRT were included. Their treatments were planned without consideration to BD. The following OARs were manually segmented retrospectively: Bowel Bag (BB-M) excluding PTV, PBM (PBM-M), and NT defined as the patient contour excluding PTV and BB-M. The AI-Rad Companion software was used to autosegment: Bowel Loops (BL-AI) and PBM (PBM-AI). For the 25 pts, two Pareto optimal treatment plans (5 Gy x 5) were generated with the Monaco treatment planning system. The first plan (Reference) was optimized aiming to limit dose outside the PTV. The second plan (Opt-BB-M) was optimized aiming firstly to limit BB-M dose and secondly to limit NT dose. A third plan (Opt-BL-AI) was generated for the 10 worst-off pts (in terms of BD) aiming instead to limit BL-AI dose. Two volume-at-dose (VD) metrics (V18Gy, V10Gy) were used as endpoints. Endpoint differences (ΔVD-OAR) were tested using one-sided Wilcoxon signed-rank tests. Spearman (rs) and Pearson (r) correlation coefficients were used to study correlation between variables (ΔVD-BB vs. ΔVD-BM, and ΔVD-BB vs. ΔVD-NT). Dice Similarity Coefficient (DCS) was used to compare PBM-M and PBM-AI. Results: After reoptimization, BB-M VD (V18Gy; V10Gy) was lower (p < 0.001; p < 0.001), PBM-M VD was higher (p = 0.002; p < 0.001), and NT VD was higher (p < 0.001; p < 0.001). For BB-M, ΔV18Gy and ΔV10Gy (median, min, max) were (-4, -46, 0) cm3 and (-33, -254, 0) cm3; for PBM-M: (+2, -4, +56) cm3 and (+33, -6, +189) cm3; for NT: (+10, -43, +194) cm3 and (+146, -18, +614) cm3. Table 1 presents results for the 10 worst-off pts. Medium/strong correlations were found for ΔV18Gy-BB vs. ΔV18Gy-PBM (rs = -0.72, p < 0.001; r = -0.74, p < 0.001), ΔV10Gy-BB vs. ΔV10Gy-PBM (rs = -0.66, p < 0.001; r = -0.32, p = 0.11), ΔV18Gy-BB vs. ΔV18Gy-NT (rs = -0.74, p < 0.001; r = -0.74, p < 0.001), ΔV10Gy-BB vs. ΔV10Gy-NT (rs = -0.74, p < 0.001; r = -0.51, p = 0.009). The DSC (median, min, max) for PBL was (92%, 87%, 94%). Conclusions: Bowel dose in pRT of rCa can be reduced at the expense of increasing dose to PBM and other NT. AI tools can be used effectively to limit RO workload. [Table: see text]
Transanal endoscopic microsurgery vs. radical surgery for mid-low rectal cancer in patients with clinical complete or near-complete response after neoadjuvant chemoradiotherapy.
Authors: Qiu Xiaoyuan , Zhou Jiaolin , Xiao Yi , Qiu Huizhong , Shen Zhan , Wu Bin , Jia Wenzhuo , Niu Beizhan , Li Fei , Yao Hongwei , WU Aiwen , Hu Ke , Xue Huadan , Zhou Weixun , Lin Guole
Published: June 2024

e15616

Background: Following neoadjuvant chemoradiotherapy (nCRT), total mesorectal excision surgery used to be the standard therapy for locally advanced rectal cancer (LARC). However, the radical surgery is associated with high complication rates and impairs patients' quality of life, especially for non-sphincter preservation procedures. For the past two decades, nCRT followed by organ preservation strategies like watch-and-wait (W&W) or local resection offers an alternative for patients being clinically evaluated with complete response or near complete response, however the oncological outcomes of these approaches require further exploration. Methods: We prospectively collected data on 80 patients with T3-4N0M0 or TanyN+M0 mid-low rectal cancer who achieved cCR or near-cCR after nCRT from May 2017 to September 2021 at 5 tertiary centers in China. Patients were divided into the TEM group (group A) or the radical surgery group (group B). Clinicopathological features, operative outcomes, oncological and functional results were analyzed. Results: A total of 76 cases were analyzed, with 38 in each group. Baseline characteristics were comparable between the two groups. Postoperative histology revealed 22 ypT0Nx(57.9%), 5 ypT1Nx(13.2%), 10 ypT2Nx (26.3%), 1 ypT3Nx(2.6%) in group A, and 18 ypT0N0 (47.4%), 5 ypT1N0 (13.2%), 11 ypT2-3N0 (28.9%), 1 ypT0N1 (2.6%), 3 ypT2-3N1 (7.9%) in group B. After a median follow-up of 61 months, 2 patients (5.26%) in group A experienced local recurrence, while none in group B. 8 patients (21.05%) in group A developed distant metastases compared to 5 (13.16%) in group B. There was no statistically significant difference between two groups in 5-year disease-free survival(P = 0.320), or 5-year overall survival (P = 0.425). Patients in group A had significantly faster postoperative recovery and a superior quality of life evaluated by the Wexner and LARS scores compared to group B. Conclusions: For cCR and near-cCR LARC patients after nCRT, organ preservation with TEM may serve as a staging method to evaluate local tumor persisrence. And it provides an alternative therapy for carefully selected patients who have needs to preserve sphincteric function or can’t tolerate radical resection, without significantly compensate long-term oncological outcomes. This strategy could relatively safely enable sphincteric function preservation for these patients with faster postoperative recovery and better quality of life. Clinical trial information: NCT03042000 .
Metabolic disorders in patients diagnosed with colorectal cancer.
Authors: Levy Julia A. , Lorona Nicole C. , Gigic Biljana , Li Christopher I. , Ose Jennifer , Shibata David , Siegel Erin M. , Toriola Adetunji T. , Ulrich Cornelia M , Hardikar Sheetal , Figueiredo Jane C.
Published: June 2024

e15618

Background: Colorectal cancer (CRC) is the third most common cancer globally and ranks second as a cause of cancer-related death. As survival rates among CRC patients continue to rise, addressing accompanying metabolic comorbidities is becoming increasingly important. This study aims to explore the prevalence of metabolic comorbidities and metabolic syndrome among CRC patients, as well as their impact on survival. Methods: The ColoCare Study is a prospective cohort study conducted across seven U.S. and European sites. Data from a single site, Cedars-Sinai Medical Center in Los Angeles, California was analyzed. Adults with newly diagnosed stage I-IV CRC and available medical records were eligible. Basic demographic information and medical history, including hypertension, hyperlipidemia, and diabetes mellitus (DM) diagnosis at or before CRC diagnosis were collected by manually reviewing electronic medical records. Additionally, BMI was calculated using patients' weight and height at the time of diagnosis and classified according to the CDC’s published ranges. Patients were considered to have metabolic syndrome if they met three or more of the following criteria: hypertension, hyperlipidemia, DM, or obesity. Overall survival rates for patients with each metabolic condition were compared. Results: A total of 295 patients (58.3% male, 41.7% female, mean age at diagnosis = 58.3) were identified. 172 were non-Hispanic White (58.3%), 52 were Hispanic/Latino (17.6%), 36 (12.2%) were Asian, 27 (9.2%) were Black, and 8 (1.8%) were unknown/other. Metabolic conditions were prevalent in the cohort: hypertension affected 33.9%, hyperlipidemia affected 21.4%, and DM affected 13% of patients. Additionally, over half of the patients (56.6%) were overweight or obese. Individuals meeting criteria for metabolic syndrome (8.8%) had lower survival rates compared to those without this condition (73.1% vs. 81.4%). Similarly, patients with DM had lower survival rates compared to their counterparts without DM (72.5% vs. 82.0%). Patients with hypertension, hyperlipidemia, and elevated BMI did not have significantly different survival rates compared to patients without such conditions. Conclusions: Our study highlights the prevalence of metabolic comorbidities, specifically metabolic syndrome and DM, among CRC patients and emphasizes how these factors can impact patient outcomes post-diagnosis. This information is valuable for physicians when considering lifestyle changes or treatment strategies following CRC diagnosis. Further, it highlights the importance of coordination between oncologists and primary care providers to effectively manage metabolic diseases in CRC patients.
The safety and efficacy of immune checkpoint inhibitor in combination with FOLFOX as neoadjuvant/adjuvant therapy in patients with locally advanced colon cancer.
Authors: Cai Changjing , Han Ying , Peng Yinghui , Zhang Xiangyang , Gan Pingping , Tang Youhong , Tang Lanhua , Liu Yiping , Shen Hong , Zeng Shan
Published: June 2024

e15621

Background: The recurrence rate of locally advanced colon cancer (T3-4 or N+, M0) after surgery is significantly high. Emerging data indicate that the combination of immunotherapy and chemotherapy demonstrates synergistic effects in other solid tumors. Consequently, a combination of immunotherapy and chemotherapy holds the potential to benefit patients with MSS and pMMR colon cancer. We have designed a prospective trial to investigate whether the immune checkpoint inhibitor (ICI) in combination with chemotherapy represents a safe and beneficial treatment approach for locally advanced colon cancer. Methods: Inclusive Criteria: Patients with locally advanced colon cancer (T3-4 or N+, M0) confirmed through pathological biopsy, with confirmed indications for neoadjuvant/adjuvant chemotherapy by the multidisciplinary team. Patients must be eligible for surgery, and a measurable mass must be identified according to RECIST version 1.1. All individuals aged over 18 years, with an estimated life expectancy of over one year and an ECOG score within 0-1, are eligible. The neoadjuvant chemoimmunotherapy group (NACI) includes mFOLFOX 6 (Q2W) and the anti-PD-1 monoclonal antibody (Toripalimab) (3mg/kg, Q2W), while the neoadjuvant chemotherapy group (NAC) receives only mFOLFOX 6 for neoadjuvant/adjuvant therapy (a total of 12 cycles, 6 cycles pre-surgery and 6 cycles post-surgery). The primary endpoint is the pathological complete response (pCR) rate. Results: From 2019 to 2022, a total of 22 patients were enrolled in the study, with 13 in the NACI group and 9 in the NAC group. The research findings indicate that in the NACI group, over 30% (4/13) of patients achieved a pathological complete response (pCR), whereas none of the patients in the NAC group reached pCR (0/9). Among the pCR patients, one was identified as MSI-H/dMMR, two as MSS/pMMR, and one had an unknown status. Tumor regression grade (TRG) levels also revealed that all patients in the NACI group were below grade 2, significantly outperforming the NAC group (P < 0.05), with statistically significant differences. However, no significant differences were observed between the NAC and NACI groups in terms of CT regression percentage, R0 resection, vascular cancer emboli, and the level of neural invasion. Adverse reactions did not show significant differences between the two groups. Conclusions: The combination of immunotherapy and chemotherapy exhibits a synergistic effect in treating locally advanced colorectal cancer. Tolerable adverse reactions suggest that neoadjuvant chemoimmunotherapy could potentially serve as a novel therapeutic option. Clinical trial information: NCT03985891 .
The relationship between mismatch repair (MMR) proteins status and the response to conventional neoadjuvant therapy in colorectal cancer (CRC).
Authors: Weng Junyong , Zhang Ruoxin , Zhu Zhonglin , Li Shanbao , Ye Zilan , Liu Qi , Li Xinxiang
Published: June 2024

e15627

Background: MMR proteins status is not routinely detected in CRC patients. Neoadjuvant use of immune checkpoint inhibitors (ICIs) in deficient mismatch repair (dMMR) CRC patients can achieve a pathological complete response (pCR) rate of 60-100%. Conversely, dMMR/MSI-H patients may exhibit a poor response to conventional neoadjuvant therapy, although supporting evidence is limited. Methods: We retrospectively collected clinical data from patients who underwent neoadjuvant chemoradiotherapy or chemotherapy at Fudan University Shanghai Cancer Center from 2008 to 2021, excluding those who received neoadjuvant ICIs. MMR proteins were detected using immunohistochemistry on surgical samples or preoperative colonoscopy biopsy samples, and some patients underwent genetic testing to evaluate their microsatellite status. This study included M0 CRC patients with complete tumor regression grading (TRG) assessment and MMR/MSI status. Responses were assessed using TRG evaluation (AJCC-TRG system) on the primary tumor. Results: Among 1005 patients, the median age was 57 years (range: 19-95), with 643 males (64.0%) and 362 females (36.0%). Seventy-two (7.2%) had right colon cancer, 80 (8.0%) had left colon cancer, and 853 (84.9%) had rectal cancer. Fifty-five (5.5%) had dMMR, and 950 (94.5%) had proficient mismatch repair (pMMR). In dMMR patients, defective proteins included hMLH1 and PMS2 combined in 22 patients, hMSH6 in 14 patients, PMS2 in 9 patients, hMSH6 and hMSH2 combined in 6 patients, hMLH1 in 2 patients, hMLH1 and hMSH6 combined in 1 patient, and hMSH6, PMS2, and hMSH2 combined in 1 patient. Compared to pMMR patients, dMMR patients showed either no response or poor response to conventional neoadjuvant therapy, with no patients exhibiting TRG = 0/1. One hundred and eleven (11.7%) pMMR patients showed a good response (TRG = 0/1). There was no statistically significant difference in overall survival between the two groups of patients (HR, 1.547; 95% CI: 0.9221-2.596; P = 0.172). Conclusions: Although our study is retrospective and some patients with pCR lacked MMR expression information, we can still conclude that dMMR patients have a poor response to conventional neoadjuvant therapy, and neoadjuvant ICIs treatment may be a better choice for dMMR patients. We recommend routine immunohistochemistry of MMR proteins in preoperative colonoscopies to guide the development of neoadjuvant strategies. [Table: see text]
Real-world multi-target stool DNA adherence in an underserved and vulnerable prison patient population.
Authors: Kasselman Jeffrey , Greene Mallik , Pew Timo , Johnson William , Ozbay Burak Burak , Brooks Durado , Limburg Paul J.
Published: June 2024

e15632

Background: In 2024, colorectal cancer (CRC) is estimated to be the fourth most diagnosed cancer, as well as the second leading cause of cancer death in the United States. While adherence to regular CRC screening has been suboptimal in the general population, this holds to be especially true in populations that are medically underserved. Non-invasive tests, such as the guideline recommended multi-target stool DNA (mt-sDNA) test, offer a more accessible option to increase screening participation in difficult to reach populations. Herein, we evaluated adherence to CRC screening in a cohort of prisoners who received the mt-sDNA test at a Nebraska Department of Corrections facility in Nebraska. Methods: This was a retrospective cohort study in a small prison population. Participants included both males and females between the ages of 45 and 75 years who underwent CRC screening evaluation at the prison’s medical center between June 1st – December 31st, 2023 and were offered multiple CRC screening options, including the mt-sDNA test. No inducements were provided for completion of the mt-sDNA test. Baseline demographics were collected for cohort description. The primary variable of interest was mt-sDNA test return rate (adherence), defined as completion of the mt-sDNA test within 60 days of kit receipt. We also evaluated mt-sDNA test results in secondary analyses. Results: Once inclusion criteria were applied, the resulting analysis cohort included 129 patients who were first time mt-sDNA screeners. The cohort was largely male (96.9%) and between the ages of 50-64 years (78.3%). Overall mt-sDNA test adherence was 95.3%, with the average time to test completion being 20 days. No significant difference was seen in test completion among males and females (95.2% vs 100%, respectively). Completion rates increased with patient age, at 90.9% (45-49 years), 95% (50-64 years), and 100% (65-75 years). The shortest time to completion in the population was observed amongst patients who were females (18.8 days), and those between the ages of 45-49 years (17.1 days). Negative and positive mt-sDNA test results were observed in 82.9% and 17.1% of the cohort, respectively. Conclusions: CRC screening with the mt-sDNA test in this single-center study of incarcerated participants yielded exceptionally high adherence rates within 60 days of kit receipt. Assessment of follow up colonoscopy rates for test-positive participants is ongoing. While based on a relatively small sample size in this initial study, the mt-sDNA test exhibited favorable completion rates in a difficult to reach population, supporting further efforts to characterize patient, provider, and system-level benefits that may be obtained through broader adoption of this highly accessible screening approach in this challenging healthcare setting.
Analysis of patch-based GCN risk score distribution corresponding to gene mutations in colorectal cancer using whole slide images.
Authors: Liang Li , Lin Jie , Deng Xikai , Qiu Weihao
Published: June 2024

e15650

Background: Colorectal cancer (CRC) is one of the most common malignancies, with the third highest incidence and the second highest mortality in the world. Risk scores are typically employed to predict outcomes such as disease risk, prognosis, or treatment response. Risk scores are usually calculated by combining biomarkers or genetic variants with statistical models, such as logistic regression or Cox proportional hazards models, and then observe the relationship between genetic variations and survival time through survival analysis. We have constructed a deep learning model based on Graph Convolutional Networks (GCNs), which is capable of predicting risk scores using Whole Slide Images (WSIs). Statistical analyses were applied to explore the distribution of risk scores associated with different variants in colorectal cancer. Methods: We performed risk scores prediction on a total of 384 samples from TCGA-COAD and TCGA-READ using our patch-based GCN model. We analyzed the distribution of risk scores in colorectal cancer samples and investigated the effects of gene mutations in key pathways on these risk scores. Results: Risk score predictions by our patch-based GCN model were conducted on 384 samples, revealing that the maximum, minimum, median, mean, and standard deviation of risk scores were -0.78, -1.89, -1.34, -1.34, and 0.20, respectively. The data overall conformed to a normal distribution ( p < 0.05 ). We selected core genes in key pathways combined with top ten genes with the highest mutation frequency in colorectal cancer for statistical analysis to explore the correlation with the predicted risk scores. These gene mutations were found in a total of 346 patients. The results indicated that mutations in the TP53 and OBSCN genes led to significant differences in risk scores as predicted by our model ( p < 0.05 ). The risk scores based on gene mutations also have significant differences and consistent trend in these genes. Conclusions: Our results indicate the risk scores generated by the patch-based GCN model have the consistent trend with the risk scores generated by mutation information of core genes in colorectal cancer. Whether risk scores based on digital pathology prediction can replace mutation detection in predicting patient survival status requires further exploration.
Broad-spectrum antibiotic use and risk of early-onset colorectal cancer.
Authors: Chao Chun , Xu Lanfang , Chubak Jessica , Figueiredo Jane C. , Getahun Darios , Cannavale Kimberly L. , Gilfillan Alec , Wu Bechien U
Published: June 2024

e15653

Background: The incidence of early-onset colorectal cancer (eoCRC) diagnosed under age 50 is rising in the United States, but the underlying causes are largely unknown. Use of broad-spectrum antibiotics can induce intense gut dysbiosis, which is strongly implicated in CRC carcinogenesis. Emerging evidence supports a link between broad-spectrum antibiotic use and CRC. We evaluated the associations between oral broad-spectrum antibiotic use and risk of eoCRC. Methods: We conducted a nested case-control study within Kaiser Permanente Southern California (KPSC). Cases were persons aged 15-49 years with invasive colorectal adenocarcinoma diagnosis between 2009-2021; controls were matched at 10:1 ratio on age, sex at birth, and length of KPSC membership. Those with less than 15 years of prior membership at diagnosis date or controls’ index date were excluded to allow evaluation of exposure up to 15 years prior. We extracted all study data, including use of antibiotics by drug type and days of prescriptions, from KSPC’s electronic medical records. Conditional logistic regression was used to evaluate antibiotic use from three etiologic periods: 10-15, 5-10, and 2-5 years prior to diagnosis/index date, adjusting for potential confounders (narrow-spectrum antibiotics use, clinical and lifestyle risk factors, race/ethnicity, body mass index) with a crude p-value < 0.10. Analyses were conducted overall and separately for colon cancer. Results: A total of 310 cases (mean age at diagnosis 44.5 years, 52% female, 33% non-Hispanic White) and 2,976 controls were included. In the 10-15 years prior to diagnosis/index date, 65% of cases and 62% of controls used broad-spectrum antibiotics. Broad-spectrum antibiotic use was not associated with eoCRC overall [OR = 1.15 (95% CI: 0.88-1.49)]. An increased risk was suggested for > 3 months of cumulative use: OR = 1.07 (0.81-1.42) for ≤1 month; 1.26 (0.87-1.84) for 1-3 months; and 1.59 (0.95-2.65) for > 3 months. The association between exposure and colon adenocarcinoma was: OR = 1.26 (0.91-1.72) for any use; OR = 1.17 (0.83-1.64) for ≤1 month; and OR = 1.50 (0.99-2.27) for > 1 month. No association was observed between broad-spectrum antibiotic use within 5-9.9 years or 2-4.9 years prior to diagnosis and risk of eoCRC overall or for the colon site. Conclusions: Our findings suggest a possible association between cumulative longer-term use of broad-spectrum antibiotics and increased risk of eoCRC. The etiologic window for assessing antibiotic exposure appears to be relevant. Larger studies with long-term follow-up are needed to confirm these findings.
Socioeconomic status and fertility counseling in patients with early onset colorectal cancer.
Authors: Littman Dalia , Peng Chengwei , Masri Lena , Sherman Scott , Makarov Danil V. , Becker Daniel Jacob
Published: June 2024

e15654

Background: The incidence of early onset colorectal cancer (EOCRC) has increased over the past several decades, with a corresponding need to counsel younger patients about options for fertility counseling. The characteristics of patients at risk for going without fertility counseling are unknown. Methods: We conducted a single site retrospective review of all patients diagnosed with colorectal cancer between 2012 and 2019 who were men age 55 or younger or women age 50 or younger. Clinical data and documentation of fertility counseling were extracted from the electronic medical record by explicit chart review. Median household income (MHI) by zip code was gathered from census data and assigned to each patient based on home address. Results: 194 subjects were identified, of whom 69% had colon cancer and 31% had rectal cancer. 61% were male with average age 44 and 39% were female with average age 42. 55% were White, 11% were Black, 14% were Asian, and 10% were Hispanic. 13% had stage II disease, 44% had stage III disease and 40% had stage IV disease. 15.5% had documented fertility counseling, of whom 43% were male and 57% were female. In univariate analysis, age less than 40 years old, female sex, curative intent treatment, and home address in areas of higher MHI were associated with higher rates of fertility counseling. Race, tumor type, stage of disease, and year of diagnosis were not associated with differences in rates of fertility counseling. Conclusions: We found low overall rates of fertility counseling in patients with EOCRC, and consistent with prior analyses, lower counseling of men and those over age 40. We found that patients who live in areas of relative poverty were less likely to receive fertility counseling. Limited fertility counseling and high out-of-pocket costs of fertility preservation may combine to deny vulnerable patients an essential service. Given the increasing diagnosis of EOCRC, efforts are needed to increase the rates of fertility counseling both systemically and equitably. [Table: see text]
Effect on cardiovascular outcome of sodium-glucose co-transporter-2 (SGLT2) inhibitors among patients with cancer treated with anthracycline: A systematic review and meta-analysis.
Authors: Wannaphut Chalothorn , Wattanachayakul Phuuwadith , Saowapa Sakditad , Ponvilawan Ben , Tanariyakul Manasawee , Kewcharoen Jakrin , Yingchoncharoen Pitchaporn , Aiumtrakul Noppawit , Acoba Jared David
Published: June 2024

e24001

Background: Sodium-glucose-co-transporter-2 (SGLT2) inhibitors have shown benefit in reducing cardiovascular outcomes in diabetes patients. Anthracycline therapy is associated with a risk of cardiomyopathy. However, the impact of SGLT2 inhibitors in the prevention of cardiomyopathy and heart failure in cancer patients undergoing anthracycline treatment remains unclear. Thus, we conducted a systematic review and meta-analysis to explore the effect of the prevention of cardiovascular outcomes in patients with cancer and diabetes who had received anthracycline therapy. Methods: We systematically reviewed Medline and EMBASE databases from inception to January 2024 for studies focusing on cancer patients with a history of anthracycline therapy. Eligible studies had to report relative risk (RR) with 95% confidence intervals for the clinical endpoints of mortality outcomes and the risk of HF exacerbation, comparing cohorts with and without SGLT2 inhibitor use. Results: Our study included 4 retrospective cohort studies in the meta-analysis (n = 6,708, 24% received SGLT2). There was significantly lower all-cause mortality in the SGLT2 inhibitors group (pooled RR of 0.52, 95% CI 0.35-0.77, I2 64%). However, there were no differences in the risk of heart failure exacerbation (pooled RR of 0.67, 95% CI 0.39-1.14, I2 17%). Conclusions: Our study found that anthracycline-treated cancer patients using SGLT2 inhibitors experienced lower all-cause mortality compared to the control group. A randomized clinical trial is necessary to further elucidate these findings.
Cardiomyopathy among recipients of immune checkpoint inhibitor therapy: A prospective study.
Authors: Zheng Haoyi , Granville Matthew J. , Miraglia Genie , Okin Emily , Weber Jonathan , Solito Stephanie , Jacob-Perez Sherly , Chung Su Yun , Roy Rajasree , Trotta Christina , Patel Dilip , Shlofmitz Richard , Cao Jane , Khalique Omar K. , Ali Ziad , Parikh Roosha , Jermyn Rita , Haag Elizabeth , Mehrotra Bhoomi , Mahmood Syed S.
Published: June 2024

e24025

Background: Patients treated with immune checkpoint inhibitors (ICI) may develop cardiomyopathy, but data are limited on the rate of cardiomyopathy incidence. The aim of this study was to assess the occurrence of cardiomyopathy among ICI recipients. Methods: In this prospective surveillance study, echocardiograms and EKG were performed at baseline, and quarterly during the first year of ICI therapy. New or worsening cardiomyopathy was defined as left ventricular ejection fraction (EF) decline of > 10% from baseline to < 50%. B-type natriuretic peptide (BNP) and troponin were assessed weekly during the first three weeks of ICI therapy. Subsequent troponin for myocarditis assessment was tested as needed per treating oncology team. Results: A total of 23 patients were enrolled with mean age 73±10 years, 35% female, 74% Caucasian, and body mass index 31±7 kg/m2. Cardiovascular risk factors included hypertension (86%), diabetes mellitus (29%), myocardial infarction (19%) and smoking (10%), and prior radiation treatment (30%). Malignancies included lung cancer (50%), renal cell carcinoma (14%), and Merkel cell carcinoma or urothelial carcinoma (9% each). ICI regimen included pembrolizumab (48%), nivolumab (43%), and ipilimumab or atezolizumab (4% each). There was no change in weekly troponin or BNP, or quarterly QRS duration on EKG, and no myocarditis cases were observed. Between baseline and at 1-year since ICI therapy initiation, there was no change in QRS duration on EKG, as well as no change in median LVEF (59% [IQR 46-67] vs 61% [IQR 58-65], p = 0.48), or global longitudinal strain (18% [IQR 15-20]) vs 19% [IQR 18-21], p = 0.11). New cardiomyopathy occurred in 1 (4%) patient at 3 months following ICI initiation with LVEF drop from 53% to 38% and without troponin elevation to suggest myocarditis, corresponding to an incidence rate of 43.5 cases per 1000 person-years of observation. Conclusions: In this prospective surveillance study, new cardiomyopathy was observed after ICI treatment, although the incidence was low. Larger studies are needed to confirm these findings.
Resident physicians’ knowledge, attitudes, and practices on advance care planning for patients with advanced cancer in a national university hospital in the Philippines.
Authors: Ting Frederic Ivan Leong , Estreller Sachiko Solis , Pilapil John Christopher Agsalud , Real Irisyl Orolfo , Dee Edward Christopher Christopher
Published: June 2024

e24037

Background: Advance Care Planning (ACP) is part of palliative care, an approach that improves the quality of life of patients and their families in the context of life-threatening illness, through the prevention and relief of suffering by means of early identification, assessment, and treatment of common problems associated with end-of-life care. Little is known about ACP and the utilization of advance directives in the Philippines, a country of 110 million people. The study aimed to explore the knowledge, attitudes, and practices of resident physicians in a national university hospital in the Philippines regarding ACP for patients with advanced cancer. Methods: Using a cross-sectional design involving resident physicians, an online survey with a self-administered questionnaire was distributed and answered by a total of 202 respondents. Results: Results show that a significant proportion of doctors: (1) view palliative and hospice medicine to be the same and without differences, (2) are comfortable with discussing ACP and prognosis of medical conditions with patients and their families, but (3) do not regularly initiate or offer ACP to them, (4) identify a lack of time, fear of imparting emotional distress to patients and their families, and personal discomfort as barriers to conducting ACP, and (5) have had no formal training for ACP but are willing to undergo such formation, given the opportunity. Conclusions: This study highlights the continuing need to bridge and unite knowledge, attitude, and practices pertaining to ACP among physicians. Further studies should be undertaken to device a proper training program and better explore the complexities of end-of-life care as it is experienced by Filipino patients with advanced cancer.
Testosterone replacement therapy (TRT) in patients with locoregional prostate cancer (LPC) treated with prior androgen deprivation therapy (ADT): A single center review.
Authors: Aglan Mostafa , Khadke Sumanth , Connell Brendan
Published: June 2024

e24045

Background: In LPC, ADT may be combined with radiation therapy (RT) for 4-24 months. Post-ADT, a significant proportion of men experience prolonged hypogonadism. TRT can alleviate symptoms and improve metabolic outcomes. Contrary to longstanding concerns, there is no substantial evidence of increased prostate cancer recurrence in patients (pts) treated with single modalities (surgery or RT). However, sparse data ( < 100 cases published to our knowledge) exist regarding recurrence risk of LPC with TRT after prior ADT, where baseline T levels may fall below the androgen receptor saturation point. Methods: We retrospectively abstracted clinical data from hospital records of men with stage I – IVA PC, treated with prior concurrent ADT and RT and subsequently received TRT between January 2014 and September 2023. Extracted data included demographics, cancer diagnosis/staging, ADT/TRT treatment details and PSA and clinical outcomes. The co-primary endpoints were change in PSA and incidence of PC recurrence. Results: 21 pts met criteria. Median age was 77. ISUP Grade Groups (GG) included: GG1: 2, GG2: 2, GG3: 8, GG4: 2, and GG5: 7. AJCC 8th ed. stages were: I: 2, II: 7, III: 7, IV-A: 5. The median duration of prior ADT was 8 months (IQR 5 – 17) and the median interval from RT to TRT was 19 months (IQR: 12 – 44). Prior to TRT, the median testosterone level was 30.5 ng/dL (IQR: 17-76). TRT formulations included: injection: 6, oral: 4, topical: 13. The median follow-up period from the start of TRT was 13 months, and the median duration on TRT was 10 months (IQR: 5-22). TRT was ongoing in 15 (71.4%) pts and discontinued in 6 (28.6%). Reasons for discontinuation included testosterone recovery (1), hospice (not PC related) (2), no perceived benefit (2), MD concern for PSA rise (1). After TRT, the median testosterone level was 336 ng/dL (IQR: 207-462). Median PSA pre- and post-TRT were undetectable and 0.08 ng/dL, respectively. None of the subjects experienced PC recurrence or PC-specific mortality. One pt showed PSA bounce without recurrence. Median BMI was unchanged before (28.3 kg/m2) and after (27.7 kg/m2) TRT (p = 0.48). Due to the nature of the study, quality of life measures and metabolic parameters could not be systematically abstracted. Conclusions: In men with LPC who remained hypogonadal long-term after prior ADT and RT, we found that TRT was not associated with a significant rise in median PSA and no cases of PC recurrence were documented. This included many with a history of very high-risk cancers (eg. GG ≥ 4, Stage ≥ III). This study adds to the sparse existing literature in this clinical setting and together they support the case for a prospective trial utilizing TRT in patients who remain hypogonadal after ADT and radiation.
Implementation of a palliative care service in a tertiary hospital in a developing country: Methods, strategies and results.
Authors: Emerick Mendes Cecilia , Chimeli Daniela , Albuquerque Merian , Ferreira Tamina , Carvalho Simone , Alves Ribeiro Carolina , Ananda Gomes Sarah Ananda
Published: June 2024

e24056

Background: In Rio de Janeiro, only 11 palliative care facilities exist, creating challenges in meeting the complex needs of patients with metastatic cancer. Our study aims to implement a palliative care service within an existing oncology practice. This approach holds promise as a model that could guide similar practices in low- and middle-income countries, offering a blueprint for the implementation of palliative care services on a broader scale. Methods: This descriptive study spans from February to December 2023, involving the monitoring of 176 patients. Eligible patients met criteria such as a FAST scale for dementia syndrome ≥ 7A, stage IV disease, ranking 5 stroke, terminal organic failure, uncontrolled symptoms, or requiring end-of-life care. The PC team, denoted as “Continued Care”, comprises a medical leader, 3 routine doctors, and 1 nurse. Activities undertaken by the team encompass consults requested by internal medicine and intensive care unit (ICU) teams, outpatient care, continuous education, and daily monitoring of patients with advance care plan (ACP). Results: Among 176 patients initially enrolled, outcomes were completed for 171 patients. Remarkably, 80% of those receiving PC assistance had an ACP in place, with 78% opting for exclusive non-invasive support. The overall death rate was 38%. Notably, among patients enrolled in the PC program, the ICU death rate was 31%. Conclusions: Institutional PC policies associated with the integration of a dedicated team into the hospital's routine, and investments in disseminating knowledge about irreversible illness processes and comfort strategies, emerge as a pivotal component in establishing a comprehensive and integrated model of PC services. This approach appears to surpass the effectiveness of traditional consult or sectorized model, emphasizing the importance of an institutionalized and holistic framework for delivering quality PC.