bluuebunny/crossref_metadata_2025 huggingface dataset:
Telehealth in long-term care facilities during the Covid-19 pandemic – Lessons learned from patients, physicians, nurses and healthcare workers
Authors: Dai Zhaoli
Published: January 2023

Background

Telehealth and telecare are particularly important and beneficial to long-term care facilities due to care demands, workforce, and the unique environment. Stemming from the recent findings on telehealth utilisation in residential aged-care facilities in Australia, this commentary seeks to identify lessons and perspectives learned during the Covid-19 pandemic from multiple users, including patients, physicians, nurses, and healthcare workers in long-term care (LTC) settings.

Main body

From patients’ perspectives, older adults residing in LTC settings often opt not to use virtual care, with the majority preferring in-person visits. This is despite residents expressing their willingness to use telehealth, and virtual care has advantages in LTC settings or in remote areas. Additionally, hearing, vision, or cognitive impairment can limit residents’ ability to use information technology to access care, so their preferences for phone or video consultations depend on the health conditions or care requirement. From physicians’ perspectives, most healthcare practitioners have a positive attitude toward using telehealth. However, telephone consultations tended to be the dominant mode during the early period of the Covid-19 pandemic. Physicians also raised several major concerns, including technical and equipment-related issues, expanded roles, or additional workloads of LTC staff that could negatively affect clinical decision-making and unequal access in rural, older, and cognitively impaired patients. Most nurses and healthcare workers perceived telehealth positively as a way to enhance patients’ care access. However, the majority had concerns about acquiring appropriate knowledge of using the technology for themselves and their patients. In remote areas, nurses expressed higher efficiency and higher care quality when utilising telehealth in caring for older patients than in the regular in-person care mode.

Conclusion

Since the beginning of the Covid-19 pandemic, telehealth has continued as an alternative platform in clinical services. However, as a healthcare platform that offers flexibilities of time, location, and improved efficiency, changing the traditional mindset is essential to shift the paradigm to use telehealth when appropriate. Importantly, telehealth needs substantial support in rural or remote long-term care facilities. Doing so will contribute to the reduction of healthcare inequity in long-term care facilities in remote settings and those with social disparities.
Bevacizumab in first-line therapy in lung metastases of colorectal cancer: An ARCAD pooled analysis.
Authors: Shmueli Einat S , Raeisi Morteza , Chibaudel Benoist , Hurwitz Herbert , Saltz Leonard B. , Kabbinavar Fairooz F. , Tebbutt Niall C. , Grothey Axel , Adams Richard , Zalcberg John Raymond , Yoshino Takayuki , Bachet Jean-Baptiste , Cohen Romain , Sharara Lama , Andre Thierry , Shi Qian , De Gramont Aimery
Published: January 2023

118

Background: Anti-VEGF is widely used in the treatment (trt) of metastatic colorectal cancer (mCRC). Only studies with bevacizumab (BEV) have shown survival benefit (bnf) in first line trt. The magnitude of bnf might differ based on the metastatic (met) site and the chemotherapy regimen (CTR) with which BEV is partnered. ARCAD database contains individual patient data (IPD) of randomized trials that evaluated BEV+ CT. In this pooled analysis, we aimed to evaluate BEV bnf in mCRC with lung metastases (mets) either as single or multiple sites. Methods: IPD from four trials (AVF2107g, N016966, AVF2192g, AGITG) comparing CT +/- BEV were pooled. The primary endpoint, overall survival (OS), was estimated using Kaplan-Meier method and prognostic value of lung mets was evaluated by stratified Cox models according to number and type of met sites and CTRs, oxaliplatin or irinotecan (OX/IRI) based. The predictive bnf of BEV was evaluated by interaction test (int) between trt and lung mets status in subgroups and considered as significant (sig) with a P < 0.1. Results: 2728 patients (pts) with known met sites and survival data were pooled. 1020 pts had single met site, 133 had only lung mets. 1708 pts had multiple met sites, 1008 had lung mets. Pts characteristics were well balanced. Sig OS bnf of BEV was observed in the whole population. In pts subgroup according to the presence or absence of lung mets, sig bnf of BEV were observed with a non-sig int ( Pint=.590). Non-sig bnf of BEV was observed in pts with single site regardless of met site (lung or no lung) or CTR. Sig bnf of BEV was observed in pts with multiple sites without lung mets whatever the CTRs. While sig bnf of BEV was observed in pts with multiple sites with lung mets, we found a sig int between BEV and OX/IRI-based regimens ( Pint=.022). The bnf of BEV was observed with IRI-based regimen but not in OX-based regimen. The bnf of BEV appears greater in multiple sites without lung mets than with lung mets with a sig stratified log-rank test ( PLRT<.001). Conclusions: In pts with multiple sites mCRC, a statistically sig OS bnf of BEV added to CT was observed mainly among pts without lung mets. The overall effect of CT partner choice when combined with BEV can be different. In pts with single site, BEV did not seem to improve OS but the evaluation of efficacy of BEV in presence or absence lung mets was based on small number of pts and needs to be evaluated in trials with larger pts sample, especially trials including pts with single site lung mets. [Table: see text]
A double-blind, randomized, placebo-controlled, parallel study to investigate the auxiliary effects of fucoidan in patients with locally advanced rectal cancer who receive neoadjuvant concurrent chemoradiotherapy before surgery.
Authors: Wang Jaw-Yuan , Tsai Hsiang-Lin
Published: January 2023

12

Background: Preoperative concurrent chemoradiotherapy (CCRT) is the standard treatment for patients with locally advanced rectal cancer (LARC). Low molecular weight fucoidan (LMF) is widely used as food supplements in cancer patients. This study is aimed to evaluate the efficacy of LMF as supplemental therapy to CCRT in LARC patients. Methods: We conducted a double-blind, prospective, randomized, placeo-controlled study to investigate the auxiliary effects of fucoidan in 107 patients with LARC who receive neoadjuvant CCRT before surgery. Finally, 87 patients were enrolled, of whom 44 were included in the study (fucodin) group and 43 in the control (placebo) group. The primary endpoint was the EORTC QLQ-C30 and FACT-C quality of life (QoL), and secondary endpoints included the overall response rate (ORR), disease control rate (DCR) and adverse events (AEs). Results: The physical well-being (PWB) was much improved after 2-month administration in the study (fucodin) group when compared with placebo group ( P= 0.007), whereas colorectal cancer subscale (CCS) was also better after 3-month administration when compared with placebo group ( P= 0.034). ORR and DCR were not significantly different between 2 groups (both P > 0.05). Moreover, skin rash ( P= 0.038) and fatigue ( P= 0.008) was less common in the fucodin group. Conclusions: This is the first clinical trial evaluating the efficacy of LMF as a supplemental therapy in the management of patients with LARC who undergoing CCRT. The results indicate that LMF would significantly improve QoL and decrease AEs of skin rash/fatigue; however, a long-term follow up is mandatory for the confirmation of oncological outcomes by LMF. Clinical trial information: NCT04342949 .
Predictive and prognostic features of metastatic colorectal cancer arising from the transverse colon: A pooled analysis of the CCTG/AGITG CO.17 and CO.20 randomized trials.
Authors: Solar Vasconcelos Joao Paulo , Chen Nan , Tu Dongsheng , Brule Stephanie Yasmin , Goodwin Rachel Anne , Jonker Derek J. , Price Timothy Jay , Zalcberg John Raymond , Moore Malcolm J. , Karapetis Christos Stelios , Siu Lillian L. , Shapiro Jeremy David , Simes John , O'Callaghan Christopher J. , Loree Jonathan M.
Published: January 2023

124

Background: Primary tumour location is predictive of anti-EGFR benefit and prognostic in metastatic colorectal cancer (mCRC). Transverse colon cancers are often categorized as right sided, but the optimal cut point is unclear. Canadian Cancer Trials Group (CCTG)/Australasian Gastro-Intestinal Trials Group ( AGITG) CO.17 compared Cetuximab (Cet) vs. best supportive care (BSC) in mCRC. CCTG/AGITG CO.20 studied the addition of Brivanib Alaninate to Cet in pre-treated KRAS wildtype (WT) mCRC. We investigated the predictive and prognostic features of transverse colon primary location in a pooled cohort from these trials. Methods: Data from patients with RAS WT mCRC from CO.17 and KRAS WT mCRC from CO.20 randomized to cetux were analyzed for treatment outcomes according to location - right, transverse and left. The cecum to transverse colon was considered right sided, while the splenic flexure to rectum was considered left sided. Results: 553 patients were included, 201 (36.3%) from CO.17 and 352 (63.7%) from CO.20. Primary site distribution was: 32 (5.8%) transverse, 101 (18.3%) right and 420 (75.9%) left. On multivariate analysis from 457 (82.6%) patients treated with Cet, left side was associated with superior OS (HR, 0.40; 95% CI, 0.24-0.68, p=0.0006) and PFS (HR, 0.48; 95% CI,0.29-0.79, p=0.004) compared to transverse colon. No significant difference was noted in OS (HR, 0.74; 95% CI, 0.41-1.31, p=0.30) and PFS (HR, 0.79; 95% CI, 0.46-1.36, p=0.40) between right side versus transverse colon. Sidedness was not associated with prognostic difference in OS or PFS in the 96 (17.4%) patients receiving BSC alone. Outcomes according to primary site and treatment are shown. Conclusions: Transverse mCRC has comparable prognostic and predictive features to right sided mCRC. In keeping with previous studies, left side was predictive of greater Cet benefit and presented better overall prognosis when single agent Cet was used after 5-FU, oxaliplatin and irinotecan. [Table: see text]
Association of patient and disease characteristics with outcomes of regorafenib in patients with metastatic colorectal cancer.
Authors: Hsieh Ronan Wenhan , Lee Matthew , Johnson Devin , Zhang Chenxin , Moon Jee-Young , Hsu Dennis , Acuna-Villaorduna Ana , Kuang Chaoyuan
Published: January 2023

135

Background: Regorafenib (rego) is a multikinase inhibitor approved for use in metastatic colorectal cancer (mCRC). No predictive biomarkers have been identified for rego. We conducted a real-world multi-institutional retrospective study to identify the patient and tumor characteristics associated with outcomes of rego in mCRC patients. Methods: Patients from University of Pittsburgh Medical Center and Montefiore Medical Center who received rego for mCRC were included. Patient characteristics, tumor pathology and molecular profiles, treatment history, and response to rego were collected. Primary and secondary outcomes were best objective response and progression free survival (PFS) on rego, respectively. Univariate and multivariate analyses were conducted using Fisher’s exact test, Mann-Whitney U test, Firth logistic regression and Cox proportional-hazards model. Results: 76 patients were included (median age 64, 42% females, 84% whites). Rego yielded a disease control rate of 32% (including 2 complete responses) and a median PFS of 3.6 months. Tumors with high microsatellite instability (MSI-H) had a significantly lower odds of progression of disease (POD) as best objective response (p = 0.01) and a significantly longer median PFS (p = 0.022) compared with tumors with microsatellite stability (MSS) in multivariable models (Table). 75% of MSI-H mCRC patients had not received immunotherapy (IO) prior to rego. Presence of peritoneal carcinomatosis and older age were associated with higher odds of POD (p = 0.093) and a significantly shorter PFS (p = 0.029), respectively. Compared to Whites, Black patients had a numerically higher odds of POD and shorter PFS. Sex, smoking, alcohol, sidedness of CRC, previous treatments, organs involved, and KRAS mutation were not associated with treatment response or PFS. Conclusions: Our study showed that MSI-H mCRC was associated with significantly better response to rego and PFS, even in the absence of prior IO. Other predicting factors for worse outcomes of rego included older age, and potentially peritoneal carcinomatosis and Black race. None of the mutations was found associated with treatment outcomes, with the limitation of lack of comprehensive molecular testing in many patients. Studies to further examine potential biomarkers such as MCL-1 and FBW7 mutations and correlation to clinical outcomes are ongoing. [Table: see text]
Outcomes of patients (pts) with metastatic colorectal cancer (mCRC) participating in phase I clinical trials: The Sarah Cannon Research Institute UK experience.
Authors: Ignatova Ekaterina , Fontana Elisa , Luo Siyun , Williams Anja , Arkenau Hendrik-Tobias
Published: January 2023

142

Background: In the last decade immunotherapy, BRAF inhibitors (inh) and trifluridine-tipiracil became new standard of care (SoC) options for selected mCRC pts through the drug development pathway. In this study we aimed to evaluate clinical characteristics and outcomes of pts with mCRC participating in phase I trials. Methods: Electronic medical records from 10/2011 to 07/2022 were reviewed; pts who received at least one dose of trial drug were included. Data were analysed with descriptive statistic. Results: 81 (100%) pts were identified; 38 (47%) female; median age: 59 (range 31-80); 31 pts (38%) - right sided; 35 (44%) - RASmut, 29 (36%) - BRAFmut, 16 (20%) - RAS/BRAFw; MSI-H status was detected in 11 pts. Eleven pts participated in >1 trial, for a total of 96 cases. Median follow-up was 7 months (m); overall response rate was 6.8%, mPFS: 2.9 m, mOS 18.8 m. Age<50 (P=0,02), low lymphocyte/monocyte ratio (LMR ≤2.8) (P=0.02), in-situ primary tumour (P<0.001), no adjuvant therapy (P=0,001), right sided tumour (P=0,02) were independently associated with shorter OS (univariate analysis); the last three variables remained significant in multivariate analysis. Outcomes according to 4 drug classes and others (chemotherapy-based +/- targeted agents) are shown. Conclusions: Phase 1 trials offer a reasonable therapeutic approach for pts with mCRC and early access to drugs with potential to become SoC in future. [Table: see text]
Neoadjuvant chemoradiation does not improve outcomes for patients undergoing resection for upper rectal cancer: A US Rectal Cancer Consortium analysis.
Authors: Medin Caroline , Gamboa Adriana C. , Warren Emilie , Regenbogen Scott E. , Hendren Samantha , Holder-Murray Jennifer , Kalady Matthew , Ejaz Aslam , Hawkins Alexander , Silviera Matthew , Maithel Shishir K. , Balch Glen C.
Published: January 2023

143

Background: The use of neoadjuvant chemoradiation (NCRT) for upper rectal cancer remains controversial. Our aim was to determine whether NCRT was associated with improved outcomes. Methods: The US Rectal Cancer Consortium was queried for patients who underwent resection of non-metastatic upper rectal cancer (≥12cm from anal verge) from 2007-2017. Primary outcomes were recurrence-free (RFS) and overall survival (OS). Secondary outcomes were postoperative complications. Results: 193 pts met inclusion criteria; 100 (52%) did not receive NCRT and 93 (48%) did. Median age was similar between groups (non-NCRT: 62 yrs; NCRT: 57 yrs; p=0.71). Patients in each group had similar gender and pathological stage (non-NCRT: 22% stage I, 32% stage II, 36% stage III; NCRT: 21% stage I, 23% stage II, 33% stage III; p=0.143). Median follow-up was 31 months (non-NCRT) and 34 months (NCRT). On Kaplan-Meier analysis, NCRT was not associated with improved RFS compared to non-NCRT (3-year RFS 85% vs. 80%; p=0.34) or OS (3-year OS 88% vs. 90%; p=0.49). This finding persisted on multivariable cox regression. R0 resection rate was similar between groups at 99% (non-NCRT) and 97% (NCRT; p=0.27). Anastomotic leak occurred in 11% of both cohorts. Creation of a diverting loop ileostomy (DLI) was nearly 3 times higher in NCRT (82%) versus non-NCRT patients (29%; p<0.001). Conclusions: Among patients with non-metastatic upper rectal cancer, NCRT did not improve survival or recurrence rates, but was associated with a nearly threefold higher DLI rate. Although NCRT is a mainstay of treatment for lower rectal cancer, our results do not support its use in upper rectal cancer. [Table: see text]
Phase II study of TAS-OX (TAS-102 and oxaliplatin) plus bevacizumab for late-line colorectal cancer.
Authors: Hochster Howard S. , Liu Hao , Berim Lyudmyla Derby , Spencer Kristen Renee , Gulhati Pat , DiRubbo Manda , Cohen Seth D. , Lee Patrick , Leitner Stuart P. , Radovich Delia , Misdary Christian , Perez Christian , Datta Sutirtha , Gonzalez Andrea , Saunders Tracie , Boland Patrick M
Published: January 2023

144

Background: TAS-102 (trifluridine/tipiracil) is a novel oral antimetabolite for late line metastatic colorectal cancer (CRC) approved in 2018. Many patients are treated early in their course with oxaliplatin (OX), particularly adjuvant, and may benefit from re-treatment. In this trial we combine the typical late line use of TAS with OX (BEV [bevacizumab] added at investigator discretion) with goal of improved response. Methods: Eligibility included measurable CRC previously treated with all approved drugs per TAS package insert (irinotecan, oxaliplatin, 5FU, anti-VEGF, anti-EGF) as appropriate, PS = 0-1, labs within usual range, neuropathy < grade 2, ability to take oral meds, appropriate contraception. If no contraindication to BEV, this could be added at patient. TAS was dosed at 35 mg/m2 days 1-5 with OX 85/m2 d1 every 14 days (and BEV 5 mg/kg, if given). All supportive care was allowed including growth factors. Results: 47 patients (pts, median age 55) were enrolled in a Simon mini-max design, including 45% female, 21% black, 11% Asian, 11% Hispanic and 5% mixed. 26 pts received BEV. For the first 40 pts, 385 cycles were given (mean = 7 cycles, median 8) with 18 pts (45%) requiring dose reductions (1 dose reduction = 9 pts, 2 = 6, 3 = 3), and 9 receiving (peg)/filgrastim. Toxicities leading to SAEs included gr 3 heme (2), heart failure, abd pain/n/v (6), sepsis (2), urinary (4); and related gr 3 included one gr 3 vomiting and one gr 3 neutropenia. Independently reviewed RECIST Response (N = 32) included PR 2(6%), SD 23 (72%), PD 7 (22%). Mean TTP was 4.5 m (median 4, range 1 – 18) with 9 (28%) pts more than 6 months. Conclusions: In patients with late-line CRC and candidates for TAS (trifluridine/tipiracil), treatment with TAS plus OX is both well tolerated and active. RR is higher than single agent and 78% (95% CI, 60-91%) of patients had stable disease or response, with 60% receiving 8 or more cycles. Randomized trials comparing to single agent TAS are warranted in this setting. Clinical trial information: NCT04294264 .
Prospective evaluation of dose-escalated preoperative concurrent chemo-radiation with image-guided intensity modulated radiation therapy in locally advanced rectal cancers.
Authors: Puri Raunaq , Rastogi Madhup , Gandhi Ajeet Kumar , Khurana Rohini , Hadi Rahat , Sapru Shanyanu , Srivastava Anoop , Bharati Avinav , Mishra Surendra Prasad
Published: January 2023

155

Background: The paradigm of locally advanced (T3/4; T1-4N1-2) rectal cancers (LARC) requires an intensified treatment for better pathological outcomes. Treatment intensification may be done by radiation dose escalation of long course neoadjuvant chemoradiation therapy (NACRT) by image guided Intensity Modulated Radiation Therapy (IG-IMRT) to increase downstaging with potentially higher local control rates. We aimed to analyze the efficacy and safety of NACRT with dose escalated IG-IMRT in LARC. Methods: 20 patients of LARC were recruited in this prospective interventional phase-II study treated by IG-IMRT with 45 Gray/25 fractions to elective nodal volumes and concomitant boost of 55 Gray/25 fractions to gross primary and nodal disease with concurrent capecitabine (825 mg/m2 twice a day on radiation days). All were planned to undergo definitive surgery 6-8 weeks post completion of NACRT with Total mesorectal excision by Low anterior resection (LAR) or Abdominoperineal resection (APR) followed by 6-8 cycles of adjuvant chemotherapy. Post operative response assessment was assessed by Modified Ryan’s scheme for regression and by tumor downstaging. Primary end point was acute toxicity assessment and secondary end points were pathological complete response (pCR) and loco-regional control (LRC). Results: Of 20 patients, 18 underwent definitive surgery and received full course adjuvant chemotherapy (90%). Median follow up was 15.1 months. 2 patients refused surgery, had complete clinical response (cCR) on assessment and were on follow up. Tumor downstaging was achieved in 14 (77.7%) patients and nodal downstaging was achieved in 15/18 (83.3%) patients. In 4 patients (22.2%) pCR was achieved and overall complete response (OCR defined as pCR and nearCR, including 2 patients with cCR) in 10 patients (50%). 4 patients planned for APR underwent LAR achieving a sphincter preservation rate of 22%. Grade 3 toxicities were observed in 2 patients which resolved on first follow up. No Grade 4 acute toxicities were reported. No loco-regional relapses were found and all patients are disease free at the time of last follow up. Conclusions: Dose escalation with IG-IMRT offers higher rates of pCR and OCR with acceptable toxicity profile and excellent short term locoregional control. [Table: see text]
Second-line bevacizumab plus FOLFOX in patients with metastatic colorectal cancer previously treated with adjuvant oxaliplatin-based chemotherapy.
Authors: Chun Sang Hoon , Kim Jung Hoon , Kwag Seung-Jin , Kang Myoung Hee , Park Ji-Ho , Lee Gyeong-Won , Kang Jung Hun
Published: January 2023

157

Background: There is a rarity of evidence for retreatment with oxaliplatin for metastatic colorectal cancer (mCRC), especially in combination with bevacizumab. This is a retrospective study of second line bevacizumab (Bev) plus FOLFOX (oxaliplatin, 5-fluorouracil, and leucovorin) in patients with metastatic colorectal cancer previously treated with adjuvant oxaliplatin-containing chemotherapy. Methods: Patients with age older than 18 and histologically confirmed metastatic colorectal cancer treated with second line bevacizumab plus FOLFOX in a single institute between 2015 and 2020 were enrolled. History of previous adjuvant chemotherapy regimens in patients with metachronous metastatic colorectal cancer was analyzed. Progression-free survival (PFS) and overall survival (OS) of the second line treatment were calculated using Kaplan-Meier method and compared between patients pretreated with adjuvant oxaliplatin (ReOx) and oxaliplatin-naive patients (control) with the log rank test. Results: A total of 72 patients were included. 23 patients (ReOx) were pretreated with adjuvant oxaliplatin and 49 patients (control) were oxaliplatin-naive before the second line treatment. There was a tendency of younger age in the ReOx group, but not statistically significant. Liver metastasis was significantly more frequent in the control group. The median PFS and OS in the ReOx group and the control group were 4.3 months (95% confidence interval [CI], 3.67–21.50) versus 5.5 months (95% CI, 4.23–8.20, hazard ratio [HR] = 0.84), and 10.5 months (95% CI, 5.40–30.37) versus 9.4 months (95% CI, 6.00–14.9, HR = 1.01) respectively. There was no significant difference of PFS ( p= 0.523) and OS ( p= 0.9745) between two groups. Conclusions: This study suggests a potential survival benefit of bevacizumab plus FOLFOX for mCRC patients previously treated with adjuvant oxaliplatin-containing treatment comparable to oxaliplatin-naive patients. [Table: see text]
Clinical characteristics and survival trends of patients with metastatic colorectal cancer (mCRC) and peritoneal carcinomatosis who receive metastases surgery in a Spanish cohort.
Authors: Bringas Marianela , Soto Javier , Gutiérrez Alonso Natalia , Muñoz Martín Andrés J. , Calvo Ferrándiz Aitana , Torres Pérez-Solero Gabriela , Ortega Laura , Martín Lozano Rocío , Jiménez Rodríguez Roberto , Gonzalez Caraballo Irene , Gutierrez Ortiz de la Tabla Ana , López Jiménez Carlos , Juliao Caamaño David Salomon , Gómez María Palma , de Lucas Mónica Benavente , Muñoz Marc Ariant Cañete , Alva Bianchi Manuel , Martínez Delfrade Íñigo , Martin Miguel , Garcia-Alfonso Pilar
Published: January 2023

159

Background: Peritoneal metastases in patients with mCRC are commonly associated with poor outcomes. Some of these patients are candidates to undergo metastases surgery, which may result in better prognosis; however, clinical and molecular characteristics of these patients remain uncertain. Methods: We conducted a retrospective analysis of 166 patients with mCRC and peritoneal metastases in a tumor registry from 2015 to 2021, analyzing the clinical and molecular characteristics, as well as progression-free survival (PFS) and overall survival (OS) of patients who received peritoneal surgery versus those who did not. Results: From the whole population, 65 patients (39%) underwent peritoneal metastases surgery, and several characteristics were more frequent in this subgroup: ECOG 0 (n = 26, OR 2.75, p = 0,0069), age <65 years (n = 43, OR 2.29, p = 0,0162), absence of hepatic metastases (n = 56, OR 3.31, p = 0,0037), single metastatic location (n = 43, OR 3.48, p = 0,0002), normal CEA levels at diagnosis (n = 33, OR 2.02, p = 0,0455) and BRAF mutation (n = 12, OR 3.32, p = 0,0345). Moreover, these patients received more lines of systemic treatment (2.8 vs 2, p = 0,006) and more metastases surgeries (1.7 vs 0.9, p = 0,000). Significant differences in tumor mutational status regardless of BRAF (KRAS, NRAS, MSI, PI3K and HER2), sex and primary tumor location between groups were not found. PFS was longer in patients receiving metastases surgery (median, 13.68 vs 7.76 months; HR for progression 0.64; 95 % confidence interval (CI) 0.46 to 0.89; p = 0,009), as well as overall survival (median NR vs 29.53; HR for death 0.39; 95 % CI, 0.25 to 0.60; p = 0,000). Conclusions: In our cohort, patients with mCRC and peritoneal carcinomatosis who underwent metastases surgery had more frequently less than 65 years, ECOG 0, absence of liver metastases, single metastatic location, normal CEA levels at diagnosis and BRAF mutation. Moreover, this subgroup showed better outcomes with a statistically significant increase in PFS and OS.
Effectiveness of biologic agents among Hispanics in the US with metastatic colorectal cancer.
Authors: Patel Riya Jayesh , Negassa Abdissa , Tolu Seda , Acuna Villaorduna Ana , Goel Sanjay
Published: January 2023

16

Background: Randomized clinical trials have demonstrated the survival benefit provided by the addition of biologic drugs to chemotherapy (biochemotherapy) in patients with metastatic colorectal cancer (mCRC). However, Hispanic patients are underrepresented in trial populations with limited data on treatment efficacy in them. We aim to compare effectiveness of chemotherapy vs biochemotherapy among Hispanic population in the US with mCRC. Methods: This study includes two cohorts of patients: 1. age ≥ 65 years mCRC diagnosed from 2004 to 2011 who had received at least 1 dose of chemotherapy and had complete Medicare claims data using the Surveillance, Epidemiology, and End Result (SEER)–Medicare linked database, and 2. local Hispanic population from two hospitals in Bronx, New York, from 2006- 2020. Patient data were classified according to whether they received chemotherapy (oxaliplatin, irinotecan, and 5-fluorouracil or capecitabine) or biochemotherapy (bevacizumab, cetuximab, panitumumab, ramucirumab, or aflibercept, started within 3 months of chemotherapy). Overall survival (OS) was defined as the time from starting chemotherapy to death or last follow-up. A weighted Cox regression model was used to assess differences in survival. Results: A total of 188 patients with mCRC were identified. Fifty three (28.2%) received chemotherapy and 135 (71.8%) received biochemotherapy. Median ages were 69 and 68 years, respectively. There were no differences based on median income, marital status, primary site or sidedness, tumor differentiation grades or Charlson Comorbidity Score between both groups. Among patients who received only chemotherapy, 9% received second or greater lines of chemotherapy when compared to 51% in the biochemotherapy group (p <0.001). The median overall survival was 6.6 (95% CI:5.7 - 15.0) months (mo) and 15.9 (12.0 -24.5) mo, respectively. Biochemotherapy conferred an OS benefit with average HR=0.62 (0.41-0.94; p=0.023). This was most evident in the first year (HR=0.53, 0.31-0.89; 0.016), less so in 2nd year (HR=0.65, 0.28 - 1.49; 0.307) and there was an apparent reversal effect beyond 2 years (HR=1.79, 0.41-7.77; 0.436). Conclusions: In this comparative effectiveness study of a cohort of Medicare recipients and the Bronx population, with mCRC, biochemotherapy was associated with an improvement in OS, especially in the 1st year. Patients receiving biochemotherapy are more likely to receive further lines of chemotherapy upon disease progression.
Phase Ib of pembrolizumab (pem) in combination with stereotactic body radiotherapy (SBRT) for resectable liver oligometastatic MMR-proficient (pMMR) colorectal cancer (CRC): Final results.
Authors: Deming Dustin A. , Lubner Sam Joseph , Uboha Nataliya Volodymyrivna , Emmerich Philip , Kraus Sean , LoConte Noelle K. , Kim David H. , Matkowskyj Kristina A. , Weber Sharon , Abbott Daniel , Eickhoff Jens C. , Bassetti Michael F.
Published: January 2023

161

Background: SBRT is a standard treatment option for oligometastatic CRC and is associated with an increase in immunogenic antigen release and influx of immune cells. We hypothesized that radiation would enhance the immunogenicity of pMMR CRC and potentiate the effectiveness of PD-1 blockade. This phase Ib study examined the safety and efficacy of the sequential combination of SBRT and Pem in patients (pts) undergoing resection of their disease. Additionally, the accumulation and proteolysis of versican (VCAN), an immunoregulatory tumor matrix proteoglycan was examined as a novel immunotherapy biomarker. Proteolysis of VCAN results in the release of an immunostimulatory fragment, versikine. Cancers with low VCAN and high versikine (VCAN proteolysis predominant (VPP)) are hypothesized to respond better to immunotherapies. Methods: Eligibility criteria included resectable liver-confined metastatic pMMR CRC. Prior surgery and systemic chemotherapy were allowed. Subjects received sequential SBRT and cycle 1 of Pem prior to operative management and adjuvant Pem. The primary objectives were to determine the safety/tolerability of this regimen and the recurrence free survival (RFS) at 1 year following operative management. Correlative studies examined tumor infiltrating CD8+ T lymphocytes (TILs), VCAN, and versikine using immunohistochemistry. Results: 15 pts (median age 61.5 [range 39-69], 26% female) were enrolled. All pts had prior FOLFOX. The number of liver lesions ranged from 1-6. SBRT median dose was 50 Gy (40-60 Gy) to 1-2 liver lesions. Grade 3/4 AEs included one case of biliary tract injury and biloma, and one case of G3 hypophosphatemia. No grade 3/4 immune-related AEs occurred. All pts completed a minimum follow-up of 1 year post resection (median follow-up 41 months [range 15-64]). In the intention to treat analysis, the 1 year RFS was 67% (historic control 50%), 40% of patients remained cancer free, and 67% of pts are still alive. 2 of 3 pts with BRAF V600E mutations have had early recurrences. 2 pts had VCAN high tumors and both recurred prior to 1 year. 6 pts had VPP cancers and 83% were recurrence free at 1 year and 66% are currently without evidence of cancer. Conclusions: The combination of SBRT with Pem was well tolerated with no signal of increased immunotherapy-related toxicity. This study met its primary endpoint and this regimen deserves further investigation in confirmatory studies. Additionally, VCAN accumulation and proteolysis are promising biomarkers in this setting. Clinical trial information: NCT02837263 .
Deep learning model for predicting treatment response for patients with rectal cancer using 3D medical imaging.
Authors: Lim June Hyuck , Heo Jaesung , Park Jeongmin , Kim Seonhwa , Jang Hanbyeol
Published: January 2023

168

Background: We developed a deep learning model to predict pathological response based on magnetic 3D resonance imaging in rectal cancer. Methods: A total of 242 patients with locally advanced rectal cancer who received preoperative chemoradiotherapy followed by surgical resection were collected from single center. Surgical resection was performed at 6 to 8 weeks after the completion of preoperative CRT. Achieving pathogic complete response (pCR) was defined as complete absence of any tumour cells, in both the primary site and the dissected lymph node in surgical specimens. Based on pre-chemoradiotherapy T1-weighted axial 3D MR images, deep learning models were developed to predict pCR, respectively. Results: We analyzed 32,000 MRI images and involved several radiation oncologists in segmenation and classification. To calculate the probability of pCR using various convolutional neural network (CNN) architectures, several deep learning models were developed. The data input to the deep learning model was 3D MRI image, clinical data, and MRI metadata. Among 242 patients, 50 (20.7%) had evidence of pCR. The best model was developed based on SeResNet using transfer learning by MONA framework. The deep learning model showed an area under the receiver operating characteristic curve, sensitivity, specificity, and accuracy of 0.926, 0.831, 0.921, and 90.2% for predicting pCR. Conclusions: The pre-chemoradiotherapy T1-weighted 3D MR image-based deep learning model showed acceptable performance in predicting pCR in patients with rectal cancer.[Table: see text]
Feasibility of establishing and drug screening patient-derived rectal organoid models from pretreatment rectal cancer biopsies.
Authors: Acklin-Wehnert Scarlett , Dayanidhi Divya , Czito Brian G. , Palta Manisha , Willett Christopher , Eyler Christine Elissa , Mantyh Christopher , Migaly John , Thacker Julie , Lan Billy , Hsu David S.
Published: January 2023

176

Background: Response to neoadjuvant chemotherapy and radiation therapy in the treatment of locally advanced rectal cancer is heterogenous and prognostic of clinical outcomes, necessitating the need for predictive biomarkers to guide personalized treatment recommendations. Sensitivity to a given chemotherapy in patient-derived organoids predicts patient response to that chemotherapy, establishing it as a promising model for efforts to ascertain predictive biomarkers and personalize treatment decisions. This study assessed the feasibility of obtaining patient-derived rectal organoids from standard of care pre-treatment proctoscopy biopsies. Methods: In this clinical trial (NCT04371198), biopsies were obtained from patients with stage II rectal adenocarcinoma prior to receipt of neoadjuvant therapy. Tissue samples were mechanically and enzymatically dissociated to obtain a single cell suspension. Cells were then mixed with matrigel at a ratio of 2,000 cells:5 µL Matrigel in a 50ul dome and plated on a 24 well tissue culture plate with colorectal cancer organoid media at 37oC/5% CO2. Established patient-derived organoids were then used to perform drug screens with clinically-applicable chemotherapeutics including oxaliplatin, irinotecan and 5-FU, followed by high throughput drug screen using our recently published MicroOrganoSpheres platform using the NCI Approved Oncology Drugs Set VI* library. Results: Of the 20 patients enrolled, 17 (85%) patient-derived organoids were created from pre-treatment specimens. 15 (88%) of these samples were successfully established as defined by the ability to passage organoids for at least two passages. All established samples were used to perform standard of care drug screens and high throughout drug screens, which demonstrated differences in drug sensitivities among the samples. Moreover, within two weeks of receiving the sample, four established quickly enough to complete drug screening with oxaliplatin, SN38, and 5-Fluorouracil. Conclusions: These results demonstrate the feasibility of establishing patient-derived rectal organoids from biopsy specimens obtained by proctoscopy, and reinforce the utility of patient-derived organoids as a tractable ex vivo platform to personalize rectal cancer treatment. Planned future directions include in vitro determination of radiation therapy sensitivity as well as systematic assessment of the correlation between individual patients and their organoid model. Clinical trial information: NCT04371198 .
TP53 gain of function mutation as a prognostic factor in high-methylated metastatic colorectal cancer: Translational research of TRICOLORE study.
Authors: Ouchi Kota , Wakayama Shonosuke , Takahashi Shin , Yamada Yasuhide , Komatsu Yoshito , Shimada Ken , Yamaguchi Tatsuro , Shirota Hidekazu , Takahashi Masanobu , Ishioka Chikashi
Published: January 2023

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Background: TP53 tumor suppressor gene is frequently inactivated by loss-of-function mutations. Some of the mutations gain additional oncogenic functions and are known as gain-of-function (GOF) mutations. This study analyzed the association among primary tumor site (PS), genome-wide DNA methylation status (GWMS), and TP53 mutation subtypes about prognosis in metastatic colorectal cancer (mCRC). Methods: Tumor tissues of mCRC patients registered in the TRICOLORE Study (clinical trial number) were analyzed for GWMS and TP53 mutation as translational research and were classified into high-methylated colorectal cancer (HMCC) and low-methylated colorectal cancer (LMCC) for GWMS, and wild-type , GOF mutation and non-GOF mutation for TP53 mutation. Overall survival (OS) was compared between single or combined subgroups, and Cox regression analysis was performed to identify factors contributing to OS. Results: A total of 209 patients were analyzed, HMCC and LMCC were 60 (28.7%) and 149 (71.3%), respectively. TP53 wild-type , GOF mutation and non-GOF mutation were 35 (16.7%), 79 (37.8%) and 95 (45.5%), respectively. HMCC showed a significantly worse prognosis than LMCC (median OS 25.3 vs. 40.3 months, P < 0.01, hazard ratio 1.87). Combining GWMS and TP53 mutation subtypes about prognosis, the HMCC/GOF (n = 26) group had a significantly poorer prognosis than the other three groups including HMCC/non-GOF (n = 22), LMCC/GOF (n = 53), and LMCC/non-GOF groups (n = 73) (median OS 17.7, 35.3, 40.3, 41.2 months, p = 0.007, p < 0.001, p < 0.001, respectively). The HMCC/GOF group had a poorer prognosis than the other 3 groups regardless of the PS. In the multivariate analysis in the GOF mutation subgroup, HMCC (p < 0.01) was the only poor prognostic factor, while right-sided colon cancer (p = 0.03) and RAS mutations (p = 0.01) were significant poor prognostic factors in the multivariate analysis in the non-GOF mutation subgroup. Conclusions: TP53 gain of function mutations are independent poor prognostic factors in high-methylated metastatic colorectal cancer.
Disparities in colorectal cancer: Trends of reduced screening among minority populations.
Authors: Ouni Ahmed , Cardiel Nunez Kristin , Garrett Aneesah , Heckman Michael , Brahmbhatt Bhaumik , Woodward Timothy A A
Published: January 2023

18

Background: Studies have shown that African Americans (AA) are at increased risk for Colorectal Cancer (CRC) compared to other groups. Despite advancements in CRC screening modalities, few studies have investigated disparities in CRC screening among this vulnerable population. Methods: We performed a retrospective review of patients of age 45 or older who were seen in Family Medicine (FM), Internal Medicine (IM), or Gastroenterology (GI) between January 1, 2015 and December 31, 2021 at the Mayo Clinic. Information was collected regarding patient characteristics (age, sex, Charlson comorbidity score, race), and outcomes (whether a Cologuard test was ordered on the same day as the initial appointment, and whether the patient underwent a colonoscopy within 1 year after the initial appointment). Categorical variables were summarized with number and percentage of patients. Outcomes were compared between race groups (Caucasian, AA, Asian, Other) using unadjusted and multivariable logistic regression models. Multivariable models were adjusted for age, sex, and Charlson comorbidity score. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. P-values <0.05 were considered as statistically significant, and all statistical tests were two-sided. Results: Overall, 558,078 were included for analysis and 14,607 (2.6%) were AA. Overall, AA patients for less likely to have Cologuard ordered compared to Caucasians (OR=0.62, p<0.001), notably driven by patient seen in the FM group (OR=0.54, p<0.001) and no statistically significant difference was observed in the IM and GI groups (p=0.055 and p=0.43, respectively). Notably, compared to Caucasian patients, Asian patients were overall more likely to have Cologuard ordered (OR=1.23, p=0.003). In multivariable analysis assessing the likelihood of having a colonoscopy performed within 1 year of the initial appointment, the likelihood of a colonoscopy within 1 year of initial clinic visit was significantly lower for AA compared to Caucasian patients (OR=0.50, p=0.028). This difference was strongest in FM patients (OR=0.26, p=0.022) and was not significant for IM (OR=0.67, p=0.37) or GI (OR=2.31, p=0.25). Conclusions: In this study, we found that AA ethnicity is associated with reduced likelihood of having Cologuard ordered compared to Caucasian patients. Furthermore, AA patients were less likely to have colonoscopy ordered within 1 year of initial visit clinic visit among the overall cohort, highlighting important disparities in CRC screening among this vulnerable patient population notably for those seen in the FM group. Future studies are needed to assess other barriers for CRC screening in this population.
Feasibility of circulating tumor DNA (ctDNA) to guide organ preservation in patients with node-negative rectal cancer undergoing neoadjuvant chemotherapy, excision, and observation in the phase II CCTG CO.28 trial.
Authors: Loree Jonathan M. , Madison Russell , O'Callaghan Christopher J. , Brown Carl J , Tu Dongsheng , Jonker Derek J. , Sherry Max , Fine Alexander D. , Huang Yanmei , Camara William , Pokharel Prapti , Aleshin Alexey , Oxnard Geoffrey R. , Kennecke Hagen Fritz
Published: January 2023

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Background: CCTG CO.28 evaluated 3 months of neoadjuvant CAPOX or FOLFOX followed by transanal excision surgery (TES) in patients (pts) with T1-T3, N0 rectal cancers with the goal of organ preservation. Total mesorectal excision (TME) was recommended for inadequate downstaging or high-risk features on TES pathology. Detection of ctDNA is associated with a high rate of recurrence in high risk resected colorectal cancer. However, the sensitivity of ctDNA in early-stage rectal cancer is unclear. Methods: Tissue CGP was performed retrospectively on pretreatment resected tumor using Foundation OneCDx (F1CDx), followed by MRD detection using FoundationOneTracker. Briefly, variants were selected from F1CDx using an algorithm that filters out non-tumor derived variants (e.g. germline). A tumor-informed personalized multiplex PCR-next generation sequencing assay, consisting of up to 16 variants, was used to detect ctDNA and quantify plasma mean variant allelic frequency (VAF) and mean tumor molecules per mL of plasma (MTM/mL). FoundationOneTracker was performed on blood samples collected pre/post-neoadjuvant chemotherapy. Buffy coat sequencing was performed at FMI to validate the monitoring variant selection algorithm. Results: 52 pts underwent F1CDx and FoundationOneTracker analysis. KRAS mutations were observed in 60% (n =31) of cases; MSI-H and BRAF V600E mutations were not detected. From 1,580 distinct variants detected in tissue and paired buffy coat sequencing, 985 had VAF >30% in the buffy coat specimen and were considered germline. The variant selection algorithm filtered 99.8% (n = 983) of germline variants; the remaining 2 were not selected for primer design. A median of 7 variants (range 2-16) were tracked per pt. Detectable ctDNA was found in 0% (0/6), 19% (6/32) and 55% (6/11) of treatment naïve T1, T2 and T3ab cases, respectively, and 83% of those which were initially positive (10/12) cleared ctDNA post chemotherapy. Three pts had detectable ctDNA pre-excision, including 1 who was negative pretreatment. From 42 pts with pre/post-treatment plasma, 19 pts were recommended for TME; 2 had detectable ctDNA, 5 had ctDNA clearance, and 12 had no ctDNA detection. Conclusions: Node-negative rectal cancer exhibited ctDNA shed in a minority of pts, with most clearing ctDNA on chemotherapy before their TES. The dynamic ctDNA signal we demonstrate could supplement clinical factors in informing organ preservation in very early-stage rectal cancer. Larger studies are needed to determine if this information can be used to personalize therapy. Clinical trial information: NCT03259035 . [Table: see text]
Evidence for diet-gene interaction in early-onset colorectal cancer.
Authors: Merchant Juanita L. , Song Heyu L , Stoffel Elena Martinez
Published: January 2023

182

Background: About 10 percent of all colorectal cancers are in subjects who are not yet 50 (EO-CRC) and the occurrence of early onset colorectal cancer (EO-CRC) is rising in the US. Patients with CRC are twice as likely to have diabetes or be overweight. Using targeted exome sequencing of germline DNA from EO-CRC subjects, we identified a missense mutation at Ala98Val within the DNA binding domain of Hepatic Nuclear Factor 1 alpha (HNF1A, 12q24.31, Rs1800574). HNF1A is the most frequently mutated gene in diabetic individuals whose onset of diabetes occurs typically before age 25 (MODY3 locus). Our aim was to demonstrate that the HNF1A variant provides a genomic landscape for EO-CRC to develop in the setting of a specific diet type. Methods: HNF1A was identified using targeted exon sequencing of archived leukocyte DNA from subjects with EO-CRC. Flag-tagged WT and HNF1AA98V expressing plasmids were transfected into HCT116 colon cancer cells and nuclear extracts were prepared for Electrophoretic Mobility Shift Assays (EMSAs) to test binding differences. An Hnf1aA98V mutant mouse model was generated using CRISPR/Cas9. WT, Hnf1a A98V/+ and Hnf1a A98V/A98V mice were placed on 3 diets--normal chow, a high fat (~34%) diet (HFD) or a high sugar (~62% fructose) diet (HSD) after weaning at 3 weeks. The mice were followed for 12 months, weighed monthly, and observed for clinical signs of morbidity. After euthanizing, blood, colon and liver were collected for histology and qPCR. Results: HNF1AA98V was identified in 13/145 subjects with EO-CRC. An additional 3 subjects exhibited mutations elsewhere in HNF1A. Flag-tagged WT and mutant HNF1A-expressing plasmids were transfected into HCT116 colon cancer cells and nuclear extracts showed reduced HNF1AA98V binding to its consensus DNA element by EMSA. Only heterozygous or homozygous Hnf1aA98V mice on the HFD showed a significant number of colon polyps (~19%). Only 1/22 heterozygous mice developed a polyp on the HSD. RNA-Seq analysis of colonic mucosa from the homozygous mutant compared to WT mice revealed an increase lipid and b-catenin regulated genes. Specifically, there was an increase in β-catenin, LEF 1 and MYC by immunohistochemistry in the polyp of HNF1AA98V, but not in the adjacent normal tissue. Liver steatosis in the Hnf1aA98V versus WT mice on the HFD was observed. Conclusions: Occurrence of the HNF1AA98V variant is increased among a cohort of EO-CRC patients and is a loss of function mutation that creates a genetic landscape for colon polyps on a HFD.