Somatic mutation landscape of appendiceal cancer.

671 Background: Appendiceal cancers are rare, comprising just 0.5% of all intestinal neoplasia, which has prevented the systematic study of these tumors in randomized clinical trials. Given this absence of clinical data, no evidence-based guidelines exist regarding the best management of this disease. Standard treatment generally follows consensus guidelines for colorectal cancer; however, there are currently no standards to guide chemotherapy selection in the adjuvant or metastatic setting. Methods: Somatic mutation profiles covering ~300 frequently mutated genes were obtained for 385 primary appendiceal tumors (Foundation Medicine). A retrospective review was performed to gather clinico-pathologic data. The primary objective was to assess the somatic mutation profile of each subtype of appendiceal cancer and to compare these to colorectal cancer. Colorectal data was obtained from TCGA cohort via cBioPortal. Results: Appendiceal adenocarcinoma (non-mucinous) and mucinous adenocarcinoma had shared somatic mutations albeit with differing frequencies. The most common mutations were KRAS (60.1% and 80.5%, respectively), GNAS (32.4%, 58.5%), TP53 (42.8%, 19.5%), and SMAD4 (14.8%, 14.6%). Tumors with goblet cell (adenocarcinoid) histology had lower prevalence of KRAS (16.0%) and GNAS mutations (8.0%), but similar prevalence of TP53 mutation (24.0%) and a greater prevalence of ARID1A mutation (20.0%). The mutation profiles of all appendiceal histologies differed from colorectal adenocarcinoma with markedly lower prevalence of ATM (7.9% vs. 71.0%). Chemotherapy data was available for 30 metastatic patients; these patients received an average of 1.76 lines of therapy (range 1-4). All 30 were treated with either 5-FU or capecitabine, 11 (36.7%) with oxaliplatin, 23 (76.7%) with irinotecan and 19 (63.3%) with bevacizumab. Analysis of survival data and correlation with molecular and histologic features is ongoing. Conclusions: Despite clear molecular differences between appendiceal and colorectal tumors, appendiceal tumors are primarily treated with colorectal chemotherapy regimens. There remains a pressing need for both pre-clinical and clinical investigation to develop treatment regimens specific to appendix cancer.

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Nintedanib in metastatic appendiceal carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.tps723 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. TPS723-TPS723

Author(s):

Birendra Kc ◽

Mufti Naeem Ahmad ◽

Kunal C. Kadakia ◽

Reza Nazemzadeh ◽

Mohamed E. Salem ◽

...

Keyword(s):

Colorectal Cancer ◽

Ovarian Cancer ◽

Metastatic Colorectal Cancer ◽

Kinase Inhibitor ◽

Objective Response ◽

Progression Free Survival ◽

Primary Objective ◽

Limited Information ◽

Appendiceal Cancer ◽

Open Label

TPS723 Background: Appendiceal carcinomas are rare with an incidence of about 0.12 cases per 1,000,000 people per year. There is limited, mostly retrospective data in the treatment of metastatic appendiceal carcinomas. Generally, fluoropyrimidine-based therapy is used in the first line, adapting regimens for metastatic colorectal cancer. However, beyond progression, no treatments have shown clear activity. In appendiceal cancer, high vascular endothelial growth factor receptor (VEGFR)2 expression has been correlated with poor survival. Moreover, malignant ascites has been demonstrated to have elevated levels of VEGF. Nintedanib is an oral tyrosine kinase inhibitor of VEGFR which demonstrated activity in lung and ovarian cancer in clinical trials, and has undergone investigation in heavily pretreated metastatic colorectal cancer. Given the analogies between appendiceal and colorectal cancer and potentially ovarian cancer, and the limited information about the optimal treatment of metastatic appendiceal carcinomas, further investigation with nintedanib is warranted. Methods: This is a single arm, open label, investigator initiated, two-stage phase II trial (NCT 03287947) in metastatic appendiceal cancer patients after failure (defined as progression on or within 6 months or intolerance) of initial fluoropyrimidine-based therapy and at least one measurable site of disease. The trial started enrolling patients in June 2018, and up to 39 subjects will be enrolled. They will be treated with 200 mg of oral nintedanib twice daily and undergo disease evaluation every two months. The primary objective of this study is to evaluate the disease control rate (DCR), the composite of objective response and stable disease per RECIST 1.1. Secondary objectives include evaluation of safety and toxicity, objective response rate (ORR), 6-month progression free survival (PFS) and overall survival (OS). DCR, ORR & 6-month PFS will be estimated with the corresponding 95% Clopper-Pearson confidence interval. PFS & OS will be estimated using Kaplan-Meier techniques. Exploratory objectives include evaluation of serum VEGF, ascites VEGF, hypertension and paracentesis frequency in subjects with ascites at study entry. Clinical trial information: NCT 03287947.

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Construction of immune-related lncRNA signature to predict aggressiveness, immune landscape, and drug resistance of colorectal cancer

10.21203/rs.3.rs-808813/v1 ◽

2021 ◽

Author(s):

Yonggan Xue ◽

Bobin Ning ◽

Hongyi Liu ◽

Baoqing JIa

Keyword(s):

Colorectal Cancer ◽

Survival Data ◽

Clinical Characteristics ◽

Risk Model ◽

Expression Patterns ◽

Risk Groups ◽

Survival Outcomes ◽

Lasso Regression ◽

Optimal Cutoff ◽

Treatment Regimens

Abstract Background Colorectal cancer (CRC) remains one of the most common malignancies across the world, threatening almost millions of lives every year and increasingly adding the social-economical burden. Thus far, a biomarker, which can comprehensively predict the survival outcomes, clinical characteristics, and therapeutic sensitivity, is still lacking. Results This study established a pair-risk model, together with, an exp-risk model to predict biological characteristics of CRC based on immune-related lncRNA (irlncRNA) expression patterns. We retrieved transcriptomic data of CRC, including 473 tumor samples and 41 normal samples, and identified 739 irlncRNA through co-expression analysis, and constructed irlncRNA pairs. After integrating with clinical survival data, we established an 11 irlncRNA pairs signature using Lasso regression analysis. We next drew the 1-, 5-, 10-year curve line of receiver operating characteristic (ROC), calculated the areas under the curve (AUC), and recognized the optimal cutoff point. Patients with CRC were stratified into high- and low-risk groups based on the optimal cutoff value. Then, we validated the pair-risk model in terms of the survival outcomes of the patients. Moreover, we tested the reliability of the pair-risk model for predicting tumor aggressiveness and therapeutic responsiveness of CRC. Additionally, we reemployed the 11 of irlncRNAs involved in the pair-risk model to constructed an expression risk model that was also highly predictive of prognostic outcomes of CRC patients. Importantly, combining the pair-risk model and exp-risk model yielded a more robust approach for predicting the survival outcomes of patients with CRC. Conclusions We suggest that the irlncRNA-based risk models can be utilized as prognostic tools to predict survival outcomes and clinical characteristics and guide treatment regimens of CRC.

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Construction of immune-related lncRNA signature to predict aggressiveness, immune landscape, and drug resistance of colorectal cancer

10.21203/rs.3.rs-808813/v2 ◽

2021 ◽

Author(s):

Yonggan Xue ◽

Bobin Ning ◽

Hongyi Liu ◽

Baoqing Jia

Keyword(s):

Colorectal Cancer ◽

Survival Data ◽

Clinical Characteristics ◽

Risk Model ◽

Survival Outcomes ◽

Lasso Regression ◽

Differential Analysis ◽

Operating Characteristics ◽

Treatment Regimens ◽

Hr Model

Abstract Background:Colorectal cancer (CRC) remains one of the most common malignancies across the world. Thus far, a biomarker, which can comprehensively predict the survival outcomes, clinical characteristics, and therapeutic sensitivity, is still lacking. Methods: We leveraged retrieved transcriptomic data of CRC from the public database, and constructed irlncRNA pairs. After integrating with clinical survival data, we performed differential analysis and constructed 11 irlncRNA pairs signature using Lasso regression analysis. We next drew the 1-, 5-, 10-year curve line of receiver operating characteristics, calculated the areas under the curve, and recognized the optimal cutoff point. Then, we validated the pair-risk model in terms of the survival outcomes of the patients. Moreover, we tested the reliability of the pair-risk model for predicting tumor aggressiveness and therapeutic responsiveness of CRC. Additionally, we reemployed the 11 of irlncRNAs involved in the pair-risk model to construct an expression risk model that was also highly predictive of prognostic outcomes of CRC patients. Results:We recognized a total of 377 DEirlcRNAs, including 28 low-expressed and 349 high-expressed irlncRNAs in CRC patients. After performing a univariant Cox analysis, we identified 115 risk irlncRNAs that were significantly correlated with survival outcomes of patients with CRC. By taking the intersection of the DEirlcRNAs and the risk irlncRNAs, we ultimately recognized 55 irlncRNA as core irlncRNAs. Then, we established a Cox HR model (pair-risk model) as well as an expression HR model (exp-risk model). We found that both of the two models significantly outperformed the common-used clinical characteristics, including age, T, N, and M stages, in terms of predicting survival outcomes. Moreover, we validated the pair-risk model can serve as a potential tool for studying the tumor microenvironment of CRC and drug response. Additionally, we noticed that combining the pair-risk model and exp-risk model yielded a more robust approach for predicting the survival outcomes of patients with CRC.Conclusions:We suggest that the irlncRNA-based risk models can be utilized as prognostic tools to predict survival outcomes and clinical characteristics and guide treatment regimens of CRC.

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First-Line Maintenance Treatment in Metastatic Colorectal Cancer (mCRC): Quality and Clinical Benefit Overview

Journal of Clinical Medicine ◽

10.3390/jcm10030470 ◽

2021 ◽

Vol 10 (3) ◽

pp. 470

Author(s):

Marta Martín-Richard ◽

Maria Tobeña

Keyword(s):

Colorectal Cancer ◽

Clinical Trials ◽

Clinical Benefit ◽

Maintenance Treatment ◽

Randomized Clinical Trials ◽

Line Treatment ◽

First Line ◽

Design Quality ◽

Primary Endpoints ◽

First Line Treatment

Different strategies of maintenance therapy (sequential CT, intermittent CT, intermittent CT and MAbs, or de-escalation MAbs monotherapy) after first-line treatment are undertaken. Many randomized clinical trials (RCT), which evaluated these approaches, suffer from incorrect design, heterogenous primary endpoints, inadequate size, and other methodology flaws. Drawing any conclusions becomes challenging and recommendations are mainly vague. We evaluated those studies from another perspective, focusing on the design quality and the clinical benefit measure with a more objective and accurate methodology. These data allowed a clearer and more exact overview of the statement in maintenance treatment.

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German oncology certification system for colorectal cancer – relative survival rates of a single certified centre vs. national and international registry data

Innovative Surgical Sciences ◽

10.1515/iss-2021-0002 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Maximilian Richter ◽

Lena Sonnow ◽

Amir Mehdizadeh-Shrifi ◽

Axel Richter ◽

Rainer Koch ◽

...

Keyword(s):

Colorectal Cancer ◽

Rectal Cancer ◽

International Comparison ◽

Cancer Registry ◽

Survival Data ◽

Survival Rates ◽

Relative Survival ◽

Registry Data ◽

Cancer Registry Data ◽

Colon And Rectal Cancer

Abstract Objectives To evaluate how the certification of specialised Oncology Centres in Germany affects the relative survival of patients with colorectal cancer (CRC) by means of national and international comparison. Methods Between 2007 and 2013, 675 patients with colorectal cancer, treated at the Hildesheim Hospital, an academic teaching hospital of the Hannover Medical School (MHH), were included. A follow-up of the entire patient group was performed until 2014. To obtain international data, a SEER-database search was done. The relative survival of 148,957 patients was compared to our data after 12, 36 and 60 months. For national survival data, we compared our rates with 41,988 patients of the Munich Cancer Registry (MCR). Results Relative survival at our institution tends to be higher in advanced tumour stages compared to national and international cancer registry data. Nationally we found only little variation in survival rates for low stages CRC (UICC I and II), colon, and rectal cancer. There were notable variations regarding relative survival rates for advanced CRC tumour stages (UICC IV). These variations were even more distinct for rectal cancer after 12, 36 and 60 months (Hildesheim Hospital: 89.9, 40.3, 30.1%; Munich Cancer Registry (MCR): 65.4, 28.7, 16.6%). The international comparison of CRC showed significantly higher relative survival rates for patients with advanced tumour stages after 12 months at our institution (77 vs. 54.9% for UICC IV; raw p<0.001). Conclusions Our findings suggest that patients with advanced tumour stages of CRC and especially rectal cancer benefit most from a multidisciplinary and guidelines-oriented treatment at Certified Oncology Centres. For a better evaluation of cancer treatment and improved national and international comparison, the creation of a centralised national cancer registry is necessary.

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Monoclonal Antibodies Targeting CGRP: From Clinical Studies to Real-World Evidence—What Do We Know So Far?

Pharmaceuticals ◽

10.3390/ph14070700 ◽

2021 ◽

Vol 14 (7) ◽

pp. 700

Author(s):

Theodoros Mavridis ◽

Christina I. Deligianni ◽

Georgios Karagiorgis ◽

Ariadne Daponte ◽

Marianthi Breza ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Real World ◽

Large Scale ◽

Randomized Clinical Trials ◽

Clinical Investigation ◽

Phase Iii ◽

Real World Evidence ◽

Symptomatic Management ◽

Repurposed Drugs ◽

Cephalic Pain

Now more than ever is the time of monoclonal antibody use in neurology. In headaches, disease-specific and mechanism-based treatments existed only for symptomatic management of migraines (i.e., triptans), while the standard prophylactic anti-migraine treatments consist of non-specific and repurposed drugs that share limited safety profiles and high risk for interactions with other medications, resulting in rundown adherence rates. Recent advances in headache science have increased our understanding of the role of calcitonin gene relate peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) pathways in cephalic pain neurotransmission and peripheral or central sensitization, leading to the development of monoclonal antibodies (mAbs) or small molecules targeting these neuropeptides or their receptors. Large scale randomized clinical trials confirmed that inhibition of the CGRP system attenuates migraine, while the PACAP mediated nociception is still under scientific and clinical investigation. In this review, we provide the latest clinical evidence for the use of anti-CGRP in migraine prevention with emphasis on efficacy and safety outcomes from Phase III and real-world studies.

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TeleNeurological evaluation and Support for the Emergency Department (TeleNS-ED): protocol for an open-label clinical trial

BMJ Open ◽

10.1136/bmjopen-2020-048293 ◽

2021 ◽

Vol 11 (5) ◽

pp. e048293

Author(s):

Jessica Mandrioli ◽

Mario Santangelo ◽

Antonio Luciani ◽

Stefano Toscani ◽

Elisabetta Zucchi ◽

...

Keyword(s):

Emergency Department ◽

Clinical Investigation ◽

Neurological Diseases ◽

Medical Personnel ◽

Primary Objective ◽

Control Group ◽

National Guidelines ◽

Open Label ◽

Time Saving ◽

Hospital Networks

IntroductionThe COVID-19 pandemic compelled health systems to protect patients and medical personnel during transit in hospitals by minimising transfers, prompting the use of telehealth systems. In the field of neurology, telemedicine has been used in emergency settings for acute stroke management between spoke and hub hospital networks, where good outcomes have been achieved. However, data on the use of telemedicine in non-stroke acute neurological conditions accessing the emergency department (ED) are currently missing.Methods and analysesThis is an interventional, open-label trial on the use of teleconsultation in the ED for neurological diseases other than stroke. The study aims to develop a remote consultancy system (TeleNeurological Evaluation and Support, TeleNS) for patients with acute neurological symptoms referred to hospital facilities without a 24-hour availability of a neurologist consultant (spoke hospitals). The study population will include 100 ED patients referred to two spoke hospitals in 6 months, who will be asked to perform teleconsultation instead of inperson visits. As a control group, retrospectively available data from patients admitted to the ED of spoke hospitals during the same time period over the last 2 years will be evaluated. The primary objective is to assess whether a TeleNS for the ED guarantees a faster but qualitatively non-inferior diagnostic/therapeutic work-up if compared with inperson examination, assuring the availability of all the necessary examinations and treatments with consistent time-saving.Ethics and disseminationThe trial was designed following the national guidelines on clinical investigation on telemedicine provided by the Italian Ministry of Health and according to the Standard Protocol Items for Randomized Trials statement guidelines. This research protocol was approved by Comitato Etico Area Vasta Emilia Nord in September 2020 (number/identification: 942/2020/DISP/AOUMO SIRER ID 805) and was written without patient involvement. Patients’ associations will be involved in the dissemination of study design and results. The results of the study will be presented during scientific symposia or published in scientific journals.Trial registration numberNCT04611295.

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Actual survival after resection of primary colorectal cancer: results from a prospective multicenter study

World Journal of Surgical Oncology ◽

10.1186/s12957-021-02207-4 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Inge van den Berg ◽

Robert R. J. Coebergh van den Braak ◽

Jeroen L. A. van Vugt ◽

Jan N. M. Ijzermans ◽

Stefan Buettner

Keyword(s):

Colorectal Cancer ◽

Postoperative Complications ◽

Multicenter Study ◽

Survival Data ◽

Standard Therapy ◽

Tumor Grade ◽

National Registry ◽

Stage I ◽

Stage Iii ◽

Curative Intent

Abstract Background Colorectal cancer is the third most common type of cancer in the world. We characterize a cohort of patients who survived up to 5 years without recurrence and identify factors predicting the probability of cure. Methods We analyzed data of patients who underwent curative intent surgery for stage I–III CRC between 2007 and 2012 and who had had been included in a large multicenter study in the Netherlands. Cure was defined as 5-year survival without recurrence. Survival data were retrieved from a national registry. Results Analysis of data of 754 patients revealed a cure rate of 65% (n = 490). Patients with stage I disease and T1- and N0-tumor had the highest probability of cure (94%, 95% and 90%, respectively). Those with a T4-tumor or N2-tumor had the lowest probability of cure (62% and 50%, respectively). A peak in the mortality rate for older patients early in follow-up suggests early excess mortality as an explanation. A similar trend was observed for stage III disease, poor tumor grade, postoperative complications, sarcopenia, and R1 resections. Patients with stage III disease, poor tumor grade, postoperative complications, sarcopenia, and R1 resections show a similar trend for decrease in CSS deaths over time. Conclusion In the studied cohort, the probability of cure for patients with stage I–III CRC ranged from 50 to 95%. Even though most patients will be cured from CRC with standard therapy, standard therapy is insufficient for those with poor prognostic factors, such as high T- and N-stage and poor differentiation grade.

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Exceptional Chemotherapy Response in Metastatic Colorectal Cancer Associated With Hyper-Indel–Hypermutated Cancer Genome and Comutation of POLD1 and MLH1

JCO Precision Oncology ◽

10.1200/po.16.00015 ◽

2017 ◽

pp. 1-12

Author(s):

Manish R. Sharma ◽

James T. Auman ◽

Nirali M. Patel ◽

Juneko E. Grilley-Olson ◽

Xiaobei Zhao ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Somatic Mutation ◽

Mutation Rate ◽

Germ Line ◽

Cancer Genome ◽

The Cancer Genome Atlas ◽

Response To Chemotherapy ◽

Cancer Genome Atlas ◽

Genome Atlas

Purpose A 73-year-old woman with metastatic colon cancer experienced a complete response to chemotherapy with dose-intensified irinotecan that has been durable for 5 years. We sequenced her tumor and germ line DNA and looked for similar patterns in publicly available genomic data from patients with colorectal cancer. Patients and Methods Tumor DNA was obtained from a biopsy before therapy, and germ line DNA was obtained from blood. Tumor and germline DNA were sequenced using a commercial panel with approximately 250 genes. Whole-genome amplification and exome sequencing were performed for POLE and POLD1. A POLD1 mutation was confirmed by Sanger sequencing. The somatic mutation and clinical annotation data files from the colon (n = 461) and rectal (n = 171) adenocarcinoma data sets were downloaded from The Cancer Genome Atlas data portal and analyzed for patterns of mutations and clinical outcomes in patients with POLE- and/or POLD1-mutated tumors. Results The pattern of alterations included APC biallelic inactivation and microsatellite instability high (MSI-H) phenotype, with somatic inactivation of MLH1 and hypermutation (estimated mutation rate > 200 per megabase). The extremely high mutation rate led us to investigate additional mechanisms for hypermutation, including loss of function of POLE. POLE was unaltered, but a related gene not typically associated with somatic mutation in colon cancer, POLD1, had a somatic mutation c.2171G>A [p.Gly724Glu]. Additionally, we noted that the high mutation rate was largely composed of dinucleotide deletions. A similar pattern of hypermutation (dinucleotide deletions, POLD1 mutations, MSI-H) was found in tumors from The Cancer Genome Atlas. Conclusion POLD1 mutation with associated MSI-H and hyper-indel–hypermutated cancer genome characterizes a previously unrecognized variant of colon cancer that was found in this patient with an exceptional response to chemotherapy.

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Comparison of Treatment, Cost, and Survival in Patients With Metastatic Colorectal Cancer in Western Washington, United States, and British Columbia, Canada

JCO Oncology Practice ◽

10.1200/jop.19.00719 ◽

2020 ◽

Vol 16 (5) ◽

pp. e425-e432 ◽

Cited By ~ 1

Author(s):

Todd A. Yezefski ◽

Dan Le ◽

Leo Chen ◽

Caroline H. Speers ◽

Shasank Chennupati ◽

...

Keyword(s):

Colorectal Cancer ◽

British Columbia ◽

Overall Survival ◽

Metastatic Colorectal Cancer ◽

Systemic Therapy ◽

Survival Data ◽

De Novo ◽

Tumor Resection ◽

Care Utilization ◽

Western Washington

PURPOSE: Few studies have directly compared health care utilization, costs, and outcomes between patients treated in the US multipayer health system and Canada’s single-payer system. Using cancer registry and claims data, we assessed treatment types, costs, and survival for patients with metastatic colorectal cancer (mCRC) in Western Washington State (WW) and British Columbia (BC). MATERIALS AND METHODS: Patients age ≥ 18 years diagnosed with mCRC in 2010 and later were identified from the BC Cancer database and a regional database linking WW SEER to claims from Medicare and two large commercial insurers. Demographics, treatment characteristics, costs of systemic therapy, and survival data were obtained from these databases and compared between the two regions. RESULTS: A total of 1,592 patients from BC and 901 from WW were included in the study. Median age was similar (BC, 66 years; WW, 63 years), but patients in BC were more likely to be male (57.1% v 51.2%; P ≤ .01) and to have de novo metastatic disease (61.0% v 38.3%; P ≤ .01). The use of radiation therapy was similar between regions (BC, 31.2%; WW, 33.9%; P = .18), but primary tumor resection was more common in BC (74.1% v 66.3%; P ≤ .01) as was hepatic metastasectomy (12.4% v 2.3%; P ≤ .01). Similar percentages of patients received systemic therapy (BC, 68.8%; WW, 67.1%; P = .40), but costs were significantly higher for first-line systemic therapy in WW ($6,226 v $15,792 per patient per month; P ≤ .01). Median overall survival was similar (BC, 16.9 months; WW, 18 months). CONCLUSION: Cost of systemic therapy for mCRC was significantly higher for patients in WW than in BC, but this did not translate to a difference in overall survival.

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