bluuebunny/crossref_metadata_2025 huggingface dataset:
Health equity challenges facing testing, evaluation, and implementation of multi-cancer early detection tests.
Authors: LeBeau Michelle M. , Kessler Larry , Guerra Carmen , Krofah Esther , Brain Kate
Published: June 2023

e15051

Background: The development of Multi Cancer Early Detection markers may herald a new approach to screening and detection of multiple cancers simultaneously via various biological assays. At each stage of development and evaluation of these tests, and especially at implementation, challenges to ensuring equitable access to advancements in cancer prevention, screening, diagnosis, and treatment arise. Diverse research study populations and methods are key when investigating the efficacy of screening tools in practice. Health equity encompasses all parts of research study and design, particularly increasing diversity in research study populations and methods to reflect intended populations of study and document how MCEDs may impact demographic groups differently. Methods: The MCED Consortium is a not-for-profit group of volunteers, advisors, and companies from the US and the UK spanning a wide range of expertise in biomarker evaluation and implementation, with a special focus on clinical practice, health equity, and communication ( https://www.mced.info/ ). We are developing recommendations for the evaluation of test utility, appropriate prioritized populations for screening or early detection, downstream actions in health systems, achieving health equity, and addressing the communication challenges related to this new, potentially revolutionary generation of tests. Results: The MCED consortium has made recommendations in the domains of investigator, participant level, and study design features. The Consortium also has identified key questions for MCED researchers and users regarding equitable access, acceptance, and follow-up. An emerging challenge relates to the release of these tests to selected populations via the laboratory-developed test pathway; which will almost certainly disproportionately increase access to insured and higher socioeconomic status populations. Conclusions: In this MCED Consortium presentation, we will discuss the barriers to ensuring adequate clinical trial diversity and evaluation of MCEDs and how to optimize equity during their current and near-term distribution.
Systematic review and meta-analysis of accuracy of tumor origin detection in blood cell-free DNA (cfDNA)-based multi-cancer early detection (MCED) assays in the general population.
Authors: Park Joo Hee , Oh Youjin , Chung Liam Il-Young , Duan Richard , Djunadi Trie Arni , Yoon Sung Mi , Shah Zunairah , Jung Chan Mi , Hong Ilene , Kim Leeseul , Choi Horyun , Chae Young Kwang
Published: June 2023

e15053

Background: Among recently developed blood-based MCED tests, the ability to determine the location of tumors is pivotal to guiding appropriate treatment. We systematically reviewed and statistically examined the accuracy of tumor of origin predictions among blood-based MCED tests. Methods: Original articles were searched from Pubmed, Cochrane, and Embase for blood-based screening tests, multiple cancer types, and asymptomatic human subjects. We excluded studies with small samples (n < 30), non-screening, and non-blood-based tests. For cfDNA-based assays, measurements of diagnostic accuracy were pooled for meta-analysis. Results: Of 1,074 records identified and screened, five case-control studies and one cohort study that used cfDNA-based diagnostic tests were analyzed. Accuracy of tissue-of-origin (TOO) prediction for 3,895 cancer samples across cancer types was 0.79 (95% CI 0.66 - 0.90). Among six cancer types, colorectal cancers had the highest accuracy and liver & bile duct cancers had the lowest, although the difference was statistically insignificant (0.89 (95% CI 0.79-0.97) vs. 0.68 (95% CI 0.40-0.90)). Additionally, cases were most frequently misclassified as colorectal cancer (Table 1). The information for localizing TOO was derived from methylation patterns of cfDNA in four studies, fragmentation profiles of cfDNA in another study, and combination of mutations in cfDNA and protein markers in the last study. Conclusions: Our results demonstrate that the primary site of cancers was accurately discerned in 79% of cases by MCED tests. However, performance varies across cancer types. Further research on performance based on cancer stages and in combination with other molecular profiling is warranted. [Table: see text]
Feasibility and clinical utility of cancer whole-genome sequencing in adult solid tumors.
Authors: Kwon Minsuk , Kim Ryul , Oh Baek-Lok , Kim Seokhwi , Roh Jin , Hur Hoon , Yu Woo Sik , Kim Chang Woo , Lee Jeong Seok , Ju Young Seok
Published: June 2023

e15055

Background: As sequencing costs decrease, whole-genome sequencing (WGS) is expected to be utilized in actual cancer patient care. However, there is insufficient evidence that WGS can be applied to the real-world cancer patient care, and how it can help in the diagnosis and treatment process. Methods: This prospective cohort study was designed to evaluate the feasibility and clinical utility of WGS in adult solid cancer care at a tertiary hospital. All solid cancer patients who were scheduled to undergo biopsy or surgery for diagnosis or treatment were eligible for the study. Either fresh or formalin-fixed paraffin-embedded tissue with match peripheral blood were obtained. Tumors were sequenced to depth of 40x, and WGS data were curated by Genome Insight Inc. The WGS reports were provided to clinician through a web-based, user-browsable reporting system in real time. Results: 97 patients were enrolled between Sep 2022 and Jan 2023. Besides 10 QC failed cases, 87 patients were provided WGS reports. Median turn-around-time was 14 day (range 12-23). The clinical utility of WGS was evaluated in 77 cancer patients, excluding 10 cases with estimated cancer cell fraction less than 15%. 31 patients (40.3%) had more than one actionable alteration targeted by on-label drugs. 49 patients (63.6%) also had more than one actionable alteration targeted by either on-label or off-label drugs. In selected cases (N = 6), WGS could suggest the diagnosis for cancer of unknown origin or the revision of pathologic diagnosis that was regarded as a double primary cancer into a metastasis of a single cancer. By providing information of total mutation counts, whole-genome-wide mutational signature analysis, copy number variation with high accuracy, germline alterations, detection of homologous recombination deficiency, and presence of loss-of-heterozygosity, WGS could further refine the actionable mutations in 39% cases, and estimate the etiology of cancer (genomic or environmental) or to determine hereditary or sporadic cancer in 60% cases. In 90% cases, WGS demonstrated clinical utility with supporting diagnosis, informing carcinogenesis, or annotating actionable alterations. Conclusions: WGS was applicable in real-world cancer care. WGS demonstrated clinical utility in the diagnosis and treatment of adult cancer patients. Clinical trial information: KCT0008118 . [Table: see text]
Physician-reported barriers and strategies to using tumor mutational burden (TMB) testing in oncology care: An interview based study.
Authors: Jones Gieira S , Szamreta Elizabeth A. , Lee Liam , Iyer Radhika , Jackson Bianca , Ning Ning , Stephens Jennifer , Hussain Arif
Published: June 2023

e15063

Background: Despite the availability of genomic technologies to inform treatment for oncology patients, widespread adoption of genomic testing in the U.S. has been challenging. Little information is available about the factors that influence clinical decision making regarding the use of TMB testing. The purpose of this study was to identify barriers to the adoption of TMB testing and preferred strategies to increase testing from the physician’s perspective. Methods: Semi-structured video-based interviews were conducted with a sample of U.S. physicians (N = 11), including 6 general medical oncologists, 3 surgical oncologists, and 2 gynecologic oncologists. Physicians were asked about practice characteristics, perceived barriers to testing, and potential strategies for alleviating these barriers. Results: Eighty-two percent (N = 9) of physicians reported utilizing TMB testing in their routine clinical practice. Reimbursement was the most commonly reported barrier (64%) including coverage policy language indicating the testing as “experimental”/“unproven”, patients having to pay out of pocket, and unclear/inconsistent payer policies (27% each) [Table 1]. Knowledge, resource-related, and logistical barriers were reported among the same proportion of physicians (45%). Suggested strategies to improve TMB testing uptake rates among physicians included better understanding of clinical utility of the test and corresponding therapies, integrating results into electronical medical records, incorporating TMB into routine testing, and shorter turnaround time for results. Conclusions: This qualitative study of physicians identified barriers to TMB testing of oncology patients. Results suggest that challenges around reimbursement, knowledge, resources, and logistics are key barriers to use of TMB testing for physicians. The findings of this study provide insights for future research and strategies to increase the adoption of TMB testing. [Table: see text]
Characterizing non-small cell lung cancer driven by mutations in ARAF and CRAF family members.
Authors: Okimoto Tamio , Amann Joseph , Elliott Andrew , Liu Stephen V. , Ma Patrick C. , Vanderwalde Ari M. , Radovich Milan , Sledge George W. , Coppola Vincenzo , Carbone David Paul
Published: June 2023

e15085

Background: Cancer genome screening is becoming standard clinical practice, but the number of actionable mutations detected is limited. To expand on our previous report of the possibility that ARAF S214C and CRAF S257L located in the conserved region 2 (CR2) were actionable driver mutations, we investigated responses to targeted therapies in mouse models and the prevalence of these alterations across many cancer types represented in a large real-world database of molecularly profiled patient tumors. Methods: Conditional transgenic mice that expressed human ARAF S214C or CRAF S257L in their lungs were established and treated with sorafenib or trametinib. Activation of the MAPK pathway following sorafenib or trametinib treatment was assessed in vitro by phospho-ERK IHC. DNA sequencing (592-gene or whole exome) was performed for patient samples submitted to Caris Life Sciences (Phoenix, AZ), and the prevalence of ARAF/CRAF variants was determined for each cancer type. Results: Both ARAF S214C and CRAF S257L dimerized to activate the MAPK pathway. Although a low concentration of sorafenib promoted ERK phosphorylation, a high concentration of sorafenib inhibited ERK phosphorylation. Transgenic mice rapidly developed lung adenocarcinoma when the mutant proteins were expressed. Sorafenib treatment induced tumor necrosis in both ARAF- and CRAF-mutated tumors, and 3 months of sorafenib treatment prolonged the survival of CRAF-mutant mice. Pan-tumor analysis of real-world patient samples revealed that ARAF and CRAF mutations in CR2 were found in 0.125% and 0.234% of tumors, respectively. ARAF mutations in CR2 were found in 0.415% of cholangiocarcinoma, 0.132% of colorectal cancer, and 0.173% of non-small cell lung cancer (NSCLC). CRAF mutations in CR2 were found in 0.509% of colorectal cancer, 0.502% of gastric cancer, 0.303% of NSCLC, and 0.978% of melanoma. The most prevalent CR2 mutations were ARAF S214F and CRAF S257L. Conclusions: Our in vitro results suggest ARAF S214C and CRAF S257L mutations are rare driver mutations that may be effectively treated with RAF inhibitors and warrant further investigation. [Table: see text]
Single-stranded linear amplification library preparation method for highly sensitive and low input amount ctDNA detection.
Authors: Hu Juan , Chen Meihong , Li Zihao , Xiao Shanshan , Wang Tao
Published: June 2023

e15096

Background: Detection of circulating tumor DNA (ctDNA) or minimum residual disease (MRD) through somatic variant identifications in plasma samples has emerged as a promising approach for monitoring the clinical outcomes after surgical resections or other therapies. However, due to very low ctDNA levels in the early-stage cancers and tumor remissions after therapies, or low plasma volumes and DNA degradation caused low qualities in clinical practice, to sensitively identify somatic mutations with low allele frequencies in those samples remains a challenging technology task. Methods: In this study, we developed a single-stranded, linear amplification based library preparation sequencing (SLA-Seq) method. In the experimental workflow, double stranded molecular templates will be converted into single strands to construct libraries, thus minimize the loss of irregular double stranded DNA molecules. Adapter ligation was carried out in two steps. During the first step, P7 adapters with unique molecular identifiers(UMI) were ligated to the 3’ end of the molecular templates, and the DNA molecules were amplified by linear amplification to improve the DNA utilization efficiency. In the second step, P5 adapters were ligated to the linear amplified PCR products, then amplified by the pre-PCR. The pre-library was enriched by hybridization and magnetic-beads capturing and then subjected to high-throughput sequencing. 30ng of the cfDNA reference standard samples containing mutations of 0.3% and 0.1% allele frequencies were used to validate the performance. Results: In the SLA-Seq method, adapter sequences were carefully optimized to eliminate adapter dimers and thus improved the DNA ligation efficiency. Compared with the double-stranded library preparation method, SLA-seq showed overall higher effective depths after removing duplications if the same start amount of the DNA was used, which indicated that the higher DNA utilization rate was achieved. To evaluate the performance, we applied SLA-Seq on 11 reference standard samples with only 30ng start amount DNA. Among them, 6 samples were diluted to 0.3% allele frequency and 5 samples were diluted to 0.1% allele frequency. Totally they had 24 and 35 mutations, respectively. The sensitivity at the 0.3% allele frequency was 100% (24/24) and it was 94.29% (33/35) at the 0.1% mutation level, which also showed the higher sensitivity achieved by SLA-Seq than double-stranded library preparation method. Conclusions: We developed a single-stranded, linear amplification based library preparation method to improve difficult sample situations such as low input amount and low qualities, and achieved high single site sensitivity at the 0.1% allele frequency. Such features imply SLA-Seq has important clinical significance in the ctDNA/MRD detection.
Cure-PROs: Next-generation targeted protein degraders.
Authors: Giardina Sarah F. , Valdambrini Elena , Peel Michael , Bacolod Manny D. , Rothenberg Mace L. , Lanman Richard B. , Warren J. David , Barany Francis
Published: June 2023

e15101

Background: Many proteins, including transcription factors and scaffolding proteins, are not amenable to targeting by traditional small molecule inhibitors due to the lack of a well-defined binding pocket or active site. Proteolysis-Targeting Chimeras (PROTACs) are a new class of hetero-bifunctional molecules that bind both a target protein and an E3 ubiquitin ligase, bringing the two into proximity for appending ubiquitin, and subsequently marking the target protein for proteasomal degradation. Currently, thirteen PROTACs are in clinical trials for oncology indications. However, the clinical utility of PROTACs is challenged by their large size and long development timelines. Also, resistance mutations in the E3 ligase or transporter overexpression inevitably evolve. Thus, a new platform for small-molecule degraders that enables ultra-rapid drug development timelines, efficient cellular uptake, and can be developed to overcome innate and acquired drug resistance is needed. Methods: Coferons, developed in our laboratory, are small molecules that self-assemble upon binding to a target, where they form reversible covalent dimers through bio-orthogonal linker chemistries. We have combined features of the Coferon platform and PROTACs to generate CURE-PROs (Combinatorial Ubiquitination REal-time PROteolysis), consisting of one target protein ligand and one E3 ligase ligand that form reversible heterodimers that lead to targeted protein degradation within cells. By modifying known ligands for BRD4, and the E3 ubiquitin ligases Cereblon, VHL, and MDM2, with linkers able to reversibly join the BRD4 to the ligase ligands, we synthesized libraries of CURE-PRO monomers that can be combined to create thousands of CURE-PRO dimer combinations. We explored whether this platform could yield meaningful BRD4 degradation in vitro and in vivo. Results: Rapid combinatorial cell-based screening identified several BRD4-E3 ligase CURE-PRO combinations that induced greater than 50% BRD4 degradation, with the most promising CURE-PRO pairs achieving more than 95% protein degradation. Consistent with a PROTAC mechanism-of-action, successful CURE-PRO combinations confirmed significant protein degradation which was inhibited by proteasome inhibitors or competition with parent ligands. Significant BRD4 degradation was also observed in mice bearing bilateral human xenograft tumors, confirming CURE-PRO proof-of-mechanism in vivo. Conclusions: The combinatorial nature of our platform has the potential to significantly reduce synthesis time and effort to identify the optimal linker length and E3 ligase for each target protein. The CURE-PRO platform consists of expanding libraries of monomers for both additional oncoprotein targets as well as E3 ligases, which can be redeployed to shorten lead development timelines.
The antinociceptive effects of selective TRPV1 antagonist RCI002 against chemotherapy-induced peripheral neuropathy.
Authors: Kim Minjung , Park Juil , Hasrul Harith , Park Sung Taek , Kim Yong Ho
Published: June 2023

e15111

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect experienced by cancer patients receiving chemotherapy. Recent reports showed that transient receptor potential (TRP) channels are involved in paclitaxel- or oxaliplatin-induced neuropathic pain. TRP vanilloid 1 (TRPV1) may contribute to the development of mechanical allodynia and thermal hyperalgesia after cisplatin or oxaliplatin treatment. Moreover, paclitaxel-induced behavioral hypersensitivity is prevented and reversed by administration of TRPV1 antagonists. RCI002 is a potent and selective TRPV1 antagonist, blocking capsaicin activation of the target, with a little affect pH or heat activation. We found that RCI002 relieves neuropathic pain by inhibiting TRPV1, an important nociceptor involved in pain signal transduction, and does not cause thermoregulation, a problem with existing TRPV1 antagonists. In this study, Calcium imaging and patch clamp were employed to examine effects of RCI002 on mouse dorsal root ganglion (DRG) neurons and HEK293t cells expressing TRPV1. We also investigated RCI002 associated paclitaxel-induced peripheral neuropathic pain using a rat model. Methods: Dorsal root ganglion (DRG) neurons and TRPV1-transfected human embryonic kidney-derived (HEK) 293 cells were used for calcium imaging or whole-cell patch-clamp recording. CIPN was induced by intraperitoneal administration of paclitaxel 2 mg/kg for 4 consecutive days using adult male Sprague-Dawley rats. RCI002 were administered intraperitoneal and the paw withdrawal thresholds were measured using von Frey filaments. Results: We previously showed that RCI002, a novel TRPV1 antagonist that could be referred to as a new class of TRPV1 modulators that produce a significant analgesic effect formalin-induced behavior and improved mechanical allodynia undergoing spinal nerve ligation(SNL) in rats without hyperthermic effect. In the present study, The selective TRPV1 inhibitor RCI002 impaired capsaicin-induced calcium influx in DRG neurons. hTRPV1 expressed in HEK293 cells mediated a hemin-induced calcium influx which was blocked by RCI002. Behavioral assessment using the von Frey filaments. SD rat that received paclitaxel developed mechanical hypersensitivity to Von Frey filament stimulations of their hindpaws. Paclitaxel-induced hypersensitivity inhibited by TRPV1 antagonist RCI002(RCI002 EC50 = 0.85mg/kg). RCI002 significantly increased the paw withdrawal threshold more than pregabalin in CIPN rats(Pregabalin EC50 = 14.77mg/kg). Conclusions: Our findings suggest that RCI002 may be a promising approach to reduce paclitaxel-induced hyperexcitability and thereby to reduce neuropathy pain.
AX-0085, a novel AXL kinase inhibitor, and effects on osimertinib-resistance in non–small-cell lung cancer.
Authors: Choi Myeong Jun , Rhie Byung-Ho , Woo SangHyeon , Yun Si-Eun , Park Young Jun , Kim Jaesang , Suresh Ramakrishna , Kim Kye-Seong
Published: June 2023

e15121

Background: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) having high efficacy in treating patients with advanced non-small cell lung cancer (NSCLC) with EGFR activating mutations and EGFR T70M mutations. Although, osimertinib is a frontline anticancer agent for treating NSCLC, many patients inevitably develop osimertinib-resistance tumor recurrence. The activation of AXL was reported to be a major factor driving osimertinib-resistance in NSCLC. Thus, AXL is a promising therapeutic target for the treatment of osimertinib-resistant NSCLC, and we developed a new small-molecule AXL inhibitor, AX-0085. Methods: We established osimertinib-resistant cell lines from EGFR-mutated NSCLC cell lines, HCC827 and H1975, after high dose exposure and stepwise exposure to osimertinib in culture. We investigated the cell viability of AX-0085 and other kinase inhibitors, and the anti-tumor activity of AX-0085 on the proliferation, migration, apoptosis, and epithelial-mesenchymal transition (EMT) in osimertinib-resistant cells. Results: Compared to the parental cells, IC50 of resistant cell to osimertinib was significantly increased and osimertinib-resistant cells showed remarkably increased expression of AXL/pAXL and p-SRC as compared to the parental HCC827 cell. AX-0085 was completely blocked the AXL and SRC activation but EGFR inhibitors (gefitinib and osimertinib) did not inhibit the activation of AXL and SRC in the osimertinib-resistant cell line. AX-0085 (IC50: 4.4nM for AXL kinase in cell-based kinase assay) was one of the most potent AXL inhibitors and showed the strongest cytotoxicity against osimertinib-resistant cells compared to other kinase inhibitors. AX-0085 effectively down-regulated mRNA level of AXL and AXL regulating transcription factors in NSCLC cell lines such as HCC827 and H1975. AX-0085 treatment effectively inhibited the activation of AXL in acquired osimertinib-resistant cells and decreased the mRNA level of AXL and AXL regulating transcription factors. AX-0085 significantly inhibited the cell proliferation, apoptosis, migration, and EMT in acquired osimertinib-resistant cells. Conclusions: Our results showed that AX-0085 selectively inhibits the activation of AXL to overcome acquired resistance to osimertinib, suggesting an effective AXL-based therapy for patients with osimertinib-resistant tumors. Currently, AX-0085 is undergoing non-clinical trials.
Portal hemodynamic effects of different TKIs in patients with advanced hepatocellular carcinoma: A prospective cohort study.
Authors: Li Pingping , Yan Tao , Cheng Jiamin , Zhang Linzhi , Peng Caiyun , Su Guodong , Li Yinyin , Lu Yinying
Published: June 2023

e15126

Background: Tyrosine kinase inhibitors (TKIs) are considered to have effects on portal collateral circulation with portal hypertension. According to previous small sample clinical reports, short-term administration of sorafenib might have an effect of decreasing portal venous pressure, while lenvatinib aggravated portal hypertension. Long-term effects of TKIs on portal pressure are still unclear. Therefore, We conducted a prospective cohort study to explore the efficacy of different TKIs for portal circulation in patients with advanced hepatocellular carcinoma. Methods: 27 Child-Pugh class A or B patients with advanced HCC were enrolled in this study, 13 patients received lenvatinib, 7 patients sorafenib, and 7 patients regorafenib. Changes of portal hemodynamic parameters were measured by duplex Doppler ultrasonography, including portal venous area (PVA), portal venous flow velocity (PVV) and congestion index (CI) before and after administration of TKIs for an average 40-50 days. Results: In both regorafenib and sorafenib cohorts, PVA decreased after treatment, although the difference was not significant. PVF significantly reduced in sorafenib cohort (24.96±5.60 vs. 15.46±4.50, P= 0.014) and regorafenib cohort (21.43±2.09 vs. 16.01±1.28, P= 0.024), therefore CI significantly increased in sorafenib cohort (0.060±0.042 vs. 0.088±0.040, P= 0.046) and regorafenib cohort (0.068±0.032 vs. 0.090±0.030, P= 0.043). In lenvatinib, both PVA and PVF have no significant change, while CI increased significantly (0.057±0.027 vs. 0.074±0.040, P= 0.030). Conclusions: In this study, TKIs showed different effects on portal hemodynamic change in advanced HCC. Large sample and long time follow-up research will be necessary to verify their clinical and mechanism effects. [Table: see text]
The clinical and genomic characteristics of KRAS G12D mutated cancers.
Authors: Lin Guomin , Yuan Shaohua , Pang Fei
Published: June 2023

e15151

Background: KRAS mutations are relatively common in solid tumors. It is once considered to be “non-druggable” due to its high affinity to GTP/GDP and lack of other binding sites. Recently, irreversible inhibitors targeting specific KRAS mutations have been developed. We aimed to investigate the correlation of clinical and genomic factors with KRAS G12D mutation in pancreatic cancer (PC), colorectal cancer (CRC) and non-small-cell lung cancer (NSCLC). Methods: We retrospectively reviewed the clinical and genomic data of patients with PC (n = 300), CRC (n = 300), and NSCLC (n = 1800) who provided tumor tissues and matched peripheral blood samples (served as control to eliminate germline variants) for targeted sequencing of 450 cancer-related genes. Experiments were carried out in OrigiMed’s laboratory following the CAP/CLIA standards. Tumor mutation burden (TMB)-high was defined as TMB > 10 muts/Mb. Results: The prevalence of KRAS G12D mutation in PC, CRC and NSCLC was 38.3% (115/300), 15.0% (45/300) and 2.0% (36/1800), respectively. In PC and CRC, G12D was the major type of KRAS mutations, accounting for 44.9% (115/256) and 30.8% (45/146) of all the KRAS mutations, respectively. In contrast, G12C was the most common KRAS mutation in NSCLC (35.9% [79/220]), followed by G12D (16.4% [36/220]). Patients were divided into three groups according to the KRAS mutation status: the G12D (mutated in KRAS G12D), non-G12D (mutated in KRAS, but not G12D), and wild-type (WT; no KRAS mutation) groups. Clinical features including age, sex and disease stage were not associated with the KRAS grouping in PC and CRC. However, the KRAS grouping was significantly correlated with sex in NSCLC (Female vs Male: 1.9% vs 2.1% in G12D, 4.4% vs 13.9% in non-G12D, 93.7% vs 84.1% in WT, P < 0.001). In PC, KRAS G12D and BRAF mutations were mutually exclusive (P < 0.01), while in CRC, KRAS G12D mutation was found to be co-occurring with PIK3CA mutation (P < 0.05). For NSCLC, KRAS G12D mutation was mutually exclusive with EGFR mutation (P < 0.01) and co-occurred with STK11 mutation (P < 0.05). TMB was comparable between the KRAS grouping in PC and CRC. In contrast, TMB was significantly higher in the non-G12D group (median 11.7 [range 0.7-89.8] muts/Mb) compared to the G12D (median 6.9 [range 0-30.9] muts/Mb; P < 0.001) and WT (median 4.6 [range 0-215.2] muts/Mb; P < 0.001) groups in NSCLC. A higher proportion of TMB-high was also observed in the non-G12D group (58.5%) compared to the G12D (22.2%) and WT (22.6%) groups in NSCLC. Conclusions: Patients with KRAS G12D mutation possessed unique clinical and genomic characteristics. It was more prevalent in PC and CRC and was correlated with sex in NSCLC. KRAS G12D mutation co-occurred with STK11 mutation and showed a relatively low TMB value in NSCLC, suggesting that immunotherapy might be ineffective. While KRAS non-G12D mutated NSCLC patients may be favorable to ICI. Our results provide insights into the precision medicine of KRAS G12D-mutated cancers.
Building liquid-liquid perfusion interface (LLPI) –based patient-derived tumoroids (PDTs) model system as clinical research tools for testing cancer therapeutics.
Authors: Giri Pradeep , Ochola Damieanus , Samuel Preethi , Barrot Jared , Dave Bhuvanesh
Published: June 2023

e15192

Background: Current in vitro cancer model systems are inadequate in their representation and application of an actual tumor. Use of three-dimensional PDTs that consists of stroma and the microenvironment vastly addresses these shortcomings. However, a complete picture of the intratumoral interactions and functions requires optimal supply of oxygen to address problems associated with poor cellular oxygenation. Soft tissue sarcomas are malignant tumors that develop in the tissues that surround and support bones and organs. For non-resectable soft tissue sarcomas, model systems and treatment options are either limited or not available. We are establishing our Matrigel-based PDTs on a Liquid-Liquid Perfusion Interface (LLPI) using a synthetic hemoglobin as a blood substitute to build a comprehensive model system that is an amalgamation of an in vitro-in vivo system. Our objective is to replicate tumor complexity and use our model to serve as an effective and reliable platform to test and investigate therapeutic options. Methods: Soft tissue sarcoma PDT models with LLPI were built and used for testing under the following groups: Drug treatments with Doxorubicin (10nM), HSP90 inhibitor (1)10 nM, (2) 100 nM and (3) 1 mM) and combination (Doxorubicin + HSP90) for 10 days was compared on Sarcoma PDT models with and without oxygenation to test the impact of oxygen on tumor volume. Currently we are pursuing downstream analysis using apoptosis, proliferation and cytokine profiling and dynamic oxygen analysis of the TME. Results: We compared the effect of Doxorubicin with HSP90 inhibitor on a Sarcoma PDT model with and without oxygenation to observe the impact of oxygen on tumor growth. We observed similar rate of cell growth in the untreated samples in both model systems. In the non-oxygenated PDTs Doxorubicin-HSP90 combination was effective in reducing tumor volume. In the oxygenated PDTs the efficacy of the combination therapy (Doxorubicin+HSP90) was no longer observed. Conclusions: The oxygenation status impacts the effect of Doxorubicin, HSP90 combination, a critical influence that would not have been observable without the use of oxygenated PDT model system. The impact of intratumoral variations on oxygenation levels warrants testing other existing and novel therapeutics on oxygenated PDT model systems to investigate the extent of the influence of oxygenation on the tumor biology. [Table: see text]
Prognostic factors of long-term outcomes after primary chemo-radiotherapy in non-metastatic anal squamous cell carcinoma: An international bicentric cohort.
Authors: Iseas Soledad , Prost Diego Martín , Bouchereau Sarah , Golubicki Mariano , Robbio Juan , Oviedo Ana , Coraglio Mariana , Carballido Marcela , Kujaruk Mirta , Mendez Guillermo , Barugel Mario Edmundo , Roca Enrique , Gros Louis , de Parades Vincent , Baba-Hamed Nabil , Adam Julien , Abba Martin C , Raymond Eric
Published: June 2023

e15501

Background: Anal squamous cell carcinoma (ASCC) is a rare malignancy with a rising incidence associated with Human papillomavirus (HPV) infection. Locally-advanced disease is associated with a 30% rate of treatment failure after standard chemoradiotherapy (CRT). We aimed to elucidate prognostic factors for ASCC after curative CRT. Methods: A retrospective multicenter study of 176 consecutive patients with ASCC having completed CRT treated between 2010 and 2017 at 2 centers. Complete response (CR), disease-free survival (DFS) and overall survival (OS) were analyzed by Kaplan–Meier estimates with log-rank tests. The hierarchical clustering on principal components (HCPC) method was employed in an unsupervised and multivariate approach. Results: CR rate was 68% and was predictive of DFS (p < 0.0001) and OS (p < 0.0001), where non-CR cases were associated shorter DFS (HR = 16.5, 95% CI 8.19-33.21) and OS (HR = 8.42, 95% CI 3.77–18.81) in univariate analysis. Median follow-up was 38 months, with 3-year DFS of 71%. Prognostic factors for DFS were cT1-T2 (p = 0.0001), N0 (p = 0.03), HIV-positive (p = 0.04), HIV-HPV coinfection (p = 0.02), and well-differentiated tumors (p = 0.03). Three-year OS was 81.6%. Female sex (p = 0.05), cT1-T2 (p = 0.019), and well-differentiated tumors (p = 0.003) were associated with better OS. This unsupervised analysis demonstrates clear segregation, identifying that poor prognosis clusters associated with shorter DFS (HR = 1.66, 95% CI = 1.21–2.27, p = 0.0012) were enriched with locally-advanced disease, anal canal location, HPV-HIV coinfection, and non-CR. Conclusions: In conclusion, our results reinforce the prognostic value of T stage, N stage, sex, differentiation status, tumor location, and HIV-HPV coinfection in ASCC after CRT.
20-year incidence trends of anal squamous cell carcinoma.
Authors: Jhaveri Khushali , Modi Karnav , Sarfraz Humaira , Saha Aditi , Buhlmann Melanie , Schell Michael J. , Kim Richard D.
Published: June 2023

e15503

Background: Anal Squamous Cell Carcinoma (SCCA) accounts for 90% of cases of anal cancer. ~95% of SCCAs are driven by Human Papilloma Virus (HPV). We did a follow-up population-based analysis to assess incidence trends of SCCA over 20 years (2000-2019) in era of HPV vaccination (available since 2006). Methods: Data was extracted from Surveillance, Epidemiology, and End Results (SEER) database for years 2000-2019. Joinpoint regression models were fitted to identify a discrete joints (year) that represented a statistically significant change in direction of the trend of overall SCCA incidence. The average annual percentage change (AAPC) in age-adjusted incidence rate in all subgroups pre- and post-2009 (statistically significant joinpoint year) was measured. (Table 1). Results: 30,294 new cases of SCCA were identified from 2000-2019, with majority in females (61.6%), white population (86.5%), and ages 40-79 years (84.1%). A significant joinpoint for SCCA incidence was observed in 2009, wherein APC of 2.8% (95% CI 2.0-3.6) in 2000-2009 was reduced to 0.5% (95% CI -0.1-1.2) in 2009-2019 (82% relative reduction [RR]). In subgroup analysis, evaluating the trends after identifying a discrete joint (2009), we found that APC for White population reduced from 3.1% (P < 0.0001) to 1.1% (P = 0.022) (65% RR), and for Black population, APC of 3.2% (P = 0.0015) seem to flatten out at 0.3% (P = 0.768) in post-2009 years (91% RR). Ages 20-39 had a -4.2% (P = 0.028) APC pre-2009 that showed increase to 1.3% (P = 0.214) post-2009, however, small sample size noted. In ages 40-59, APC of 4.7% (P < 0.0001) seem to flatten out at -0.5% (P = 0.393) (111% RR). Ages 60-79 had a similar APC (2.4% [P = 0.0011] and 2.5% [P = 0.0001], respectively). In males, APC of 2.8% (P = 0.002) flattened out to 0.5% (P = 0.249) and females reduced from 3.2% (P < 0.001) to 1.2% (P = 0.009). Conclusions: In this study, we found a trend of decrease in the rate of growth of SCCA incidence pre- and post-2009, overall and among various subgroups. Furthermore, our results suggest that widespread education and scaling up access to HPV vaccination can decrease and potentially reverse the SCCA incidence. [Table: see text]
The long journey of patients with anal carcinoma in a Mexican cohort.
Authors: Martinez Moyano Javier Alejandro , Reyna de la Garza Roberto Adrián , Torres-Cisneros Eduardo Rey , Hernandez Barajas David , Ruiz Sanchez Daneli , Burguete-Torres Alan , Alcorta Garza Adelina , González Guerrero Juan Francisco , Vidal-Gutiérrez Oscar
Published: June 2023

e15504

Background: Yearly 1000 new cases of anal cancer will be diagnosed in the USA, in Mexico this information is limited. Increasing incidence is the reflection of improvements in knowledge of risk factors and diagnostic studies. Female sex, HPV infection, genital warts, number of sexual partners, receptive anal intercourse, smoking and HIV infection are well established risk factors. Methods: We performed a retrospective analysis of patients with pathology-confirmed anal carcinoma treated at an Oncology Reference Center in North-East Mexico from 2010 to 2020. Using the digital database of our center we searched the time passed since debut of symptoms to first medical contact, date of biopsy and first oncology consultation. Results: 81 patients were found in the database from January 2010 to December 2020. Forty-one patients were included in the final analysis, 11 patients where reassessed as rectal cancer and 29 patients only attended one consultation and did not continue follow up. Mean age at diagnosis was 61.4 +/- 13.8 years and 58.5% were women. 69% of patients had an education degree lower than highschool. HIV status was known only in 9.8% as they were living with HIV before the diagnosis of anal cancer was made, contrasting from 63.4% of cases who had unknown status at cancer diagnosis. The time from symptom onset until the patient attended a healthcare provider was a mean of 7.6 months (5 – 1000 days) and 11.4 months (9-1435 days) to receive a diagnosis. Patients had an average delay of 80 days from biopsy result to be evaluated by an oncologist. 44% of patients were initially misdiagnosed as hemorrhoids. None of the female patients had history of recent Pap smear test. 65% of patients had nodal involvement at presentation. Conclusions: There is notable delay between the onset of symptoms and diagnosis of anal cancer. This information is crucial for the general population and all healthcare providers not only oncology related workers. The stigma as well as the cultural barriers associated with this disease may negatively impact the prognosis and quality of life by delaying promptly treatment. Although it is a rare disease, conducting educational campaigns with the intention of improving clinical suspicion and an early recognition may shorten the long journey of patients bearing with anal carcinoma.
The impact of COVID-19 on mortality, length of stay, and cost of care among patients with gastrointestinal malignancies: A propensity score-matched analysis.
Authors: Ulanja Mark Bilinyi , Beutler Bryce D. , Governor Samuel B , Asafo-Agyei Kwabena Oppong , Edusa Samuel , Antwi-Amoabeng Daniel , Ulanja Reginald N. , Amankwah Millicent , Neelam Vijay , Mabrouk Tarig , Rahman Ganiyu A. , Djankpa Francis T. , Alese Olatunji B.
Published: June 2023

e15510

Background: The SARS-CoV-2 (COVID-19) pandemic has had a lasting impact on the care of cancer patients. Multiple studies have shown that individuals with cancer are at high risk of serious complications in the setting of COVID-19 infection, but the impact in patients with gastrointestinal (GI) malignancies remain incompletely understood. We aimed to assess the impact of COVID-19 infection on mortality, length of stay (LOS), and cost of care among patients with GI malignancies, and identify differences in outcomes based on primary tumor site. Methods: We analyzed discharge encounters collected from the National Inpatient Sample (NIS) between March 2020 and December 2020, using propensity score-matching (PSM), and COVID- 19 as treatment effect. Results: Of the 87,684 patient discharges with GI malignancies, 1,892 were positive for COVID-19 (C+ve) and eligible for matching in the PSM model. Proportion for C+ve; male (61.2%), female (38.8%), White (55.8%), Black (17.9%), Hispanic (18.6%) and other (7.6%). Median age was 69 years (1QR: 61-77). Monthly variation reflected the wave and plateau dynamics of the spread of COVID-19. Following PSM analysis, C+ve patients with GI tumors demonstrated increased mortality compared to their COVID-19-negative (C-ve) counterparts (21.3% versus 11.9%, p < 0.001). C+ve patients with colorectal cancer (CRC) had significantly higher mortality compared to those who were C-ve; 39.95% [161/403] versus 24% [54/225], p = 0.035). In addition, C+ve patients with GI tumors had a longer LOS (9.42 days versus 6.95 days, p < 0.001) and increased cost of care ($26,048.29 versus $21,625.24, p = 0.001) compared to C-ve. Higher odds of mortality from myocardial infarction among C+ve(OR = 3.54, P = 0.001) while mortality due to pulmonary embolism or liver failure was not significantly different between C+ve and C-ve groups. Conclusions: This PSM analysis suggests that prior to the introduction of vaccines, C+ve patients with GI tumors faced approximately double the odds of mortality, an increased LOS of 2.5 days, and increased cost of care of about $4,400 compared to their C-ve counterparts. The disparity of outcomes was most pronounced among CRC patients. It is possible that the direct effects of the SARS-CoV-2 virus on the GI tract may predispose to mortality and disease severity, warranting further investigation. [Table: see text]
Cost-effectiveness of ColoSTAT for primary colorectal cancer screening in the United States.
Authors: He Emily , Deak Elena , Schmitt Laetitia Helene Marie , Alesso Sonia Maria , Gilbert Glenn
Published: June 2023

e15525

Background: Colorectal cancer (CRC) screening is at the cornerstone of strategies for reducing the mortality, healthcare and societal cost burden of CRC, the third most common cancer in the United States (US). ColoSTAT immunoassay is a simple, highly accurate, minimally invasive blood-based screening test for CRC that will be launched in the US market. Using a de novo decision analytic model, we compared the health benefits and cost-effectiveness of CRC screening with ColoSTAT with current screening offered by private insurers assuming a 5-yearly colonoscopy (COL) or biennial fecal immunochemical test (FIT) for the US population. Methods: For the three screening strategies, the expected number of CRC cases detected, and total screening program cost were estimated using a decision-analytic model based on: published CRC incidence in the US, tests performance characteristics, adherence rates to screening (61% for COL; 46% for FIT) and to diagnostic assessment via COL after a positive FIT or ColoSTAT test (80.4%). The gain in quality-adjusted life year (QALY) associated with every CRC case detected through screening, and confirmed by diagnostic assessment, was estimated by linking US-specific estimates of: CRC deaths by age-subgroups, life expectancies at the time of CRC death, quality of life projections for the general population and reduction in CRC mortality associated with screening. Healthcare cost savings associated with every CRC case detected through screening were estimated based on the distribution of CRC across disease stages by diagnosis method (screening versus symptomatically) and stage-specific CRC treatment costs. Results: Biennial screening with ColoSTAT, compared with 5-yearly COL screening offered by private insurers, is estimated to generate cost savings on screening programs of around $40 million per 100,000 people of screening age (PoSA) per one-off screening. When scaled up to the total US population within screening age covered by private insurance (66%), the estimated cost savings with ColoSTAT exceed $30 billion per one-off screening. The reduction in the number of CRC cases detected would generate a modest loss of 58 discounted QALYs per 100,000 people, that could be mitigated if ColoSTAT were to boost screening uptake. In the context of government-sponsored screening programs, replacing FIT with ColoSTAT is estimated to increase the number of CRC cases detected via screening by 9% (to 50 cases per 100,000 PoSA), assuming an unchanged screening uptake of 46%. At the commonly used value of $100,000 per QALY, this would equate to a discounted benefit of $834,820 per 100,000 PoSA per one-off screening. Conclusions: CRC screening with ColoSTAT as an alternative to COL could result in multi-billion-dollar cost savings to US private insurers while still detecting most CRC cases and generate population-health gains if used as an alternative to FIT in government-sponsored screening programs.
Immune activation-related risk score: A new tool to predict prognosis and immunotherapy applicability in colorectal cancer.
Authors: Zhu Changbin , Su Wenqing , Chen Yanhua , Gai Fei , Wang Jin
Published: June 2023

e15534

Background: In colorectal cancer (CRC), the therapeutic potential of immune checkpoint inhibitors (ICIs) is limited to the patients with mismatch repair deficient (dMMR)/high microsatellite instable (MSI-H) tumors, which accounts for less than 5% of CRC patients. While, patients with mismatch repair proficient (pMMR)/microsatellite stable (MSS) tumors represent the vast majority (≈ 95%), particularly those with similar inflammatory tumour microenvironment characteristics to dMMR/MSI-H patients are at risk of losing the opportunity to receive appropriate treatment. Thus, there is an urgent clinical need for biomarkers that can accurately predict prognosis of CRC patients, and assist in selection of patients who may benefit from immunotherapy. Methods: A public database, GEO (GSE39582, n = 502), was used as a training cohort to assess the characteristics associated with immune activation. Individuals with immune characteristics similar to dMMR/MSI-H were identified through GSVA and unsupervised clustering analysis, and defined as MSI-Like. Limma analysis identified MSI-Like immune activation characteristic, and immune activation-related prognostic models were developed by LASSO and COX regression. In addition, the applicability of immunotherapy for immune activation-related prognostic score was estimated in an external validation cohort (n = 96) from an Asian institution. Results: 113 differentially expressed genes between MSI-Like and non-MSI-Like pMMR/MSS samples were defined as immune activation- related characteristics of MSI-Like. After stepwise regression analysis, the characteristics were reduced to 6 key genes, and combined with their regression coefficients to construct a model. Overall survival was significantly shorter in high-risk [Immune Activation-related Risk Score (IARS) ≥ 0] group than in low-risk (IARS < 0) group (p < 0.0001). The area under the ROC curve (AUC) values at 1, 5 and 10 years were 0.683, 0.708 and 0.765, respectively. Furthermore, in multiple CRC data sets, the IARS can screen out the low-risk group with significantly better prognosis (p < 0.05). Additionally, low-risk group showed more expression of immune activation-related genes compared to high-risk group. IARS did not shown significant correlations with clinically characteristic factors (e.g., gender, age, stage, etc.) or gene mutations (including TP53, KRAS and BRAF). Conclusions: For a subset of pMMR/MSS patients with immune activation characteristics similar to those of dMMR/MSI-H patients, an immune activation-related risk score model was constructed based on 6 genes associated with immune activation characteristics. This model can effectively predict the prognosis of patients and also help to assess the adaptability of patients to immunotherapy. These findings have the potential to provide new insights into the immunotherapy of patients with pMMR/MSS CRC.