Clinical Cancer Research Articles

Exploration of the pattern of lymph node metastasis in esophageal cancer based on membrane anatomy theory

AbstractObjectiveTo analyze the pattern of lymph node metastasis in esophageal cancer based on the theory of membrane anatomy.MethodsA retrospective analysis was conducted on 143 patients who underwent esophageal surgery at the Cancer Hospital of the Chinese Academy of Medical Sciences from March 2021 to March 2022. Lymph node metastasis was observed and categorized according to postoperative T staging. The characteristics and patterns of lymph node metastasis in different regions were observed, and the lymph node metastasis patterns in patients with clinical T3 esophageal cancer were analyzed using membrane anatomy theory.ResultsAmong the 143 patients with esophageal squamous cell carcinoma, 21 were treated with surgery alone, while the rest received preoperative adjuvant therapy. A total of 5456 lymph nodes were cleared from the 143 patients, with 204 positive lymph nodes, resulting in a positive rate of 3.74%. In the thoracic lymph node dissection, the metastatic rates exceeded 5% for the following regions: 106recR (17.36%), 106recL (12.5%), 107 (10.42%), and 108 (5.56%) station. When analyzing the abdominal lymph node metastasis, the metastatic rates exceeded 5% for regions 7 (13.19%), 3a (7.64%), 2 (6.94%), and 1 (6.25%) station. Group analysis of patients with esophageal squamous cell carcinoma before postoperative pathological T3 stage revealed an increasing trend in tumor lymph node metastasis rate with later T staging. Lymph node metastasis in region 106recR can occur early, with a metastasis rate of 18.37% in T1 tumors. Analysis of lymph node metastasis characteristics in 103 patients clinically staged as T3 showed that 3966 lymph nodes were cleared, with 186 positive nodes, resulting in a positive rate of 4.69%. Lymph node metastasis rates were higher in regions 106recL, 106recR, 107, 108, 110, 1, 2, 3a, and 7, all exceeding 5%.ConclusionThe theory of membrane anatomy can effectively explain the pattern of lymph node metastasis in esophageal cancer.

Unveiling Biomarkers in Head and Neck Squamous Cell Carcinoma through Bioinformatics: The Role of SPP1 and KRT78

Head and neck squamous cell carcinoma (HNSCC) is the most common form of head and neck cancer, ranking sixth in global cancer incidence. Identifying molecular drivers of tumorigenesis and metastasis is essential for early detection and treatment. This study analyzed gene expression profiles from three datasets (GSE6791, GSE29330, and GSE58911) to identify differentially expressed genes (DEGs) in HNSCC. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were employed to functionally annotate these DEGs. A protein–protein interaction (PPI) network was constructed for selecting hub genes using the STRING database. Finally, hub gene and protein expression levels were evaluated in patients with HNSCC, along with their association with overall survival. Our analysis identified twenty-eight co-DEGs comprising eight up-regulated and twenty down-regulated genes, primarily involved in extracellular matrix (ECM) organization, proteolysis, ECM disassembly, and keratinization processes. Furthermore, the PPI network revealed eight hub genes based on their high degree of connectivity. Notably, SPP1 demonstrated up-regulation, while KRT78 was down-regulated in HNSCC. Remarkably, the expression levels of these hub genes correlated with tumor grade, clinical cancer stage, and poor prognosis in HNSCC. Our findings hold significant clinical potential for early diagnosis and the development of novel therapeutic targets for patients with HNSCC.

The radiosensitivity of niraparib tosylate to esophageal squamous cell carcinoma is stronger under hypoxia and higher-pressure conditions

Background: Radiotherapy is an effective method for esophageal squamous cell carcinoma (ESCC) treatment show reduced effectiveness in long-term due to reduced sensitivity of cancer cells to radiotherapy. Niraparib tosylate, a poly ADP-ribose polymerase (PARP) inhibitor may enhance the radiosensitivity of these cells. Hence, the present study was aimed to study the effects of niraparib tosylate on ESCC proliferation, apoptosis and cell cycle along with radiosensitivity enhancement efficiency. Materials and methods: ESCC cell lines, KYSE-30 were subjected to niraparib tosylate or irradiation treatments or combination of both. CCK8 and colony formation assays were performed to monitor cell growth status. Cell cycle and apoptosis level were investigated through flow cytometry. The expressions of targeted genes were detected at protein levels by western blot. Besides, xenografts were successfully established in immunocompromised mice. Student’s t-test was used to compare data and P < 0.05 was considered statistically significant. Results: Treatment with niraparib tosylate showed G2/M cycle arrest and apoptosis in KYSE-30 cells and the rate was observed to be more significant with combination therapy. These effects were further strengthened when cells were cultured under hypoxia and high atmospheric pressure. An enhanced susceptibility to radiotherapy was observed with niraparib tosylate combination. The homologous recombination related regulator, Rad51, showed remarkable upregulation in cancer cells exposed to combination of drug-radiation treatment. The tumor burden was also relieved in xenograft mouse models with combination of drug-radiation treatment, indicating the potential of niraparib tosylate use clinical cancer therapy. Conclusion: From the results, a novel function of niraparib tosylate can be established, impairing DNA damage repair efficiency to increase the susceptibility of ESCC to radiotherapy, resulting in cell apoptosis and G2/M cycle arrest in vitro and in vivo.

Impact of the coronavirus pandemic on the diagnosis and treatment of head and neck cancer

After the first appearance of COVID-19cases, the virus spread worldwide within afew months. This led to adecrease in medical consultations. The present study investigates whether this effect had an impact on the diagnosis and treatment of head and neck cancer during the period from 2018 to 2022. Data from the clinical cancer registration center (KKR) of Mecklenburg-Vorpommern from the 2020-2022 period were compared to those from the two previous years (2018, 2019). Demographic data, case numbers, diagnosis data, International Classification of Diseases (ICD) codes, and TNM classifications were recorded. COVID-19case numbers were obtained from the Robert Koch Institute (RKI). Data were analyzed using the Mann-Whitney Utest and Pearson's correlation. Atotal of 2332 patient cases could be included in this study. During the lockdown there was neither asignificant reduction in tumor diagnoses registered at the KKR nor acorrelation between COVID-19case numbers and tumor diagnoses. Significant differences were found in terms of Tcategory in the year 2022 compared to the pre-COVID years 2018 and 2019. Furthermore, there was ashift in the relative frequencies of some ICD-10codes. During the COVID-19 pandemic, no significant differences in tumor diagnoses were observed upon comparing the years 2018 to 2022. Contrary to the expectation of adecrease in case numbers during the pandemic due to the lockdown with an increase in tumor stages, areduction of the Tcategory could be found in 2022, and ashift in the relative frequencies of some ICD-10codes in the pandemic period was observed.

New Emerging Therapeutic Strategies Based on Manipulation of the Redox Regulation Against Therapy Resistance in Cancer.

Background: Resistance to standard therapeutic methods, including chemotherapy, immunotherapy, and targeted therapy, remains a critical challenge in effective cancer treatment. Redox homeostasis modification has emerged as a promising approach to address medication resistance. Objective: This review aims to explore the mechanisms of redox alterations and signaling pathways contributing to treatment resistance in cancer. Methods: In this study, a comprehensive review of the molecular mechanisms underlying drug resistance governed by redox signaling was conducted. Emphasis was placed on understanding how tumor cells manage increased reactive oxygen species (ROS) levels through upregulated antioxidant systems, enabling resistance across multiple therapeutic pathways. Results: Key mechanisms identified include alterations in drug efflux, target modifications, metabolic changes, enhanced DNA damage repair, stemness preservation, and tumor microenvironment remodeling. These pathways collectively facilitate tumor cells' adaptive response and resistance to various cancer treatments. Conclusion: Developing a detailed understanding of the interrelationships between these redox-regulated mechanisms and therapeutic resistance holds potential to improve treatment effectiveness, offering valuable insights for both fundamental and clinical cancer research. Antioxid. Redox Signal. 00, 000-000.

Glucocorticoid Receptor Isoforms in Breast Cancer Raise Implications for Personalised Supportive Therapies

Glucocorticoid receptor (GR) activation may promote metastasis in oestrogen receptor-negative and triple-negative breast cancer (TNBC). However, the role of the GRβ isoform, which has opposing effects to the main isoform, has not been studied in clinical samples. We aimed to analyse the intracellular localisation of total GR and GRβ in vitro using plasmid constructs and fluorescent immunocytochemistry. Additionally, our goal was to perform immunostaining for total GR and GRβ on two cohorts: (i) on 194 clinical breast cancer samples to compare the expression in different molecular subtypes, and (ii) on 161 TNBC samples to analyse the association of GR with survival. We supplemented our analysis with RNA data from 1097 TNBC cases. We found that in the absence of the ligand, GR resided in the cytoplasm of breast cancer cells, while upon ligand activation, it translocated to the nucleus. A negative correlation was found between cytoplasmic GRtotal and Ki67 in luminal A tumours, while the opposite trend was observed in TNBC samples. Tumours with strong lymphoid infiltration showed higher cytoplasmic GRtotal staining compared to those with weaker infiltration. Patients with high nuclear GRtotal staining had shorter progression-free survival in univariate analysis. High cytoplasmic GRβ was a marker for better overall survival in multivariate analysis (10-year overall survival HR [95% CI]: 0.46 [0.22–0.95], p = 0.036). As a conclusions, this study is the first to investigate GRβ expression in breast tumours. Different expression and cellular localisation of GRtotal and GRβ were observed in the context of molecular subtypes, underscoring the complex role of GR in breast cancer. An inverse association between cytoplasmic GRtotal and the Ki67 proliferation index was observed in luminal A and TNBC. Regarding the impact of GR on outcomes in TNBC patients, while cytoplasmic GRβ was associated with a better prognosis, patients with nuclear GRtotal staining may be at a higher risk of disease progression, as it negatively affects survival. Caution should be exercised when using glucocorticoids in patients with nuclear GR staining, as it may negatively impact survival.

Glatiramer Acetate Complexes CpG Oligodeoxynucleotides into Nanoparticles and Boosts Their TLR9-Driven Immunity.

Unmethylated cytosine-guanine oligodeoxynucleotides (CpG ODNs) have a storied history as agonists for Toll-like receptor 9 (TLR9). CpG ODNs have shown promising antitumor effects in preclinical studies by inducing potent proinflammatory immune responses. However, clinical success has been hindered by inconsistent efficacy and immune-related toxicities caused by systemic exposure to CpG ODNs. We previously identified that glatiramer acetate (GA), an FDA-approved, lysine-rich polypeptide, could complex class B CpG into cationic nanoparticles which persist at the intratumoral injection site while mitigating the induction of systemic proinflammatory cytokines in mouse tumor models. To extend GA applications across subtypes of CpG ODN (class A, B, and C), we evaluated physiochemical properties and identified the immunological signaling of GA and its complexes with different classes of CpG ODNs. We compared the physiochemical characteristics of three types of GA-CpG nanoparticles, followed by assessments of cell uptake efficiency and endolysosomal trafficking. We then performed successive in vitro and in vivo assays to evaluate immunological discrepancies. Complexation with GA preserved the immunological activity of CpG ODN subtypes while encapsulating them into cationic spherical nanoparticles. GA improved the cellular uptake of CpG ODNs, generally increased retention in early endosomes, and amplified immunological responses. A subsequent in vivo experiment confirmed the achievement of potent tumor suppression while mitigating systemic immune-related toxicities. Together, these data help elucidate the noncanonical role of GA to serve as a nucleic acid delivery scaffold that can improve the efficacy and safety of CpG adjuvant for clinical cancer immunotherapy.

Knowledge and Awareness of Emerging Cancer Therapies and their Regulations among Budding Scientists in India: A Survey

Background: Academic clinical research is considered the most important for cancer research because it frequently tests novel drug combinations, investigates rarer diseases, and lowers the risk for future commercial investments. However, due to the potential risks to the cancer patient, clinical research is governed by strict regulations. In high-income countries, comprehensive cancer centers (CCCs) have been established to align academic clinical cancer research with the regulatory framework. In comparison, academic clinical cancer research is considered ineffective in low-income countries. Methods: A cross-sectional, online survey was conducted to evaluate the knowledge of Indian health science students regarding cutting-edge cancer therapeutics and their underlying regulatory requirements. Results: The survey found that 163 out of the 265 respondents were aware of the challenges of developing safe and effective anticancer therapeutics. 43 respondents found no challenges, while 59 respondents were unaware of any. Out of 163, 44 respondents identified technical challenges, 31 identified regulatory issues, and 88 identified both challenges in developing novel anticancer therapeutics. Interestingly, only 83 students out of 265, study cancer therapy regulations in their curriculum. This clearly indicates that most of India's health science students have a significant lack of understanding about the regulations for new cancer treatments. Conclusion: Academic clinical cancer research in India is just recognized as a prerequisite for degree completion due to a lack of regulatory foundation. An emphasis should be placed on restructuring the coursework offered to health science students to improve their ability to translate theoretical cancer research to real-world clinical care.

Establishing Medical Intelligence-Leveraging Fast Healthcare Interoperability Resources to Improve Clinical Management: Retrospective Cohort and Clinical Implementation Study.

FHIR (Fast Healthcare Interoperability Resources) has been proposed to enable health data interoperability. So far, its applicability has been demonstrated for selected research projects with limited data. This study aimed to design and implement a conceptual medical intelligence framework to leverage real-world care data for clinical decision-making. A Python package for the use of multimodal FHIR data (FHIRPACK [FHIR Python Analysis Conversion Kit]) was developed and pioneered in 5 real-world clinical use cases, that is, myocardial infarction, stroke, diabetes, sepsis, and prostate cancer. Patients were identified based on the ICD-10 (International Classification of Diseases, Tenth Revision) codes, and outcomes were derived from laboratory tests, prescriptions, procedures, and diagnostic reports. Results were provided as browser-based dashboards. For 2022, a total of 1,302,988 patient encounters were analyzed. (1) Myocardial infarction: in 72.7% (261/359) of cases, medication regimens fulfilled guideline recommendations. (2) Stroke: out of 1277 patients, 165 received thrombolysis and 108 thrombectomy. (3) Diabetes: in 443,866 serum glucose and 16,180 glycated hemoglobin A1c measurements from 35,494 unique patients, the prevalence of dysglycemic findings was 39% (13,887/35,494). Among those with dysglycemia, diagnosis was coded in 44.2% (6138/13,887) of the patients. (4) Sepsis: In 1803 patients, Staphylococcus epidermidis was the primarily isolated pathogen (773/2672, 28.9%) and piperacillin and tazobactam was the primarily prescribed antibiotic (593/1593, 37.2%). (5) PC: out of 54, three patients who received radical prostatectomy were identified as cases with prostate-specific antigen persistence or biochemical recurrence. Leveraging FHIR data through large-scale analytics can enhance health care quality and improve patient outcomes across 5 clinical specialties. We identified (1) patients with sepsis requiring less broad antibiotic therapy, (2) patients with myocardial infarction who could benefit from statin and antiplatelet therapy, (3) patients who had a stroke with longer than recommended times to intervention, (4) patients with hyperglycemia who could benefit from specialist referral, and (5) patients with PC with early increases in cancer markers.

Development and validation of a tumor marker-based model for the prediction of lung cancer: an analysis of a multicenter retrospective study in Shanghai, China

BackgroundThe incidence and mortality rates of cancer are the highest globally. Developing novel methodologies that precisely, safely, and economically differentiate between benign and malignant lung conditions holds immense clinical importance. This research seeks to construct a predictive model utilizing a combination of diverse biomarkers to effectively discriminate between benign and malignant lung diseases.MethodsThis retrospective study included patients admitted to the two general hospitals in Shanghai from 2014 to 2015. This study was developed using five tumor markers: carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA199), cytokeratin fragment 21-1 (CA211), squamous cell carcinoma antigen (SCC), and neuron specific enolase (NSE). The entire sample was divided into two groups according to the hospital: 1033 cases were included in the development cohort and 300 cases in the validation cohort. Logistic regression analysis was used for univariate analysis to explore individual correlations between each selected clinical variable and lung cancer diagnostic outcome. Diagnostic prediction models were constructed and validated based on independent prognostic factors identified using multifactorial analysis. A nomogram was created using these tumor markers (age and sex were additionally included) and validated using the concordance index and calibration curves. Clinical prediction models were evaluated using decision curve analysis.ResultsFully adjusted multivariate analysis showed that the risk of lung cancer was 2.38 times higher in men than in women. CEA positivity was associated with an 13.41-fold increased risk in lung cancer. The area under the curve (AUC) values for the development cohort and validation cohort models were 0.907 and 0.954, respectively. In the established nomogram, the AUC for the receiver operating characteristic curve was 0.907 (95% CI, 0.889–0.925). The validation model confirmed the strong discriminative power of the nomogram (AUC = 0.954). The described calibration curves demonstrated good fit predictions and observation probabilities. In addition, decision curve analysis concluded that the newly established nomogram has important implications for clinical decision making.ConclusionsCombined prediction models based on CEA, CA199, CA211, SCC, and NSE biomarkers could significantly the differentiation between benign and malignant lung diseases, thus facilitating better clinical decision making.

Therapeutic Immunomodulation of Tumor-Lymphatic Crosstalk via Intratumoral Immunotherapy.

Intra- and peritumoral lymphatics and tumor-draining lymph nodes play major roles in mediating the adaptive immune response to cancer immunotherapy. Despite this, current paradigms of clinical cancer management seldom seek to therapeutically modulate tumor-lymphatic immune crosstalk. This review explores recent developments that set the stage for how this regulatory axis can be therapeutically manipulated, with a particular emphasis on tumor-localized immunomodulation. Building on this idea, the nature of tumor-lymphatic immune crosstalk and relevant immunotherapeutic targets and pathways are reviewed, with a focus on their translational potential. Engineered drug delivery systems that enhance intratumoral immunotherapy by improving drug delivery to both the tumor and lymph nodes are also highlighted.

Evaluation and Use of Natural Language Processing (NLP) Reasoning and Classification Models to Support Clinical Trial Patient Identification and Enrollment in the Community Oncology Setting

Clinical trial research in oncology relies heavily on clinical documentation within the electronic medical record (EMR) to ascertain patient eligibility in clinical trials based on inclusion and exclusion criteria. The structured data elements within the EMR serve as the primary information source for defining patient cohorts, with clinical cancer stage and performance status being two pivotal criteria determining trial eligibility. The challenge arises from the inconsistent availability of clinical stage and performance status data within the structured fields of the EMR despite their consistent presence in clinical notes. Additionally, there is a deficiency of standardization of this data that exists in the unstructured field. Hence, due to lack of structured data and standardization of said data, there are limitations in developing artificial intelligence (AI) models. To increase the comprehensiveness of clinical records, a clinical research team at a community oncology practice was consulted to identify requirements and extract essential clinical features from de-identified data. The methods outlined in this paper focused on eliminating false positives to allow future development of Large Language Models (LLM) using the outputted structured fields which resulted in an increase in patient record completeness with high accuracy. The accuracy ranged from 97.5-97.75% for the models that were developed. Out of the 60,000+ patients, the numerical staging, TNM (tumor, node, metastasis) staging, and Karnofsky performance score models added a structured field for 29.62%, 21.01%, and 40.64% patients respectively. Additionally, a semi-supervised NLP algorithm was applied on the performance status algorithm which achieved a mean absolute error (MAE) of 1.57. This work demonstrates the use case of natural language processing (NLP) in optimizing the clinical research enrollment process by providing an efficient and accurate method to detect key clinical values in unstructured patient data. Similar methodology with more advanced algorithms such as LLM can be employed to detect additional patient elements such as molecular biomarkers, imaging reports, postoperative surgical outcomes (i.e., clear margins etc.) and patient treatment outcomes using the extracted structured fields.

Association between Clinical Features and Risk Factors for Breast Cancer through a Cross-Sectional Study

Introduction: Breast cancer was responsible for 685,000 deaths worldwide in 2020. Approximately half of all breast cancers arise in women who have no identifiable risk factors other than their gender and age. Objectives: The goal of this study was to determine the association between clinical features and breast cancer risk factors. Methods: This cross-sectional study was conducted among 50 histologically confirmed breast cancer patients included by purposive sampling technique in the Surgery Department of Rangpur Medical College, Rangpur. Results: The presence of breast lump was significantly associated with the residence of patients (p value<0.011). The significant association between nipple retraction and family history may indicate a hereditary predisposition that affects the course of the disease (p value<0.031). Conclusion: This research provides insights into vital aspects of breast cancer within a particular demographic, under scoring the necessity for focused approaches to public health to address the discrepancies in breast cancer presentation and outcomes. J Bangladesh Coll Phys Surg 2024; 42: 321-328

Definitive-dose adjuvant radiotherapy following endoscopic submucosal dissection for superficial esophageal cancer.

Prophylactic chemoradiation therapy (CRT) using 40-41.4Gy post-endoscopic submucosal dissection (ESD) for clinical T1N0M0 esophageal cancer reportedly yields favorable outcomes. However, it cannot completely prevent locoregional lymph node (LN) metastases. We retrospectively analyzed outcomes and adverse events associated with our dose-escalated treatment regimen (definitive-dose radiotherapy [RT] of 50-61.2Gy, with/without chemotherapy) for these patients, and predictors of progression-free survival (PFS) and overall survival (OS). Between 2006 and 2018, 44 consecutive patients (42 men and 2 women; median age, 70years) who underwent definitive-dose RT post-ESD and had a pathological depth of the muscularis mucosa with lymphovascular invasion (LVI) or the upper-middle submucosal third at our institution were included. We excluded patients who could not obtain a margin-free resection by ESD. If feasible, systemic chemotherapy with 5-fluorouracil plus high- or low-dose cisplatin or nedaplatin was administered concurrently. Five-year PFS, OS, and disease-specific survival rates were 78.8%, 88.4%, and 97.7%, respectively. Six metachronous esophagus (14%), two locoregional LN within the irradiated area with a prophylactic dose of 41.4Gy (5%), and two locoregional LN plus liver (5%) recurrences occurred. No LN recurrence occurred within the definitive dose of ≥ 50Gy in the irradiated area. Metachronous esophageal recurrence involved areas receiving ≥ 50Gy. Univariate and multivariate analyses revealed that age was an independent prognostic factor for both PFS and OS. Definitive-dose RT/CRT post-ESD could provide favorable locoregional LN control and PFS/OS regardless of patient characteristics, including pathological findings and chemotherapy regimen/course, except for age. These results need to be interpreted carefully given several limitations, therefore, definitive-dose RT/CRT should be conducted with caution in clinical practice until high-quality prospective clinical trials evaluating the effectiveness and safety.

3D cultivation of non-small-cell lung cancer cell lines using four different methods

PurposeThe aim of this study was to set up reliable and reproducible culture conditions for 3D tumoroids derived from non-small cell lung cancer (NSCLC) cell lines to enable greater opportunity for successful cultivation of patient-derived samples.MethodsFour NSCLC cell lines, two adenocarcinomas (A549, NCI-H1975) and two squamous cell carcinomas (HCC-95, HCC-1588), were first cultured in traditional 2D settings. Their expected expression profiles concerning TTF-1, CK7, CK5, and p40 status were confirmed by immunohistochemistry (IHC) before the generation of 3D cultures. Tumoroids were established in the hydrogel GrowDex®-T, Nunclon™ Sphera™ flasks, BIOFLOAT™ plates, and Corning® Elplasia® plates. Western blot was used to verify antigen protein expression. Hematoxylin-eosin staining was used to evaluate the cell morphology in the 2D and 3D cultures. Mutational analysis of KRAS and EGFR by PCR on extracted DNA from 3D tumoroids generated from cells with known mutations (A549; KRAS G12S mutation, NCI-H1975; EGFR L858R/T790M mutations).ResultsWe successfully established 3D cultures from A549, NCI-H1975, HCC-95, and HCC-1588 with all four used cultivation methods. The adenocarcinomas (A549, NCI-H1975) maintained their original IHC features in the tumoroids, while the squamous cell carcinomas (HCC-95, HCC-1588) lost their unique markers in the cultures. PCR analysis confirmed persistent genetic changes where expected.ConclusionThe establishment of tumoroids from lung cancer cell lines is feasible with various methodologies, which is promising for future tumoroid growth from clinical lung cancer samples. However, analysis of relevant markers is a prerequisite and may need to be validated for each model and cell type.

Reporting of somatic variants in clinical cancer care: recommendations of the Swiss Society of Molecular Pathology.

Somatic variant testing through next-generation sequencing (NGS) is well integrated into Swiss molecular pathology laboratories and has become a standard diagnostic method for numerous indications in cancer patient care. Currently, there is a wide variation in reporting practices within our country, and as patients move between different hospitals, it is increasingly necessary to standardize NGS reports to ease their reinterpretation. Additionally, as many different stakeholders-oncologists, hematologists, geneticists, pathologists, and patients-have access to the NGS report, it needs to contain comprehensive and detailed information in order to answer the questions of experts and avoid misinterpretation by non-experts. In 2017, the Swiss Institute of Bioinformatics conducted a survey to assess the differences in NGS reporting practices across ten pathology institutes in Switzerland. The survey examined 68 reporting items and identified 48 discrepancies. Based on these findings, the Swiss Society of Molecular Pathology initiated a Delphi method to reach a consensus on a set of recommendations for NGS reporting. Reports should include clinical information about the patient and the diagnosis, technical details about the sample and the test performed, and a list of all clinically relevant variants and variants of uncertain significance. In the absence of a consensus on an actionability scheme, the five-class pathogenicity scheme proposed by the ACMG/AMP guideline must be included in the reports. The Swiss Society of Molecular Pathology recognizes the importance of including clinical actionability in the report and calls on the European community of molecular pathologists and oncologists to reach a consensus on this issue.

Establishment of a clinical cancer genetics program for breast cancer in a resource-limited country; challenges and opportunities.

Breast cancer is the most common cancer among women worldwide, and its incidence rate is still increasing, especially among younger women. Nationally, it constitutes one-fifth of all cancer cases and almost 40% of all female cancers. With a median age of 51 years, breast cancer is diagnosed at least a decade earlier, and at more advanced stages compared to Western societies. Hereditary cancers account for 10% or more of all cancer burden worldwide. With expanded indications, increased number of genes tested, and significant decline in cost of testing, such proportion will probably increase. Individuals with pathogenic variants of BRCA1 and BRCA2 are at higher risk of breast, ovarian, pancreatic and many other cancers. Over the past two decades, several highly penetrant cancer-susceptibility genes were identified across almost all tumor sites, thus increasing the need for comprehensive cancer genetic programs that address the testing process, counselling patients and at-risk family members, and then deal with all testing results and its consequences. In addition to its important role in preventing more cancers in index patients themselves and among their close relatives, identification of pathogenic or likely pathogenic variants, mostly in BRCA1 or BRCA2, may inform therapeutic decisions in common cancers including breast, ovarian, prostate and pancreatic cancers. In this manuscript, we describe the experience of a comprehensive cancer center, in a resource-limited country in establishing a comprehensive clinical cancer genetics program that can serve as an example for others who share similar demographic and financial restrains.

Contribution of an Artificial Intelligence Tool in the Detection of Incidental Pulmonary Embolism on Oncology Assessment Scans

Introduction: The incidence of venous thromboembolism is estimated to be around 3% of cancer patients. However, a majority of incidental pulmonary embolism (iPE) can be overlooked by radiologists in asymptomatic patients, performing CT scans for disease surveillance, which may significantly impact the patient’s health and management. Routine imaging in oncology is usually reviewed with delayed hours after the acquisition of images. Nevertheless, the advent of AI in radiology could reduce the risk of the diagnostic delay of iPE by an optimal triage immediately at the acquisition console. This study aimed to determine the accuracy rate of an AI algorithm (CINA-iPE) in detecting iPE and the duration until the management of cancer patients in our center, in addition to describing the characteristics of patients with a confirmed pulmonary embolism (PE). Materials and Methods: This is a retrospective analysis of the role of Avicenna’s CE-certified and FDA-cleared CINA-iPE algorithm in oncology patients treated at Gustave Roussy Cancer Campus. The results obtained from the AI algorithm were compared with the attending radiologist’s report and were analyzed by both a radiology resident and a senior radiologist. In case of any discordant results, the reason for this discrepancy was further investigated. The duration between the exact time of the CT scan and analysis was assessed, as well as the duration from the result’s report and the start of active management. Results: Out of 3047 patients, 104 alerts were detected for iPE (prevalence of 1.3%), while 2942 had negative findings. In total, 36 of the 104 patients had confirmed PE, while 68 alerts were false positives. Only one patient reported as negative by the AI tool was deemed to have a PE by the radiologist. The sensitivity and specificity of the AI model were 97.3% and 97.74%, while the PPV and NPV were 34.62% and 99.97%, respectively. Most causes of FP were artifacts (22 cases, 32.3%) and lymph nodes (11 cases, 16.2%). Seven patients experienced delayed diagnosis, requiring them to return to the ER for treatment after being sent home following their scan. The remaining patients received prompt care immediately after their testing, with a mean delay time of 8.13 h. Conclusions: The addition of an AI system for the detection of unsuspected PEs on chest CT scans in routine oncology care demonstrated a promising efficacy in comparison to human performance. Despite a low prevalence, the sensitivity and specificity of the AI tool reached 97.3% and 97.7%, respectively, with detection of all the reported clinical PEs, except one single case. This study describes the potential synergy between AI and radiologists for an optimal diagnosis of iPE in routine clinical cancer care. Clinical relevance statement: In the oncology field, iPEs are common, with an increased risk of morbidity when missed with a delayed diagnosis. With the assistance of a reliable AI tool, the radiologist can focus on the challenging analysis of oncology results while dealing with urgent diagnosis such as PE by sending the patient straight to the ER (Emergency Room) for prompt treatment.

ERN GENTURIS guidelines on constitutional mismatch repair deficiency diagnosis, genetic counselling, surveillance, quality of life, and clinical management.

Constitutional mismatch repair deficiency (CMMRD), first described 25 years ago, confers an extremely high and lifelong cancer risk, including haematologic, brain, and gastrointestinal tract malignancies, and is associated with several non-neoplastic features. Our understanding of this condition has improved and novel assays to assist CMMRD diagnosis have been developed. Surveillance protocols need adjustment taking into account recent observational prospective studies assessing their effectiveness. Response to immune checkpoint inhibitors and the effectiveness and toxicity of other treatments have been described. An update and merging of the different guidelines on diagnosis and clinical management of CMMRD into one comprehensive guideline was needed. Seventy-two expert members of the European Reference Network GENTURIS and/or the European care for CMMRD consortium and one patient representative developed recommendations for CMMRD diagnosis, genetic counselling, surveillance, quality of life, and clinical management based on a systematic literature search and comprehensive literature review and a modified Delphi process. Recommendations for the diagnosis of CMMRD provide testing criteria, propose strategies for CMMRD testing, and define CMMRD diagnostic criteria. Recommendations for surveillance cover each CMMRD-associated tumour type and contain information on starting age, frequency, and surveillance modality. Recommendations for clinical management cover cancer treatment, management of benign tumours or non-neoplastic features, and chemoprevention. Recommendations also address genetic counselling and quality of life. Based on existing guidelines and currently available data, we present 82 recommendations to improve and standardise the care of CMMRD patients in Europe. These recommendations are not meant to be prescriptive and may be adjusted based on individual decisions.

Structure-based discovery of first inhibitors targeting the helicase activity of human PIF1.

PIF1 is a conserved helicase and G4 DNA binding and unwinding enzyme, with roles in genome stability. Human PIF1 (hPIF1) is poorly understood, but its functions can become critical for tumour cell survival during oncogene-driven replication stress. Here we report the discovery, via an X-ray crystallographic fragment screen (XChem), of hPIF1 DNA binding and unwinding inhibitors. A structure was obtained with a 4-phenylthiazol-2-amine fragment bound in a pocket between helicase domains 2A and 2B, with additional contacts to Valine 258 from domain 1A. The compound makes specific interactions, notably through Leucine 548 and Alanine 551, that constrain conformational adjustments between domains 2A and 2B, previously linked to ATP hydrolysis and DNA unwinding. We next synthesized a range of related compounds and characterized their effects on hPIF1 DNA-binding and helicase activity in vitro, expanding the structure activity relationship (SAR) around the initial hit. A systematic analysis of clinical cancer databases is also presented here, supporting the notion that hPIF1 upregulation may represent a specific cancer cell vulnerability. The research demonstrates that hPIF1 is a tractable target through 4-phenylthiazol-2-amine derivatives as inhibitors of its helicase action, setting a foundation for creation of a novel class of anti-cancer therapeutics.