A Deep Learning Model for Cancer Type Prediction Sets a New Standard.

SUMMARY: Classifying tumor types using machine learning approaches is not always trivial, particularly for challenging cases such as cancers of unknown primary. In this issue of Cancer Discovery, Darmofal and colleagues describe a new tool that uses information from a clinical sequencing panel to diagnose tumor type, and show that the model is particularly robust. See related article by Darmofal et al., p. 1064 (1).

Optimus-Era Dose Finding for Rare Cancers.

SUMMARY: Advances in cancer biology and diagnostics have led to the recognition of a multitude of rare cancer subtypes, emphasizing the pressing need for strategies to accelerate drug development for patients with these cancers. This paper addresses the unique challenges of dose finding in trials that accrue small numbers of patients with rare cancers; strategies for dose optimization are proposed, in line with evolving approaches to dose determination in the age of the US Food and Drug Administration's Project Optimus.

PPIH acts as a potential predictive biomarker for patients with common solid tumors.

BACKGROUND: Our previous studies have indicated that mRNA and protein levels of PPIH are significantly upregulated in Hepatocellular Carcinoma (LIHC) and could act as predictive biomarkers for patients with LIHC. Nonetheless, the expression and implications of PPIH in the etiology and progression of common solid tumors have yet to be explored, including its potential as a serum tumor marker. METHODS: We employed bioinformatics analyses, augmented with clinical sample evaluations, to investigate the mRNA and protein expression and gene regulation networks of PPIH in various solid tumors. We also assessed the association between PPIH expression and overall survival (OS) in cancer patients using Kaplan-Meier analysis with TCGA database information. Furthermore, we evaluated the feasibility and diagnostic efficacy of PPIH as a serum marker by integrating serological studies with established clinical tumor markers. RESULTS: Through pan-cancer analysis, we found that the expression levels of PPIH mRNA in multiple tumors were significantly different from those in normal tissues. This study is the first to report that PPIH mRNA and protein levels are markedly elevated in LIHC, Colon adenocarcinoma (COAD), and Breast cancer (BC), and are associated with a worse prognosis in these cancer patients. Conversely, serum PPIH levels are decreased in patients with these tumors (LIHC, COAD, BC, gastric cancer), and when combined with traditional tumor markers, offer enhanced sensitivity and specificity for diagnosis. CONCLUSION: Our findings propose that PPIH may serve as a valuable predictive biomarker in tumor patients, and its secreted protein could be a potential serum marker, providing insights into the role of PPIH in cancer development and progression.

Parallel DNA/RNA NGS Using an Identical Target Enrichment Panel in the Analysis of Hereditary Cancer Predisposition.

Germline DNA testing using the next-gene-ration sequencing (NGS) technology has become the analytical standard for the diagnostics of hereditary diseases, including cancer. Its increasing use places high demands on correct sample identification, independent confirmation of prioritized variants, and their functional and clinical interpretation. To streamline these processes, we introduced parallel DNA and RNA capture-based NGS using identical capture panel CZECANCA, which is routinely used for DNA analysis of hereditary cancer predisposition. Here, we present the analytical workflow for RNA sample processing and its analytical and diagnostic performance. Parallel DNA/RNA analysis allowed credible sample identification by calculating the kinship coefficient. The RNA capture-based approach enriched transcriptional targets for the majority of clinically relevant cancer predisposition genes to a degree that allowed analysis of the effect of identified DNA variants on mRNA processing. By comparing the panel and whole-exome RNA enrichment, we demonstrated that the tissue-specific gene expression pattern is independent of the capture panel. Moreover, technical replicates confirmed high reproducibility of the tested RNA analysis. We concluded that parallel DNA/RNA NGS using the identical gene panel is a robust and cost-effective diagnostic strategy. In our setting, it allows routine analysis of 48 DNA/RNA pairs using NextSeq 500/550 Mid Output Kit v2.5 (150 cycles) in a single run with sufficient coverage to analyse 226 cancer predisposition and candidate ge-nes. This approach can replace laborious Sanger confirmatory sequencing, increase testing turnaround, reduce analysis costs, and improve interpretation of the impact of variants by analysing their effect on mRNA processing.

DHCR24 in Tumor Diagnosis and Treatment: A Comprehensive Review.

As an important nutrient in the human body, cholesterol can not only provide structural components for the body's cells, but also can be transformed into a variety of active substances to regulate cell signaling pathways. As an important cholesterol synthase, DHCR24 participates in important regulatory processes in the body. The application of DHCR24 in tumor clinical diagnosis and treatment also attracts much attention. This article reviews the structure and regulatory characteristics of DHCR24, and the research of DHCR24 on tumor progression. We summarize the possible mechanisms of DHCR24 promoting tumor progression through reactive oxygen species (ROS), p53, Ras and PI3K-AKT pathways. Through our review, we hope to provide more research ideas and reference value for the application of DHCR24 in tumor prevention and treatment.

Implementation of Universal Pan-Cancer Germline Genetic Testing in an Arab Population: The Jordanian Exploratory Cancer Genetics Study.

PURPOSE: Germline genetic testing (GGT) significantly affects cancer care. While universal testing has been studied in Western societies, less is known about adoption elsewhere. MATERIALS AND METHODS: In this study, 3,319 unselected, pan-cancer Jordanian patients diagnosed between April 2021 and September 2022 received GGT. Pathogenic germline variant (PGV) frequency among patients who were in-criteria (IC) or out-of-criteria (OOC; 2020 National Comprehensive Cancer Network criteria) and changes in clinical management in response to GGT results were evaluated. Statistical analysis was performed using two-tailed Fisher's exact test with significance level P < .05. RESULTS: The cohort was predominantly female (69.9%), with a mean age of 53.7 years at testing, and 53.1% were IC. While patients who were IC were more likely than patients who were OOC to have a PGV (15.8% v 9.6%; P < .0001), 149 (34.8%) patients with PGVs were OOC. Clinical management recommendations in response to GGT, including changes to treatment and/or follow-up, were made for 57.3% (161 of 281) of patients with high- or moderate-risk PGVs, including 26.1% (42 of 161) of patients who were OOC. CONCLUSION: Universal GGT of patients with newly diagnosed cancer was successfully implemented in Jordan and led to identification of actionable PGVs that would have been missed with guidelines-based testing.

Predictability: A new distinguishing feature of cancer?

Cancer is a consequence of stochastic (mutations, genetic, and epigenetic instabilities) and deterministic (evolutionary bottlenecks) events. Stochastic events are less amenable to prediction, whereas deterministic events yield more predictable results. The relative contribution of these opposing forces determines cancer predictability, which affects the accuracy of our prognostic predictions and is critical for treatment planning. In this study, we attempted to quantify predictability. The predictability index (PI) was defined as the median overall-survival at any time point divided by the standard error at that time. Using data obtained from the SEER program, we found striking differences in the PI of different tumors. Highly predictable tumors were malignancies of the breast, thyroid, prostate, and testis (5-year PI of 3516, 1920, 1919, and 1805, respectively). Less predictable tumors were colorectal, melanoma, and bladder (5-year PI of 1264, 1197, and 760, respectively). Least predictable were pancreatic cancer and chronic myelogenous leukemia (5-year PI of 129, and 42). PI decreased during follow-up in all examined tumors and showed sex differences in some cases. Thyroid cancer was significantly more predictable in women (5-year PI of 2579 vs. 748, p = 0.00017) and bladder cancer more predictable in men (5-year PI of 723 vs. 385, p = 0.012), Predictability is a potentially new distinguishing feature of malignancy. This study sheds light on prognostic accuracy and provides insight into the relative roles of stochastic and deterministic forces during carcinogenesis.

Cancer Screening in Low- and Middle-Income Countries.

The worldwide cancer burden is growing, and populations residing in low- and middle-income countries (LMICs) are experiencing a disproportionate extent of this growth. Breast, colorectal, and cervical cancers are among the top 10 most frequently diagnosed malignancies, and they also account for a substantial degree of cancer mortality internationally. Effective screening strategies are available for all three of these cancers. Individuals from LMICs face substantial cost and access barriers to early detection programs, and late stage at diagnosis continues to be a major cause for cancer mortality in these communities. This chapter will review the epidemiology of breast, colorectal, and cervical cancers, and will explore prospects for improving global control through novel approaches to screening in cost-constrained environments.

Prognostic potential of lipid profiling in cancer patients: a systematic review of mass spectrometry-based studies.

Cancer prognosis remains a critical clinical challenge. Lipidomic analysis via mass spectrometry (MS) offers the potential for objective prognostic prediction, leveraging the distinct lipid profiles of cancer patient-derived specimens. This review aims to systematically summarize the application of MS-based lipidomic analysis in prognostic prediction for cancer patients. Our systematic review summarized 38 studies from the past decade that attempted prognostic prediction of cancer patients through lipidomics. Commonly analyzed cancers included colorectal, prostate, and breast cancers. Liquid (serum and urine) and tissue samples were equally used, with liquid chromatography-tandem MS being the most common analytical platform. The most frequently evaluated prognostic outcomes were overall survival, stage, and recurrence. Thirty-eight lipid markers (including phosphatidylcholine, ceramide, triglyceride, lysophosphatidylcholine, sphingomyelin, phosphatidylethanolamine, diacylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylethanolamine, lysophosphatidic acid, dihydroceramide, prostaglandin, sphingosine-1-phosphate, phosphatidylinosito, fatty acid, glucosylceramide and lactosylceramide) were identified as prognostic factors, demonstrating potential for clinical application. In conclusion, the potential for developing lipidomics in cancer prognostic prediction was demonstrated. However, the field is still nascent, necessitating future studies for validating and establishing lipid markers as reliable prognostic tools in clinical practice.

[Cancer registration in Iceland for 70 years - incidence, mortality and survival].

INTRODUCTION: The Icelandic Cancer Registry (ICR) was founded seventy years ago by the Icelandic Cancer Society. In 2007 the ICR became one of the health registers of the Directorate of Health. In this paper we present cancer incidence, mortality, and survival in Iceland over 70 years. MATERIAL AND METHODS: The ICR receives information on cancer diagnoses from histopathological laboratories, the Hospital Discharge Registry and the Cause of Death Registry. Iceland participates in the Nordic cancer database NORDCAN. Because of the small population size, random variation in numbers is very prominent. Therefore, data from ICR are published as five-year averages. RESULTS: For all malignancies combined, age-standardized incidence (ASI) in men rose steadily until around 15 years ago when a decline started. This is in line with prostate- and lung cancer incidence trends. In women, the ASI was lower than in men, but it is still on the rise despite declining lung cancer incidence. ASI for breast cancer, the most common cancer in women, is increasing. Simultaneously, cancer mortality for both sexes has declined in recent years and cancer survival is improving. CONCLUSIONS: Population-based cancer registration for over 70 years makes it possible to monitor the epidemiology of cancer in Iceland and compare with other countries. The changes in trends in ASI are in line with changes of cancer risk factors and diagnostic policy. The decline in cancer mortality and improvement in survival reflects advances in cancer treatment as well as effects of early detection and prevention.

Cancer literacy differences of basic knowledge, prevention, early detection, treatment and recovery: a cross-sectional study of urban and rural residents in Northeast China.

Background: Cancer literacy as a potential health intervention tool directly impacted the success of cancer prevention and treatment initiatives. This study aimed to evaluate the cancer literacy in Northeast China, and explore the factors contributing to urban-rural disparities. Methods: A cross-sectional survey was conducted in 14 cities across Liaoning Province, China, from August to October 2021, using the multistage probability proportional to size sampling (PPS) method. The survey comprised 4,325 participants aged 15-69 and encompassed 37 core knowledge-based questions spanning five dimensions. Associations between sociodemographic factors and the cancer literacy rate were evaluated using chi-square tests and multivariate logistic regression model. Results: The overall cancer literacy rate was 66.9% (95% CI: 65.6-68.2%). In the primary indicators, cancer literacy were highest in treatment (75.8, 95% CI: 74.2-77.4%) and early detection (68.2, 95% CI: 66.8-69.6%), followed by basic knowledge (67.2, 95% CI: 65.8-68.6%), recovery (62.6, 95% CI: 60.7-64.5%) and prevention (59.7, 95% CI: 58.2-61.3%). Regarding secondary indicators, the awareness rates regarding cancer-related risk factors (54.7, 95% CI: 52.8-56.5%) and early diagnosis of cancer (54.6, 95% CI: 52.7-56.6%) were notably inadequate. Rural participates exhibited lower cancer literacy across all dimensions compared to urban. Multi-factor analysis showed that factors such as advanced age, limited education or low household income were barriers to health literacy in rural areas. Conclusion: Strengthening awareness concerning prevention and early detection, particularly among key populations, and bridging the urban-rural cancer literacy gap are imperative steps toward achieving the Healthy China 2030 target.

On-Chip Magnetic Extraction of Circulating Cell-Free DNA from Biological Samples.

In recent years, the analysis of circulating cell-free DNA (cfDNA) containing tumor-derived DNA has emerged as a noninvasive means for cancer monitoring and personalized medicine. However, the isolation of cfDNA from peripheral blood has remained a challenge due to the low abundance and high fragmentation of these molecules. Here, we present a dynamic Magnetic ExTRactiOn (METRO) protocol using microfluidic fluidized bed technology to isolate circulating cfDNA from raw biological materials such as undiluted serum. This protocol maximizes the surface area for DNA binding within the chip in order to capture short DNA fragments. It uses only a few µL of sample and reagents. The protocol can be automated, and it is fully compatible with sensitive DNA amplification methods such as droplet-based digital PCR (ddPCR).

Real-world implications of IMACS malignancy screening guidelines for idiopathic inflammatory myopathies: An evaluation of compliance and economic impact at a tertiary referral center.

AIM: An inaugural set of consensus guidelines for malignancy screening in idiopathic inflammatory myopathy (IIM) were recently published by an international working group. These guidelines propose different investigation strategies based on "high", "intermediate" or "standard" malignancy risk groups. This study compares current malignancy screening practices at an Australian tertiary referral center with the recommendations outlined in these guidelines. METHODS: We conducted a retrospective analysis of newly diagnosed IIM patients. Relevant demographic and clinical data regarding malignancy screening were recorded. Existing practice was compared with the guidelines using descriptive statistics; costs were calculated using the Australian Medicare Benefit Schedule. RESULTS: Of the 47 patients identified (66% female, median age: 63 years [IQR: 55.5-70], median disease duration: 4 years [IQR: 3-6]), only one had a screening-detected malignancy. Twenty patients (43%) were at high risk, while 20 (43%) were at intermediate risk; the remaining seven (15%) had IBM, for which the proposed guidelines do not recommend screening. Only three (6%) patients underwent screening fully compatible with International Myositis Assessment and Clinical Studies recommendations. The majority (N = 39, 83%) were under-screened; the remaining five (11%) overscreened patients had IBM. The main reason for guideline non-compliance was the lack of repeated annual screening in the 3 years post-diagnosis for high-risk individuals (0% compliance). The mean cost of screening was substantially lower than those projected by following the guidelines ($481.52 [SD 423.53] vs $1341 [SD 935.67] per patient), with the highest disparity observed in high-risk female patients ($2314.29/patient). CONCLUSION: Implementation of the proposed guidelines will significantly impact clinical practice and result in a potentially substantial additional economic burden.

The effect of local hospital waiting times on GP referrals for suspected cancer.

INTRODUCTION: Reducing waiting times is a major policy objective in publicly-funded healthcare systems. However, reductions in waiting times can produce a demand response, which may offset increases in capacity. Early detection and diagnosis of cancer is a policy focus in many OECD countries, but prolonged waiting periods for specialist confirmation of diagnosis could impede this goal. We examine whether urgent GP referrals for suspected cancer patients are responsive to local hospital waiting times. METHOD: We used annual counts of referrals from all 6,667 general practices to all 185 hospital Trusts in England between April 2012 and March 2018. Using a practice-level measure of local hospital waiting times based on breaches of the two-week maximum waiting time target, we examined the relationship between waiting times and urgent GP referrals for suspected cancer. To identify whether the relationship is driven by differences between practices or changes over time, we estimated three regression models: pooled linear regression, a between-practice estimator, and a within-practice estimator. RESULTS: Ten percent higher rates of patients breaching the two-week wait target in local hospitals were associated with higher volumes of referrals in the pooled linear model (4.4%; CI 2.4% to 6.4%) and the between-practice estimator (12.0%; CI 5.5% to 18.5%). The relationship was not statistically significant using the within-practice estimator (1.0%; CI -0.4% to 2.5%). CONCLUSION: The positive association between local hospital waiting times and GP demand for specialist diagnosis was caused by practices with higher levels of referrals facing longer local waiting times. Temporal changes in waiting times faced by individual practices were not related to changes in their referral volumes. GP referrals for diagnostic cancer services were not found to respond to waiting times in the short-term. In this setting, it may therefore be possible to reduce waiting times by increasing supply without consequently increasing demand.

Analytical validation of a novel comprehensive genomic profiling informed circulating tumor DNA monitoring assay for solid tumors.

Emerging technologies focused on the detection and quantification of circulating tumor DNA (ctDNA) in blood show extensive potential for managing patient treatment decisions, informing risk of recurrence, and predicting response to therapy. Currently available tissue-informed approaches are often limited by the need for additional sequencing of normal tissue or peripheral mononuclear cells to identify non-tumor-derived alterations while tissue-naïve approaches are often limited in sensitivity. Here we present the analytical validation for a novel ctDNA monitoring assay, FoundationOne®Tracker. The assay utilizes somatic alterations from comprehensive genomic profiling (CGP) of tumor tissue. A novel algorithm identifies monitorable alterations with a high probability of being somatic and computationally filters non-tumor-derived alterations such as germline or clonal hematopoiesis variants without the need for sequencing of additional samples. Monitorable alterations identified from tissue CGP are then quantified in blood using a multiplex polymerase chain reaction assay based on the validated SignateraTM assay. The analytical specificity of the plasma workflow is shown to be 99.6% at the sample level. Analytical sensitivity is shown to be >97.3% at ≥5 mean tumor molecules per mL of plasma (MTM/mL) when tested with the most conservative configuration using only two monitorable alterations. The assay also demonstrates high analytical accuracy when compared to liquid biopsy-based CGP as well as high qualitative (measured 100% PPA) and quantitative precision (<11.2% coefficient of variation).

Molecular methods in cancer diagnostics: a short review.

BACKGROUND: One of the ailments with the greatest fatality rates in the 21st century is cancer. Globally, molecular methods are widely employed to treat cancer-related disorders, and the body of research on this subject is growing yearly. A thorough and critical summary of the data supporting molecular methods for illnesses linked to cancer is required. OBJECTIVE: In order to guide clinical practice and future research, it is important to examine and summarize the systematic reviews (SRs) that evaluate the efficacy and safety of molecular methods for disorders associated to cancer. METHODS: We developed a comprehensive search strategy to find relevant articles from electronic databases like PubMed, Google Scholar, Web of Science (WoS), or Scopus. We looked through the literature and determined which diagnostic methods in cancer genetics were particularly reliable. We used phrases like 'cancer genetics', genetic susceptibility, Hereditary cancer, cancer risk assessment, 'cancer diagnostic tools', cancer screening', biomarkers, and molecular diagnostics, reviews and meta-analyses evaluating the efficacy and safety of molecular therapies for cancer-related disorders. Research that only consider treatment modalities that don't necessitate genetic or molecular diagnostics fall under the exclusion criteria. RESULTS: The results of this comprehensive review clearly demonstrate the transformative impact of molecular methods in the realm of cancer genetics.This review underscores how these technologies have empowered researchers and clinicians to identify and understand key genetic alterations that drive malignancy, ranging from point mutations to structural variations. Such insights are instrumental in pinpointing critical oncogenic drivers and potential therapeutic targets, thus opening the door for methods in precision medicine that can significantly improve patient outcomes. LIMITATION: The search does not specify a timeframe for publication inclusion, it may have missed recent advancements or changes in the field's landscape of molecular methods for cancer. As a result, it may not have included the most recent developments in the field. CONCLUSION: After conducting an in-depth study on the molecular methods in cancer genetics, it is evident that these cutting-edge technologies have revolutionized the field of oncology, providing researchers and clinicians with powerful tools to unravel the complexities of cancer at the genetic level. The integration of molecular methods techniques has not only enhanced our understanding of cancer etiology, progression, and treatment response but has also opened new avenues for personalized medicine and targeted therapies, leading to improved patient outcomes.

Radiopharmaceuticals for Cancer Diagnosis and Therapy: New Targets, New Therapies-Alpha-Emitters, Novel Targets.

ABSTRACT: Radiopharmaceutical therapy has emerged as a promising approach for the treatment of various cancers. The exploration of novel targets such as tumor-specific antigens, overexpressed receptors, and intracellular biomolecules using antibodies, peptides, or small molecules has expanded the scope of radiopharmaceutical therapy, enabling precise and effective cancer treatment for an increasing number of tumor types. Alpha emitters, characterized by their high linear energy transfer and short path length, offer unique advantages in targeted therapy due to their potent cytotoxicity against cancer cells while sparing healthy tissues. This article reviews recent advancements in identifying novel targets for radiopharmaceutical therapy and applications in utilizing α-emitters for targeted treatment.

Positron Emission Tomography Imaging of Tumor Proliferation and DNA Repair.

ABSTRACT: Positron emission tomography (PET) is an established tool for molecular imaging of cancers, and its role in diagnosis, staging, and phenotyping continues to evolve and expand rapidly. PET imaging of increased glucose utilization with 18F-fluorodeoxyglucose is now entrenched in clinical oncology practice for improving prognostication and treatment response assessment. Additional critical processes for cancer cell survival can also be imaged by PET, helping to inform individualized treatment selections for patients by improving our understanding of cell survival mechanisms and identifying relevant active mechanisms in each patient. The critical importance of quantifying cell proliferation and DNA repair pathways for prognosis and treatment selection is highlighted by the nearly ubiquitous use of the Ki-67 index, an established histological quantitative measure of cell proliferation, and BRCA mutation testing for treatment selection. This review focuses on PET advances in imaging and quantifying cell proliferation and poly(ADP-ribose)polymerase expression that can be used to complement cancer phenotyping approaches that will identify the most effective treatments for each individual patient.