Contemporary Oncology Research Articles

The Young: Early-Onset Colon Cancer

AbstractEarly-onset colorectal cancer (EO-CRC), characterized by diagnosis before the age of 50 years, has emerged as a significant healthcare challenge with increasing global incidence. While traditional risk factors such as family history and inherited syndromes contribute to EO-CRC, a substantial proportion of cases remain sporadic, necessitating further investigation into additional etiological factors. Molecular studies reveal heterogeneity in EO-CRC, with distinct mutational profiles compared to late-onset CRC. Clinical management presents unique considerations, including challenges in early detection and treatment strategies tailored to younger patients. Addressing EO-CRC requires a multidisciplinary approach integrating epidemiological, molecular, and clinical insights to improve prevention, diagnosis, and therapeutic outcomes. Emerging research avenues explore novel biomarkers and therapeutic targets, offering promise for advancing understanding and management of this disease in contemporary oncology practice.

A comprehensive analysis of patient demographics and disparities in contemporary oncology clinical trials (2022-2023).

e13748 Background: Overcoming disparities in cancer research is a major challenge that needs to be prioritized in clinical trials in oncology. In this study, we aimed to assess the current representation of patient demographics in phase 2 and 3 clinical trials in oncology to illuminate healthcare inequities during clinical trial recruitment. Methods: We identified published phase 2 and phase 3 oncology studies in five medical journals (New England Journal of Medicine, Journal of Clinical Oncology, Lancet, Lancet Oncology, and JAMA Oncology). We extracted data on patient demographics including sex, age, race, and ethnicity. We also extracted information on trial sponsorship (industry vs investigator initiated). Results: We included 381 articles published between 2022 and 2023 (108 investigator-initiated; 273 industry-sponsored). Details on age groups (<65 vs >65) were available in 149 studies (n=78,523 patients) including 47,192 (60.1%) < 65; and 31,331 (39.9%) >65. Data on gender were available in 373 studies (n=159,836 patients) including 73,308 (45.9%) males and 86,526 (54.1%) females (2 patients were listed as other). Race was reported in 214 studies (n=92,562) including 65,876 Caucasian (71.2%), 3,428 (3.7%) Black, 18,235 (19.7%) Asian, and 5,023 (5.4%) other/missing. Ethnicity data were available in 52 studies including 2,570 Hispanics (12.4%) and 18,234 non-Hispanics or unknown (87.6%). Conclusions: While there are efforts being made to diversify the recruitment of clinical trials, inequities in trial recruitment remains a major issue. Caucasian and younger patients represented the majority of patients, which may not be reflective of real-world practice. There is an important need to focus on increasing enrollment of underrepresented populations and understanding barriers to enrollment.

Is 18F-FDG-PET/CT an Optimal Imaging Modality for Detecting Immune-Related Adverse Events after Immune-Checkpoint Inhibitor Therapy? Pros and Cons.

Immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized contemporary oncology, presenting efficacy in various solid tumors and lymphomas. However, ICIs may potentially overstimulate the immune system, leading to immune-related adverse events (irAEs). IrAEs may affect multiple organs, such as the colon, stomach, small intestine, kidneys, skin, lungs, joints, liver, lymph nodes, bone marrow, brain, heart, and endocrine glands (e.g., pancreas, thyroid, or adrenal glands), exhibiting autoimmune inflammation. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is commonly used in oncology for staging and assessment of therapy responses, but it may also serve as a tool for detecting irAEs. This review aims to present various patterns of metabolic activation associated with irAEs due to ICI treatment, identifiable through 18F-FDG PET/CT. It describes the advantages of early detection of irAEs, but also presents the challenges in differentiating them from tumor progression. It also delves into aspects of molecular response assessment within the context of pseudoprogression and hyperprogression, along with typical imaging findings related to these phenomena. Lastly, it summarizes the role of functional PET imaging in oncological immunotherapy, speculating on its future significance and limitations.

Current advances in cancer treatment: A comprehensive review of therapeutic strategies and emerging innovations

Cancer stands as a pressing global health crisis, claiming one in every six lives across the world. The treatment of cancer has evolved into a remarkably intricate endeavour. In recent years, there have been significant advancements in the field of cancer treatment, alongside the longstanding methods of surgery, chemotherapy, and radiotherapy. In the realm of oncology, there has been a surge of innovative treatments, encompassing stem cell therapy, targeted therapy, ablation therapy, nanoparticles, natural antioxidants, radionics, chemo dynamic therapy, sonodynamic therapy, and ferroptosis-based therapy. Contemporary oncology is predominantly dedicated to the progression of cancer nanomedicines, with notable promise found in stem cell therapy, offering the potential to rejuvenate and mend afflicted tissues at both primary and metastatic cancer sites. Nanoparticles have ushered in new avenues for both diagnosis and treatment. Targeted therapy presents a groundbreaking strategy that hinders the proliferation and dissemination of particular cancer cells, while minimizing harm to healthy ones. Ablation therapy, characterized by its minimally invasive nature, enables the elimination of cancer using methods like controlled burning or freezing, eliminating the necessity for open surgery. In the ongoing pursuit of improved cancer therapies, numerous innovative technologies are currently undergoing clinical trials, and some have already gained approval. This review provides a comprehensive update on the recent advancements and breakthroughs in the realm of cancer treatment.

Knowledge mapping of immunotherapy for breast cancer: A bibliometric analysis from 2013 to 2022

ABSTRACT Breast cancer is the leading cause of cancer-related death among women globally. Immunotherapy has emerged as a major milestone in contemporary oncology. This study aims to conduct a bibliometric analysis in the field of immunotherapy for breast cancer, providing a comprehensive overview of the current research status, identifying trends and hotspots in research topics. We searched and retrieved data from the Web of Science Core Collection, and performed a bibliometric analysis of publications on immunotherapy for breast cancer from 2013 to 2022. Current status and hotspots were evaluated by co-occurrence analysis using VOSviewer. Evolution and bursts of knowledge base were assessed by co-citation analysis using CiteSpace. Thematic evolution by bibliometrix package was used to discover keywords trends. The attribution and collaboration of countries/regions, institutions and authors were also explored. A total of 7,975 publications were included. In co-occurrence analysis of keywords, 6 major clusters were revealed: tumor microenvironment, prognosis biomarker, immune checkpoints, novel drug delivery methods, immune cells and therapeutic approaches. The top three most frequently mentioned keywords were tumor microenvironment, triple-negative breast cancer, and programmed cell death ligand 1. The most productive country, institution and author were the USA (2926 publications), the University of Texas MD Anderson Cancer Center (219 publications), and Sherene Loi (28 publications), respectively. There has been a rapid growth in studies on immunotherapy for breast cancer worldwide. This research area has gained increasing attention from different countries and institutions. With the rising incidence of breast cancer, immunotherapy represents a research field of significant clinical value and potential.

The Use of Natural Language Processing Elements for Computer-Aided Diagnostics and Monitoring of Body Image Perception in Enterally Fed Patients with Head and Neck or Upper Gastrointestinal Tract Cancers.

Psycho-oncology care has emerged as a significant concern in contemporary oncology practice, given its profound impact on patient psychological well-being. Patients undergoing treatment for head-neck or upper gastrointestinal tract cancers often experience complex emotional and psychological challenges, necessitating specialized support and intervention. Traditional approaches to psycho-oncological care may be limited in their ability to comprehensively assess and address patients' needs. Therefore, exploring innovative methodologies, such as leveraging natural language processing (NLP) elements, is crucial to enhancing the effectiveness of psycho-oncological interventions. In this study, we developed a method utilizing natural language processing (NLP) elements to augment psycho-oncological care for patients with head-neck or upper gastrointestinal tract cancers. The method aimed to facilitate vocabulary, sentiment, and intensity analysis of five basic emotions (happiness, sadness, anger, disgust, and fear), as well as to explore potential areas of difficulty such as body image, pain, and self-esteem. We conducted research involving 50 patients across three treatment stages. Our method facilitated the identification of characteristic features at each treatment stage, aiding in the tailoring of appropriate therapies to individual patient needs. The results offer insights valuable to psychologists and psychiatrists for expedited diagnosis and intervention, potentially influencing therapy outcomes. Additionally, the data may inform treatment decisions by addressing patient-specific concerns. Furthermore, our method holds promise for optimizing the allocation of psychological care resources, particularly at the initial stages of patient contact. The main problem in the research was the fairly wide age range of participants, which explains the potential diversity of vocabulary. In conclusion, our study demonstrates the potential utility of integrating natural language processing (NLP) elements into psycho-oncological care for patients with head-neck or upper gastrointestinal tract cancers. The developed method offers a novel approach to comprehensively assessing patients' emotional states and areas of difficulty, thereby facilitating tailored interventions and treatment planning. These findings underscore the importance of continued research and innovation in psycho-oncology to enhance patient care and outcomes.

Dual Checkpoint Aptamer Immunotherapy: Unveiling Tailored Cancer Treatment Targeting CTLA-4 and NKG2A.

Recent strides in immunotherapy have illuminated the crucial role of CTLA-4 and PD-1/PD-L1 pathways in contemporary oncology, presenting both promises and challenges in response rates and adverse effects. This study employs a computational biology tool (in silico approach) to craft aptamers capable of binding to dual receptors, namely, inhibitory CTLA4 and NKG2A, thereby unleashing both T and NK cells and enhancing CD8+ T and NK cell functions for tumor cell lysis. Computational analysis highlighted AYA22T-R2-13 with HADDOCK scores of -78.2 ± 10.2 (with CTLA4), -60.0 ± 4.2 (with NKG2A), and -77.5 ± 5.6 (with CD94/NKG2A). Confirmation of aptamer binding to targeted proteins was attained via ELISA and flow cytometry methods. In vitro biological functionality was assessed using lactate dehydrogenase (LDH) cytotoxicity assay. Direct and competitive assays using ELISA and flow cytometry demonstrated the selective binding of AYA22T-R2-13 to CTLA4 and NKG2A proteins, as well as to the cell surface receptors of IL-2-stimulated T cells and NK cells. This binding was inhibited in the presence of competition from CTLA4 or NKG2A proteins. Remarkably, the blockade of CTLA4 or NKG2A by AYA22T-R2-13 augmented human CD8 T cell- and NK cell-mediated tumor cell lysis in vitro. Our findings highlight the precise binding specificity of AYA22T-R2-13 for CTLA4-B7-1/B7-2 (CD80/CD86) or CD94/NKG2A-HLA-E interactions, positioning it as a valuable tool for immune checkpoint blockade aptamer research in murine tumor models. These in vitro studies establish a promising foundation for further enhancing binding capacity and establishing efficacy and safety in animal models. Consequently, our results underscore the potential of AYA22T-R2-13 in cancer immunotherapy, offering high specificity, low toxicity, and the potential for cost-effective production.

Comprehensive analysis of nationwide anticancer drug-related complications in Korea: incidence, types, and cancer-specific considerations in contemporary oncology.

The rising global incidence of cancer has increased the demand for chemotherapy, which is a crucial treatment modality. Recent advancements in cancer treatment, including targeted agents and immunotherapy, have introduced complications owing to their specific mechanisms. However, comprehensive studies of the combined complications of these approaches are lacking. This study aimed to comprehensively assess and analyze the overall incidence of anticancer drug-related complications in a nationwide patient cohort, utilizing a customized National Health Insurance Sharing Service database in Korea. Retrospective cohort study. We included patients who were prescribed anticancer drugs (excluding endocrine agents) and diagnosed with cancer. For the type of cancer classification, the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) was used and anticancer drugs were classified based on the Anatomical Therapeutic Chemical code. We classified cancer into 18 types based on the ICD-10 code and delineated cancer-related complications into 12 categories. Complications included hematological, gastrointestinal, infectious, cardiovascular, major bleeding, endocrine, neurotoxic, nephrotoxic, dermatological, pulmonary, musculoskeletal, and hepatotoxic effects. We included 294,544 patients diagnosed with cancer and administered anticancer drugs between 2016 and 2018, with follow-up continuing until 2021. We identified 486,929 anticancer drug-related complications, with an incidence of 1843.6 per 1000 person-years (PY). Anemia was the most common complication, with a rate of 763.7 per 1000 PY, followed by febrile neutropenia (295.7) and nausea/vomiting (246.9). Several complications peaked during the first months following the initiation of anticancer drug therapy; however, herpes, skin infection, heart failure, and peripheral neuropathy peaked at 6-12 months. Among major cancers, breast cancer had the lowest overall incidence of complications. Targeted therapies revealed lower complication rates than cytotoxic chemotherapy; however, they also required careful monitoring of rash. This study highlights the importance of the proactive management of anticancer drug-related complications for patient care improvement.

Selected meeting abstracts of 2nd International Conference on Contemporary Oncology.

Selected meeting abstracts of 2nd International Conference on Contemporary Oncology.

Prevalence and implications of significance testing for baseline covariate imbalance in randomised cancer clinical trials: The Table 1 Fallacy

BackgroundThe ‘Table 1 Fallacy’ refers to the unsound use of significance testing for comparing the distributions of baseline variables between randomised groups to draw erroneous conclusions about balance or imbalance. We performed a cross-sectional study of the Table 1 Fallacy in phase III oncology trials. MethodsFrom ClinicalTrials.gov, 1877 randomised trials were screened. Multivariable logistic regressions evaluated predictors of the Table 1 Fallacy. ResultsA total of 765 randomised controlled trials involving 553,405 patients were analysed. The Table 1 Fallacy was observed in 25% of trials (188 of 765), with 3% of comparisons deemed significant (59 of 2353), approximating the typical 5% type I error assertion probability. Application of trial-level multiplicity corrections reduced the rate of significant findings to 0.3% (six of 2345 tests). Factors associated with lower odds of the Table 1 Fallacy included industry sponsorship (adjusted odds ratio [aOR] 0.29, 95% confidence interval [CI] 0.18–0.47; multiplicity-corrected P < 0.0001), larger trial size (≥795 versus <280 patients; aOR 0.32, 95% CI 0.19–0.53; multiplicity-corrected P = 0.0008), and publication in a European versus American journal (aOR 0.06, 95% CI 0.03–0.13; multiplicity-corrected P < 0.0001). ConclusionsThis study highlights the persistence of the Table 1 Fallacy in contemporary oncology randomised controlled trials, with one of every four trials testing for baseline differences after randomisation. Significance testing is a suboptimal method for identifying unsound randomisation procedures and may encourage misleading inferences. Journal-level enforcement is a possible strategy to help mitigate this fallacy.

Basal Cell Carcinoma After High Dose Rate Brachytherapy: Medium-term Dermoscopic Evaluation of Cancer's Response.

Basal cell carcinoma of the facial region remains a challenge for contemporary oncology due to the presence of aesthetic regions and critical organs. Surgery is not always the optimal solution, and high dose rate (HDR) brachytherapy has emerged as an organ-sparing treatment method whose effectiveness has been proven by a growing number of publications. Dermoscopy is a diagnostic tool that bridges clinical and pathological examination of skin lesions. It is routinely used for diagnosis, monitoring of treatment, and post-treatment evaluation; however, the literature lacks data concerning changes in dermoscopic patterns of skin cancers during and after irradiation. Our team conducted a prospective non-randomized trial of 39 patients with high-risk basal cell carcinomas (BCCs), mostly localized within the high-risk zone (H-zone) of the facial region, and who qualified for HDR brachytherapy. HDR contact brachytherapy with custom-made surface molds was introduced, delivering a dose of 45Gy in 9 fractions prescribed to the tumor. Every patient was observed clinically and dermoscopically at three observational points: before treatment, at the end of treatment (3rd week), and 24weeks after the end of therapy. The evolution of clinical and dermoscopic patterns was observed by two independent dermoscopists using current diagnostic criteria. A database of 12,088 photographic observations was evaluated. Univariate logistic regression proved that brachytherapy decreases the number of clinical and dermoscopic patterns typical for basal cell carcinoma, as well as dermoscopic features not related to BCC, presumably due to the formation of scar tissue. In addition, univariate logistic regression with random effects proved a positive correlation between tumor size and presence of various dermoscopic patterns typical for BCC. Dermoscopy is proven to be easy to perform and an adequate monitoring tool for patients with BCCs undergoing HDR brachytherapy.

Integration of single-cell RNA sequencing and spatial transcriptomics to reveal the glioblastoma heterogeneity.

Glioblastoma (GBM), a deadly brain tumor, is still one of a few lasting challenges of contemporary oncology. Current therapies fail to significantly improve patient survival due to GBM tremendous genetic, transcriptomic, immunological, and sex-dependent heterogeneity. Over the years, clinical differences between males and females were characterized. For instance, higher incidence of GBM in males or distinct responses to cancer chemotherapy and immunotherapy between males and females have been noted. Despite the introduction of single-cell RNA sequencing and spatial transcriptomics, these differences were not further investigated as studies were focused only on revealing the general picture of GBM heterogeneity. Hence, in this mini-review, we summarized the current state of knowledge on GBM heterogeneity revealed by single-cell RNA sequencing and spatial transcriptomics with regard to genetics, immunology, and sex-dependent differences. Additionally, we highlighted future research directions which would fill the gap of knowledge on the impact of patient's sex on the disease outcome.

The Role of Alpha-Fetoprotein (AFP) in Contemporary Oncology: The Path from a Diagnostic Biomarker to an Anticancer Drug.

This article presents contemporary opinion on the role of alpha-fetoprotein in oncologic diagnostics and treatment. This role stretches far beyond the already known one-that of the biomarker of hepatocellular carcinoma. The turn of the 20th and 21st centuries saw a significant increase in knowledge about the fundamental role of AFP in the neoplastic processes, and in the induction of features of malignance and drug resistance of hepatocellular carcinoma. The impact of AFP on the creation of an immunosuppressive environment for the developing tumor was identified, giving rise to attempts at immunotherapy. The paper presents current and prospective therapies using AFP and its derivatives and the gene therapy options. We directed our attention to both the benefits and risks associated with the use of AFP in oncologic therapy.

Pyramidal Decision Support Framework Leverages Subspecialty Expertise across Enterprise to Achieve Superior Cancer Outcomes and Personalized, Precision Care Plans.

The complexity of cancer care requires integrated and continuous support to deliver appropriate care. An expert network with complementary expertise and the capability of multidisciplinary care is an integral part of contemporary oncology care. Appropriate infrastructure is necessary to empower this network to deliver personalized precision care to their patients. Providing decision support as cancer care becomes exponentially more complex with new diagnostic and therapeutic choices remains challenging. City of Hope has developed a Pyramidal Decision Support Framework to address these challenges, which were exacerbated by the COVID pandemic, health plan restrictions, and growing geographic site diversity. Optimizing efficient and targeted decision support backed by multidisciplinary cancer expertise can improve individual patient treatment plans to achieve improved care and survival wherever patients are treated.

Assessment of added activity of an antitumor agent

An unprecedented number of novel oncology drugs are under preclinical and clinical development, and nearly all are developed in combinations. With an over-reliance on biological hypotheses, there is less effort to establish single agent activity before initiating late clinical development. This may be contributing to a decreased success rate going from phase 1 to approval in the immunotherapy era. Growing evidence in clinical trial data shows that the treatment benefit from most approved combination therapies can be explained by the independent drug action model. Using this working model, we develop a simple index to measure the added antitumor activity of a new drug based on mean response duration, an endpoint that naturally combines both response status and duration information for all patients, which is shown to be highly predictive of clinical benefit of FDA-approved anti-PD-(L)1 immunotherapies. This index sheds light on challenges and opportunities in contemporary oncology drug development and provides a practical tool to assist with decision-making in early clinical trials.

Immune Checkpoint Inhibitors and Novel Immunotherapy Approaches for Breast Cancer.

To critically review the existing evidence on immune checkpoint inhibitors (ICIs) in early-stage and metastatic breast cancer and discuss emerging strategies in the different breast cancer subtypes. Immunotherapy has become one of the major milestones in contemporary oncology, revolutionizing the treatment of multiple solid tumors. ICI agents combined with chemotherapy have demonstrated significant efficacy in both early-stage and metastatic triple-negative breast cancer. However, only a subgroup of patients responds to those agents and some associated toxicities, although infrequent, can be life-disabling. Emerging data from immunotherapy studies in advanced hormone receptor-positive (HR +) breast cancer as well as HER2-positive disease are arising with mixed results. Although breast cancer has not classically been considered a hot tumor, ICIs have proven to be effective in a subset of breast cancer patients. However, much remains to be learned, and the identification of new biomarkers beyond PD-L1 expression is essential not only to improve the efficacy of ICI but also to identify patients who can avoid them, together with their toxicities and costs.

Integration of single-cell RNA sequencing and spatial transcriptomics to reveal the glioblastoma heterogeneity.

Glioblastoma (GBM), a deadly brain tumor, is still one of the few lasting challenges of contemporary oncology. Current therapies fail to significantly improve patient survival due to GBM's tremendous genetic, transcriptomic, immunological, and sex-dependent heterogeneity. Over the years, clinical differences between males and females were characterized. For instance, higher incidence of GBM in males or distinct responses to cancer chemotherapy and immunotherapy between males and females have been noted. However, despite the introduction of single-cell RNA sequencing and spatial transcriptomics, these differences were not further investigated as studies were focused only on exposing the general picture of GBM heterogeneity. Hence, in this study, we summarized the current state of knowledge on GBM heterogeneity exposed by single-cell RNA sequencing and spatial transcriptomics with regard to genetics, immunology, and sex-dependent differences. Additionally, we highlighted future research directions which would fill the gap of knowledge on the impact of patient's sex on the disease outcome.

5-ALA Is a Potent Lactate Dehydrogenase Inhibitor but Not a Substrate: Implications for Cell Glycolysis and New Avenues in 5-ALA-Mediated Anticancer Action.

Simple SummaryIn the present work, we found that 5-ALA, a natural precursor of heme, can hinder cell glycolysis, which is the main path of energy production for most cancer cells. More specifically, we found that 5-ALA can block an enzyme involved in glycolysis, called lactate dehydrogenase (LDH). We found that 5-ALA has a potency of LDH inhibition comparable to other established LDH inhibitors, such as oxamate or tartronic acid. Nevertheless, 5-ALA has a high accumulation rate in cancers and specifically in the incurable brain cancer glioblastoma multiforme (GBM), which is an important advantage. In fact, because of its high specificity to GBM, 5-ALA is used in the clinic to accurately guide the resection of the tumours, through the light emission of its photoactive product protoporphyrin IX (PpIX). PpIX is the penultimate step in the heme production. Importantly, we show here that continuous administration of 5-ALA killed GBM cells according to their dependence on glycolysis. We additionally found that 20% of externally administered 5-ALA is engaged in the inhibition of LDH, as when LDH was pre-loaded by another inhibitor, tartronic acid, then the cell production of PpIX from 5-ALA was increased by 20%. Since PpIX is an important drug for photodynamic therapy of cancer (excitation by light of PpIX produces oxygen by-products that can kill cancer cells), we additionally discovered that preloading LDH with its inhibitor tartronic acid before performing 5-ALA PDT increases the cancer cell death by 15%.In a course of metabolic experiments, we determined that the addition of δ-aminolevulinic acid (5-ALA) to a panel of glioblastoma multiforme (GBM) cells caused a steep reduction in their glycolytic activity. This reduction was accompanied by a decrease in adenosine triphosphate (ATP) production from glycolysis. These results suggested that 5-ALA is an inhibitor of glycolysis; due to the structural similarity of 5-ALA to the established lactate dehydrogenase (LDH) inhibitors oxamate (OXM) and tartronate (TART), we initially investigated LDH inhibition by 5-ALA in silico. The modelling revealed that 5-ALA could indeed be a competitive inhibitor of LDH but not a substrate. These theoretical findings were corroborated by enzymatic and cell lysate assays in which 5-ALA was found to confer a potent LDH inhibition comparable to that of OXM and TART. We subsequently evaluated the effect of 5-ALA-induced glycolysis inhibition on the viability of GBM cells with diverse metabolic phenotypes. In the Warburg-type cell lines Ln18 and U87, incubation with 5-ALA elicited profound and irreversible cell death (90–98%) at 10 mM after merely 24 h. In T98G, however, which exhibited both high respiratory and glycolytic rates, LD95 was achieved after 72 h of incubation with 20 mM 5-ALA. We additionally examined the production of the 5-ALA photosensitive metadrug protoporphyrin IX (PpIX), with and without prior LDH inhibition by TART. These studies revealed that ~20% of the 5-ALA taken up by the cells was engaged in LDH inhibition. We subsequently performed 5-ALA photodynamic therapy (PDT) on Ln18 GBM cells, again with and without prior LDH inhibition with TART, and found a PDT outcome enhancement of ~15% upon LDH pre-inhibition. We expect our findings to have a profound impact on contemporary oncology, particularly for the treatment of otherwise incurable brain cancers such as GBM, where the specific accumulation of 5-ALA is very high compared to the surrounding normal tissue.

Designing phase I oncology dose escalation using dose-exposure-toxicity models as a complementary approach to model-based dose-toxicity models.

One of the objectives of oncology phase I dose‐escalation studies has been to determine the maximum tolerated dose (MTD). Although MTD is no longer set as the dose for further development in contemporary oncology drug development, MTD determination is still important for informing the therapeutic index. Bayesian adaptive model‐based designs are becoming mainstream in oncology first‐in‐human trials. Herein, we illustrate via simulations the use of systemic exposure in Bayesian adaptive dose–toxicity models to estimate MTD. We extend traditional dose–toxicity models to incorporate pharmacokinetic exposure, which provides information on exposure–toxicity relationships. We pursue dose escalation until the maximum tolerated exposure (corresponding to the MTD) is reached. By leveraging pharmacokinetics, dose escalation considers exposure and interindividual variability on a continuous rather than discrete domain, offering additional information for dose‐escalation decisions. To demonstrate this, we generated 1000 simulations (starting dose of 1/25th the reference dose and six dose levels) for several different scenarios. Both rule‐based and model‐based designs were compared using metrics of potential safety, accuracy, and reliability. The mean results over simulations and different toxicity scenarios showed that model‐based designs were better than rule‐based methods and that exposure–toxicity model‐based methods have the potential to valuably complement dose–toxicity model‐based methods. Exposure–toxicity model‐based methods had decreased underdose risk accompanied by a relatively smaller increase in overdose risk, resulting in improved net reliability. MTD estimation accuracy was compromised when exposure variability was large, emphasizing the importance of appropriate control of pharmacokinetic variability in phase I dose‐escalation studies.

Milestones in Hematology and Oncology: From Fatal to Curable Disease.

Background: The comprehensive management of patients with Hodgkin's lymphoma (HL) is a success story in contemporary oncology. Over the past decades, the survival rate of patients with HL has significantly improved. The objective of this analysis is to evaluate and document the progress in the management of Hodgkin's lymphoma in patients in our country, reflected in their vital statistics, over time periods defined by the respective standard of treatment. Material and methods: The present study is designed as a retrospective-prospective study. We analyzed different modalities of treatment and compared 5 and 10-year overall survival rates in a total of 588 Hodgkin's lymphoma patients treated at the University Clinic for Hematology in Skopje during two consecutive time periods, before 2000 and after 2000. The entire observation period is from 1980 to 2020. All patients are above the age of 14, with a documented histopathological diagnosis of Hodgkin's lymphoma and with evaluable medical documentation, including clinical and laboratory data on their initial condition, the administered therapy, as well as the clinical follow-up of the patients. Results: The basic clinical features of the analyzed population across the two periods correlate with those reported in the relevant medical literature, with only slight deviations. Ten-year overall survival rates improved by 31.7% through the two calendar periods. During the last two decades of the previous century (1980-2000) the initial treatment options were COPP and COPP-like regimens for the vast majority of patients (94.7%), leading to disease remission in 80% of them. After 2000, 95.8% of de novo diagnosed patients have been treated with ABVD chemotherapy as a frontline choice and the complete response rate is 88.4%. We confirmed the superiority of ABVD in terms of efficacy, improved tumor and disease control, as well as its long-term clinical outcome. While in the past we had very limited options for relapsed/refractory HL patients, the analysis of the results of HL patients treated with various therapeutic approaches in the latter period, defines BEACOPP as the preferred choice. High-dose chemotherapy, followed by autologous hematopoietic stem cell graft, as a strategy for our R/R patients in the timeframe after 2000, ensures a 5-year overall survival for 51% of them, whereas 45% of the patients survive more than 10 years. Conclusion: This analysis from our Hodgkin's lymphoma database illustrates that there has been tremendous improvement in the long-term survival rates since the turn of this century. At our institution we strive to implement positive trends in practice, as suggested by relevant guidelines, regarding the evolution and progress in the diagnostic workup, treatment, and the overall management of patients with Hodgkin's disease. The objective would be to secure favorable vital statistics for our patient population, now reaching 83.5% at 10 years, which closely correlates with the data of more developed countries and centers. In future clinical trials we will also evaluate the efficacy of brentuximab-vedotin and new PD-1 blocking antibodies.