Advances In Clinical Oncology Research Articles

Two decades of advances in clinical oncology - lessons learned and future directions.

Two decades of advances in clinical oncology - lessons learned and future directions.

Leveraging State-of-the-Art AI Algorithms in Personalized Oncology: From Transcriptomics to Treatment

Background: Continuous breakthroughs in computational algorithms have positioned AI-based models as some of the most sophisticated technologies in the healthcare system. AI shows dynamic contributions in advancing various medical fields involving data interpretation and monitoring, imaging screening and diagnosis, and treatment response and survival prediction. Despite advances in clinical oncology, more effort must be employed to tailor therapeutic plans based on each patient’s unique transcriptomic profile within the precision/personalized oncology frame. Furthermore, the standard analysis method is not compatible with the comprehensive deciphering of significant data streams, thus precluding the prediction of accurate treatment options. Methodology: We proposed a novel approach that includes obtaining different tumour tissues and preparing RNA samples for comprehensive transcriptomic interpretation using specifically trained, programmed, and optimized AI-based models for extracting large data volumes, refining, and analyzing them. Next, the transcriptomic results will be scanned against an expansive drug library to predict the response of each target to the tested drugs. The obtained target-drug combination/s will be then validated using in vitro and in vivo experimental models. Finally, the best treatment combination option/s will be introduced to the patient. We also provided a comprehensive review discussing AI models’ recent innovations and implementations to aid in molecular diagnosis and treatment planning. Results: The expected transcriptomic analysis generated by the AI-based algorithms will provide an inclusive genomic profile for each patient, containing statistical and bioinformatics analyses, identification of the dysregulated pathways, detection of the targeted genes, and recognition of molecular biomarkers. Subjecting these results to the prediction and pairing AI-based processes will result in statistical graphs presenting each target’s likely response rate to various treatment options. Different in vitro and in vivo investigations will further validate the selection of the target drug/s pairs. Conclusions: Leveraging AI models will provide more rigorous manipulation of large-scale datasets on specific cancer care paths. Such a strategy would shape treatment according to each patient’s demand, thus fortifying the avenue of personalized/precision medicine. Undoubtedly, this will assist in improving the oncology domain and alleviate the burden of clinicians in the coming decade.

Tumor Anti-angiogenesis: Nano-Arsenal will Kill the Crab

Angiogenesis: the process of developing new blood vessels from the pre-existing ones is a very crucial process in tumor formation, growth, progression and metastasis. The central role of angiogenesis in tumor growth and progression compels targeting tumor vasculature as a therapeutic mean. Nanoparticles have revolutionized the domain of cancer therapeutics, molecularly targeted anti-cancer drugs represents one of the most significant recent advances in clinical oncology. Various types of nano-drug complexes which targets tumor vasculature preferentially, are being increasingly tested for optimal therapeutic efficacy and minimal side-effects. Here, we review some of these anti-angiogenic nano-drug complexes.

Steatosis, Steatohepatitis and Cancer Immunotherapy: An Intricate Story.

Immune checkpoint inhibitors represent one of the most significant recent advances in clinical oncology, since they dramatically improved the prognosis of deadly cancers such as melanomas and lung cancer. Treatment with these drugs may be complicated by the occurrence of clinically-relevant adverse drug reactions, most of which are immune-mediated, such as pneumonitis, colitis, endocrinopathies, nephritis, Stevens Johnson syndrome and toxic epidermal necrolysis. Drug-induced steatosis and steatohepatitis are not included among the typical forms of cancer immunotherapy-induced liver toxicity, which, instead, usually occurs as a panlobular hepatitis with prominent lymphocytic infiltrates. Nonetheless, non-alcoholic fatty liver disease is a risk factor for immunotherapy-induced hepatitis, and steatosis and steatohepatitis are frequently observed in this condition. In the present review we discuss how these pathology findings could be explained in the context of current models suggesting immune-mediated pathogenesis for steatohepatitis. We also review evidence suggesting that in patients with hepatocellular carcinoma, the presence of steatosis or steatohepatitis could predict a poor therapeutic response to these agents. How these findings could fit with immune-mediated mechanisms of these liver diseases will also be discussed.

Hedgehog-induced PD-L1 on tumor-associated macrophages is critical for suppression of tumor-infiltrating CD8+ T cell function.

The programmed death-1 (PD-1) and the PD ligand 1 (PD-L1) interaction represents a key immune checkpoint within the tumor microenvironment (TME), and PD-1 blockade has led to exciting therapeutic advances in clinical oncology. Although IFN-γ–dependent PD-L1 induction on tumor cells was initially thought to mediate the suppression on effector cells, recent studies have shown that PD-L1 is also expressed at high level on tumor-associated macrophages (TAMs) in certain types of tumors. However, the precise role of PD-L1 expression on TAMs in suppressing antitumor immunity within the TME remains to be defined. Using a myeloid-specific Pdl1-knockout mouse model, here we showed definitive evidence that PD-L1 expression on TAMs is critical for suppression of intratumor CD8+ T cell function. We further demonstrated that tumor-derived Sonic hedgehog (Shh) drives PD-L1 expression in TAMs to suppress tumor-infiltrating CD8+ T cell function, leading to tumor progression. Mechanistically, Shh-dependent upregulation of PD-L1 in TAMs is mediated by signal transducer and activator of transcription 3, a cascade that has not been previously reported to our knowledge. Last, single-cell RNA sequencing analysis of human hepatocellular carcinoma revealed that PD-L1 is mainly expressed on M2 TAMs, supporting the clinical relevance of our findings. Collectively, our data revealed an essential role for Shh-dependent PD-L1 upregulation in TAMs in suppressing antitumor immunity within the TME, which could lead to the development of new immunotherapeutic strategies for treating cancer.

Exercise Oncology and Immuno-Oncology; A (Future) Dynamic Duo.

Recent advances in clinical oncology is based on exploiting the capacity of the immune system to combat cancer: immuno-oncology. Thus, immunotherapy of cancer is now used to treat a variety of malignant diseases. A striking feature is that even patients with late-stage disease may experience curative responses. However, most patients still succumb to disease, and do not benefit from treatment. Exercise has gained attention in clinical oncology and has been used for many years to improve quality of life, as well as to counteract chemotherapy-related complications. However, more recently, exercise has garnered interest, largely due to data from animal studies suggesting a striking therapeutic effect in preclinical cancer models; an effect largely mediated by the immune system. In humans, physical activity is associated with a lower risk for a variety of malignancies, and some data suggest a positive clinical effect for cancer patients. Exercise leads to mobilization of cells of the immune system, resulting in redistribution to different body compartments, and in preclinical models, exercise has been shown to lead to immunological changes in the tumor microenvironment. This suggests that exercise and immunotherapy could have a synergistic effect if combined.

Multiclonal tumor origin: Evidence and implications.

An accurate understanding of the clonal origins of tumors is critical for designing effective strategies to treat or prevent cancer and for guiding the field of cancer risk assessment. The intent of this review is to summarize evidence of multiclonal tumor origin and, thereby, contest the commonly held assumption of monoclonal tumor origin. This review describes relevant studies of X chromosome inactivation, analyses of tumor heterogeneity using other markers, single cell sequencing, and lineage tracing studies in aggregation chimeras and engineered rodent models. Methods for investigating tumor clonality have an inherent bias against detecting multiclonality. Despite this, multiclonality has been observed within all tumor stages and within 53 different types of tumors. For myeloid tumors, monoclonal tumor origin may be the predominant path to cancer and a monoclonal tumor origin cannot be ruled out for a fraction of other cancer types. Nevertheless, a large body of evidence supports the conclusion that most cancers are multiclonal in origin. Cooperation between different cell types and between clones of cells carrying different genetic and/or epigenetic lesions is discussed, along with how polyclonal tumor origin can be integrated with current perspectives on the genesis of tumors. In order to develop biologically sound and useful approaches to cancer risk assessment and precision medicine, mathematical models of carcinogenesis are needed, which incorporate multiclonal tumor origin and the contributions of spontaneous mutations in conjunction with the selective advantages conferred by particular mutations and combinations of mutations. Adherence to the idea that a growth must develop from a single progenitor cell to be considered neoplastic has outlived its usefulness. Moving forward, explicit examination of tumor clonality, using advanced tools, like lineage tracing models, will provide a strong foundation for future advances in clinical oncology and better training for the next generation of oncologists and pathologists.

Multifaceted Interpretation of Colon Cancer Stem Cells.

Colon cancer is one of the leading causes of cancer-related deaths worldwide, despite recent advances in clinical oncology. Accumulating evidence sheds light on the existence of cancer stem cells and their role in conferring therapeutic resistance. Cancer stem cells are a minor fraction of cancer cells, which enable tumor heterogeneity and initiate tumor formation. In addition, these cells are resistant to various cytotoxic factors. Therefore, elimination of cancer stem cells is difficult but essential to cure the malignant foci completely. Herein, we review the recent evidence for intestinal stem cells and colon cancer stem cells, methods to detect the tumor-initiating cells, and clinical significance of cancer stem cell markers. We also describe the emerging problems of cancer stem cell theory, including bidirectional conversion and intertumoral heterogeneity of stem cell phenotype.

In vitro inhibition of angiogenesis by heat and low pH stable hydroalcoholic extract of Peganum harmala seeds via inhibition of cell proliferation and suppression of VEGF secretion

Context: Progression of cancer cells is completely dependent on its angiogenesis. Inhibition of tumor angiogenesis has shed new light on cancer treatment. As a result, anti-angiogenesis therapy represents one of the most significant advances in clinical oncology. Peganum harmala L. (Zygophyllaceae) is a native plant from the eastern Iranian region, which is used as a traditional folk medicine. Although some biological properties of this plant are determined, its effect on angiogenesis is still unclear.Objective: We investigated the anti-angiogenic effects of heat and low pH stable hydroalcoholic extract of P. harmala seeds on endothelial cells (ECs) proliferation and VEGF secretion.Materials and methods: Dried Peganum seeds were purchased from Kermanshah Traditional Bazar in 2011. Hydroalcoholic extract of dried seeds (0, 10, 20, 40, 60, 80, 100, 120, and 150 μg/ml) was used for in vitro evaluation of its cytotoxicity, anti-proliferative, and anti-angiogenic effects on ECs. In vitro effect of the extract on VEGF secretion was assayed using ELISA.Results: Treatment with hydroalcoholic extract at seven different concentrations resulted in significant decrease of ECs proliferation and angiogenesis with an ID50 of ∼85 μg/ml. VEGF secretion was (inhibited) decreased by the extracts at concentrations higher than 10 μg/ml.Discussion and conclusion: Herbal plant extracts still attract attention owing to their fewer side effects comparing to synthetic drug agents. Current study indicated that hydroalcoholic extract of P. harmala seeds contains a potent anti-angiogenic component, which exerts its inhibitory effect mainly through down-regulation of essential mediators such as VEGF.

The NCI Alliance for Nanotechnology in Cancer: achievement and path forward

Nanotechnology is a 'disruptive technology', which can lead to a generation of new diagnostic and therapeutic products, resulting in dramatically improved cancer outcomes. The National Cancer Institute (NCI) of National Institutes of Health explores innovative approaches to multidisciplinary research allowing for a convergence of molecular biology, oncology, physics, chemistry, and engineering and leading to the development of clinically worthy technological approaches. These initiatives include programmatic efforts to enable nanotechnology as a driver of advances in clinical oncology and cancer research, known collectively as the NCI Alliance for Nanotechnology in Cancer (ANC). Over the last 5 years, ANC has demonstrated that multidisciplinary approach catalyzes scientific developments and advances clinical translation in cancer nanotechnology. The research conducted by ANC members has improved diagnostic assays and imaging agents, leading to the development of point-of-care diagnostics, identification and validation of numerous biomarkers for novel diagnostic assays, and the development of multifunctional agents for imaging and therapy. Numerous nanotechnology-based technologies developed by ANC researchers are entering clinical trials. NCI has re-issued ANC program for next 5 years signaling that it continues to have high expectations for cancer nanotechnology's impact on clinical practice. The goals of the next phase will be to broaden access to cancer nanotechnology research through greater clinical translation and outreach to the patient and clinical communities and to support development of entirely new models of cancer care.

P15 Clinical and dermoscopical diagnosis of micro-melanoma

Melanoma Research is a well established international forum for the dissemination of new findings relating to melanoma. The aim of the Journal is to promote the level of informational exchange between those engaged in the field. Melanoma Research aims to encourage an informed and balanced view of experimental and clinical research and extend and stimulate communication and exchange of knowledge between investigators with differing areas of expertise. This will foster the development of translational research. The reporting of new clinical results and the effect and toxicity of new therapeutic agents and immunotherapy will be given emphasis by rapid publication of Short Communications. ​Thus, Melanoma Research seeks to present a coherent and up-to-date account of all aspects of investigations pertinent to melanoma. Consequently the scope of the Journal is broad, embracing the entire range of studies from fundamental and applied research in such subject areas as genetics, molecular biology, biochemistry, cell biology, photobiology, pathology, immunology, and advances in clinical oncology influencing the prevention, diagnosis and treatment of melanoma.

What’s new in clinical oncology?

This review summarizes the major advances in clinical oncology presented at the 2009 ASCO annual meeting, with emphasis on studies that are potentially practice-changing. Emerging new drugs are also discussed.

The Case for Observational Management of Suspected Small Choroidal Melanoma

I N DECEMBER 1997, THE ARCHIVES reported the outcome of the Collaborative Ocular Melanoma Study small tumor observational study documenting factors predictive of growth and treatment in this multicenter clinical trial. Accompanying that issue was an editorial that delineated the pros and cons to observation vs early treatment for small choroidal melanoma. In that editorial, an argument was made for a randomized clinical trial to definitively address the critical clinical question, “Do I treat now or do I wait?” Now approaching the latter half of a decade from this discussion, we as the ophthalmologists managing patients with suspected small choroidal melanomas are still faced with the dilemma as to the best treatment approach for these patients. Recent advances in clinical oncology and in ocular oncology have focused on delivering early, targeted, definitive therapy to primary malignancies. Cutaneous melanoma management has benefited from aggressive screening programs to identify suspicious lesions, to evaluate these lesions with new imaging techniques, and to excisionally manage atypical lesions to prevent progression and increased risk of tumor metastasis. The ease of identification and monitoring of cutaneous lesions has improved the early detection of stage I cutaneous melanoma and enhanced longterm survival. Recent histopathologic classification for cutaneous melanoma has noted significant decrease in mortality as a factor of tumor thickness. For cutaneous malignant melanoma undergoing excisional surgery, patient survival is 90% for lesions less than 0.76 mm in thickness, 79% for lesions 0.76 to 1.50 mm in thickness, and 62% for lesions 1.51 to 2.50 mm in thickness. Using this analysis, one could argue to remove all pigmented cutaneous lesions, but the significant caveat is that this study included only lesions undergoing excision and having malignant histopathology. Nonetheless, cutaneous melanoma differs significantly from ocular melanoma in its patterns of growth, vascularity, immunologic profile, sites for metastasis, and response to treatment. Ocular melanoma is clearly a distinct entity that requires independent evaluation as a unique tumor type. The National Eye Institute and National Cancer Institute (Bethesda, Md) devoted significant resources to the Collaborative Ocular Melanoma Study, targeting randomized evaluations for treatment of medium and large choroidal melanoma. These studies documented no benefit to pre-enucleation radiation therapy followed by enucleation for large choroidal melanoma and no benefit of enucleation relative to globeconserving brachytherapy in medium choroidal melanoma. Further, this study documented melanomaspecific 5-year mortality rates of 27% and 10%, respectively, for large and medium choroidal melanoma. The Collaborative Ocular Melanoma Study small tumor observational study included 204 patients with tumors between 1.0 and 3.0 mm in apical height and 5.0 and 16.0 mm in largest basal dimension. This observational study noted a 5-year documented tumor growth rate of 31% and a 5-year melanomaspecific mortality rate of 1.0% and defined features predictive of tumor growth to include larger tumor size, presence of orange pigment, absence of drusen, and absence of retinal pigment epithelium alterations adjacent to the small choroidal tumor. This observational study was devised to provide a framework for a small tumor randomized clinical trial to evaluate immediate vs deferred treatment for globe-conserving therapy. In the absence of clinical trials data, the clinician must use his or her best judgment from existing information, focusing on the best evidencebased data. Theophthalmologicmanagement ofsuspectedsmallchoroidalmelanoma isuniqueinseveralways,includingthe inability toadequatelyexciseatypical choroidal lesions, thevariationwithin thesesmall lesionsonhistopathologic review precluding effective nonexcisional biopsy, the potential for vision andglobecompromisewithdefinitive therapy(retinopathy,neuropathy),and the extremely low mortality rates associatedwiththemanagementofsmall choroidal malignant melanoma. The issueofmanaging these lesions is criticalbecauseapproximately10%of the population harbor 1 or more pigmented choroidal lesions (typically evaluatedwithinanon-Hispanicwhite population study). Several advances in the clinical management of intraocular lesions have come to the forefront over the last decade, including enhanced ocular imaging with digital photography(Panoret,Medibell,YoqneamIpit, Israel; RetCam, Clarity Medical SysAuthor Affiliations: Ocular Oncology Service, Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Fla (Dr Murray); and Massachusetts Eye and Ear Infirmary, Boston (Dr Sobrin).

Free radical theory of autoimmunity

BackgroundDespite great advances in clinical oncology, the molecular mechanisms underlying the failure of chemotherapeutic intervention in treating lymphoproliferative and related disorders are not well understood.HypothesisA hypothetical scheme to explain the damage induced by chemotherapy and associated chronic oxidative stress is proposed on the basis of published literature, experimental data and anecdotal observations. Brief accounts of multidrug resistance, lymphoid malignancy, the cellular and molecular basis of autoimmunity and chronic oxidative stress are assembled to form a basis for the hypothesis and to indicate the likelihood that it is valid in vivo.ConclusionThe argument set forward in this article suggests a possible mechanism for the development of autoimmunity. According to this view, the various sorts of damage induced by chemotherapy have a role in the pattern of drug resistance, which is associated with the initiation of autoimmunity.

Recent advances in clinical oncology 1. C. J. Williams and J. M. A. Whitehouse. 230 × 155 mm. Pp. 405 + xiii. Illustrated. 1982. Edinburgh: Churchill Livingstone. £19·50

Recent advances in clinical oncology 1. <i>C. J. Williams and J. M. A. Whitehouse. 230 × 155 mm. Pp. 405 + xiii. Illustrated. 1982. Edinburgh: Churchill Livingstone. £19·50</i>

A relationship between ethics of clinical trials and therapeutic advances in cancer

6090 Background: We hypothesized that there is a predictable relationship between equipoise and the outcomes of trials, i.e. the equipoise principle bounds therapeutic advances in a such way that, over time, distribution of successes between experimental and standard treatments is expected to be about equal, reflecting the unpredictability of treatment success for a particular intervention. We tested this hypothesis in randomized controlled trials (RCT) performed by the National Cancer Institute (NCI) sponsored Cooperative Groups (CG), systematically taking into account all factors (publication bias, methodological quality, choice of control intervention) known to affect outcomes. Methods: All completed (published and unpublished) phase 3 RCTs from 6 CGs (563 trials, ∼ 149,000 patients) since 1955 were evaluated. Success of experimental vs. standard treatments was evaluated semi-quantitatively and quantitatively using a meta-analytic technique. Results: Investigator’s preference for experimental vs. standard treatments were 43% and 57%, respectively (p=0.002). Hazard ratio for overall survival was 0.96 [99% CI (0.95, 0.98), p=0.00001] and for event-free survival was 0.92, [99%CI (0.90, 0.93), p=0.0001] slightly favoring experimental treatments but at the expense of increased treatment-related mortality [HR 1.12, 99%CI (1.01, 1.25), p=0.04]. The results adhere to the equipoise hypothesis and were not affected by any factors known to bias outcomes. Conclusions: While many successful treatments are discovered in phase 3 RCTs, innovative treatments in cancer which have progressed to testing in RCTs are, on average, as likely to be inferior or superior to standard treatments. This result was predicted, which amounts to description of the law of therapeutic advances in clinical oncology. If the distribution of the results were significantly skewed to consistently and predictably favor one type of treatments over another, the clinical trial system would come to a halt (patients would naturally request only those treatments that are expected to be superior making randomization impossible). Progress in treating cancer is ultimately determined by the ethical principle of equipoise which should guide clinical research. No significant financial relationships to disclose.

Antibiotics, new pathogens, new drug resistance

The 20th century is the century of the discovery of numerous pathogenic microorganisms. It is also the century of discovery of antimicrobial drugs and the beginning of the antibiotic era. While the development of antifungal drugs and of antivirals is on its rise, many infectious disease physicians and microbiologists feel that we might be on the edge of the beginning of the post-antibiotic era--50 years after antibiotic use in man and animals. Antibiotics have certainly been a major progress in modern medicine. Mortality and morbidity from many infectious diseases have been substantially reduced by effective antimicrobial therapy. The use of antibiotics has also been a prerequisite for major advances in clinical oncology, transplantation medicine, and surgery. The emergence and spread of resistant pathogens, however, has necessitated the development of broader and more active drugs and has resulted in excessive antimicrobial drug use with consequent selective pressure. Every 3rd patient admitted to a hospital is given antibiotics--often in the form of stepwise escalated therapy eventually including combinations of expensive agents. If the aim is to minimize the emergence of resistance and to contain costs, a much more critical indication for antimicrobial drug therapy will be necessary. Also, programmes on a local, regional, and perhaps even national level will be needed to help rationalize antimicrobial drug use.

Attitudes of Non-Oncology Physicians Dealing with Cancer Patients. A Survey Based on Clinical Scenarios in Ancona Province, Central Italy

With this study we attempted to determine to what extent recent acquisitions in clinical oncology had reached categories of physicians involved in the management of patients with cancer, namely general surgeons, internists and family doctors. A questionnaire was prepared with scenarios based on the following clinical situations: Scenario A, Adjuvant therapy in colon cancer; Scenario B, Treatment of small-cell lung cancer; Scenario C, Adjuvant therapy in high-risk, node-negative breast cancer; Scenario D, Treatment of early stage breast cancer; Scenario E, Asymptomatic transient myelosuppression during chemotherapy. Questionnaires were mailed to 365 family doctors, 54 general surgeons and 61 internists of the Province of Ancona in central Italy. A total of 198 completed questionnaires were returned (41%). Respondents were 36.7% of family doctors, 54.1% of internists and 57.4% of surgeons. Less than half of respondents selected an adequate approach such as adjuvant chemotherapy for colon cancer and high-risk, node-negative breast cancer or chemotherapy as first-line treatment for small-cell lung cancer. Conservative surgery plus radiotherapy (QUART) for early stage breast cancer was indicated by 69% of respondents. Over three quarters of physicians would give treatment for asymptomatic transient chemotherapy-induced leukopenia. In most of the scenarios, significant differences were detected in the distribution of preferences according to category of physicians. Family doctors and young physicians (< 40 years) generally performed worse than hospital-based physicians (general surgeons and internists) and older physicians. Non-oncology physicians showed insufficient awareness of currently available knowledge in cancer treatment. Basic concepts in cancer management should be part of the professional knowledge of all medical doctors, and key advances in clinical oncology should spread outside the oncologic environment more promptly, with a wide circulation among all physicians who care for cancer patients.

Hodgkin's Disease — New Insights from Immunoglobulin Genetics

Chemotherapy and radiotherapy of Hodgkin's disease are among the major advances in clinical oncology, but these successes have not been matched by progress in identifying the target cell. Further i...

Melanocyte growth regulation

Melanoma Research is a well established international forum for the dissemination of new findings relating to melanoma. The aim of the Journal is to promote the level of informational exchange between those engaged in the field. Melanoma Research aims to encourage an informed and balanced view of experimental and clinical research and extend and stimulate communication and exchange of knowledge between investigators with differing areas of expertise. This will foster the development of translational research. The reporting of new clinical results and the effect and toxicity of new therapeutic agents and immunotherapy will be given emphasis by rapid publication of Short Communications. ​Thus, Melanoma Research seeks to present a coherent and up-to-date account of all aspects of investigations pertinent to melanoma. Consequently the scope of the Journal is broad, embracing the entire range of studies from fundamental and applied research in such subject areas as genetics, molecular biology, biochemistry, cell biology, photobiology, pathology, immunology, and advances in clinical oncology influencing the prevention, diagnosis and treatment of melanoma.