bluuebunny/crossref_metadata_2025_split huggingface dataset:
Precision Medicine in Oncology Drug Development
Authors: Tsimberidou Apostolia M. , Fountzilas Elena , Kurzrock Razelle 
Published: October 2022

OverviewIn recent years, advances in technology have led to identification of complex and unique biologic mechanisms of tumorigenesis. Precision medicine uses tumor and cell‐free DNA profiling, immune markers, RNA and proteomic analyses, and other biomarkers in combination with patients' unique characteristics and comorbidities to individualize anticancer therapy. The focus of selected clinical trials has shifted from tumor type‐centered to gene‐directed, and in some cases, histology‐agnostic approaches. Innovative trial designs tailored to biomarker profiling aim to improve treatment outcomes. These designs enable the dynamic evolution of the studies, allow the elimination of treatment arms with inferior outcomes and modification of patient randomization, and optimize biomarker selection based on real‐time study outcomes. They also accelerate regulatory approval of novel drugs by empowering seamless transition from phase I to phase II and III clinical trials. Companion diagnostic biomarkers provide essential information for the safe and effective use of the corresponding targeted or immune treatments and lead to improved clinical outcomes of patients with molecular alterations treated with matched targeted treatments. However, the complex interaction between tumors, immune cells, and the tumor microenvironment complicates the identification of robust biomarkers. To overcome biologic complexity and tumor heterogeneity, clinical trials evaluate combinations of gene‐targeted therapy with immune‐targeted approaches (e.g., checkpoint blockade, personalized vaccines, oncolytic viruses, and/or adoptive cell therapy), hormonal therapy, chemotherapy, and/or novel agents, customized to individuals in an N‐of‐1 fashion. In this article, we discuss the rapid evolution of precision medicine in oncology and the challenges and opportunities associated with its implementation into daily clinical practice.
Drug Development of Small Molecule Cancer Therapeutics in an Academic Cancer Center
Authors: Coss Christopher C. , Patrick Jeffrey T. , Gerald Damien , Hilinski Gerard , Shakya Reena , Byrd John C. 
Published: October 2022

OverviewDrug development of small molecules in the context of an academic cancer center is a challenging but imminently achievable process. The process involves stage‐gated, strategic decision‐making informed by the best experimental data that can be obtained. In addition to validating and comprehensively testing the drug molecule in all of the ways suggested, one of the most vital components in drug development aimed at achieving commercialization is intellectual property (IP). Most academic cancer centers are likely going to have access to an internal or external partner who establishes and maintains intellectual property. Intellectual property is in fact what a commercial partner will license with regard to a drug development program. Whether the IP is related to novelty of molecule structure, a synthesis process, an unanticipated (nonobvious) effect or a specific utility against a disease or in combination with another agent, the IP suite established for a drug development asset is the key value attribution that will garner interest from commercial entities.A robust preclinical development data package depicting clarity of mechanism of action, a tolerable or acceptable toxicity profile along with comparative data to similar programs and finally a robust intellectual property position strongly enhances the likelihood of obtaining a commercial partner as well as enabling full clinical development and commercialization. In addition to advancing basic research to enable translation to clinical research, cancer drug development can also provide a commercial resource support mechanism that can help fuel future research at the developing center based on the financial returns to the academic center from the commercialization process. With all of the available resources, with the right team and vision in place, drug development can be a rewarding process that also aligns to the academic research goals and needs.
DNA
Topoisomerase Targeting Drugs
Authors: Thomas Anish , Bates Susan , Figg William D. , Pommier Yves 
Published: October 2022

Overview
Topoisomerases are an important class of enzymes that are ubiquitously expressed across all organisms, and function to resolve deoxyribonucleic acid (DNA) supercoiling and prevent and resolve ribonucleic acid (RNA) entanglements. These biochemically distinct enzymes play a critical role in DNA replication, transcription, and cellular division. Inhibitors that target specific topoisomerases, therefore, represent a major component of the anticancer chemotherapeutic armamentarium. In this chapter, we provide an overview of topoisomerase biology and topoisomerase inhibitors. We review the common and specific mechanisms of action and the molecular pharmacology of the drugs that target the topoisomerase cleavage complexes by interfacial inhibition. Molecular pathways for cancer cell death and DNA repair associated with each specific topoisomerase inhibitor are discussed. Other mechanisms of anticancer activity of selected topoisomerase inhibitors that include DNA intercalation and/or generation of oxygen radicals destabilizing and damaging chromatin structure are described. We summarize the clinical use, toxicity profile, and the molecular basis of sensitivity and resistance to topoisomerase inhibitors. We also discuss the pharmacogenomics focusing on genetic variants in drug‐metabolizing enzymes, transporters, and other proteins associated with topoisomerase inhibitors. Evolving data demonstrate the important role of molecular profiling and analysis of genetic variants in individuals that enable personalized dosing and enhance therapeutic efficacy, minimizing toxicity. Ongoing efforts focus on optimization of treatment selection, identification of novel combination therapies, elucidation of the molecular basis of response and resistance, and development of strategies for tumor‐targeted delivery based on tumor molecular signatures.
Vaccines and Immunomodulators
Authors: Schlom Jeffrey , Gameiro Sofia R. , Palena Claudia , Gulley James L. 
Published: October 2022

OverviewThis article provides an overview of vaccine trials for a range of human cancers. It is not meant to be a compendium of all completed and ongoing trials. The vast majority of ongoing trials involve combination therapies with checkpoint inhibitor monoclonal antibodies and/or other immunomodulators. This article also deals with two concepts that are emerging as important to consider in cancer vaccine trials: tumor cell plasticity and epigenetic modulation of tumor cells and immune cells.
Hematopoietic Cell Transplantation
Authors: Bashir Qaiser , Shpall Elizabeth J. , Champlin Richard E. 
Published: October 2022

Overview
Hematopoietic cell transplantation (HCT) is an essential component of therapy for various malignant and nonmalignant conditions and provides the only curative modality for several high‐risk disorders. While HCT can be associated with significant morbidity, meaningful progress has been made to reduce treatment‐related toxicities and improve patient outcomes following HCT. Together with the development of international donor registries and the feasibility of alternative donor transplants, these advances have broadened the indications of HCT in recent years.
Cancer and Aging
Authors: Rosko Ashley E. , Presley Carolyn J. , Williams Grant R. , Olin Rebecca L. 
Published: October 2022

Overview
Cancer is a disease of older adults; with over half of cancers diagnosed in adults 65 years and older. Older adults are also comprising a larger portion of cancer survivors, accounting for 62%. The therapeutic landscape and treatment approaches are highly variable as is the health of older adults. The unique factors that older adults face must be considered when developing treatment strategies for maximum care and quality of life.
Disparities in Cancer Care
Authors: Brawley Otis W. 
Published: October 2022

Overview
With the tremendous progress in cancer over the past half‐century, increased emphasis has been placed on the study of outcomes. One glaring finding is that some populations have done better than others. This has led to the academic discipline of the study of disparities in health. The causes of cancer are both genetic and environmental; a few of the differences are due to differences in population biology. Most of the disparities are due to population differences in the practice and receipt of prevention and risk‐reduction activities. Population differences also occur in receipt of quality treatment. It is estimated that at least one in five cancer deaths in the US is avoidable. The study of health disparities focuses on how to get adequate care to those who often do not receive it.
Neoplasms of the Endocrine Glands and Pituitary Neoplasms
Authors: Feng Rui , Gandhi Chirag D. , Pain Margaret , Post Kalmon D. 
Published: October 2022

Overview
Pituitary neoplasms represent a phenotypically and pathologically diverse family of tumors. Symptoms may derive from abnormal hormone production, compression of adjacent nervous system structures, and in rare cases, metastases. New cell lineage classification based on transcription factors brings new insights into pathogenesis and treatment. Transsphenoidal surgery represents a command well‐tolerated treatment for most pituitary adenomas; however, advances in radiation and chemotherapy have increased treatment options enhancing treatment efficacy and eligibility.
Neoplasms of the Head and Neck
Authors: Ferris Robert L. , Garden Adam S. , Saba Nabil F. 
Published: October 2022

OverviewHead and neck cancers (HNCs) comprise a diverse group of malignancies affecting the upper aerodigestive tract. The most common tumor type is squamous cell carcinoma. While the main risk factors for HNC remain tobacco and alcohol abuse, oncogenic viruses such as human papilloma virus and Epstein–Barr virus play a major carcinogenic role in tumors of the oropharynx and nasopharynx respectively. The management of head and neck malignancies is site and histology specific and requires a multidisciplinary team approach. Immunotherapy has become the standard of care in the treatment of advanced metastatic squamous cell cancers. In this article, we will review the current knowledge of HNC, with focus on squamous and salivary cancers, and discuss ongoing and future research aiming to improve the management and outcomes of patients with these malignancies.
Tumors of the Heart and Great Vessels
Authors: Wyler von Ballmoos Moritz C. , Reardon Michael J. 
Published: October 2022

Overview
The most common neoplasms of the heart and great vessels are metastatic from other primary tumors, followed by benign primary cardiac tumors and then malignant primary tumors of the heart and great vessels. Cardiac‐specific symptoms are due to mass effect, disruption of normal conduction, and embolic events. Echocardiography is the most commonly used and widely available imaging modality, while cardiac MRI provides more detailed resolution, tissue characteristics, and functional assessment that help with differential diagnosis, staging, and surgical planning. Most benign and malignant tumor benefit from surgical resection, when amenable, but overall prognosis for malignant neoplasm is poor with limited or no other options for treatment.
Primary Germ Cell Tumors of the Thorax
Authors: Hainsworth John D. , Greco Frank A. 
Published: October 2022

Overview
Primary germ cell tumors (GCT) of the thorax are rare but potentially curable. Benign teratomas, which account for approximately 60–70% and usually appear in young adults, are curable with surgical resection. Malignant mediastinal GCT usually occur in young men and can be divided histologically into pure seminoma (about 52% of cases) and various nonseminoma histologies. Pure seminomas are highly sensitive to chemotherapy; treatment with three cycles of a standard cisplatin‐based testicular GCT regimen is curative in more than 80%. Selected patients with small (<6 cm) localized seminomas have high cure rates with radiation therapy alone. Nonseminomatous mediastinal GCT are associated with Klinefelter syndrome (5–10% of cases) and are also associated with various acute leukemias. Optimal treatment includes four cycles of a standard cisplatin‐based testicular GCT regimen, followed by resection of residual mediastinal masses. Since most patients require surgical resection following chemotherapy, use of a bleomycin‐containing first‐line regimen should be avoided if possible. The cure rate for these relatively poor prognosis GCT is approximately 45%.
Gallbladder and Bile Duct Cancer
Authors: Eskander Mariam F. , Aquina Christopher T. , Pawlik Timothy M. 
Published: October 2022

Overview
Biliary tract malignancy, which includes gallbladder cancer and cholangiocarcinoma, is an aggressive disease that is often advanced at the time of diagnosis and thus associated with a poor prognosis. In this article, we will review the epidemiology, risk factors, pathology, clinical presentation, diagnostic imaging modalities, and current treatment recommendations for gallbladder adenocarcinoma and cholangiocarcinoma.
Endometrial Cancer
Authors: Westin Shannon N. , Lu Karen H. , Rahaman Jamal 
Published: October 2022

Overview
Endometrial carcinoma is the most frequent gynecologic cancer in the United States with over 65,000 new cases diagnosed per year. Over 80% have the classic estrogen‐dependent endometrioid histology with a favorable prognosis. Nonendometrioid histology types, including uterine serous carcinomas (USC), carcinosarcomas, and clear cell carcinomas, have a different molecular profile associated with more virulent disease and diminished survival. The Cancer Genome Atlas (TCGA) has defined four molecular subtypes of endometrial cancer, based on somatic mutations, copy number alterations, and microsatellite instability status. Over 75% of patients present with irregular or post‐menopausal bleeding. Surgical staging includes a hysterectomy, bilateral salpingo‐oophorectomy, with or without pelvic and para‐aortic lymph node sampling done via a laparotomy, laparoscopy, or robotic surgery. Surgery, where possible, constitutes the definitive primary treatment for most patients with endometrial carcinoma. Primary radiation therapy and primary hormonal therapy are alternatives for inoperable patients. Adjuvant therapy for stage I disease is determined by age, depth of myometrial invasion, lymph‐vascular space invasion, and tumor grade. For patients with advanced and recurrent disease radiation therapy, chemotherapy, and hormonal therapy are utilized. The combination of paclitaxel and carboplatin is the most effective and tolerable chemotherapy combination and currently serves as the backbone for a number of investigational strategies. Immune check‐point inhibitors are FDA approved for the treatment of metastatic endometrial cancer, including pembrolizumab alone for microsatellite instability‐high (MSI‐H) cancers and pembrolizumab and lenvatinib for microsatellite stable (MSS) disease. The growing understanding of the molecular aberrations common in endometrial cancer has led to exploration of a number of therapies, targeting angiogenesis and the PI3K/AKT, HER2, RAS/RAF, and DNA damage repair pathways.
Nonepithelial Ovarian Malignancies
Authors: Berek Jonathan S. , Renz Malte , Friedlander Michael L. , Bast Robert C. 
Published: October 2022

OverviewCompared with epithelial ovarian cancers, nonepithelial ovarian tumors are uncommon, constituting <10% of all ovarian malignancies. They include germ cell malignancies, sex cord‐stromal tumors, and a variety of extremely rare ovarian cancers, including sarcomas and lipoid cell tumors. Although there are many similarities in presentation, evaluation, and management of the patients, these tumors also have unique features that require special approaches to management.1–5Germ cell malignancies are derived from primordial germ cells of the ovary and can be distinguished by histotype and expression of the biomarkers α‐fetoprotein (AFP) and/or human chorionic gonadotropin (hCG). They include dysgerminomas (AFP− hCG−), embryonal carcinomas (AFP+ hCG+), immature teratomas (AFP− hCG−), endodermal sinus (yolk sac) tumors (AFP+ hCG−), and ovarian choriocarcinomas (AFP− hCG+). Germ cell tumors occur in premenarchal girls and young women, grow rapidly, and can present with a symptomatic pelvic mass. As preservation of fertility is almost always an important priority, unilateral salpingo‐oophorectomy should be performed often followed by adjuvant platinum‐based therapy. Of note, dysgerminomas can be bilateral in 10–15% and are associated with gonadal dysgenesis in 5% of cases. Metastatic germ cell cancers are very sensitive to chemotherapy and the long‐term survival rate is high, even in advanced stages. At some institutions, young patients with stage IA germ cell tumors are followed carefully after resection with excellent outcomes and chemotherapy given only if there is recurrence with excellent outcomes. Sex cord‐stromal tumors include granulosa‐stromal tumors, juvenile granulosa tumors, and Sertoli–Leydig cell tumors. Granulosa‐stromal tumors can occur at all ages and produce estrogen resulting in pseudo‐precocious puberty in a small fraction of girls, amenorrhea in premenopausal women, and endometrial hyperplasia in postmenopausal adults. Granulosa‐stromal tumors are indolent and often confined to one ovary where surgery can cure stage I disease in more than 75% of cases. Adjuvant chemotherapy is generally not given after complete resection. Late recurrence has, however, been observed. Persistent or recurrent disease has responded to platinum‐based and hormonal therapy, including progestational agents, GnRH agonists, and aromatase inhibitors. Inhibin B has been a useful biomarker. Sertoli–Leydig cell tumors generally present in the third or fourth decade, produce androgens, and induce virilization in more than 70% of patients. As many Sertoli–Leydig cell tumors are in early‐stage and rarely bilateral, unilateral salpingo‐oophorectomy is often performed with 70–90% 5‐year survival.
Gynecologic Sarcomas
Authors: Rahaman Jamal , Cohen Carmel J. 
Published: October 2022

Overview
Sarcomas are extremely rare and account for less than 1.5% of gynecologic cancers. Carcinosarcoma and leiomyosarcoma each account for 35–40% of uterine sarcomas, with endometrial stromal sarcoma (ESS) accounting for 10–15% and other sarcomas including adenosarcomas comprising 5–10 %. Uterine carcinosarcoma should be classified as a metaplastic carcinoma of the uterus. Most adenosarcomas and ESSs have good prognosis and respond to hormonal therapy. Undifferentiated endometrial sarcoma (UES) and adenosarcomas with sarcomatous overgrowth are rare and have poor prognosis and require chemotherapy. ESS are histologically and clinically distinct from UES and each have distinct gene rearrangements. More than 50% of stage I leiomyosarcomas and carcinosarcomas patients will recur. Chemotherapy is required for advanced or recurrent disease. In leiomyosarcomas, the active drugs are doxorubicin, ifosfamide, gemcitabine, and docetaxel. For uterine carcinosarcomas, the drugs of choice are ifosfamide, cisplatin/carboplatin, and paclitaxel. Adjuvant radiation therapy may provide locoregional control in select cases of uterine carcinosarcomas. Hormonal therapy, including progestational agents, GnRH analogs, and aromatase inhibitors, has a role in the treatment of advanced or recurrent low‐grade ESSs and adenosarcomas.
Neoplasms of the Breast
Authors: Tripathy Debu , Makhnoon Sukh , Arun Banu , Sahin Aysegul , Kettner Nicole M. , Damodaran Senthil , Keyomarsi Khandan , Yang Wei , Hunt Kelly K. , Clemens Mark , Woodward Wendy A. , Mitchell Melissa P. , Layman Rachel , Hobbs Evthokia A. , Lim Bora , Dupuis Megan , Murthy Rashmi , Alhalabi Omar , Ibrahim Nuhad , Subbiah Ishwaria M. , Barcenas Carlos 
Published: October 2022

OverviewBreast cancer is the most common cancer among women in the United States and growing in incidence worldwide, while mortality due to breast cancer is slowly decreasing. The last two decades have witnessed many changes in the diagnostic landscape both in terms of imaging studies and laboratory tests, most notably next‐generation sequencing both on tumor and blood. Our understanding of breast oncogenesis, tumor heterogeneity, and metastasis has deepened. Segmental mastectomy and sentinel lymph node (SLN) biopsy have been used in the majority of cases coupled with radiation therapy. In cases managed with mastectomy, radiation of one to three positive nodes has been utilized more often. Gene expression profiling has been used to identify women with hormone receptor‐positive (HR+) breast cancer who would benefit from adjuvant chemotherapy. Targeted therapy has been developed for HR+, HER2 amplified, and triple‐negative breast cancer. Immune checkpoint inhibitors have improved the management of triple‐negative disease. poly(adenosine diphosphate [ADP]–ribose) (PARP) inhibitors have improved outcomes for breast cancer patients with BRCA1/2 mutations. Combinations of targeted therapies and hormonal therapies have proved effective for adjuvant therapy and in recurrent disease.
Other Skin Cancers
Authors: McMurray Stacy L. , Stebbins William G. , Millican Eric A. , Neel Victor A. 
Published: October 2022

OverviewNonmelanoma skin cancer (NMSC) includes squamous cell carcinoma (SCC), basal cell carcinoma (BCC), Merkel cell carcinoma (MCC), and other premalignant and malignant tumor types. The incidence of NMSC has increased significantly in recent years. These cancers are diverse in their clinical presentation, biology, and capacity to metastasize. Our understanding of the molecular biology of NMSC has grown considerably in recent years, leading to the development of new treatment options. In addition to malignant NMSC, this article will discuss several benign skin tumors that arise due to underlying internal malignancies.
Bone Tumors
Authors: Damron Timothy A. 
Published: October 2022

Overview
As a group, bone tumors are uncommon lesions arising from a wide array of cells, affecting all ages of patients, and involving any bone in the body. Benign bone lesions are quite common and range from inactive to active and aggressive tumors. Treatment of inactive bone lesions is most often observation. Active benign bone lesions are frequently treated surgically by curettage. Benign aggressive tumors often require extended intralesional curettage with adjuncts. Among malignant bone lesions, the most common bone malignancy is metastatic carcinoma, and the most common primary bone malignancy is myeloma. The focus on bone involvement in these tumors is fixation of pathologic fractures and prediction of impending fractures. Primary bone sarcomas are rare tumors with characteristic clinical, radiographic, and pathologic features. Treatment of bone sarcomas most often requires wide surgical resection with or without chemotherapy and/or radiotherapy. Although often numerous specialties may contribute to their evaluation and care, orthopedic oncology is the only subspecialty focused specifically on all aspects of bone tumors.