A Brief History, the Progress in the Variants of Therapies against Metastatic Neoplasms, and the Role of Pathologists.

Chemotherapy originated in the early 1960s. The initial chemotherapeutic agents focused on blocking metabolic pathways and found substantial success in certain types of tumors, but they are generally considered toxic to all normal and tumor cells, and they have significant side effects. As more scientific studies began to identify many new, specific targets and mutations, along with a multitude of growth pathways in tumor cells, new agents targeting cell growth pathways began to emerge in the late 1990s and early 2000s. In 2003, a method called morphoproteomics was developed to evaluate the immunohistochemical protein expressions of target markers in tumors, and it has been considered a pioneering method for guiding targeted therapy. Subsequently, many genomic techniques have been established for identifying specific mutations and tumor markers in order to guide the targeted therapy. More recently, immuno-oncology therapy targeting specific immune markers has been rapidly developed, and the immunohistochemical evaluation of specific immune markers such as PD-L1 demonstrates further expansion of oncologic morphoproteomics. This brief review will focus on the role of pathologists in developing various techniques and guiding targeted therapies during the era of personalized medicine.

The road from Rous sarcoma virus to precision medicine.

In 1911, more than a century ago, Peyton Rous described a curious observation, later explained by a virus named for him that led to the discovery of oncogenes, the modern era of cancer research, and the emergent field of precision medicine (1911. J. Exp. Med. https://doi.org/10.1084/jem.13.4.397).

State of Melanoma: An Historic Overview of a Field in Transition.

The management of melanoma significantly improved within the last 25 years. Chemotherapy was the first approved systemic therapeutic approach and resulted in a median overall of survival less than 1 year, without survival improvement in phase III trials. High-dose interferon α2b and IL-2 were introduced for resectable high-risk and advanced disease, respectively, resulting in improved survival and response rates. The anti-CTLA4 and anti-programmed death 1 monoclonal antibodies along with BRAF/MEK targeted therapies are the dominant therapeutic classes of agent for melanoma. This article provides an historic overview of the evolution of melanoma management.

From Breslow to BRAF and immunotherapy: evolving concepts in melanoma pathogenesis and disease progression and their implications for changing management over the last 50 years.

Since it was first recognized as a disease entity more than two centuries ago, advanced melanoma has, until recently, followed a very aggressive and almost universally fatal clinical course. However, over the past 50 years crucial ground breaking research has greatly enhanced our understanding of the etiology, risk factors, genomic pathogenesis, immunological interactions, prognostic features and management of melanoma. It is this combined body of work which has culminated in the exciting improvements in patient outcomes for those with advanced melanoma over the last ten years. In this the 50th anniversary of Human Pathology, we highlight the key developments in melanoma over this period.

[Therapeutic antibodies in hemostasis. From the past to the future]. / Les anticorps thérapeutiques en hémostase - D'hier, d'aujourd'hui et de demain .

TITLE: Les anticorps thérapeutiques en hémostase - D'hier, d'aujourd'hui et de demain…. ABSTRACT: L'hémostase est un processus complexe qui implique de nombreux acteurs cellulaires et moléculaires. En pathologie, les thromboses d'une part, et les pathologies hémorragiques constitutionnelles dominées par l'hémophilie d'autre part, ont bénéficié ces dernières années du développement d'anticorps thérapeutiques qui révolutionnent aujourd'hui la prise en charge des malades.

A fascinating story of the discovery & development of biologicals for use in clinical medicine.

A young physician starting a fresh career in medicine in this millennium would hardly stop to think about the genesis of a particular biological drug that he/she will be prescribing for a patient evaluated in the morning outpatient department. For him/her, this is now routine, and the question of 'Who', 'How' and 'When' about these biologicals would be the last thing on their mind. However, for those who came to the medical profession in the 1950s, 1960s and 1970s, these targeted drugs are nothing short of 'miracles'. It would be a fascinating story for the young doctor to learn about the long journey that the dedicated biomedical scientists of yesteryears took to reach the final destination of producing such wonder drugs. The story is much like an interesting novel, full of twists and turns, heart-breaking failures and glorious successes. The biologicals acting as 'targeted therapy' have not only changed the natural history of a large number of incurable/uncontrollable diseases but have also transformed the whole approach towards drug development. From the classical empirical process, there is now a complete shift towards understanding the disease pathobiology focusing on the dysregulated molecule(s), targeting them with greater precision and aiming for better results. Seminal advances in understanding the disease mechanism, development of remarkably effective new technologies, greater knowledge of the human genome and genetic medicine have all made it possible to reach the stage where artificially developed 'targeted' drugs are now therapeutically used in routine clinical medicine.

Successful Targeted Therapies for Breast Cancer: the Worcester Foundation and Future Opportunities in Women's Health.

The signing of the National Cancer Act in 1971 was designed to take laboratory discoveries rapidly from the bench to the bedside. A "war on cancer" had been declared. Combination cytotoxic chemotherapy was predicted to cure all cancers, based on the stunning success in treating childhood leukemia. Breast cancer treatments were primitive; radical mastectomy and radiation were standard of care for disease that had not spread. Ablative endocrine surgery (oophorectomy, hypophysectomy, and adrenalectomy) was a palliative last option for metastatic breast cancer. However, only 30% responded, surviving for only 1 or 2 years: every patient soon died. The discovery of the estrogen receptor (ER) and translation to breast cancer treatment triggered a revolution in women's health. Two important but interconnected events occurred in 1972 at the Worcester Foundation for Experimental Biology (WFEB) that would exploit the breast tumor ER as the first target to save lives and prevent breast cancer development. Two new groups of medicines-selective ER modulators (SERMs) and aromatase inhibitors (AIs)-would continue the momentum of research at the WFEB to improve women's health. Here, we recount the important progress made in women's health based on knowledge of the endocrinology of breast cancer. We propose future opportunities in SERM therapeutics to "refresh" the current standards of care for breast cancer treatment. The opportunity is based on emerging knowledge about acquired resistance to long-term adjuvant AI therapy used to treat breast cancer.

Frontline therapy of ovarian cancer: trials and tribulations.

PURPOSE OF REVIEW: The current article reviews the advances and challenges in the fight with cancer and the hope for cure, with a focus on clinical trials, at the one time with the best outcomes; first-line therapy. RECENT FINDINGS: To date there have been four great stories that bridge inception to development of new drugs in ovarian cancer: Serendipitous insight into the role of platinum, discovery of taxanes, understanding the microenvironment and angiogenesis, and following the science in the development of Poly (ADP-Ribose) Polymerase (PARP) inhibitors. There is a fundamental difference between overall survival (OS), simply living longer; and eradicating disease, cure. The scientific underpinning of both our understanding and the recent developments encourages an optimistic view of the remaining hurdles. SUMMARY: There has been an unprecedented explosion in the number of new drugs approved for the treatment of ovarian cancer with three new classes of agent, and five new drugs receiving food and drug administration approval in the last 3 years (Fig. 2). Getting the right drug truly transforms patients' experience with the seminal event being the development of imatinib in CML. In 1980, an average patient would have lived only 3 years, and now they only live 3 years less than a full lifespan [Bower et al. (2016). J Clin Oncol 34:2851].

[Cancer: three eras of personalized medicine]. / Cancer : les trois époques de la médecine personnalisée - Chroniques génomiques.

Since the completion of the first human DNA sequence, genomic approaches have penetrated into cancer research and therapy: first through expression profiling for diagnostic, prognostic and predictive purposes, then by sequencing of tumour DNA in order to define and apply targeted therapies. These overlapping changes occurred quite rapidly and are now overshadowed by immuno-oncology approaches that show much promise. There is however still much left to understand to make this more widely applicable, and the extreme cost of these therapies is a serious concern.

[From "Karzinos" to modern urologic oncology : A long way from the first surgical procedures to targeted therapy]. / Von "Karzinos" zur modernen Uroonkologie : Der lange Weg von den ersten Operationen zur "targeted therapy".

Cancer can be traced back to the Iron Age. Both the ancient Egyptians and Hippocrates dealt with the disease. Urological tumor treatment is an integral part of urology and has undergone interesting developments. Today, it comprises all possible forms of treatment-from radical surgery to the most modern radiological therapies, including antihormal therapy, chemotherapy, and modern targeted therapy.

Chronic myeloid leukemia: reminiscences and dreams.

With the deaths of Janet Rowley and John Goldman in December 2013, the world lost two pioneers in the field of chronic myeloid leukemia. In 1973, Janet Rowley, unraveled the cytogenetic anatomy of the Philadelphia chromosome, which subsequently led to the identification of the BCR-ABL1 fusion gene and its principal pathogenetic role in the development of chronic myeloid leukemia. This work was also of major importance to support the idea that cytogenetic changes were drivers of leukemogenesis. John Goldman originally made seminal contributions to the use of autologous and allogeneic stem cell transplantation from the late 1970s onwards. Then, in collaboration with Brian Druker, he led efforts to develop ABL1 tyrosine kinase inhibitors for the treatment of patients with chronic myeloid leukemia in the late 1990s. He also led the global efforts to develop and harmonize methodology for molecular monitoring, and was an indefatigable organizer of international conferences. These conferences brought together clinicians and scientists, and accelerated the adoption of new therapies. The abundance of praise, tributes and testimonies expressed by many serve to illustrate the indelible impressions these two passionate and affable scholars made on so many people's lives. This tribute provides an outline of the remarkable story of chronic myeloid leukemia, and in writing it, it is clear that the historical triumph of biomedical science over this leukemia cannot be considered without appreciating the work of both Janet Rowley and John Goldman.

NCI-60 Cell Line Screening: A Radical Departure in its Time.

The year 2015 marked the 30th anniversary of National Cancer Institute's (NCI's) initial effort to establish a human cell line panel as the basis for discovering new cancer drugs. At its inception, the NCI-60 panel was a controversial departure, born of frustration with previous efforts that employed murine tumors and grounded in the hope that the biology of human tumors was diverse and somehow quite different than the murine leukemia used for the previous 30 years. And while the NCI-60 has not revolutionized cancer drug discovery in terms of the new drugs that resulted, it represents a turning point in the philosophy and practice of cancer drug research.

Current Therapy and New Directions in the Treatment of Hairy Cell Leukemia: A Review.

Hairy cell leukemia (HCL) is a chronic B-cell leukemia noted for an indolent course that ultimately results in cytopenias and massive splenomegaly. Whereas treatment with the nucleoside purine analogues cladribine and pentostatin results in lengthy remissions in nearly all patients with HCL, most patients will experience relapse while a small percentage of patients' disease fails to respond to therapy in the first place. Retreatment with a purine nucleoside analogue often leads to an effective but limited response. For decades, few other viable therapeutic options were available to these patients who required retreatment. Recently, new insights into the mechanism of disease of HCL have led to research in new potential treatment agents, either alone or with a purine nucleoside analogue. Clinical trials with rituximab, bendamustine, and conjugate immunotoxins will reveal what role these therapies will have in HCL treatment. A better understanding of the BRAF/MEK/ERK pathway and the B-cell signaling pathway has allowed further exploration into the novel drugs vemurafenib, dabrafenib, trametinib, and ibrutinib.

Exploring cell apoptosis and senescence to understand and treat cancer: an interview with Scott Lowe.

Scott W. Lowe is currently principal investigator at the Memorial Sloan-Kettering Cancer Center. After beginning his studies in chemical engineering, he decided to take another path and became fascinated by biochemistry, genetics and molecular biology, which ultimately led to an interest in human disease, particularly cancer. During his PhD at the Massachusetts Institute of Technology (MIT), Scott had the opportunity to benefit from the exceptional mentorship of Earl Ruley, David Housman and Tyler Jacks, and contributed to elucidating how the p53 (TP53) tumor suppressor gene limits oncogenic transformation and modulates the cytotoxic response to conventional chemotherapy. This important work earned him a fellowship from the Cold Spring Harbor Laboratory, which helped to launch his independent career. Scott is now a leading scientist in the cancer field and his work has helped to shed light on mechanisms of cell apoptosis and senescence to better understand and treat cancer. In this interview, he talks about this incredible scientific journey.

A conversation with Susan Band Horwitz.

Susan Band Horwitz is a Distinguished Professor and holds the Falkenstein Chair in Cancer Research at Albert Einstein College of Medicine in New York. She is co-chair of the Department of Molecular Pharmacology and associate director for therapeutics at the Albert Einstein Cancer Center. After graduating from Bryn Mawr College, Dr. Horwitz received her PhD in biochemistry from Brandeis University. She has had a continuing interest in natural products as a source of new drugs for the treatment of cancer. Her most seminal research contribution has been in the development of Taxol(®). Dr. Horwitz and her colleagues made the discovery that Taxol had a unique mechanism of action and suggested that it was a prototype for a new class of antitumor drugs. Although Taxol was an antimitotic agent blocking cells in the metaphase stage of the cell cycle, Dr. Horwitz recognized that Taxol was blocking mitosis in a way different from that of other known agents. Her group demonstrated that the binding site for Taxol was on the ß-tubulin subunit. The interaction of Taxol with the ß-tubulin subunit resulted in stabilized microtubules, essentially paralyzing the cytoskeleton, thereby preventing cell division. Dr. Horwitz served as president (2002-2003) of the American Association for Cancer Research (AACR). She is a member of the National Academy of Sciences, the Institute of Medicine, the American Academy of Arts and Sciences, and the American Philosophical Society. She has received numerous honors and awards, including the C. Chester Stock Award from Memorial Sloan Kettering Cancer Center, the Warren Alpert Foundation Prize from Harvard Medical School, the Bristol-Myers Squibb Award for Distinguished Achievement in Cancer Research, the American Cancer Society's Medal of Honor, and the AACR Award for Lifetime Achievement in Cancer Research. The following interview was conducted on January 23, 2014.