bluuebunny/crossref_metadata_2025 huggingface dataset:
Desmoid-Type Fibromatosis in Children: A Step Forward in the Cooperative Group Setting
Authors: Pounds Natalie , Skapek Stephen X.
Published: February 2020

Overview:

Desmoid-type (aggressive) fibromatosis (desmoid tumor) is a soft tissue neoplasm that can occur in both children and adults. Although it is formally classified as an intermediate-grade neoplasm because of its propensity for locally invasive growth, it can lead to severe and life-threatening problems. Because metastases do not arise from desmoid tumor, therapeutic interventions have historically focused on surgery or radiation to achieve local tumor control. These approaches may be ineffective or impractical for some children. In those cases, systemic therapy with cytotoxic or noncytotoxic therapy has been used. Because of the relative rarity of this neoplasm in children, knowledge on the use of chemotherapy is based largely on anecdotal reports or retrospective series. Limited conclusions can be drawn, though, from these types of reports. In the last 10 years, two prospective phase II clinical trials of chemotherapy for children with desmoid tumor have been conducted in cooperative clinical trials centered in North America. We review the results of those clinical trials and suggest future directions for systematically approaching this disease to better define the role of chemotherapy for children with desmoid tumor.
Surgical Treatment of Colorectal Cancer Liver Metastases
Authors: Curley Steven A.
Published: February 2020

Overview:

Treatment strategies for patients with stage IV colorectal cancer have changed markedly in the last decade. Patients with colorectal cancer metastases to the liver have always been a fascinating group to consider biologically and for local-regional treatment strategies. In the late 1980s through the 1990s, resection was performed for a select subset of patients who had resectable disease. However, a high proportion of patients had bilobar unresectable disease and were treated with either 5-fluorouracil–based systemic chemotherapy or implanted hepatic arterial infusion pumps. The advent of the new millennium was associated with the availability of several new cytotoxic and biologic agents active in colorectal cancer. These agents have completely changed the approach to the treatment of patients with colorectal cancer liver metastases and thus have increased the complexity of the decision-making process for treatment of these patients.
Management of Human Papillomavirus–Induced Oropharynx Cancer
Authors: Brizel David
Published: February 2020

Overview:

Oropharynx cancer (OPC) constitutes the most common location for squamous-cell head and neck cancer, and most OPC is caused by the human papilloma virus (HPV). Early-stage (American Joint Committee on Cancer [AJCC] stage I and II) disease should be treated with single modality surgery or radiotherapy whenever possible. More advanced presentations generally require combined-modality therapy with various combinations of surgery, radiotherapy, and chemotherapy or molecularly targeted therapy. All of these approaches expose patients to a substantial risk of serious long-term functional morbidity. HPV-induced OPC has a very favorable prognosis compared with its HPV-negative counterpart irrespective of the treatment platform that is used. Current clinical trials are investigating the concept of therapeutic deintensification with the dual objectives of decreasing toxicity and maintaining efficacy.
International Perspective on the Global Advances in Gynecologic Oncology
Authors: Denny Lynette
Published: February 2020

Overview:

The treatment of gynecologic cancer has evolved over the years, with greater emphasis on tailored surgery and reducing morbidity and mortality related to surgery, particularly in the management of vulvar and cervical cancer. The addition of concurrent chemotherapy to radiation regimens has improved survival of patients with cervical cancer in developed countries; however, most women with cancer in developing countries have advanced, untreatable disease and minimal access to anticancer therapies. In the past 15 years there has been intense research into alternatives to cervical cytologic testing, particularly in low resourced regions but also in an attempt to improve on cytologic testing in developed countries. Surgical staging in endometrial cancer has enabled the use of adjuvant radiation to be individualized to the patient's particular risk factors for recurrence. The management of ovarian cancer, long stagnant since the introduction of platinum and paclitaxel as chemotherapeutic agents, is set to change with the onset of molecular and genetic profiling and the introduction of novel therapies.
Dose-Dense Chemotherapy and Neoadjuvant Chemotherapy for Ovarian Cancer
Authors: Fujiwara Keiichi , Katsumata Noriyuki , Onda Takashi
Published: February 2020

Overview:

Two of the innovative chemotherapeutic approaches to ovarian cancer treatment, dose-dense chemotherapy and neoadjuvant chemotherapy, will be discussed herein. The primary concept of dose-dense chemotherapy is to administer the same cumulative dose of chemotherapy over a shorter period. Increased dose density is achieved by reducing the interval between each dose of chemotherapy. The Japanese Gynecologic Oncology Group (JGOG) first demonstrated the survival advantage of dose-dense weekly administration of paclitaxel in 2009. However, there are unanswered questions, such as the question of dose-dense carboplatin versus less dose-intensive regimens. Clear cell or mucinous carcinomas seem to need other strategies, such as targeted agents. The aim of neoadjuvant chemotherapy is to reduce tumor volume or spread before main treatment. This could then make the main procedures easier or less invasive, just like breast-conserving surgery after neoadjuvant chemotherapy. In advanced ovarian cancer, standard procedure is maximum primary debulking surgery followed by chemotherapy. Recently, a prospective randomized trial demonstrated that neoadjuvant chemotherapy followed by interval debulking surgery was not inferior to the standard procedure. However, there are several questions that remain unanswered, such as the suitable number of chemotherapy cycles before interval debulking surgery. Some of those questions regarding dose-dense chemotherapy or neoadjuvant chemotherapy may be resolved by ongoing or future prospective trials.
Treatment of Chronic Myelogenous Leukemia as a Paradigm for Solid Tumors: How Targeted Agents in Newly Diagnosed Disease Transformed Outcomes
Authors: Westin Jason R. , Kantarjian Hagop , Kurzrock Razelle
Published: February 2020

Overview:

Although chronic myelogenous leukemia (CML) is rare, with approximately 5000 new cases in the United States annually, it may be the poster child for the future of oncology. Imatinib mesylate, a selective Bcr-Abl tyrosine kinase inhibitor (TKI), transformed the course of CML from a rapidly fatal disease (median survival, 3 to 6 years) to a functionally curable, indolent disease with an estimated median survival of more than 25 years. This transformation can be attributed to several key factors: the identification of a causal and actionable molecular aberration— BCR-ABL; the development of a potent and selective Bcr-Abl TKI—imatinib; and, importantly the application of imatinib in the earliest phase of CML. In contrast, imatinib, if used in CML blastic phase, improves median survival to only about 1 year. Similar to CML blastic phase, metastatic solid malignancies have undergone genetic evolution, and their molecular aberrations are complex. As a result, resistance is common and eradication is difficult. The key to the dramatic improvement in the survival of patients with CML involved using imatinib in newly diagnosed disease, before blastic transformation. We hypothesize that metastatic solid tumors are analogous to CML blastic phase, and that to achieve improvements in solid tumor outcomes similar to those seen in CML, application of targeted agents to newly diagnosed disease may be required to prevent disease transformation (i.e., metastases). Targeting driver mutations at the time of diagnosis may be critical to the goal of markedly changing the outlook for patients with cancer.
How Does Biology Affect Local Therapy Decisions?
Authors: Buchholz Thomas A.
Published: February 2020

Overview:

Breast cancer represents a biologically diverse set of diseases. Previous data suggest that the estrogen/progesterone receptor (ER/PR) status and HER2/ neu status are important determinants of prognosis and response to various systemic treatments. Recent data also suggest that these receptors correlate with outcomes of local-regional therapies. Specifically, patients with ER-positive HER2/ neu-negative disease have an excellent outcome with radiation treatments, either given as a component of breast-conservative therapy (BCT) or for those with more advanced disease, when given after mastectomy. For patients with triple-negative disease, data suggest that the proportional benefits offered from radiation in reducing local-regional recurrences may be less. This article will highlight some of these data and discuss strategies for new local-regional research avenues that are based on breast cancer biologic subtype.
Intraperitoneal Treatment in Ovarian Cancer: The Gynecologic Oncology Group Perspective in 2012
Authors: Armstrong Deborah K. , Fujiwara Keiichi , Jelovac Danijela
Published: February 2020

Overview:

The peritoneal cavity is the major site of disease in ovarian cancer. The peritoneal predominance of disease provides a rationale for administration of chemotherapy within the peritoneal cavity. Intraperitoneal (IP) chemotherapy for ovarian cancer has been studied rigorously for more than 30 years and has been reproducibly shown to improve the survival of patients with ovarian cancer. Three large randomized trials of IP compared with intravenous (IV) therapy have demonstrated statistically significant improvement in clinical outcome measures. Despite this, the IP approach has not gained widespread acceptance in the treatment of ovarian cancer. Here, we review reported, recently completed, and ongoing trials of IP therapy in ovarian cancer including attempts to improve the tolerability and acceptance of this proven approach.
Capturing the Patient Perspective: Patient-Reported Outcomes as Clinical Trial Endpoints
Authors: Bruner Deborah Watkins , Movsas Benjamin , Basch Ethan
Published: February 2020

Overview:

Just as clinical trial design and rigor have evolved with improvements in methods and processes, so too have methods for capturing patient data in clinical trials. Substantial evidence suggests that standard physician reporting of symptoms for which we lack objective diagnostics (e.g., pain) is often discordant with patient self-report. Current reporting using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTC[AE]) for symptom capture relies on a filtering system, from patient to physician to medical record to medical record abstraction to data entry, with each step requiring interpretation and the possibility of error. In contrast, patient-reported outcomes (PROs) eliminate the filter and rely on direct report. Furthermore, the lack of validation and training in use of the CTC(AE) creates an inadequate data capture system. Inadequacies might be observed as underreporting or overreporting symptom prevalence and severity compared with patient self-report. Inaccuracies in symptom reporting can lead to missing important prognostic information, lack of understanding of patient adherence with therapies, and lack of information for patient decision making. They can also lead to opportunities lost in terms of labeling claims and comparative effectiveness analyses. New developments in patient-reported outcome (PRO) reporting, including the PRO-CTC(AE) and models for incorporation of PROs in clinical trials, might facilitate routine PRO reporting complementary to CTC(AE) in clinical trials. In addition, the cadre of validated PRO instruments already in existence allows for more in-depth, hypothesis-driven evaluations. For standard toxicity reporting, the time has come for mandatory routine PRO symptom reporting complementary to the CTC(AE).
A Balanced Approach to Physician Responsibilities: Oncologists' Duties toward Themselves
Authors: Abernethy Amy P.
Published: February 2020

Overview:

Although critical to the provision of best patient care, physician self-care is an underattended aspect of responsibility in the medical professions, including oncology. Neglecting self-care bears negative consequences for the individual oncologist, ranging from burnout and fatigue to interpersonal and relationship stress, addiction, and disruptive behavior. It may also contribute to medical errors, disinterest in or depersonalization of patient care, and lower quality of care. Because of its effect on physicians, patients, and the health care environment, physician self-care is increasingly recognized as an important professional responsibility. Nonetheless, professional obligations, competing demands on time, and personal priorities conspire to prevent a large proportion of oncologists from adequately attending to self-care in even simple ways, such as getting sufficient exercise and sleep. This chapter discusses the need for physician self-care and the repercussions of not meeting this fundamental responsibility. Self-care is described in the context of three life domains: professional, personal (physical, psychological, mental, and spiritual), and interpersonal (relationships, family, social, and community). Strategies are provided for caring for the self in each domain.
New Developments in Prostate Cancer Therapy
Authors: Bajaj Madhuri , Heath Elisabeth I.
Published: February 2020

Overview:

Prostate cancer is the most common nonskin malignant neoplasm in men worldwide. In the United States, 241,740 new diagnoses of prostate cancer and 28,170 prostate cancer deaths have been estimated for 2012, representing 28% of new cancer cases and 10% of male cancer deaths. 1 Although metastatic prostate cancer remains an incurable disease, substantial advances have been made in therapeutic options available for men in the past several years. Development of novel agents that modulate the androgen receptor pathway, growth factor signaling pathways, and immune function and bone targeting pathways has been the focus of therapeutic strategies because of its significance in the biology of prostate cancer progression. Several of the agents have gained U.S. Food and Drug Administration (FDA) approval, whereas many are in late-stage clinical trials. With the growth of available treatment options, a major challenge as we move forward will be to determine the best sequence and/or combination of therapy that will result in maximum clinical efficacy with minimum toxicity. Highlighted in this publication are several of the exciting advances in prostate cancer therapy for patients with metastatic, castrate-resistant prostate cancer.
Genetic Alterations in Childhood Melanoma
Authors: Navid Fariba
Published: February 2020

Overview:

Melanoma is rare in children. However, the clinical features of the disease in this population have been well-documented through single-institution experiences and population-based analyses. Still, our understanding of the etiologic factors in children remains unclear and diagnosis of melanoma remains challenging in certain cases. This article reviews emerging evidence indicating that molecular characterization of these lesions in children may be of diagnostic and therapeutic value.
Translating Genomic Research into Clinical Practice: Promise and Pitfalls
Authors: Sparano Joseph A. , Ostrer Harry , Kenny Paraic A.
Published: February 2020

Breast cancer is a heterogeneous disease associated with variable clinical outcomes despite standard local therapy for the primary tumor and systemic adjuvant therapy to prevent distant recurrence. Management decisions are typically made using classical prognostic and predictive clinicopathologic factors, and more recently gene expression profiling assays are commonly used in practice. Recent advances in genomic sequencing—often referred to collectively as next-generation sequencing (NGS)—have facilitated more in-depth evaluation of the cancer genome than could be afforded by the initial generation of gene expression studies, including DNA single nucleotide variants, small insertions and deletions, structural alterations, and copy number alterations (CNAs). In addition, this information has been integrated with other molecular profiling methods of processes that affect gene transcription (e.g., epigenetic, microRNA) and protein expression—the ultimate readout of the genetic code. Although NGS has provided new insights on the classification of breast cancer and identified potential predictive biomarkers and novel targets, there are formidable logistical and scientific obstacles that must be addressed before the promise of this technology is fully realized.
Rare but Real: Management of Small Bowel Adenocarcinoma
Authors: Overman Michael J.
Published: February 2020

Despite representing the longest segment of the alimentary tract, small bowel adenocarcinomas are rare. The diagnosis of small bowel adenocarcinoma is frequently delayed because of the nonspecific clinical symptoms and the limitations of small bowel imaging. The majority of patients will present with either lymph node or distant metastatic disease. Though the role of adjuvant therapy for resected small bowel adenocarcinoma is unclear, recent research efforts have led to an improvement in our management of advanced disease. Prospective phase II studies have successfully enrolled patients with this rare tumor type and have established the combination of a fluoropyrimidine and oxaliplatin as the most appropriate front-line chemotherapy for patients with advanced disease. Currently, five prospective clinical trials have been designed for patients with small bowel adenocarcinoma and enrollment to these clinical trials should be encouraged.
Treatment and Trials: Ovarian Cancer in Older Women
Authors: Freyer G. , Tew W. P. , Moore K. N.
Published: February 2020

Ovarian cancer (OC) is a disease of elderly women. The disease spreads insidiously and presents at an advanced stage at initial diagnosis for most patients. Several groups reported at least a two-fold increased risk of death in women older than 65. Various theories have been proposed to explain this survival disparity in older women, including: (1) more aggressive cancer with advanced age, (2) inherent resistance to chemotherapy, (3) individual patient factors such as multiple concurrent medical problems, and (4) physician and health-care biases toward the elderly that lead to inadequate surgery, less than optimal chemotherapy, and poor enrollment in clinical trials. As a result of this high clinical variability, oncologists need to be more familiar with the comprehensive geriatric assessment to better identify vulnerable patients at higher risk of complications. Several geriatric tools are available to assess the physiologic and functional capacities of older patients and to better individualize treatment. This paper gives an overview of the management of elderly patients with OC, in particular the integration of chemotherapy, surgery, and geriatric assessment to improve treatment tolerance and survival outcomes.
Difficult to Swallow: Issues Affecting Optimal Adherence to Oral Anticancer Agents
Authors: Cheung Winson Y.
Published: February 2020

The number of anticancer drugs currently available in oral formulation has increased dramatically over the past 15 to 20 years, especially with the recent development of new hormonal and targeted therapies. 1 , 2 At present, approximately 25% of all cancer drugs are available in oral formulation, with numbers expected to increase exponentially in the coming years. 1 , 3 , 4 The convenience associated with the self-administration of oral therapy, the requirement of fewer trips to the physician's office, and the lack of infusion reactions are all benefits for patients, allowing them to potentially maintain their relative independence while undergoing active anticancer treatment. On the other hand, there are growing concerns regarding patients' poor adherence to oral therapy as well as the challenges of monitoring patient compliance when treatment administration does not occur in the presence of health care professional (HCPs). More importantly, poor adherence to proven therapies may detrimentally affect the patients' clinical outcomes, such as survival. Thus, there is an urgent need to identify more effective strategies to measure and monitor adherence to oral anticancer agents in an effort to maximize their therapeutic benefits.
Monitoring and Managing Minimal Residual Disease in Acute Lymphoblastic Leukemia
Authors: Hoelzer Dieter
Published: February 2020

In adult acute lymphoblastic leukemia (ALL) the complete remission (CR) rates have improved to 85% to 90%. Despite this high CR rate, 40% to 50% of patients eventually relapse. 1 This occurs because of the limited sensitivity of cytomorphology in assessing complete molecular remission. Thus, more sensitive methods that detect leukemic cells on a molecular level and identify minimal residual disease are needed.
Monoclonal Antibody-Based Therapies in the Treatment of Acute Lymphoblastic Leukemia
Authors: Litzow Mark R.
Published: February 2020

Recent studies have suggested that pediatric-intensive chemotherapy regimens can improve outcomes in adults with acute lymphoblastic leukemia (ALL) up to the age of 45. Above this age, toxicities increase. Monoclonal antibody-based therapies bring the promise of increased response rates without excessive toxicity. The addition of rituximab to combination chemotherapy has shown encouraging results. Newer monoclonal antibody-based therapies linked to cytotoxic agents show promise. These include inotuzumab ozogamicin, an anti-CD22 antibody linked to calicheamicin that has produced significant single-agent responses in relapsed and refractory ALL. Other monoclonal antibodies linked to plant or bacterial toxins are in earlier stages of development. Blinatumomab is a novel bispecific T-cell engaging antibody that combines single chain antibodies to CD19 and CD3 and brings a T cell in close proximity to a leukemic lymphoblast with resulting redirected lysis. This agent has demonstrated encouraging results in both the minimal residual disease setting and the relapsed/refractory setting. Autologous chimeric antigen receptor cells have shown promising responses in indolent B-cell lymphoid malignancies and are being tested in ALL. Many of these agents have the potential to increase response rates in older adults. Trials of many of these monoclonal antibody-based therapies are in various stages of development in the treatment of newly diagnosed ALL.
Adjuvant Chemotherapy: Which Patient? What Regimen?
Authors: Turner Natalie , Biganzoli Laura , Malorni Luca , Migliaccio Ilenia , Moretti Erica , Pestrin Marta , Sanna Giuseppina , Siclari Olimpia , Di Leo Angelo
Published: February 2020

In the past, treatment decisions regarding adjuvant chemotherapy in early breast cancer (EBC) were made solely based on clinicopathologic factors. However, with increased awareness of the importance of underlying tumor biology, we are now able to use genomic analyses to determine molecular breast cancer subtype and thus identify patients with tumors that are chemotherapy resistant and unlikely to benefit from the addition of chemotherapy. Although genomics has allowed some patients to avoid chemotherapy—specifically those with luminal A–like breast cancer—these assays do not indicate which regimen is most appropriate. For this, consideration must be given to the combination of underlying tumor biology, tumor stage, and patient characteristics, such as age and tolerability of side effects.
Emerging Molecular-Targeted Therapies in Early-Phase Clinical Trials and Preclinical Models
Authors: Ferguson Michael , Hingorani Pooja , Gupta Abha A.
Published: February 2020

Within the context of modern cooperative group trials, modification of standard cytotoxic chemotherapy has not improved survival in patients with rhabdomyosarcoma (RMS) over the last 30 years. There is need and interest to incorporate novel targeted anticancer agents into the treatment plans for children and adolescents with newly diagnosed RMS; however, targets directly driven by FOXO1 translocation remain elusive, and molecular events driving translocation negative tumors similarly remain ill-defined. Thus, alternate pathways driving the tumors require identification and targeting. Herein, we describe targeted therapies that could be of interest in RMS, but whose inclusion in clinical trials is thus far limited by scientific and regulatory criteria. Sorafenib, pazopanib, crizotinib, TH-302, aurora-kinase inhibitors, and anaplastic lymphoma kinase (ALK)/c-MET inhibitors will be discussed. The current preclinical and clinical data available, as well as limitations and challenges for each, will be outlined.
Which Patients with Sentinel Node–Positive Breast Cancer Can Avoid Axillary Dissection?
Authors: Ho Alice Y. , Cody Hiram S.
Published: February 2020

Sentinel lymph node (SLN) biopsy is standard care for patients with cN0 breast cancer. An extensive literature, including seven randomized trials, has established that patients with negative SLN do not require axillary dissection (ALND), that axillary local recurrence after a negative SLN biopsy is rare, that disease-free and overall survival are unaffected by the addition of ALND to SLN biopsy, and that the morbidity of SLN biopsy is substantially less than that of ALND. It is now clear that many patients with positive SLN do not require ALND. In ACOSOG Z0011, 6-year locoregional control and survival were equivalent with versus without the performance of ALND in cT1–2N0 patients with ≤2 positive SLN treated by breast conservation with whole breast radiation therapy. A small but growing body of data now suggests that ALND may not be required for selected patients outside the Z0011 eligibility criteria, specifically those treated by mastectomy (without post-mastectomy radiation therapy), by partial breast irradiation, and by neoadjuvant chemotherapy. Looking ahead, the principal goals of axillary staging, prognostication, and local control will be accomplished by SLN biopsy for a substantial majority of patients, and the role of ALND will continue to diminish.
Drug Development: Neoadjuvant Opportunities in Breast Cancer
Authors: Rastogi Priya , Geyer Charles E. , Mamounas Eleftherios P. , DeMichele Angela
Published: February 2020

Preoperative therapy allows for a higher rate of breast conserving surgery and has been shown equivalent to adjuvant therapy. Preoperative therapy provides an opportunity to obtain insights into breast cancer biology and to accelerate the evaluation of new therapies. Clinical trials have shown that women who achieve a pathologic complete response (pCR) have substantially improved outcomes compared with those who do not achieve a pCR. The U.S. Food and Drug Administration (FDA) meta-analysis demonstrated that the association of pCR and long-term outcomes is greater in women with aggressive breast cancer subtypes. In patients with HER2+ breast cancer, the addition of trastuzumab to chemotherapy in the neoadjuvant setting has doubled pCR and correlated with improved outcomes. Clinical trials will evaluate tailoring the use of radiation therapy in patients who have received neoadjuvant therapy. Trials have established neoadjuvant endocrine therapy as a valid treatment and research option for ER-rich breast cancer. The neoadjuvant setting allows for evaluation of endocrine therapies in combination with newer targeted therapies in the appropriate patient populations. The neoadjuvant setting provides opportunity to accelerate the evaluation of new agents, improve pCR rates, and identify predictive biomarkers for response. This setting provides the opportunity for screening new agents in combination with chemotherapy while obtaining serial biopsies to understand biology of response and resistance. Although current standard therapies provide substantial benefits for patients with a pCR, patients with residual disease are at substantial risk for disease recurrence. New agents are being evaluated in patients with high-risk residual disease following standard treatment regimens.
The Rationale and Evidence for Radiotherapy in the Management of Gastroesophageal Junction Tumors
Authors: Haustermans Karin
Published: February 2020

Adenocarcinoma of the gastroesophageal junction (GE-junction) is a frequent disease with a rising incidence. The optimal treatment of localized disease is the subject of many randomized trials and meta-analyses studying the role of preoperative chemotherapy or preoperative chemoradiation compared with surgery alone. A complicating factor in interpreting the results of these trials is the fact that GE-junction tumors are sometimes regarded as esophageal tumors, although in other studies they are regarded as gastric cancers. A thorough review of the literature including meta-analyses clearly indicates that there is a role for preoperative chemoradiation in locally advanced GE-junction tumors. Based on the available evidence a surgery alone arm in future randomized trials for locally advanced GE junction tumors can no longer be regarded as a standard arm.
Therapeutic Vaccines and Immunotherapy in Castration-Resistant Prostate Cancer: Current Progress and Clinical Applications
Authors: Gulley James L. , Madan Ravi A. , Heery Christopher R.
Published: February 2020

Results of recent clinical trials have intensified interest in immunotherapy for cancer. Among the most promising candidates for immunotherapy are patients with prostate cancer. Results of therapeutic vaccine clinical trials in this population have suggested statistically significant and clinically meaningful improvements in overall survival, with substantially fewer side effects than with chemotherapy. Of particular interest are sipuleucel-T, the first U.S. Food and Drug Administration-approved therapeutic cancer vaccine, and PSA-TRICOM (PROSTVAC), a therapeutic cancer vaccine in phase III testing. The immune checkpoint inhibitor ipilimumab is also stirring considerable interest, with two phase III trials ongoing in prostate cancer. This article highlights data emerging from these trials and addresses remaining questions and practical clinical implications of this therapeutic strategy.
The Life and Times of Low-Grade Serous Carcinoma of the Ovary
Authors: Gershenson David M.
Published: February 2020

For the past several years, all women with epithelial ovarian cancer have been treated identically, whether in a clinical trial or off protocol. Over the past decade, we have come to appreciate the magnitude of the heterogeneity of ovarian cancer. The development of the binary grading system for serous carcinoma was a major advance, leading to separate clinical trials for patients with this subtype, originating from the Gynecologic Oncology Group's Rare Tumor Committee. The mitogen-activated protein kinase (MAPK) pathway appears to play a prominent role in the pathogenesis of this subtype. Approximately 20% to 40% of low-grade serous carcinomas have a KRAS mutation, while BRAF mutations are rare—approximately 5%. In genomic profiling studies, these tumors appear to cluster with serous tumors of low malignant potential. Compared with high-grade serous carcinomas, low-grade serous carcinomas are also characterized by a low frequency of p53 mutations, greater expression of ER and PR, and greater expression of PAX2 and IGF-1. Primary treatment of low-grade serous carcinoma includes surgery plus platinum-based chemotherapy (either adjuvant or neoadjuvant). Clinical behavior is characterized by young age at diagnosis, relative chemoresistance, and prolonged overall survival. Current options for treatment of relapsed disease include secondary cytoreduction in selected patients, salvage chemotherapy, or hormone therapy. A recently completed trial of a MEK inhibitor for women with recurrent disease demonstrated promising activity. Future directions will include further investigations of the molecular biology and biomarker-driven clinical trials with targeted agent monotherapy and combinations.
Updates in the Management of Ovarian Germ Cell Tumors
Authors: Matei Daniela , Brown Jubilee , Frazier Lindsay
Published: February 2020

Ovarian germ cell tumors are rare events at all ages—in pediatrics, adolescence, and during young adulthood. Combining the knowledge and experience of pediatric and gynecologic oncologists can lead to better outcomes for all. In this review, we intend to present the latest consensus on management of women and children with this disease and highlight the opportunities for collaboration and clinical research going forward.
Myelodysplastic Syndromes: Recent Advancements in Risk Stratification and Unmet Therapeutic Challenges
Authors: Bejar Rafael , Tiu Ramon V. , Sekeres Mikkael A. , Komrokji Rami S.
Published: February 2020

Significant advances have been achieved in understanding and treating myelodysplastic syndromes (MDS) in the past decade. For the first time, three drugs were approved specifically for this disease. Novel sequencing techniques have expanded our understanding of the molecular basis of MDS. Several clinically significant recurrent gene mutations have been identified. The classification and risk stratification of MDS continues to evolve in light of such advances. However, treatment options remain limited and novel therapeutic strategies are needed. In this review we address key questions for management of MDS. How do we better classify and risk stratify MDS, tailoring treatment accordingly? How do we diagnose and manage the challenging group of patients with MDS/myeloproliferative neoplasms (MPN) overlap? And finally, what is on the horizon for novel therapies?
Treatment Algorithms for Hormone Receptor–Positive Advanced Breast Cancer: Going Forward in Endocrine Therapy—Overcoming Resistance and Introducing New Agents
Authors: Johnston Stephen R. D. , Schiavon Gaia
Published: February 2020

Overcoming de novo or acquired endocrine resistance remains critical to further enhancing the benefit of existing endocrine therapies. Recent progress has been made in understanding the molecular biology associated with acquired endocrine resistance, including adaptive “cross-talk” between ER and various growth factor receptor and cell-signaling pathways. Strategies that combine endocrine therapy with targeted inhibitors of growth factor receptors or cell-survival pathways to further enhance first-line response have largely been disappointing, suggesting that any attempts to prevent endocrine resistance by blocking specific pathways from the outset will be futile. In contrast, success has been seen by selecting patients with acquired endocrine resistance and enhancing response to further endocrine therapy by the addition of mTOR antagonists. Numerous other therapeutics are being evaluated in combination with endocrine therapies based on varying levels of preclinical science to support their use, including inhibitors of PI3K, HDAC, Src, IGFR-1, and CDK4/6. Enriching trial recruitment by molecular profiling of different ER+ subtypes will become increasingly important to maximize any additional benefit that these new agents may bring to current endocrine therapies for breast cancer.
Exploring Novel Immune-Related Toxicities and Endpoints with Immune-Checkpoint Inhibitors in Non-Small Cell Lung Cancer
Authors: Chow Laura QM
Published: February 2020

Because of dramatic tumor regressions reported with the anti-programmed death-1 (PD-1) and anti-programmed death ligand-1 (PDL-1) antibodies inhibiting the PD-1 immune checkpoint, non-small cell lung cancer (NSCLC) is now recognized as an immune-modifiable disease. As responses were observed in smaller numbers in phase I trials, the immunologic profiles and unique toxicities of these agents have not been fully established in NSCLC. Moreover, PD-1 checkpoint inhibitors in development by different companies may demonstrate diverse spectrums of activity and toxicity. Although the cytotoxic T-lymphocyte antigen-4 (CTLA-4) checkpoint inhibitors in earlier phase studies appeared to have less impressive responses in NSCLC, their safety profile has been more broadly defined. The anti-CTLA-4 antibody, ipilimumab, has the best characterized immune-related toxicities (predominantly skin, gastrointestinal, hepatic, and endocrine) and management strategies in melanoma. Despite the lack of studies directly comparing these agents, toxicities from PD-1 inhibition seem milder than those of CTLA-4 inhibition, with distinct toxicities of pneumonitis infrequently observed with the BMS-936558 anti-PD-1 antibody, nivolumamb, and frequent mild infusion reactions reported with the BMS-936559 anti-PDL-1 antibody. As lungs are critical organs often already compromised in NSCLC patients, immune-mediated pneumonitis can cause worrisome morbidity and mortality. Even though immune checkpoint inhibitors are being rapidly developed in a multitude of trials, optimal immune-mediated toxicity management has not been determined, is evolving, and will be further explored. Early diagnosis and symptom management with corticosteroids form the basis of treatment. Assessment of new immune-response criteria and use of primary endpoints of overall survival (OS) will be important in the development of these immunotherapies in NSCLC.
Aberrant Epigenetic Regulation: A Central Contributor to Lung Carcinogenesis and a New Therapeutic Target
Authors: Juergens Rosalyn A. , Rudin Charles M.
Published: February 2020

Carcinogenesis is driven by a combination of genetic and epigenetic abnormalities. Aberrancies in gene promoter methylation patterns and histone acetylation are associated with silencing of tumor suppressor genes in lung cancer and other solid tumors. Identification of key epigenetic modifications has been shown to be prognostic in early-stage non-small cell lung cancer. Previous clinical trials aimed at modifying the epigenome with single-agent demethylating agents or histone deacetylase inhibitors given at maximally tolerated doses have provided disappointing results. A recent clinical trial using a combination of a demethylating agent and a histone deacetylase inhibitor at “epigenetically targeted” doses concomitantly has shown promising results, including a patient with a complete objective response. Biomarkers associated with this clinical trial suggest that patients who undergo robust demethylation, as detected in the peripheral blood after a month on treatment, identifies those who gain the most benefit from this novel treatment strategy. Based on observations of unusually durable responses to subsequent therapy after administration of combined epigenetic therapy, epigenetic therapy may also play a role in “priming” patients to better respond to standard cytotoxic therapy or immunotherapy. This manuscript will review the data on the role of epigenetics in lung cancer and the history of epigenetic treatments in lung cancer spanning over the last 40 years.
Update on the Initial Therapy of Multiple Myeloma
Authors: Reece Donna
Published: February 2020

Advances in myeloma biology and the identification of new anti-myeloma agents have resulted in improved management of younger, transplant-eligible, and older patients. The first novel agents—thalidomide, bortezomib, and lenalidomide—have been integrated into induction therapy before autologous stem cell transplant (ASCT) as well as into first-line therapy in elderly individuals; phase III trials have established the superiority of these approaches in terms of better response rates, progression-free survival (PFS), and, in some studies, overall survival. With more experience, improvements in dosing have decreased the toxicity of these regimens. Before ASCT, four phase III studies have shown that bortezomib-based regimens confer better outcomes than older regimens. Posttransplant consolidation and maintenance strategies with novel agents provide additional benefit, particularly in terms of a longer PFS. In the elderly population, novel agents can be combined with melphalan plus prednisone (MP). MP plus thalidomide and MP plus bortezomib are commonly utilized, and the regimen of MP plus lenalidomide with lenalidomide maintenance (MPR + R) produces superior response rates and longer PFS compared with MP alone. Prolonged maintenance with bortezomib plus thalidomide also appears to extend PFS when given following combinations of MP plus bortezomib. Treatment of very elderly patients, however, remains challenging due to comorbidities and side effects. Lenalidomide plus weekly dexamethasone is also effective in elderly patients, and results of a trial comparing this regimen with MP plus thalidomide should be available soon. Finally, better methods of risk stratification and the availability of even newer drugs will allow future refinements in myeloma treatment.
Evidence-Based Clinical Practice Guidelines on the Use of Sentinel Lymph Node Biopsy in Melanoma
Authors: Sondak Vernon K. , Wong Sandra L. , Gershenwald Jeffrey E. , Thompson John F.
Published: February 2020

Sentinel lymph node biopsy (SLNB) was introduced in 1992 to allow histopathologic evaluation of the “sentinel” node, that is, the first node along the lymphatic drainage pathway from the primary melanoma. This procedure has less risk of complications than a complete lymphadenectomy, and if the sentinel node is uninvolved by tumor the likelihood a complete lymphadenectomy would find metastatic disease in that nodal basin is very low. SLNB is now widely used worldwide in the staging of melanoma as well as breast and Merkel cell carcinomas. SLNB provides safe, reliable staging for patients with clinically node-negative melanomas 1 mm or greater in thickness, with an acceptably low rate of failure in the sentinel node-negative basin. Evidence-based guidelines jointly produced by ASCO and the Society of Surgical Oncology (SSO) recommend SLNB for patients with intermediate-thickness melanomas and also state that SLNB may be recommended for patients with thick melanomas. Major remaining areas of uncertainty include the indications for SLNB in patients with thin melanomas, pediatric patients, and patients with atypical melanocytic neoplasms; the optimal radiotracers and dyes for lymphatic mapping; and the necessity of complete lymphadenectomy in all sentinel node-positive patients.
Do Our Current Clinical Trial Designs Help to Guide Clinical Practice?
Authors: Blay Jean-Yves , Derbel Olfa , Ray-Coquard Isabelle
Published: February 2020

There is a markedly increasing contrast between the current refinement of nosologic classification of sarcoma integrating molecular typing with a growing number of subtypes and the usually standardized approach proposed in clinical practice guidelines for both local and systemic treatment. Although gastrointestinal stromal tumor (GIST), dermatofibrosarcoma protuberans, and a few other subtypes now have specific therapeutic strategies, the majority of sarcomas are still lumped together in clinical trials investigating novel therapeutic options. These trials may not provide sufficient information to guide routine clinical practice. Proof-of-concept trials exploring a targeted agent in a selected molecular subtype, randomized phase II trials, and trials focusing on histologic subtypes—all integrating translational research and aiming to identify the mechanisms of sensitivity and resistance to the treatment—are needed. This paper discusses the limitations of previous clinical trial designs to guide clinical practice in this complex context.
Possibilities and Prospects for the Development of Criminalistics
Authors: Hrehorowicz Małgorzata
Published: February 2020

The aim of this paper is to present the possibilities and prospects for the development of modern criminalistics. Discussion of this matter is of importance due to the observa-tion that criminalistics has, of late, lost its original form. The new techniques, including forensic analysis and biometrics, for example, are applied in traditional criminalistics. Fields of knowledge such as forensic archeology and forensic entomology play a signifi-cant role in solving common crimes and are also gradually forming part of criminalistics. There are still no effective tools, however, to combat economic crime. This paper presents the research capabilities that academic research institutes have in this field and possible ways to equip the authority conducting the proceedings with algorithms for identify-ing and combating economic crime. The paper is divided into three parts. The first part demonstrates the shortcomings of criminalistics in terms of the fight against economic crime. The second part presents the author’s achievements, such as establishing the types of economic opinions and presenting typical traces of economic crime. The third part presents the possibilities for further development of criminalistics.
Digital Currencies Trading under Polish and EU Public Law
Authors: Bałdowski Michał
Published: February 2020

Digital currencies are a worldwide phenomenon gaining an increasing interest among investors, economists and legal scholars. They are used mainly as a new mean of ex-change and as a new way of investing funds, since the rapid changes in their value allow to gain extraordinary profits. Up to this point the legal status of digital currencies has not been clearly established under neither Polish nor EU public law, although some of the existing regulations may be indirectly applied to them. Under current regulations digital currencies cannot be treated as a legal mean of payment, as an electronic money nor a financial instrument. Creation of a complex regulation regarding digital currencies and granting administrative authorities supervisory powers over their trade seems to be necessary. Because of the evolution of financial markets, classifying digital currencies as financial instruments is a possible way of regulating their trade.
Kinetic models of the extraction of vanillic acid from pumpkin seeds
Authors: Mitić Milan , Janković Sonja , Mašković Pavle , Arsić Biljana , Mitić Jelena , Ickovski Jovana
Published: February 2020

Vanillic acid is used in the food industry and perfumery, and the optimization of its extraction process from the natural source is important for saving time and money. The presence of vanillic acid in pumpkin seeds was proven using HPLC analysis. Computational optimization of the extraction shows that for the concentration of ethanol 40% and solmodul: V/m=20, the optimum condition for the extraction of vanillic acid from pumpkin seeds was 100 min and 450C. The estimation of fitting for each kinetic model to the experimental kinetic data was performed using the root mean square, standard deviation, and the correlation coefficient. Ponomarev model was shown as the most suitable with the highest accuracy among the six considered kinetic models. The enthalpy and entropy changes were positive, while the Gibbs free energy was negative and decreased when temperature increased during the thermodynamic analysis. Therefore, the extraction of vanillic acid from pumpkin seeds was endothermic, spontaneous, and irreversible.
Block-Adaptive Cross Approximation of Discrete Integral Operators
Authors: Bauer Maximilian , Bebendorf Mario
Published: February 2020

In this article, we extend the adaptive cross approximation (ACA) method known for the efficient approximation of discretisations of integral operators to a block-adaptive version.
While ACA is usually employed to assemble hierarchical matrix approximations having the same prescribed accuracy on all blocks of the partition, for the solution of linear systems, it may be more efficient to adapt the accuracy of each block to the actual error of the solution as some blocks may be more important for the solution error than others.
To this end, error estimation techniques known from adaptive mesh refinement are applied to automatically improve the blockwise matrix approximation.
This allows to interlace the assembling of the coefficient matrix with the iterative solution.