bluuebunny/crossref_metadata_2025 huggingface dataset:
Simple Post-Processing of Continuous Glucose Monitoring Measurements Improves Endpoints in Clinical Trials
Authors: Jensen Morten Hasselstrøm , Dethlefsen Claus , Hejlesen Ole , Vestergaard Peter
Published: May 2019

Background:

Continuous glucose monitoring (CGM) is a powerful tool to be considered both in clinical practice and clinical trials. However, CGM has been criticized for being inaccurate for many reasons including a physiological delay. This study sought to investigate the current delay issue and propose a simple post-processing procedure.

Method:

More than a million hours of the Dexcom G4 CGM from 472 subjects investigated in a state-of-the-art clinical trial were analyzed by time shifting the CGM measurements and comparing them to plasma glucose (PG) measurements. The resultant CGM measurements were then assessed in relation to real-world clinical research endpoints.

Results:

A CGM time shift of −9 minutes was optimal and reduced mean absolute relative difference (MARD) statistically significantly with 1.0% point. The MARD reduction resulted in better clinical research endpoints of hypoglycemia and postprandial glucose increments.

Conclusions:

The delay in CGM is still an issue. The delay in this study was identified to be 9 minutes compared to PG. With a simple post-processing approach of time shifting the CGM measurements with −9 minutes, it was possible to obtain a statistically significantly lower MARD and subsequently obtain clinical research endpoints of improved validity.
Cutaneous squamous cell carcinoma arising in hidradenitis suppurativa: A case report
Authors: Roy Catherine F , Roy Simon F , Ghazawi Feras M , Patocskai Erica , Bélisle Annie , Dépeault Alexandra
Published: May 2019

We present a case of a 64-year-old man who presented with a rapidly growing tumor in the left buttock and intergluteal cleft area, which was affected by hidradenitis suppurativa. The patient was on tumor necrosis factor-alpha inhibitors for hidradenitis suppurativa for 2 years prior to the development of the mass. Initial biopsy of the mass showed a well-differentiated squamous cell carcinoma with spindle cells and positive epithelial immunomarkers. Subsequent excisional biopsy of the tumor showed an infiltrating poorly differentiated squamous cell carcinoma composed of islands of atypical sarcomatoid spindle cells. Squamous cell carcinoma arising in hidradenitis suppurativa is a rare complication which may occur secondary to chronic inflammation and epidermal hyperproliferation in hidradenitis suppurativa–affected areas.
Effect Size Reporting Practices in Applied Linguistics Research: A Study of One Major Journal
Authors: Wei Rining , Hu Yuhang , Xiong Jianhui
Published: May 2019

Many surveys of effect size (ES) reporting practices have been conducted in social science fields such as psychology and education, but few such studies are available in applied linguistics. To bridge this gap and to echo the recent calls for more robust statistics from scholars in applied linguistics and beyond, this study represents the first attempt, in the field of applied linguistics, to focus upon ES reporting practices. With an innovative “two-standards” approach for coding, which overcomes the limitations with similar studies in other social science fields (e.g., communication), this study assesses the ES reporting practices over a span of 6 years in a major journal. Findings include the following: (a) the ES reporting rate is about 50% and (b) some improvement of ES reporting over time is in evidence. Future research directions (e.g., examining whether and how ES is interpreted after being reported) are suggested.
External Stakeholder Management Strategies and Resources in Megaprojects: An Organizational Power Perspective
Authors: Ninan Johan , Mahalingam Ashwin , Clegg Stewart
Published: May 2019

Megaprojects involve managing external stakeholders with diverse interests. Using an Indian megaproject case study, we discuss how the project managed external stakeholders through strategies such as: persuasion, deputation, give and take, extra work for stakeholders, and flexibility. Drawing from theories and frameworks of power, we explain how these strategies emerge through a process of tactical clustering. We also analyze the resources available to the project team—such as recruitment discretion, government backing, and fund discretion—that influence these power dynamics and enable these strategies. We posit that changes in the resource base can significantly affect strategic action and, in turn, megaproject outcomes.
Targeting glycogen synthase kinase 3 for therapeutic benefit in lymphoma
Authors: Wu Xiaosheng , Stenson Mary , Abeykoon Jithma , Nowakowski Kevin , Zhang Lianwen , Lawson Joshua , Wellik Linda , Li Ying , Krull Jordan , Wenzl Kerstin , Novak Anne J. , Ansell Stephen M. , Bishop Gail A. , Billadeau Daniel D. , Peng Kah Whye , Giles Francis , Schmitt Daniel M. , Witzig Thomas E.
Published: May 2019

Targeting the B-cell receptor and phosphatidylinositol 3-kinase/mTOR signaling pathways has shown meaningful, but incomplete, antitumor activity in lymphoma. Glycogen synthase kinase 3 (GSK3) α and β are 2 homologous and functionally overlapping serine/threonine kinases that phosphorylate multiple protein substrates in several key signaling pathways. To date, no agent targeting GSK3 has been approved for lymphoma therapy. We show that lymphoma cells abundantly express GSK3α and GSK3β compared with normal B and T lymphocytes at the messenger RNA and protein levels. Utilizing a new GSK3 inhibitor 9-ING-41 and by genetic deletion of GSK3α and GSK3β genes using CRISPR/CAS9 knockout, GSK3 was demonstrated to be functionally important to lymphoma cell growth and proliferation. GSK3β binds to centrosomes and microtubules, and lymphoma cells treated with 9-ING-41 become arrested in mitotic prophase, supporting the notion that GSK3β is necessary for the progression of mitosis. By analyzing recently published RNA sequencing data on 234 diffuse large B-cell lymphoma patients, we found that higher expression of GSK3α or GSK3β correlates well with shorter overall survival. These data provide rationale for testing GSK3 inhibitors in lymphoma patient trials.
Cysteine depletion targets leukemia stem cells through inhibition of electron transport complex II
Authors: Jones Courtney L. , Stevens Brett M. , D’Alessandro Angelo , Culp-Hill Rachel , Reisz Julie A. , Pei Shanshan , Gustafson Annika , Khan Nabilah , DeGregori James , Pollyea Daniel A. , Jordan Craig T.
Published: May 2019

We have previously demonstrated that oxidative phosphorylation is required for the survival of human leukemia stem cells (LSCs) from patients with acute myeloid leukemia (AML). More recently, we demonstrated that LSCs in patients with de novo AML rely on amino acid metabolism to drive oxidative phosphorylation. Notably, although overall levels of amino acids contribute to LSC energy metabolism, our current findings suggest that cysteine may be of particular importance for LSC survival. We demonstrate that exogenous cysteine is metabolized exclusively to glutathione. Upon cysteine depletion, glutathione synthesis is impaired, leading to reduced glutathionylation of succinate dehydrogenase A (SDHA), a key component of electron transport chain complex (ETC) II. Loss of SDHA glutathionylation impairs ETC II activity, thereby inhibiting oxidative phosphorylation, reducing production of ATP, and leading to LSC death. Given the role of cysteine in driving LSC energy production, we tested cysteine depletion as a potential therapeutic strategy. Using a novel cysteine-degrading enzyme, we demonstrate selective eradication of LSCs, with no detectable effect on normal hematopoietic stem/progenitor cells. Together, these findings indicate that LSCs are aberrantly reliant on cysteine to sustain energy metabolism, and that targeting this axis may represent a useful therapeutic strategy.
Blood DNA methylation and breast cancer risk: a meta-analysis of four prospective cohort studies
Authors: Bodelon Clara , Ambatipudi Srikant , Dugué Pierre-Antoine , Johansson Annelie , Sampson Joshua N. , Hicks Belynda , Karlins Eric , Hutchinson Amy , Cuenin Cyrille , Chajès Veronique , Southey Melissa C. , Romieu Isabelle , Giles Graham G. , English Dallas , Polidoro Silvia , Assumma Manuela , Baglietto Laura , Vineis Paolo , Severi Gianluca , Herceg Zdenko , Flanagan James M. , Milne Roger L. , Garcia-Closas Montserrat
Published: May 2019

Background

Environmental and genetic factors play an important role in the etiology of breast cancer. Several small blood-based DNA methylation studies have reported risk associations with methylation at individual CpGs and average methylation levels; however, these findings require validation in larger prospective cohort studies. To investigate the role of blood DNA methylation on breast cancer risk, we conducted a meta-analysis of four prospective cohort studies, including a total of 1663 incident cases and 1885 controls, the largest study of blood DNA methylation and breast cancer risk to date.

Methods

We assessed associations with methylation at 365,145 CpGs present in the HumanMethylation450 (HM450K) Beadchip, after excluding CpGs that did not pass quality controls in all studies. Each of the four cohorts estimated odds ratios (ORs) and 95% confidence intervals (CI) for the association between each individual CpG and breast cancer risk. In addition, each study assessed the association between average methylation measures and breast cancer risk, adjusted and unadjusted for cell-type composition. Study-specific ORs were combined using fixed-effect meta-analysis with inverse variance weights. Stratified analyses were conducted by age at diagnosis (< 50, ≥ 50), estrogen receptor (ER) status (+/−), and time since blood collection (< 5, 5–10, > 10 years). The false discovery rate (q value) was used to account for multiple testing.

Results

The average age at blood draw ranged from 52.2 to 62.2 years across the four cohorts. Median follow-up time ranged from 6.6 to 8.4 years. The methylation measured at individual CpGs was not associated with breast cancer risk (q value > 0.59). In addition, higher average methylation level was not associated with risk of breast cancer (OR = 0.94, 95% CI = 0.85, 1.05; P = 0.26; P for study heterogeneity = 0.86). We found no evidence of modification of this association by age at diagnosis (P = 0.17), ER status (P = 0.88), time since blood collection (P = 0.98), or CpG location (P = 0.98).

Conclusions

Our data indicate that DNA methylation measured in the blood prior to breast cancer diagnosis in predominantly postmenopausal women is unlikely to be associated with substantial breast cancer risk on the HM450K array. Larger studies or with greater methylation coverage are needed to determine if associations exist between blood DNA methylation and breast cancer risk.
The Changing Face of HIV-Associated Malignancies: Advances, Opportunities, and Future Directions
Authors: Lurain Kathryn , Yarchoan Robert , Ramaswami Ramya
Published: May 2019

Because of tremendous advances in HIV care, the survival of many people living with HIV (PLWH) now approaches that of the general population. This has led to a shift in the types of malignancies diagnosed among PLWH from AIDS-defining cancers during the height of the HIV epidemic toward more non-AIDS−defining cancers and age-related incidental cancers in the last 2 decades. Despite these trends, positive cancer outcomes still lag behind patients without HIV, and many PLWH never receive appropriate cancer therapy. We explore the reasons for the epidemiologic shift that has been observed, as well as the factors that influence treatment disparities. Furthermore, several studies have demonstrated similar cancer survival rates when PLWH and certain cancers receive the same treatment as those who are HIV-negative. Among possible solutions to improve cancer outcomes include increasing the inclusion of PLWH in clinical trials, using guidelines specific for the treatment of HIV-associated malignancies, and incorporating a multidisciplinary approach to cancer management in PLWH.
Enrollment of Racial Minorities in Clinical Trials: Old Problem Assumes New Urgency in the Age of Immunotherapy
Authors: Nazha Bassel , Mishra Manoj , Pentz Rebecca , Owonikoko Taofeek K.
Published: May 2019

Minority U.S. populations are underrepresented in cancer clinical trials. This review appraises the impact of the disparity in clinical trial participation by minority patients in the current era of cancer immunotherapy. Enrollment on pivotal trials leading to U.S. regulatory approval of immune checkpoint inhibitors showed poor representation of minority ethnic groups. Specifically, we found that black patients constitute less than 4% of all patients enrolled across multiple trials that supported the approval of immune checkpoint inhibitors for the treatment of lung cancer. Similar underrepresentation was observed for trials conducted in renal cell carcinoma and other tumor types. Since efficacy of immunotherapy is only observed in a subset of patients, the use of predictive biomarkers to identify responders along with new strategies to expand the benefit to a larger subset of patients are current areas of active investigation. The inadequate representation of minority patients on immunotherapy clinical trials could perpetuate outcome disparity because the unique biology of the host and the tumors from this subpopulation is not accounted for as new treatment algorithms to guide optimal use of immunotherapy are developed for use in the real world.
The Value and Future Developments of Multidisciplinary Team Cancer Care
Authors: Selby Peter , Popescu Razvan , Lawler Mark , Butcher Hugh , Costa Alberto
Published: May 2019

Multidisciplinary teams (MDTs) have been recommended as a key part of best cancer care for 25 years. Here, we set out the functions and approaches of MDTs and review their impact. Although the literature is patchy in quality, MDTs contribute to improving cancer care and outcomes. They must be well organized, efficient, and well led; work with sound and timely information; and communicate well within the team and with their patients. Patients need carefully prepared information to help them share in the decision-making process. MDTs will be improved by a series of ongoing innovative developments. Increasing information from molecular pathology will increase the precision of their decisions, although the technologies remain expensive and may not be accessible in all countries for some time. New point-of-care testing technologies will improve the quality and timeliness of testing. Good informatics is essential to deliver the information to patients and the MDT. MDTs should be research active, delivering clinical trials, and this should improve outcomes for all of their patients. Patient engagement and empowerment in MDTs should improve patient satisfaction and outcomes. Patient-reported outcome measures will improve MDTs' insights into their patients’ problems and symptoms and can improve patient outcomes.
Weight Management and Physical Activity for Breast Cancer Prevention and Control
Authors: Ligibel Jennifer A. , Basen-Engquist Karen , Bea Jennifer W.
Published: May 2019

Observational evidence has consistently linked excess adiposity and inactivity to increased breast cancer risk and to poor outcomes in individuals diagnosed with early-stage, potentially curable breast cancer. There is less information from clinical trials testing the effect of weight management or physical activity interventions on breast cancer risk or outcomes, but a number of ongoing trials will test the impact of weight loss and other lifestyle changes after cancer diagnosis on the risk of breast cancer recurrence. Lifestyle changes have additional benefits beyond their potential to decrease primary or secondary breast cancer risk, including improvements in metabolic parameters, reduction in the risk of comorbidities such as diabetes and heart disease, improvement of physical functioning, and mitigation of side effects of cancer therapy. Despite these myriad benefits, implementation of lifestyle interventions in at-risk and survivor populations has been limited to date. This article reviews the evidence linking lifestyle factors to breast cancer risk and outcomes, discusses completed and ongoing randomized trials testing the impact of lifestyle change in primary and secondary breast cancer prevention, and reviews efforts to implement and disseminate lifestyle interventions in at-risk and breast cancer survivor populations.
Advanced Non–Small Cell Lung Cancer: Sequencing Agents in the EGFR-Mutated/ALK-Rearranged Populations
Authors: Singhi Eric K. , Horn Leora , Sequist Lecia V. , Heymach John , Langer Corey J.
Published: May 2019

Personalized therapy based on actionable molecular markers has completely transformed the therapeutic landscape in advanced non–small cell lung cancer (NSCLC). In less than 15 years, multiple molecular targets, led by EGFR and anaplastic lymphoma kinase (ALK), have been identified, and myriad oral tyrosine kinase inhibitors (TKIs) are now available to target these oncogenic drivers, with the expectation that the majority of patients will respond to treatment and that progression-free survival (PFS) will exceed 10 to 30 months, far better than we observed historically with chemotherapy alone. As a result, prognosis has improved dramatically in this subset of patients. Osimertinib has largely displaced first- and second-generation EGFR TKIs, including gefitinib, erlotinib, and afatinib, in the management of EGFR-mutated NSCLC. PFS now exceeds 18 months, and central nervous system penetrance is enhanced. Dacomitinib has the distinction of being the first EGFR TKI to demonstrate a survival advantage compared with older TKIs. Recent data suggest therapeutic additivity, if not synergy, for the concurrent use of chemotherapy, as well as monoclonal antibodies targeting angiogenesis, with EGFR TKIs. Alectinib and brigatinib, very specific ALK inhibitors, have proven superior to the erstwhile standard crizotinib in treatment-naive ALK+ NSCLC; PFS now routinely exceeds 2 to 3 years. In addition, these newer agents have far superior central nervous system penetration. As a result, many patients with ALK+ advanced NSCLC with brain metastases, even some who are symptomatic, can defer or indefinitely avoid brain irradiation. Mechanisms of resistance in ALK are complicated, with multiple new agents being developed in this arena. Although many patients with molecular targets can reasonably expect to live 5 years or more, the emergence of molecular resistance is virtually inevitable. In this regard, systemic platinum-based chemotherapy is the final common therapeutic pathway for virtually all patients with oncogenic drivers. Standard regimens include pemetrexed and carboplatin, as well as the E4599 regimen, combination solvent-based paclitaxel, carboplatin, and bevacizumab. Checkpoint inhibitors, as single agents, have not yielded much benefit, even in those with high levels of PD-L1 expression. However, in a subanalysis of patients with ALK and EGFR mutations enrolled in IMpower150, the addition of atezolizumab to the E4599 regimen led to a major overall survival benefit (hazard ratio < 0.40). In the absence of systemic chemotherapy, combining checkpoint inhibitors with TKIs in this setting remains investigational; several studies have demonstrated untoward pulmonary and hepatic toxicity.
Role of Immunotherapy in Small Cell Lung Cancer, Thymic Epithelial Tumors, and Mesothelioma
Authors: Hann Christine L. , Scherpereel Arnaud , Hellyer Jessica A. , Wakelee Heather A.
Published: May 2019

The introduction of programmed death receptor ligand-1 (PD-L1) and programmed death receptor-1 (PD-1) inhibitors into the field of non–small cell lung cancer (NSCLC) was practice changing. The pivotal trials consistently showed a clinically meaningful improvement in overall survival (OS) for patients with driver mutation–negative NSCLC, a field in which outcomes had been stagnant for decades. The success of immune checkpoint inhibitor (ICI) therapy in NSCLC has led to enthusiasm to expand the reach of these drugs into other thoracic malignancies such as thymic epithelial tumors (TETs), mesothelioma, and small cell lung cancer (SCLC). Unfortunately, the improvement in outcomes with ICI therapy in these rarer thoracic tumors has been somewhat modest, and in the case of thymoma, rates of adverse events are too high to routinely justify their use. Although the response rates seen in ICI therapy in these tumor types are similar to those seen with other available single-agent therapies for advanced disease, ICIs do present another option for clinicians treating patients with mesothelioma, small cell carcinoma, and thymic carcinoma (TC), diseases in which approved treatment options are limited. Here we review the latest trials of ICI therapy in mesothelioma, SCLC, and TETs.
Interpreting Randomized Clinical Trials in Gynecologic Oncology Surgery: Does One Size Fit All?
Authors: Cantrell Leigh A. , Pfisterer Jacobus , Boggess John , Duska Linda R.
Published: May 2019

Randomized clinical trials (RCTs) are considered the gold standard of clinical research. They are designed to eliminate bias and to produce objective and generalizable results about new treatment paradigms. Although RCTs have recognized limitations, including long completion time and high cost, they also have transformed clinical research and improved the quality of health care by rigorously evaluating countless new treatment options. Surgical RCTs present their own unique set of limitations including an inability to standardize surgical technique and expertise; an inability to overcome enrollment bias by enrolling surgeons; and a lack of generalizability with respect to institutional resources and abilities.

Here, we discuss surgical RCTs in two domains: upfront management of advanced ovarian cancer and surgical management of early-stage cervical cancer. Familiarity with the abundant retrospective data available for both of these clinical scenarios as well as recognition of the strengths and limitations of surgical RCTs are critical to determine the best treatment for an individual patient.
Effective Communication for Newly Diagnosed Pediatric Patients With Cancer: Considerations for the Patients, Family Members, Providers, and Multidisciplinary Team
Authors: Dobrozsi Sarah , Trowbridge Amy , Mack Jennifer W. , Rosenberg Abby R.
Published: May 2019

Hearing that a child has been diagnosed with cancer is invariably difficult for both patients and their caregivers. Effective communication among patients, caregivers, and medical teams is necessary not only to deliver information and facilitate cancer care delivery but also to support patient and family coping and well-being. In this review, we focus on early communication in pediatric oncology care to (1) highlight the importance of communication between clinicians and patients and within the medical team and (2) describe resources and opportunities for clinicians to improve communication skills. For example, communication between patients and the medical team has several core functions, including the development of shared knowledge and decision-making and the formation of a therapeutic relationship. High-quality communication, regardless of the news being shared, supports and facilitates patient and parent adjustment to diagnosis, hope, and trust. Communication within the medical team supports the delivery of high-quality, personalized care. Despite these critical roles of communication in pediatric cancer care and evidence suggesting communication skills can be learned, formal training is limited. Resources include educational efforts, practical tools, and specific strategies to enhance systematic multidisciplinary team communication. Taken together, continued recognition of the importance of communication in pediatric cancer care has the potential to improve patient, family, and clinician experiences.
Point/Counterpoint: Do We De-escalate Treatment of HPV-Associated Oropharynx Cancer Now? And How?
Authors: Wirth Lori J. , Burtness Barbara , Nathan Cherie-Ann O. , Grégoire Vincent , Richmon Jeremy
Published: May 2019

HPV-positive (HPV+) oropharyngeal carcinoma (OPC) continues to increase in incidence across the globe. Multimodality treatment offers a high likelihood of cure in HPV+ OPC but comes at a high cost of treatment-related morbidity. As a result, de-escalation of treatment to limit toxicity without compromising high cure rates has emerged as a major trend in head and neck cancer clinical research. Primary surgery with minimally invasive resection of the primary disease may allow for the elimination of chemotherapy and decrease radiation dose intensity. Primary dose-reduced radiation, with or without systemic therapy, is also under study, as is replacing concurrent cisplatin with newer systemic agents. Numerous institutional series and phase II trials have been presented, and the first generation of de-escalation randomized phase III trials have now been published. The various combinatorial multimodality strategies to achieve less intensive and toxic therapy are many. Has the time come for de-escalation as a standard approach to HPV+ OPC? The pros and cons, as well as the best approaches for de-escalated treatment of HPV+ OPC, are debated here.
Immunotherapy Mythbusters in Head and Neck Cancer: The Abscopal Effect and Pseudoprogression
Authors: Lauber Kirsten , Dunn Lara
Published: May 2019

Atypical patterns of response to immunotherapy have been observed, including the abscopal effect and pseudoprogression. Although both are infrequent in head and neck squamous cell carcinoma, the synergism between radiation and checkpoint blockade therapy has generated excitement for exploitation of the abscopal effect. However, robust abscopal tumor regression observed in preclinical models has not translated to clinical experience. The optimal sequencing of radiotherapy with immunotherapy and dosage of radiation to target lesions to elicit this effect is being explored in clinical trials. Predictive markers of efficacy must be studied further to identify patients who may benefit from an abscopal effect and continued checkpoint inhibitor blockade beyond initial signs of radiologic progression. Given the rarity of pseudoprogression in head and neck squamous cell carcinoma, patients should be carefully selected to continue on immunotherapy, despite early radiologic signs of progression, given the risk of aggressive true progression and clinical deterioration that may result in missed opportunities for alternate treatments.
Management for Different Glioma Subtypes: Are All Low-Grade Gliomas Created Equal?
Authors: Tom Martin C. , Cahill Daniel P. , Buckner Jan C. , Dietrich Jörg , Parsons Michael W. , Yu Jennifer S.
Published: May 2019

Following the identification of key molecular alterations that provided superior prognostication and led to the updated 2016 World Health Organization (WHO) Central Nervous System (CNS) Tumor Classification, the understanding of glioma behavior has rapidly evolved. Mutations in isocitrate dehydrogenase (IDH) 1 and 2 are present in the majority of adult grade 2 and 3 gliomas, and when used in conjunction with 1p/19q codeletion for classification, the prognostic distinction between grade 2 versus grade 3 is diminished. As such, the previously often used term of “low-grade glioma,” which referred to grade 2 gliomas, has now been replaced by the phrase “lower-grade glioma” to encompass both grade 2 and 3 tumors. Additional molecular characterization is ongoing to even further classify this heterogeneous group of tumors. With such a colossal shift in the understanding of lower-grade gliomas, management of disease is being redefined in the setting of emerging molecular-genetic biomarkers. In this article, we review recent progress and future directions regarding the surgical, radiotherapeutic, chemotherapeutic, and long-term management of adult lower-grade gliomas.
Many Shades of Disparities in Myeloma Care
Authors: Ganguly Siddhartha , Mailankody Sham , Ailawadhi Sikander
Published: May 2019

Treatment of multiple myeloma (MM) has notably evolved with improved patient outcomes over the past few years. Several new drugs have become available, and large national and international clinical trials have set the stage for evidence-based medicine guidelines for the treatment of patients with MM. Although patient outcomes have undoubtedly improved, data increasingly show that several disparities exist at varying levels of health care and that these disparities make the care of patients heterogenous and potentially result in inferior outcomes. These disparities have been described with regard to patient age, race/ethnicity, rural-urban residence, socioeconomic status, and insurance type, among other factors. Looking at the global picture of MM care, there is substantial variation among different countries, primarily depending on the disparate availability of anti-MM drugs and access to quality health care across the world, limiting the delivery of innovative therapeutic approaches at the individual patient level. The causes of these national and international disparities could be multifactorial, intricate, and difficult to isolate. Yet the ongoing research in this field is encouraging, and there seems to be growing momentum to understand such disparities and their causes. It is hoped that this research will lead to solutions that can be implemented in the near future. This review focuses on certain aspects of disparities in MM care, highlighting disparities among different racial/ethnic subgroups, rural-urban differences in America, and global disparities at an international level.
The Other Side of CAR T-Cell Therapy: Cytokine Release Syndrome, Neurologic Toxicity, and Financial Burden
Authors: Santomasso Bianca , Bachier Carlos , Westin Jason , Rezvani Katayoun , Shpall Elizabeth J.
Published: May 2019

Immune effector cells, including T cells and natural killer cells, which are genetically engineered to express a chimeric antigen receptor (CAR), constitute a powerful new class of therapeutic agents to treat patients with hematologic malignancies. Several CAR T-cell trials have shown impressive remission rates in patients with relapsed/refractory hematologic cancers. Although the clinical responses of these agents in hematologic malignancies have been very encouraging, they have also produced substantial morbidity and occasionally mortality resulting from toxicity. With more experience and collaboration, hopefully the toxicities and the costs will come down, increasing the availability of CAR T cells to patients in need.
The Role of BRCA Testing in Hereditary Pancreatic and Prostate Cancer Families
Authors: Pilarski Robert
Published: May 2019

Beyond breast and ovarian cancers, mutations in the BRCA1 and BRCA2 genes increase risks for pancreatic and prostate cancers and contribute to the prevalence of these cancers. Mutations in a number of other genes have also been shown to increase the risk for these cancers as well. Genetic testing is playing an increasingly important role in the treatment of patients with pancreatic and prostate cancer and is now recommended for all patients with pancreatic or metastatic prostate cancer, as well as patients with high Gleason grade prostate cancer and a remarkable family history. Identification of an inherited mutation can direct evaluation of the patient for other cancer risks as well as identification and management of disease in at-risk relatives. Growing evidence suggests improved responses to PARP inhibitors and other therapies in patients with mutations in the BRCA and other DNA repair genes. Although more work must be done to clarify the prevalence and penetrance of mutations in genes other than BRCA1 and BRCA2 in patients with pancreatic and prostate cancer, in most cases, testing is now being done with a panel of multiple genes. Because of the complexities in panel testing and the increased likelihood of finding variants of uncertain significance, pre- and post-test genetic counseling are essential.
The Evolving Landscape of Chemotherapy in Newly Diagnosed Advanced Epithelial Ovarian Cancer
Authors: Monk Bradley J. , Randall Leslie M. , Grisham Rachel N.
Published: May 2019

The treatment of women with advanced-stage epithelial ovarian cancer (EOC) is aggressive surgical cytoreduction and a combination of platinum plus taxane chemotherapy. The timing and extent of surgery has direct implications on the selection of subsequent treatment as well as the prognosis of patients with EOC. Frontline chemotherapeutic regimens have evolved through a series of large multi-institutional randomized clinical trials that focused on targeted agents as maintenance therapy. On June 13, 2018, the U.S. Food and Drug Administration (FDA) approved adding bevacizumab to adjuvant intravenous chemotherapy followed by maintenance based on the results of Gynecologic Oncology Group protocol 218. Maintenance olaparib was FDA-approved on December 19, 2018, for frontline maintenance among those with advanced EOC who respond to frontline chemotherapy and harbor a germline or somatic BRCA1 or BRCA2 mutation. This was based on the results of SOLO-1. Despite a strong rationale and extensive study, intraperitoneal chemotherapy has not been adopted in clinical practice. Alternatively, heated intraperitoneal chemotherapy has shown promise as a more tolerable and technically feasible method of regional therapy, but widespread application will require more evidence. Significant strides have also been made in understanding the biology of EOC, resulting in a personalized approach to first-line therapy. One approach calls for recognizing differences in histologic subtypes and molecular alterations, which may open up alternative therapeutic interventions.
One Size Does Not Fit All: Who Benefits From Maintenance After Frontline Therapy for Follicular Lymphoma?
Authors: Roschewski Mark , Hill Brian T.
Published: May 2019

Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma and the most common indolent B-cell malignancy. The disease often presents in advanced stage and can often be observed before initiation of therapy. Although the incidence is only approximately 15,000 new cases per year, the prevalence is substantially higher owing to the favorable overall survival (OS) of most patients. The most impactful advance responsible for the improvement of OS in FL was the introduction of the anti-CD20 monoclonal antibody (mAb) rituximab over 20 years ago. Phase III trials demonstrate that rituximab improves the OS in FL when combined with chemotherapy. However, unlike aggressive B-cell lymphomas, advanced stage FL is generally incurable and often displays a pattern of progressively shorter remissions with subsequent lines of therapy. Hence, maintenance strategies have been developed to prolong remissions achieved with frontline therapy. The value of maintenance after frontline therapy has been most extensively studied with extended treatment of anti-CD20 mAb, but recent approaches include chemotherapy-free combinations and targeted therapies given for extended durations. Here, we review relevant data that provide rationale in support of maintenance therapy in FL as well as the risks and limitations of a “one-size-fits-all” approach. Importantly, we note the biologic and clinical heterogeneity across patients with FL that must be considered when making clinical decisions. Finally, we highlight ongoing research that explores response-adapted approaches based on the depth of response as defined by PET scans and assays for minimal residual disease (MRD) that aim to better personalize individual management strategies.
Addressing Depression, Burnout, and Suicide in Oncology Physicians
Authors: McFarland Daniel C. , Hlubocky Fay , Susaimanickam Bibiana , O’Hanlon Robin , Riba Michelle
Published: May 2019

The best practice of oncology relies heavily on a mentally and physically healthy oncology clinician workforce. Historically, the mental health of physicians and clinicians has largely been ignored, perhaps in the spirit of a collective collusion to maintain the illusion of Oslerian equanimity. With exceedingly high and unacceptable rates of burnout and suicide in the practice of medicine and oncology in particular, a tacit disavowal of the problem is no longer acceptable. The practice of oncology presents several unique work-related issues that challenge the mental health of its clinicians and contribute to burnout, depression, and suicide. Oncologists work with patients at or nearing the end of life and face administrative and insurance hurdles to obtain needed anticancer medications, heavy workloads, paperwork and electronic medical record demands, and keeping up with expanding pertinent oncologic knowledge for practice and public relations issues. Although oncologists exhibit higher rates of depression with longer work hours than many other internal medicine colleagues, they have higher job satisfaction ratings. This article will (1) review the mental health of professionals in oncology, (2) explore similarities and differences between depression and burnout, (3) describe the unique nature of the oncology work environment, (4) examine suicide and its implications for oncology, and (5) review the evidence for interventions to prevent burnout and suicide. Although individual and system-level strategic approaches to the problem of burnout and its consequences are effective, combinatorial approaches offer the most hope for affecting the most long-lasting change and lessening burnout, depression, and suicide in oncology.
More Versus Less Therapy for Older Adults With Acute Myeloid Leukemia: New Perspectives on an Old Debate
Authors: Klepin Heidi D. , Estey Elihu , Kadia Tapan
Published: May 2019

Most patients with newly diagnosed acute myeloid leukemia (AML) are at least age 65 and continue to have short survival, with many patients receiving no specific anti-AML therapy, particularly if they are older than age 75. Although consensus regarding optimal treatment of this growing population is lacking, treatment options are expanding even for the oldest patients. A fundamental question when seeing an older patient with AML is whether to recommend “more intensive” or “less intensive” induction therapy. Existing data can support more intensive treatment strategies for selected older adults, although there is growing evidence to support less intensive therapies as well. Randomized trials to provide clear comparisons between treatment strategies among well-characterized older adult populations are lacking. Reliance on age alone to determine treatment choice is problematic, as “fitness” or “unfitness” varies dramatically among patients of the same chronologic age and remains poorly characterized in existing studies. This article will provide differing perspectives on the “more” versus “less” question, with particular attention to recent drug approvals. Issues relevant to both treatment decision-making in practice and alternative trial design to inform gaps in knowledge will be discussed. Given the heterogeneity, an important conclusion will be that there is unlikely to be a single best approach and that appropriate decision-making requires considerations of many factors specific to individual patients.
A Career in Lung Cancer: Pushing Beyond Chemotherapy
Authors: Patil Pradnya Dinkar , Shepherd Frances , Johnson David H.
Published: May 2019

The landscape of treatments for non–small cell lung cancer (NSCLC) has evolved dramatically over the past 3 decades. A better understanding of the disease biology and identification of actionable genetic alterations heralded an era of targeted therapies that has led to unprecedented survival benefits in patients with oncogene-driven NSCLC. More recent breakthroughs in immunotherapy led to the development of immune checkpoint inhibitors that have changed the treatment paradigm for patients with advanced NSCLC because of their ability to produce durable responses, resulting in improved survival outcomes. Despite the unparalleled success of these agents, primary and acquired resistance to these therapies pose a formidable challenge. In this article, we provide an overview of the therapeutic advances in the treatment of NSCLC, mechanisms of resistance, and potential strategies to overcome resistance to targeted therapies and immune checkpoint inhibitors.
Modern Management of Central Nervous System Metastases in the Era of Targeted Therapy and Immune Oncology
Authors: Brastianos Priscilla , Davies Michael A. , Margolin Kim , Yu Helena A.
Published: May 2019

Metastases to the central nervous system (CNS) are associated with considerable morbidity and mortality in patients with cancer. Historically, very few systemic therapies have shown efficacy in this patient population. Emerging data are now demonstrating that whole-brain radiation therapy, previously considered the mainstay of treatment of brain metastases, is associated with high rates of neurotoxicity. In this new era of targeted therapy and immunotherapy, clinical outcomes are improving, and patients are living longer. Despite these improvements, there is an urgent need to design central nervous system–penetrant compounds that target the genetic mutations enriched in brain metastases and to bring these to clinical trials.
Quality Improvement at the Health System Level: Measurement, Risk Stratification, Disparity Populations, and Governance
Authors: Rocque Gabrielle Betty , Lennes Inga T. , Rhoads Kim Felder , Yu Peter Paul
Published: May 2019

Value-based health systems encompass a range of care-delivery models from small independent practices to large integrated delivery systems and academic medical centers. In addition, public and private payers, federal and state agencies, professional societies, and not-for-profit organizations collect and analyze data for quality and value improvement in health care–delivery outcomes. In this article, we review the multidimensional aspects of data collection, aggregation, analysis, and use for and by value-based health systems.
A Big World Made Small: Using Social Media to Optimize Patient Care
Authors: Subbiah Ishwaria M. , Hamilton Erika , Knoll Miriam , Shanahan Kelly , Meisel Jane
Published: May 2019

Emerging modalities of communication have transformed the landscape of information dissemination particularly in the context of health care. Within oncology, stakeholders in all roles have formed both role-specific and multidisciplinary communities within the modalities of social media. Two platforms with particularly high adoption and penetration within oncologic practice for clinicians and general oncologic care as well as for patients and the community have been Facebook and Twitter. On both platforms, patients have come together to form disease-specific (or even mutation-specific) groups ripe with discussion on all aspects of their cancer, including disease and treatment symptoms, novel therapeutics, and clinical trial participation. Similarly, clinicians have united within professional communities to facilitate collaboration and community building in this rapidly changing medical practice landscape. Here, we investigate the current state of stakeholder engagement within social media and review strategies and platforms to maximize the impact of social media for patients and clinicians.
Establishing a Mutually Respectful Environment in the Workplace: A Toolbox for Performance Excellence
Authors: Duma Narjust , Maingi Shail , Tap William D. , Weekes Colin D. , Thomas Charles R.
Published: May 2019

Most health care professionals spend a substantial amount of their time at the workplace. Our interactions with team members can define our daily experiences, impact our work performance, and influence our overall job satisfaction. Over the last years, how we interact with colleagues and patients has changed with the introduction of social media, a tenser political climate, and an evolving health care system. In oncology, a team can be composed of medical students, clinicians, and support and administrative staff within a heavy emotional environment where some of our patients are facing the risk of early mortality and most are dealing with the unmeasurable burden of cancer. Many of these factors can increase the risk for professionalism lapses. We discuss common challenges faced in the practice of cancer care, including the generational gap between medical trainees and senior members, gender disparities, and microaggressions. Microaggressions represent verbal, behavioral, and environmental indignities that communicate hostile, derogatory, and negative slights that insult a target person or group. Microaggressions should not be accepted as the norm in the workplace. It is essential to recognize these negative behaviors and manage them effectively to reduce or even prevent the long-term toxicities that these behaviors can bring to the workplace environment. Ultimately, we must acknowledge that these issues exist and remember that education and collaboration are the pillars of an inclusive workplace. We owe such efforts to our patients who deserve good care, to our partners in the care of patients so that they feel supported and included, and to ourselves.
Nivolumab Alone and With Ipilimumab in Previously Treated Metastatic Urothelial Carcinoma: CheckMate 032 Nivolumab 1 mg/kg Plus Ipilimumab 3 mg/kg Expansion Cohort Results
Authors: Sharma Padmanee , Siefker-Radtke Arlene , de Braud Filippo , Basso Umberto , Calvo Emiliano , Bono Petri , Morse Michael A. , Ascierto Paolo A. , Lopez-Martin Jose , Brossart Peter , Rohrberg Kristoffer , Mellado Begoña , Fischer Bruce S. , Meadows-Shropshire Stephanie , Abdel Saci  , Callahan Margaret K. , Rosenberg Jonathan
Published: May 2019

PURPOSE

CheckMate 032 is an open-label, multicohort study that includes patients with unresectable locally advanced or metastatic urothelial carcinoma (mUC) treated with nivolumab 3 mg/kg monotherapy every 2 weeks (NIVO3), nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks (NIVO3+IPI1), or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks (NIVO1+IPI3). We report on the expanded NIVO1+IPI3 cohort and extended follow-up for the NIVO3 and NIVO3+IPI1 cohorts.

METHODS

Patients with platinum-pretreated mUC were enrolled in this phase I/II multicenter study to receive NIVO3, NIVO3+IPI1, or NIVO1+IPI3 until disease progression or unacceptable toxicity. Primary end point was investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, including duration of response.

RESULTS

Seventy-eight patients were treated with NIVO3 (minimum follow-up, 37.7 months), 104 with NIVO3+IPI1 (minimum follow-up, 38.8 months), and 92 with NIVO1+IPI3 (minimum follow-up, 7.9 months). Objective response rate was 25.6%, 26.9%, and 38.0% in the NIVO3, NIVO3+IPI1, and NIVO1+IPI3 arms, respectively. Median duration of response was more than 22 months in all arms. Grade 3 or 4 treatment-related adverse events occurred in 21 (26.9%), 32 (30.8%), and 36 (39.1%) patients treated with NIVO3, NIVO3+IPI1, and NIVO1+IPI3, respectively. Grade 5 treatment-related pneumonitis occurred in one patient each in the NIVO3 and NIVO3+IPI1 arms.

CONCLUSION

With longer follow-up, NIVO3 demonstrated sustained antitumor activity alone and in combination with ipilimumab. NIVO1+IPI3 provided the greatest antitumor activity of all regimens, with a manageable safety profile. This result not only supports additional study of NIVO1+IPI3 in mUC, but demonstrates the potential benefit of immunotherapy combinations in this disease.