How we treat advanced stage cutaneous T-cell lymphoma - mycosis fungoides and Sézary syndrome.

T-cell lymphomas (TCLs) constitute a rare subset of non-Hodgkin lymphomas, with mycosis fungoides/Sézary syndrome (MF/SS) being the most common subtype of cutaneous TCLs (CTCLs). Considered an incurable but treatable disease, MF/SS management presents several challenges including diagnostic delays, debilitating effect on patients' quality of life, need for several lines of therapies, multidisciplinary care and cumulative drug toxicities limiting duration of use. The present review intends to provide an overview of the recent advances in our understanding of the biology of CTCL and how these are being leveraged to provide additional treatment options for management of advanced and recurrent disease. In addition, the discussion of the different modalities of treatment is summarised to further outline the importance of multidisciplinary care and early referral to CTCL centres.

Three-dimensional Radiologic Assessment of Chemotherapy Response in Ewing Sarcoma Can Be Used to Predict Clinical Outcome.

Purpose To compare the agreement of three-dimensional (3D) tumor measurements for therapeutic response assessment of Ewing sarcoma according to the Children's Oncology Group (COG) criteria, one-dimensional (1D) Response Evaluation Criteria in Solid Tumors (RECIST), and two-dimensional (2D) measurements defined by the World Health Organization (WHO) with tumor volume measurements as the standard of reference and to determine which method correlates best with clinical outcomes. Materials and Methods This retrospective study was approved by the institutional review board of three institutions. Seventy-four patients (mean age ± standard deviation, 14.5 years ± 6.5) with newly diagnosed Ewing sarcoma treated at three medical centers were evaluated. Primary tumor size was assessed on pre- and posttreatment magnetic resonance images according to 1D RECIST, 2D WHO, and 3D COG measurements. Tumor responses were compared with the standard of reference (tumor volume) on the basis of RECIST, COG, and WHO therapeutic response thresholds. Agreement between the percentage reduction measurements of the methods was assessed with concordance correlation, Bland-Altman analysis, and Spearman rank correlation. Agreement between therapeutic responses was assessed with Kendall tau and unweighted κ statistics. Tumor responses were compared with patient survival by using the log-rank test, Kaplan-Meier plots, and Cox regression. Results Agreement with the reference standard was significantly better for 3D measurement than for 1D and 2D measurements on the basis of RECIST and COG therapeutic response thresholds (concordance correlation of 0.41, 0.72, and 0.84 for 1D, 2D, and 3D measurements, respectively; P < .0001). Comparison of overall survival of responders and nonresponders demonstrated P values of .4133, .0112, .0032, and .0027 for 1D, 2D, 3D, and volume measurements, respectively, indicating that higher dimensional measurements were significantly better predictors of overall survival. Conclusion The 3D tumor measurements according to COG are better predictors of therapeutic response of Ewing sarcoma than 1D RECIST or 2D WHO measurements and show a significantly higher correlation with clinical outcomes. (©) RSNA, 2016 Online supplemental material is available for this article.

Histology-Specific Uses of Tyrosine Kinase Inhibitors in Non-gastrointestinal Stromal Tumor Sarcomas.

OPINION STATEMENT: Adult sarcomas, especially those with metastatic or unresectable disease, have limited treatment options. Traditional chemotherapeutic options have been limited by poor response rates in patients with advanced sarcomas. The important clinical question is whether the success of targeted therapy in GIST can be extended to other sarcomas and also if preclinical data describing targets across this heterogeneous group of cancers can be translated to clinical efficacy of known and upcoming target specific agents. Multi-targeted tyrosine kinase inhibitors (TKI) such as pazopanib, sorafenib, sunutinib, cediranib have shown benefits across various histologies of soft tissue sarcoma as well as bone sarcomas. The efficacy of imatinib in Dermatofibrosarcoma Protruberans; sunitinib and cediranib in alveolar soft part sarcoma; and sorafenib and imatinib in chordomas have provided a treatment option of these rare tumors where no effective options existed. TKIs are being tested in combination with chemotherapy as well as radiation to improve response. Although traditional RECIST criteria may not adequately reflect response to these targeted agents, the studies have shown promise for the efficacy of TKIs across the spectrum of sarcomas. The integration of biomarker studies with clinical trials may help further identify responders beyond that defined by histology. With the current data, TKIs are being used both as first-line treatment and beyond in non-GIST sarcomas.

Evaluation of prognostic factors in patients with high-risk classical Hodgkin lymphoma undergoing autologous transplantation.

ABSTRACT: There are limited data assessing the risk scores for primary treatment failure (PTF) in patients with classical Hodgkin lymphoma (cHL; PTF-cHL) undergoing autologous hematopoietic cell transplantation (auto-HCT). ECLIPSE (Evaluation of Classical Hodgkin Lymphoma patients wIth Primary treatment failure and analySis of outcomEs) is a multicenter retrospective cohort of patients with PTF-cHL (aged ≥15 years) diagnosed on or after 1 January 2005, at 15 US medical centers. PTF was defined as 1 of the following patterns of failure: (1) progressive disease by imaging during or within 6 weeks of completion of frontline chemotherapy (primary progression [PP]); (2) partial response (PR) or stable disease (SD) by imaging after completion of frontline treatment (PR/SD); (3) progression of disease by imaging (and confirmed by biopsy) within 12 months of frontline therapy completion after prior documentation of complete response (CR; early relapse [ER]). A total of 478 patients were included in the analysis. Among these, 217 (45%) were PP, 86 (18%) were PR/SD, and 175 (37%) were ER. The 6-month and 1-year cumulative incidence of nonrelapse mortality after auto-HCT were 0.9% and 1.1%, respectively. The median progression-free survival (PFS) and overall survival (OS) after auto-HCT were 4.33 and 10.09 years, respectively. Although those not in CR at the time of auto-HCT were associated with inferior PFS and OS, advanced age and diagnosis before 2011 were associated with inferior OS. This study showcases the safety and long-term efficacy of auto-HCT, even in patients with high-risk disease who are traditionally considered chemotherapy refractory, and will serve as a benchmark for the ongoing transplant vs no transplant trials.

Radon and lung cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide. Radon exposure is the second leading cause of lung cancer, following tobacco smoke. Radon is not only an independent risk factor; it also increases the risk of lung cancer in smokers. Numerous cohort, case-control, and experimental studies have established the carcinogenic potential of radon. The possibility of radon having a causative effect on other cancers has been explored but not yet proven. One of the postulated mechanisms of carcinogenesis is DNA damage by alpha particles mediated by the production of reactive oxygen species. The latter are also thought to constitute one of the common mechanisms underlying the synergistic effect of radon and tobacco smoke. With an estimated 21,000 lung cancer deaths attributable to radon in the United States annually, the need for radon mitigation is well acknowledged. The Environmental Protection Agency (EPA) has established an indoor limit of 4 picocuries (pCi)/L, and various methods are available for indoor radon reduction when testing shows higher levels. Radon mitigation should accompany smoking cessation measures in lung cancer prevention efforts.

Breakthrough concepts in immune-oncology: Cancer vaccines at the bedside.

Clinical approval of the immune checkpoint blockade (ICB) agents for multiple cancer types has reinvigorated the long-standing work on cancer vaccines. In the pre-ICB era, clinical efforts focused on the Ag, the adjuvants, the formulation, and the mode of delivery. These translational efforts on therapeutic vaccines range from cell-based (e.g., dendritic cells vaccine Sipuleucel-T) to DNA/RNA-based platforms with various formulations (liposome), vectors (Listeria monocytogenes), or modes of delivery (intratumoral, gene gun, etc.). Despite promising preclinical results, cancer vaccine trials without ICB have historically shown little clinical activity. With the anticipation and expansion of combinatorial immunotherapeutic trials with ICB, the cancer vaccine field has entered the personalized medicine arena with recent advances in immunogenic neoantigen-based vaccines. In this article, we review the literature to organize the different cancer vaccines in the clinical space, and we will discuss their advantages, limits, and recent progress to overcome their challenges. Furthermore, we will also discuss recent preclinical advances and clinical strategies to combine vaccines with checkpoint blockade to improve therapeutic outcome and present a translational perspective on future directions.

Treatment of newly diagnosed primary central nervous system lymphoma: current and emerging therapies.

Primary central nervous lymphoma (PCNSL) is a rare extra-nodal subtype of non-Hodgkin lymphoma and most cases are of diffuse large B-cell lymphoma histology with an aggressive presentation. The treatment of PCNSL has evolved over the years from radiation alone to multi-agent chemotherapy with the goal of minimizing long-term toxicity. Recent studies have evaluated autologous stem cell transplant as consolidation in eligible patients with success. The prognosis of relapsed disease remains poor and hence the emphasis is on effective and less toxic frontline strategies. Our growing understanding of the pathogenetic pathways in PCNSL is giving way to an exciting new era of targeted and immunotherapy options with the potential for inclusion in upfront therapy in the future. This review critically evaluates the current evidence including ongoing studies for the frontline treatment of PCNSL.

Clinicopathologic correlates of MYD88 L265P mutation and programmed cell death (PD-1) pathway in primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) patients have a poorer prognosis than systemic lymphoma. Gain-of-function MYD88 c.794T > C (p. L265P) mutation and programed cell death-1 (PD-1) pathway alterations are potential targetable pathways. Our study objective was to determine the clinicopathologic correlates of MYD88 mutation and PD-1 alterations in PCNSL and the impact of Epstein-Barr virus (EBV) infection. We studied 53 cases including 13 EBV-associated (EBVpos) PCNSL, 49% harbored MYD88 mutation, none seen in EBVpos PCNSL. MYD88 protein expression did not correlate with MYD88 mutation. T-cell and macrophage infiltration was common. All PD-L1-positive tumors were EBVpos. Two PD-L1 positive tumors showed 9p24.1/PD-L1 locus alterations by Fluorescence In Situ Hybridization. T cells and macrophages expressed PD-1 and/or PD-L1 in 98% and 83% cases, respectively. MYD88 mutation or protein expression and PD-1 or PD-L1 expression did not predict outcome. We hypothesize that EBVpos PCNSL has a distinct activation mechanism, independent of genetic alterations.

Magnetic Resonance Imaging of Tumor-Associated Macrophages: Clinical Translation.

Purpose: Tumor-associated macrophages (TAMs) in malignant tumors have been linked to tumor aggressiveness and represent a new target for cancer immunotherapy. As new TAM-targeted immunotherapies are entering clinical trials, it is important to detect and quantify TAM with noninvasive imaging techniques. The purpose of this study was to determine if ferumoxytol-enhanced MRI can detect TAM in lymphomas and bone sarcomas of pediatric patients and young adults.Experimental Design: In a first-in-patient, Institutional Review Board-approved prospective clinical trial, 25 pediatric and young adult patients with lymphoma or bone sarcoma underwent ferumoxytol-enhanced MRI. To confirm ferumoxytol enhancement, five pilot patients (two lymphoma and three bone sarcoma) underwent pre- and postcontrast MRI. Subsequently, 20 patients (10 lymphoma and 10 bone sarcoma) underwent ferumoxytol-enhanced MRI 24 to 48 hours after i.v. injection, followed by tumor biopsy/resection and macrophage staining. To determine if ferumoxytol-MRI can differentiate tumors with different TAM content, we compared T2* relaxation times of lymphomas and bone sarcomas. Tumor T2* values of 20 patients were correlated with CD68+ and CD163+ TAM quantities on histopathology.Results: Significant ferumoxytol tumor enhancement was noted on postcontrast scans compared with precontrast scans (P = 0.036). Bone sarcomas and lymphomas demonstrated significantly different MRI enhancement and TAM density (P < 0.05). Within each tumor group, T2* signal enhancement on MR images correlated significantly with the density of CD68+ and CD163+ TAM (P < 0.05).Conclusions: Ferumoxytol-enhanced MRI is immediately clinically applicable and could be used to stratify patients with TAM-rich tumors to immune-targeted therapies and to monitor tumor response to these therapies. Clin Cancer Res; 24(17); 4110-8. ©2018 AACR.

Beyond Anthracyclines: Preemptive Management of Cardiovascular Toxicity in the Era of Targeted Agents for Hematologic Malignancies.

Advances in drug discovery have led to the use of effective targeted agents in the treatment of hematologic malignancies. Drugs such as proteasome inhibitors in multiple myeloma and tyrosine kinase inhibitors in chronic myeloid leukemia and non-Hodgkin lymphoma have changed the face of treatment of hematologic malignancies. There are several reports of cardiovascular adverse events related to these newer agents. Both "on-target" and "off-target" effects of these agents can cause organ-specific toxicity. The need for long-term administration for most of these agents requires continued monitoring of toxicity. Moreover, the patient population is older, often over 50 years of age, making them more susceptible to cardiovascular side effects. Additional factors such as prior exposure to anthracyclines often add to this toxicity. In light of their success and widespread use, it is important to recognize and manage the unique side effect profile of targeted agents used in hematologic malignancies. In this article, we review the current data for the incidence of cardiovascular side effects of targeted agents in hematologic malignancies and discuss a preemptive approach towards managing these toxicities.