Meng Xu-Welliver

Extranodal NK/T Cell Lymphoma, Nasal Type (ENKTL-NT): An Update on Epidemiology, Clinical Presentation, and Natural History in North American and European Cases

Purpose of ReviewExtranodal NK/T cell lymphoma, nasal type (ENKTL-NT) is an aggressive extranodal non-Hodgkin lymphoma most commonly occurring in East Asia and Latin America but with increasing incidence in the United States. Data on epidemiology, disease presentation, and outcome for European and North American (“Western”) cases are very limited. We review published landmark clinical studies on ENKTL-NT in the West and report in detail recent data, including our institutional experience.Recent FindingsWe highlight key observations in its epidemiology, natural history, and trends in clinical management. In the USA, ENKTL-NT is more common among Asian Pacific Islanders (API) and Hispanics compared to non-Hispanic whites. Published studies indicate less heterogeneity in clinical presentation in Western ENKTL-NT compared to Asian patients. While there is variation in age at diagnosis, presence of antecedent lymphoproliferative disorders, and outcomes among racial/ethnic groups, the universal association of ENKTL-NT with EBV and the poor response of this neoplasm to anthracycline-based therapy is consistent across all geographic areas.SummaryData on epidemiology, disease presentation, and clinical outcomes in mature T cell and NK cell (T/NK cell) neoplasms, including ENKTL-NT, in Europe and North America are very limited. As the classification and diagnostic characterization of the currently recognized T/NK cell lymphoma disease entities continue to evolve, gaps and inconsistencies in data reporting across different studies are being recognized. Despite these limitations, several studies from the USA suggest that the incidence of ENKTL-NT is higher in Asian Pacific Islanders (API) and non-white Hispanics and that outcomes may be worse in non-whites. However, the universal association of ENKTL-NT with Epstein-Barr virus (EBV) across all ethnic groups suggests a common pathogenesis. Given the overlap between the entities included in the category of T/NK cell neoplasms, there is a need to further define biological and clinical differences that may affect diagnosis, treatment, and outcome.

Prognostic Value of Primary Tumor Volume Changes on kV-CBCT during Definitive Chemoradiotherapy for Stage III Non–Small Cell Lung Cancer

Introduction Kilovoltge cone beam computed tomography (kV‐CBCT) allows for tumor localization and response assessment during definitive chemoradiotherapy for locally advanced NSCLC. We hypothesize that significant tumor volume loss occurs early during radiotherapy and that the extent of volume loss correlates with clinical outcomes. Methods A total of 52 patients with locally advanced NSCLC treated with definitive chemoradiotherapy were reviewed. kV‐CBCT images were used to contour primary gross tumor volumes at four time points during treatment. Patients were dichotomized according to absolute and relative volume changes at each time point. Statistical analyses were performed to evaluate correlations between volume changes and clinical outcomes. Results The median gross tumor volumes were 77.1, 48.3, 42.5, and 29.9 cm3 for fractions 1, 11, 21, and final, respectively. Greater relative volume loss between fractions 1 and 21 correlated with improved distant control (hazard ratio [HR] = 0.35, 95% confidence interval [CI]: 0.13–0.94, p = 0.038) and overall survival (HR = 0.40, 95% CI: 0.16–0.98, p = 0.046). Greater relative volume loss between fractions 11 and 21 correlated with improved progression‐free survival (HR = 0.39, 95% CI: 0.17–0.88, p = 0.02) and trended toward improved overall survival (HR = 0.43, 95% CI: 0.17–1.06, p = 0.07). On multivariate analysis, greater relative volume loss between fractions 11 and 21 correlated with improved progression‐free survival (HR = 0.39, 95% CI: 0.16–0.97, p = 0.041) and overall survival (HR = 0.31, 95% CI: 0.11–0.88, p = 0.027). Conclusions Significant primary tumor volume loss occurs early during radiotherapy for locally advanced NSCLC. Greater relative tumor volume loss during treatment correlates with improved disease control and overall survival. Thus, kV‐CBCT has potential to be used as a practical prognostic imaging marker.

Imaging across the Life Span: Innovations in Imaging and Therapy for Gynecologic Cancer

The focus of this article is radiation therapy for gynecologic cancers, with emphasis on imaging-based treatment planning and delivery. For the various gynecologic cancers, radiation oncologists rely on essential clinical information to triage treatment options, and various imaging studies are performed for treatment planning and radiation therapy delivery. A practical approach is provided to help radiologists tailor their reports for the needs of their radiation oncology and gynecologic oncology colleagues, to optimize multidisciplinary care for patients with gynecologic cancer. Template radiology reports are proposed to address the specific information needs of oncologists at each phase-before, during, and after treatment. Fueled by the rapid progress in engineering and computer sciences during the past 2 decades, remarkable advances have been made in anatomic, functional, and molecular imaging and in radiation treatment planning and delivery in patients with gynecologic cancer. Radiation therapy has evolved from a nontargeted approach to a precisely targeted, highly conformal treatment modality, to further improve treatment outcomes and reduce morbidity. High-quality imaging has become essential for staging of the disease, delineation of tumor extent for treatment planning and delivery, and monitoring therapy response. Anatomic and functional imaging has also been shown to provide prognostic information that allows clinicians to tailor therapy on the basis of personalized patient information. This field is an area of active research, and future clinical trials are warranted to validate preliminary results in the field.

Inter-Fraction Tumor Volume Response during Lung Stereotactic Body Radiation Therapy Correlated to Patient Variables

Purpose Analyze inter-fraction volumetric changes of lung tumors treated with stereotactic body radiation therapy (SBRT) and determine if the volume changes during treatment can be predicted and thus considered in treatment planning. Methods and Materials Kilo-voltage cone-beam CT (kV-CBCT) images obtained immediately prior to each fraction were used to monitor inter-fraction volumetric changes of 15 consecutive patients (18 lung nodules) treated with lung SBRT at our institution (45–54 Gy in 3–5 fractions) in the year of 2011–2012. Spearmans (ρ) correlation and Spearmans partial correlation analysis was performed with respect to patient/tumor and treatment characteristics. Multiple hypothesis correction was performed using False Discovery Rate (FDR) and q-values were reported. Results All tumors studied experienced volume change during treatment. Tumor increased in volume by an average of 15% and regressed by an average of 11%. The overall volume increase during treatment is contained within the planning target volume (PTV) for all tumors. Larger tumors increased in volume more than smaller tumors during treatment (q = 0.0029). The volume increase on CBCT was correlated to the treatment planning gross target volume (GTV) as well as internal target volumes (ITV) (q = 0.0085 and q = 0.0039 respectively) and could be predicted for tumors with a GTV less than 22 mL. The volume increase was correlated to the integral dose (ID) in the ITV at every fraction (q = 0.0049). The peak inter-fraction volume occurred at an earlier fraction in younger patients (q = 0.0122). Conclusions We introduced a new analysis method to follow inter-fraction tumor volume changes and determined that the observed changes during lung SBRT treatment are correlated to the initial tumor volume, integral dose (ID), and patient age. Furthermore, the volume increase during treatment of tumors less than 22mL can be predicted during treatment planning. The volume increase remained significantly less than the overall PTV expansion, and radiation re-planning was therefore not required for the purpose of tumor control. The presence of the studied correlations suggests that the observed volumetric changes may reflect some underlying biologic process rather than random fluctuations.

Blood-based biomarkers in lung cancer: prognosis and treatment decisions

Despite recent advances, non-small cell lung cancer (NSCLC) remains a devastating disease with overall poor prognosis. Major contributing factors include obstacles to diagnosing the disease early in its course during the asymptomatic stage as well as diversity and complexity of its biology underlying tumorigenesis and tumor progression. Advances in molecularly targeted therapies which drives the development of personalized cancer care require precise and comprehensive understanding of tumor biology, not only at the time of diagnosis but also during treatment course and surveillance. As lung tumor tissue can be difficult to obtain without invasive and potentially risky procedures, it is difficult to monitor treatment response with serial tissue biopsies. Development of non-invasive but reliable blood based tumor markers has become an important research area. In this review, we focus on the following circulating biomarkers that have been identified in recent years: circulating tumor cells (CTCs); circulating cell-free nucleic acids, such as circulating tumor DNA (ctDNA) and microRNA (miR); and other biomarkers such as genomic and proteomic features. These biomarkers not only have prognostic values, but also can help guild treatment decisions by monitoring tumor burden, detecting minimal residual disease and/or recurrent disease, as well as monitoring evolution of genetic alterations throughout the treatment course.

Patterns of major wound complications following multidisciplinary therapy for lower extremity soft tissue sarcoma

The purpose of this study was to determine the pattern and timing of major wound complications (MWCs) in patients at our institution who received multimodality treatment for lower extremity soft tissue sarcoma (LE‐STS) and to evaluate the impact of MWCs on tumor control and patient outcomes.

Radiation Dose to the Thoracic Vertebral Bodies is Associated with Acute Hematologic toxicities in Patients Receiving Concurrent Chemoradiation for Lung Cancer: Results of a Single Center Retrospective Analysis

PURPOSEnToxa0test the hypothesis that increasing radiation therapy (RT) dose to the thoracic vertebral bodies (TVBs) contributes to the development of hematologic toxicities (HTs) in patients with lung cancer.nnnMETHODS AND MATERIALSnCases of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) treated with definitive chemoradiation with concurrent platinum-based doublet chemotherapy at our institution from 2007 to 2016 were identified. Mean TVB dose and the volume of TVBs receiving at least 5 to 60xa0Gyxa0(V5-V60) were retrospectively recorded. Logistic regression was used to test associations between grade ≥3 HT (HT3+) and dosimetric/clinical parameters. Normal tissue complication probability was evaluated using the Lyman-Kutcher-Burman (LKB) model for HT3+, and receiver operating characteristics analysis was used to determine dosimetric cut-points.nnnRESULTSnWe identified 201 patients, the majority having NSCLC (n=162, 81%) and stage III to IV disease (n=179, 89%). All patients received either cisplatin/etoposide (n=107, 53%) or carboplatin/paclitaxel (n=94, 47%). Median RT dose was 60xa0Gy (range, 60-70xa0Gy). The rate of HT3+ was 49% (n=99). Increasing mean TVB dosexa0(per Gy) was associated with higher odds of developing HT3+ (odds ratio 1.041, 95% confidence interval 1.004-1.080, P=.032), as were increasing TVB V5 to V20. Thesexa0dosimetric correlates to HT3+ persisted on multivariate analysis. Constrained optimization of the LKB model for HT3+ yielded the parameters: n=1, m=1.79, and TD50=21.4xa0Gy. Optimal cut-points identified were V5=65%, V10=60%, V20=50%, and mean dose=23.5xa0Gy. Patients with values above these cut-points had an approximately 2-fold increased risk of HT3+.nnnCONCLUSIONSnWe found that mean TVB dose and low-dose parameters (V5-V20) were associated with HT3+ in chemoradiation for lung cancer. Per the LKB model, bone marrow behaves like a parallel organ (n=1), implying that mean TVB dose is a useful predictor for toxicity. These data suggest that efforts to spare dose to the TVBs may reduce rates of severe HT.

Identifying patterns of care for elderly patients with non-surgically treated stage III non-small cell lung cancer: an analysis of the national cancer database

BackgroundTo compare patterns of care for elderly patients versus non-elderly patients with non-surgically treated stage III non-small cell lung cancer (NSCLC) using the National Cancer Database (NCDB). We hypothesize that elderly patients are less likely to receive curative treatments, including concurrent chemoradiation (CCRT), compared to non-elderly patients.MethodsWe identified patients from the NCDB between 2003 and 2014 with non-surgically treated stage III NSCLC. We defined elderly as ≥70xa0years old and non-elderly <70xa0years old. Treatment categories included: no treatment, palliative treatment (chemotherapy alone, radiation (RT) alone <59.4xa0Gy or chemoradiation (CRT)u2009<59.4xa0Gy), or definitive treatment (RT alonexa0≥59.4xa0Gy or CRTu2009≥59.4xa0Gy). Differences in treatment between elderly and non-elderly were tested using the χ2 test.ResultsWe identified 57,602 elderly and 55,928 non-elderly patients. More elderly patients received no treatment (24.5% vs. 13.2%, Pu2009<xa00.0001) and the elderly were less likely to receive definitive treatment (48.5% vs. 56.3%, Pu2009<xa00.0001). CCRT was delivered in a significantly smaller proportion of elderly vs. non-elderly patients (66.0% vs. 78.9%, Pu2009<xa00.0001 in patients treated with definitive intent; 32.0% vs. 44.5%, Pu2009<xa00.0001 in patients receiving any treatment; and 24.2% vs. 38.6%, Pu2009<xa00.0001 amongst all patients).ConclusionsIn this large study of patients with non-surgically treated stage III NSCLC, elderly patients were less likely to receive any treatment or treatment with definitive intent compared to the non-elderly. The lack of use of concurrent or sequential chemotherapy in the elderly with stage III NSCLC suggests that the optimal treatment approach for this vulnerable population remains undefined.

Stereotactic body radiation therapy (SBRT) for early stage nonsmall cell lung cancer (NSCLC): contemporary insights and advances

The standard-of-care treatment for early-stage non-small cell lung cancer (NSCLC) continues to be surgery in the form of lobectomy or pneumonectomy. Stereotactic body radiation therapy (SBRT) has evolved as a viable alternative to surgery for medically inoperable patients, achieving excellent local control (LC) with relatively minimal toxicity in standard-risk patients. Nevertheless, the maturation of SBRT has fostered debate regarding its use, technique, dose, and fractionation, particularly in the context of patient- and disease-specific characteristics such as tumor size and location. This review will cover the recent trends and future directions of SBRT as it becomes an increasingly individualized modality in the treatment of early-stage NSCLC.

Urinary miRNAs as Biomarkers for Noninvasive Evaluation of Radiation-Induced Renal Tubular Injury

Radiation nephropathy is one of the common late effects in cancer survivors who received radiotherapy as well as in victims of radiation accidents. The clinical manifestations of radiation nephropathy occur months after exposure. To date, there are no known early biomarkers to predict the future development of radiation nephropathy. This study focuses on the development of urinary biomarkers providing readout of acute responses in renal tubular epithelial cells. An amplification-free hybridization-based nCounter assay was used to detect changes in mouse urinary miRNAs after irradiation. After a single LD50 of total-body irradiation (TBI) or clinically relevant fractionated doses (2 Gy twice daily for 3 days), changes in urinary levels of microRNAs followed either an early pattern, peaking at 6–8 h postirradiation and gradually declining, or later pattern, peaking from 24 h to 7 days. Of 600 miRNAs compared, 12 urinary miRNAs showed the acute response and seven showed the late response, common to both irradiation protocols. miR-1224 and miR-21 were of particular interest, since they were the most robust acute and late responders, respectively. The early responding miR-1224 also exhibited good dose response after 2, 4, 6 and 8 Gy TBI, indicating its potential use as a biomarker for radiation exposure. In situ hybridization of irradiated mouse kidney sections and cultured mouse primary renal tubular cells confirmed the tubular origin of miR-1224. A significant upregulation in hsa-miR-1224-3p expression was also observed in human proximal renal tubular cells after irradiation. Consistent with mouse urine data, a similar expression pattern of hsa-miR-1224-3p and hsa-miR-21 were observed in urine samples collected from human leukemia patients preconditioned with TBI. This proof-of-concept study shows the potential translational utility of urinary miRNA biomarkers for radiation damage in renal tubules with possible prediction of late effects.