Richard J. Cassidy

BRAF inhibitor and stereotactic radiosurgery is associated with an increased risk of radiation necrosis.

We retrospectively compared the outcomes and toxicities of melanoma brain metastases (MBM) patients treated with BRAF inhibitors (BRAFi) and stereotactic radiosurgery (SRS) with SRS alone. We identified 87 patients with 157 MBM treated with SRS alone from 2005 to 2013. Of these, 15 (17.2%) patients with 32 MBM (21.4%) received BRAFi therapy: three (20.0%) before SRS, two (13.3%) concurrent, and 10 (66.7%) after SRS. Overall survival (OS) was compared between cohorts using the product limit method. Intracranial outcomes were compared using cumulative incidence with competing risk for death. Baseline patient characteristics were similar between groups, except for the SRS cohort, which had higher rates of chemotherapy and more recent year of diagnosis. Radiation characteristics, including dose per fraction, total dose, gross tumor volume size, and prescription isodose, were also similar between cohorts. One-year outcomes – OS (64.3 vs. 40.4%, P=0.205), local failure (3.3 vs. 9.6%, P=0.423), and distant intracranial failure (63.9 vs. 65.1%, P=0.450) were not statistically different between the SRS+BRAFi and SRS-alone groups, respectively. The SRS+BRAFi group showed higher rates of radiographic radiation necrosis (RN) (22.2 vs. 11.0% at 1 year, P<0.001) and symptomatic radiation necrosis (SRN) (28.2 vs. 11.1% at 1 year, P<0.001). Multivariable analysis showed that BRAFi predicted an increased risk of both radiographic and SRN. SRS and BRAFi predicted for an increased risk of radiographic and SRN compared with SRS alone. Approaches to mitigate RN for patients receiving SRS and BRAFi should be considered until the clinical trial (http//:www.clinicaltrials.gov: NCT01721603) evaluating this treatment regimen is completed.

The role of adjuvant radiotherapy in pathologically lymph node positive prostate cancer

Postoperative management of prostate cancer with lymph node involvement (LNI) is controversial. Retrospective evidence supports the selective use of radiotherapy (RT) after extended pelvic lymph node dissection. It is unclear whether this is generalizable to practice in the United States, where extended dissection is uncommon. The authors identified patients with LNI who potentially could derive a survival benefit with adjuvant RT plus androgen‐deprivation therapy (ADT).

Can we eliminate neoadjuvant chemoradiotherapy in favor of neoadjuvant multiagent chemotherapy for select stage II/III rectal adenocarcinomas: Analysis of the National Cancer Database

Stage II and III rectal cancers have been effectively treated with neoadjuvant chemoradiotherapy (NCRT) followed by definitive resection. Advancements in surgical technique and systemic therapy have prompted investigation of neoadjuvant multiagent chemotherapy (NMAC) regimens with the elimination of radiation (RT). The objective of the current study was to investigate factors that predict for the use of NCRT versus NMAC and compare outcomes using the National Cancer Data Base (NCDB) for select stage II and III rectal cancers.

Quantitative Ultrasonic Nakagami Imaging of Neck Fibrosis After Head and Neck Radiation Therapy

PURPOSE To investigate the feasibility of ultrasound Nakagami imaging to quantitatively assess radiation-induced neck fibrosis, a common sequela of radiation therapy (RT) to the head and neck. METHODS AND MATERIALS In a pilot study, 40 study participants were enrolled and classified into 3 subgroups: (1) a control group of 12 healthy volunteers; (2) an asymptomatic group of 11 patients who had received intensity modulated RT for head and neck cancer and had experienced no neck fibrosis; and (3) a symptomatic group of 17 post-RT patients with neck fibrosis. Each study participant underwent 1 ultrasound study in which scans were performed in the longitudinal orientation of the bilateral neck. Three Nakagami parameters were calculated to quantify radiation-induced tissue injury: Nakagami probability distribution function, shape, and scaling parameters. Physician-based assessments of the neck fibrosis were performed according to the Radiation Therapy Oncology Group late morbidity scoring scheme, and patient-based fibrosis assessments were rated based on symptoms such as pain and stiffness. RESULTS Major discrepancies existed between physician-based and patient-based assessments of radiation-induced fibrosis. Significant differences in all Nakagami parameters were observed between the control group and 2 post-RT groups. Moreover, significant differences in Nakagami shape and scaling parameters were observed among asymptomatic and symptomatic groups. Compared with the control group, the average Nakagami shape parameter value increased by 32.1% (P<.001), and the average Nakagami scaling parameter increased by 55.7% (P<.001) for the asymptomatic group, whereas the Nakagami shape parameter increased by 74.1% (P<.001) and the Nakagami scaling parameter increased by 83.5% (P<.001) for the symptomatic group. CONCLUSIONS Ultrasonic Nakagami imaging is a potential quantitative tool to characterize radiation-induced asymptomatic and symptomatic neck fibrosis.

Outcomes for patients with locally advanced pancreatic adenocarcinoma treated with stereotactic body radiation therapy versus conventionally fractionated radiation.

As systemic therapy has improved for locally advanced pancreatic cancer (LAPC), efforts to improve local control with optimal radiotherapy may be critical. Although conventionally fractionated radiation therapy (CFRT) has more recently shown a limited role in LAPC, stereotactic body radiation therapy (SBRT) is an emerging approach with promising results. With no studies to date comparing SBRT with CFRT for LAPC, this study used the National Cancer Data Base (NCDB) to evaluate these 2 modalities.

The role of radiotherapy for patients over age 60 with diffuse large B-cell lymphoma in the rituximab era

Abstract The role of consolidative radiotherapy (RT) in patients ≥60 years old with DLBCL in the rituximab era is controversial. We examined the impact on disease control and overall survival by the addition of consolidative RT after completion of chemotherapy, while adjusting for known adverse risk factors. Retrospective chart review from 2004 to 2012 of 83 consecutive patients ≥60 years old with DLBCL treated in the rituximab era, 68 of which had a complete response to chemotherapy, was performed. Amongst patients with a complete response, consolidative RT use was associated with 100% 5-year local control, improved progression-free survival (p = 0.047), and a trend for overall survival (p = .098) on multivariate analysis. Amongst all patients, the use of consolidative RT was associated with improved overall survival (p = 0.03). The use of consolidative RT should be considered for patients ≥60 years old independent of stage and response to chemotherapy.

T cells display mitochondria hyperpolarization in human type 1 diabetes.

T lymphocytes constitute a major effector cell population in autoimmune type 1 diabetes. Despite essential functions of mitochondria in regulating activation, proliferation, and apoptosis of T cells, little is known regarding T cell metabolism in the progression of human type 1 diabetes. In this study, we report, using two independent cohorts, that T cells from patients with type 1 diabetes exhibited mitochondrial inner-membrane hyperpolarization (MHP). Increased MHP was a general phenotype observed in T cell subsets irrespective of prior antigen exposure, and was not correlated with HbA1C levels, subject age, or duration of diabetes. Elevated T cell MHP was not detected in subjects with type 2 diabetes. T cell MHP was associated with increased activation-induced IFNγ production, and activation-induced IFNγ was linked to mitochondria-specific ROS production. T cells from subjects with type 1 diabetes also exhibited lower intracellular ATP levels. In conclusion, intrinsic mitochondrial dysfunction observed in type 1 diabetes alters mitochondrial ATP and IFNγ production; the latter is correlated with ROS generation. These changes impact T cell bioenergetics and function.

Function Preservation After Conservative Resection and Radiotherapy for Soft-tissue Sarcoma of the Distal Extremity: Utility and Application of the Toronto Extremity Salvage Score (TESS).

Objective:To evaluate outcomes after conservative resection and radiotherapy (RT) for soft-tissue sarcoma (STS) of the distal extremity, with assessment of functional quality of life using the validated Toronto Extremity Salvage Score (TESS) questionnaire and Common Terminology Criteria for Adverse Events (CTCAE), v4.0. Methods:Thirty-three patients with STS involving the hand/wrist (N=18) or foot/ankle (N=15) complex received adjuvant RT with conservative resection and were evaluated for local tumor control, survival, toxicities, and preservation of objective functional ability. Eight patients were treated with preoperative RT (median dose, 50.4 Gy) and 25 with postoperative RT (median dose, 61.8 Gy). Median follow-up was 11.5 years. Functional outcomes were measured using TESS; patients with amputations were excluded from the TESS analysis. Adverse events related to gait, limb edema, skin infection, wound complication, and wound dehiscence were assessed using the CTCAE. Results:The 5- and 10-year local control rates were both 90%. The 10-year cause-specific, absolute, and distant metastasis-free survival rates were 97%, 87%, and 84%, respectively. Three patients had an amputation for reasons other than local recurrence or treatment complications and underwent amputation for patient preference. One third of the subjects (11/33 patients) were able to complete the TESS questionnaire; scores ranged from 88 to 100 (mean, 98.2). CTCAEv4 acute adverse events occurred in 2 cases: 1 patient had a grade 3 skin infection and 1 had a grade 2 wound complication of dehiscence. Conclusions:For management of distal extremity STS, the combination of adjuvant RT and conservative surgery achieves excellent local control and overall survival with few adverse events. In addition, through application of the TESS survey instrument, we have demonstrated that this treatment plan achieves robust functional preservation objectively and quantifiably.

Guideline-concordant Care Improves Overall Survival for Locally Advanced Non–Small-cell Lung Carcinoma Patients: A National Cancer Database Analysis

Background Current evidence‐based guideline‐concordant care (GCC) for locally advanced non–small‐cell lung cancer (NSCLC) patients with good performance status is concurrent chemoradiation. In this study we evaluated factors associated with lack of GCC and its effects on overall survival (OS). Patients and Methods Unresectable stage III NSCLC patients, diagnosed from 2005 to 2013 with a Charlson–Deyo score of 0, were identified from the National Cancer Database. Primary outcomes were receipt of GCC, defined as concurrent chemoradiation (thoracic radiotherapy, starting within 2 weeks of chemotherapy, to at least 60 Gy), and OS. Multivariable logistic regression modeling identified variables associated with non‐GCC. Cox proportional hazard modeling was used to examine OS. Results Twenty‐three percent of patients (n = 10,476) received GCC. Uninsured patients were more likely to receive non‐GCC (odds ratio [OR], 1.54; P < .001) compared with privately insured patients. Other groups with greater odds of receiving non‐GCC included: patients treated in the western, southern, or northeastern United States (ORs, 1.39, 1.37, and 1.19, respectively; all Ps < .001) compared with the Midwest; adenocarcinoma histology (OR, 1.48; P < .001) compared with squamous cell carcinoma; and women (OR, 1.08; P = .002). Those who received non‐GCC had higher death rates compared with those who received GCC (hazard ratio [HR], 1.42; P < .001). The uninsured (HR, 1.53; P < .001), patients treated in the western, southern, or northeastern United States (HRs, 1.56, 1.41, and 1.34, respectively; P < .001), adenocarcinomas (HR, 1.39; P < .001), and women (HR, 1.44; P < .001) also all had lower OS for non‐GCC versus GCC. Conclusion Socioeconomic factors, including lack of insurance and geography, are associated with non‐GCC. Patient‐ and disease‐specific factors, including increasing adenocarcinoma histology and sex, are also associated with non‐GCC. Non‐GCC diminishes OS. Micro‐Abstract Several socioeconomic factors, including lack of insurance and geography, and patient‐ and disease‐specific factors, including increasing adenocarcinoma histology and sex, are associated with receipt of non–guideline‐concordant care. Non–guideline‐concordant care is associated with poorer survival outcomes.

Radiation therapy and neutropenia

Acute radiation injury typically manifests as cytopenias: anemia, neutropenia, and thrombocytopenia; however, the measurement of peripheral blood counts belies the complex mechanism and timing of RT effects on hematopoietic stem cell (HSC) populations. There are several potential mechanisms for RT effects on the bone marrow, which are not mutually exclusive and may be complimentary. These include direct damage to HSC and reduction in their number and function, changes to the surrounding bone marrow stroma and microenvironment, and injury to ancillary cell populations that serve to regulate the hematopoietic process (eg, colony-stimulating factor [CSF] or erythropoietin-secreting cells). These effects are most likely with large volume irradiation of the pelvis or spine, as the primary site of functional bone marrow is the pelvis and vertebrae, which account for approximately 60% of total volume. Most of the data for detailed hematopoietic effects of RT are derived from large single fraction total body radiation exposures or from extended field administrations that are no longer used in routine practice. Even very low RT doses (as low as 0.3 Gy) can lead to measurable changes in peripheral blood counts (primarily lymphocytes at these doses) owing to the exquisite radiosensitive nature of these cells. With larger doses, lymphopenia typically occurs almost immediately due to radiation-induced apoptosis in interphase, followed by granulocytopenia, then thrombocytopenia, and ultimately anemia. Granulocyte counts may actually have an initial transient rise owing to mobilization from the periphery into the circulation, followed by a subsequent rapid decline. After an intermediate dose of total body radiation, initial decline in cell counts occurs approximately in 1, 4, 8, and 12 days for lymphocytes, granulocytes, platelets, and red blood cells, respectively. Clinical cytopenia occurs in approximately 1 day, 1 week, 2-3 weeks, and 2-3 months, respectively. These differences between cell lineages are owing to inherent radiosensitivity differences, variations in cell population reserves and mobilization, time required for hematopoietic cell replacement, and the life span of the differentiated peripheral cell (with red blood cells have the longest life cycle).