Tumor microenvironments contain immune cells such as macrophages that can be polarized in either a pro- or anti-tumor fashion, including in glioblastoma. Targeting a receptor on macrophages, triggering receptor expressed on myeloid cells 1 (TREM-1), has demonstrated anti-tumor effects in preclinical mouse studies in pancreatic and non-small cell lung cancer. A TREM-1 inhibitory peptide, GF9, has been developed within a blood-brain barrier permeable vehicle that mimics high density lipoproteins (HDL). This peptide was designed to disrupt association of TREM-1 with its signaling adaptor protein DAP12, inhibiting downstream effects, including the recruitment/polarization of pro-tumor macrophages. In this study, we examined the potential of GF9 treatment to sensitize glioblastoma tumors to radiation using a mouse model. In a survival experiment, thirty C57BL/6 mice were implanted with 20,000 GL261 glioblastoma tumor cells intracranially into the right caudate putamen. 4 days after tumor implantation, 10 mice were injected intraperitoneally daily with Tris-buffered saline (TBS/control), 10 mice with HDL (vehicle), and 10 mice with GF9 (2.5 mg/kg) in HDL (GF9-HDL) for 10 days. 7 days after tumor implantation, 5 (half) of the mice of each group were administered 2 Gy of whole brain radiation, one-field PA, every other day to a total dose of 6 Gy. Macrophages were isolated from harvested tumors using anti-F4/80 microbeads and RNA was then isolated. qPCR was performed on a panel of macrophage markers. Median survival of the control mice was 20 days, HDL mice was 22 days, GF9-HDL alone mice was 21 days, TBS+RT and HDL+RT mice was 23 days, and the GF9-HDL+RT combination mice was 26 days. The only significant difference in survival was found between the GF9-HDL+RT combination group and control group with a p=0.04 on a Mantel-Cox log-rank test. qPCR analysis showed a 6-fold decrease of mRNA levels of TGF-β, previously noted to be regulated by TREM-1 signaling in vitro, in tumor-associated macrophages in GF9-treated mice as compared to controls. The results from this preliminary pre-clinical study suggest that TREM-1 blockade using GF9 has the potential to stimulate the therapeutic effects of radiation in a preclinical mouse model of glioblastoma. TGF-β levels in brain tumor-associated macrophages were lowered with GF9 administration consistent with data from in vitro studies of TREM-1 signaling. Additional animal survival studies, serum analysis, and immunohistochemical staining will be performed to further examine the role of tumor-associated macrophages in the radioresistance of glioblastoma tumors.

In an academic tertiary care setting, we have developed a multidisciplinary palliative care team, which includes members of radiation oncology, medical oncology, and palliative care, that performs daily inpatient rounds. We look to examine the impact this initiative has had on recommendations for radiation therapy, patient length of stay, and for those patients recommended radiation treatment, treatment completion rates. Multidisciplinary palliative care rounds (MPCR) were initiated in July 2017. We retrospectively reviewed all medical records for patients treated at this inpatient facility from 1/2017 – 12/2017, and recorded demographic data, treatment details, and length of inpatient stay after a radiation oncology consultation. We compared the 6 month baseline data prior to the initiative (1/17-6/17) with that from the 6 months immediately following (7/17-12/17) using Chi-square and two sample, two tailed t-tests. A total of 176 inpatients received radiation therapy during this 12-month interval. There was a 35% increase in number of inpatient radiation treatment courses in the 6 months after development of MPCR as compared to the 6 months prior (104 treatment courses post-MPCR versus 77 treatment courses pre-MPCR). Number of fractions recommended was not different (mean of 6.1 fractions pre-MPCR versus mean of 5.5 fractions post-MPCR, p=0.37). The median number of fractions recommended for both time periods was 5. There was a trend towards increased recommendation of single fraction RT (7 courses pre-MPCR versus 16 courses post-MPCR, p=0.16). Early treatment terminations, defined as patients who received less than the prescribed number of treatments, was not different (11.7% pre-MPCR versus 13.5% post-MPCR, p=0.72). There was, however, a trend towards decreased length of stay (median of 14 days pre-MPCR versus median of 12 days post-MPCR, p=0.36). We found that multidisciplinary palliative care rounds are feasible and result in changes in practice patterns of palliative care patients. There was a large increase in the number of patients treated with radiation therapy and a trend towards decreased length of stay. This likely is due to better recognition of indications for palliative radiation therapy as well as improved communication between the treatment teams. While the median number of treatments recommended was 5, we did see a trend toward increased recommendation of single fraction treatments. Longer term follow-up is needed to confirm these findings.

The objective of this prospective study was to assess the safety and efficacy of Kypho-IORT for painful vertebral body (VB) fractures in cancer patients. Patients with symptomatic osteolytic vertebral body metastasis underwent Kypho-IORT: kyphoplasty procedures and intraoperative radiotherapy with the ZEISS INTRABEAM System followed by cement augmentation. Tumors were limited to vertebral body (sector 1) using the International Spine Radiosurgery Consortium (ISRC) anatomic classification system, SINS scores of 7-12, and Bilsky grade of 0. Intraoperative CT delineation of gross tumor volume, needle applicator tip, and OAR was done with deformable image registration, integrating pre-operative CT and MRI images. 10 Gy was prescribed to a distance from the source tip to the distal boundary, based on the mean radius plus SD. The prescription was limited by a maximum dose limit to the spinal cord of 12 Gy. Quality of Life Measurements were done using the QOL [EORTC QLQ-C30 (version 3)], the Brief Pain Inventory (BPI), Numerical Rating Pain Scale (NRPS), ambulation, and narcotic use pre- and post-procedure at 1-week, 3-month, 6-month, 9-month, 1-year, and 2-year intervals. The involved spine will be imaged at 3-month intervals up to one year and at 2 years post-procedure. 7 vertebral levels were treated. All patients were discharged home within 12 hours of the Kypho-IORT procedure. There was a statistically significant reduction in patient reported NPRS scores from preoperative baseline within 2 weeks (6.57±1.4 preoperative versus 3.57±2.57 postoperatively; p=0.0189). After 3 months, one patient with metastatic rectal cancer suffered local progression. Patients also experienced better quality of life with respect to bone metastasis-specific issues. The QLQ-C30 is able to discriminate among patients with varying responses. Kypho-IORT is a safe treatment option for potentially unstable spinal metastases. Patient reported pain scores significantly improve within two weeks with improved quality of life. Long-term follow up is necessary to further evaluate efficacy.

Purpose: The objective of this study was to assess a contemporary cohort of patients with multiple myeloma referred for palliative radiation to the mobile spine for clinical and radiological responses. Materials/Methods: The records of patients treated between 2009 and 2016 with radiotherapy for multiple myeloma of the spine were retrospectively reviewed. Demographics, systemic therapy, radiation dose, number of fractions, radiographic response based upon adapted RECIST criteria, and symptomatic response were recorded. Results: Eighty eight patients and 98 treatment courses were analyzed. All courses were analyzed for symptomatic response and 61 of the treatment courses were available for radiologic follow-up. The median follow-up was 9.7 months with a median radiation dose of 25 Gy (12.5-50 Gy) delivered in a median of 10 fractions (5-25 fractions). Fifty-four percent of patients had a high-risk lesion. Symptomatic response as measured by a decrease of ≤5 points on the pain related scale was 83% and 34% of patients had a decrease of >5 points. Of 35% of patients that had neurologic impairments prior to treatment, improvement was identified 83% of the time. Radiographic response was noted as 13% complete response, 16% partial response, 57% stable disease, and 13% disease progression. Specifically, high-risk lesions treated with radiation alone demonstrated no regression with only 10% demonstrating partial response. Conclusion: This retrospective series of patients treated with palliative intent for multiple myeloma using various dose and fractionation schemes showed favorable symptomatic relief in most patients. Radiographic response did not correlate with clinical response with fewer patients having radiologic disease regression. Longer follow-up is necessary to determine if the lack of radiologic response is associated with clinically relevant recurrent pain.

Our group has an ongoing clinical research project investigating the immunology of the otitis–prone (OP) phenotype. In light of evidence that this condition arises from underlying immunological defects, we examined our sample population of stringently defined OP (sOP) children suffering 3 episodes of acute otitis media within 6 months or 4 within a year for a familial association with the sOP phenotype.We analyzed the frequency of sOP within and between families and the nasopharyngeal (NP) otopathogen colonization patterns within and between families.The presence of sOP siblings significantly predicted that additional children in the same family would likewise become sOP, with an odds ratio of 3.7 (95% CI 0.77–15.2, 95% lower bound 0.95). We further present evidence for an environmental contribution to this effect by means of prolonged exposure to otopathogens within family units.sOP children have a significant familial association. The tendency of siblings to share similar patterns of microbial NP colonization contributes to this association. Further research is necessary to determine whether and to what extent genetics are involved.

Malnutrition is a common problem for head and neck cancer patients. Loss of skeletal muscle mass, or sarcopenia, has been associated with malnutrition, poor tolerance of cancer therapy, and poorer outcomes in a number of malignancies. At our institution, we initiated a nutritional program where patients treated with definitive radiation therapy (RT) are evaluated and closely followed by a registered oncologic dietitian. In this report, we analyze nutritional factors and compliance with dietary recommendations for associations with overall survival (OS) and progression-free survival (PFS) in patients receiving definitive RT for laryngeal and oropharyngeal cancers. We identified 352 patients with non-metastatic oropharyngeal (146) and laryngeal (206) cancer who were treated with definitive RT between 2004 and 2013. Disease and patient characteristics, treatment information, compliance with nutritional program, and clinical outcomes data were tabulated. Adherence to the nutritional program was scored weekly and patients were deemed non-compliant with nutritional program if they cancelled >25% of their appointments with the dietitian, refused nutritional counseling or did not follow recommendations. Of the 352 patients, 158 patients had a pretreatment CT including the abdomen within 30 days of RT start date to assess sarcopenia. Sarcopenia was defined based on muscle areas at the level of L3 using cutoffs established by Prado et al. Descriptive statistics, Kaplan Meier survival analysis, and log rank tests were performed, and Cox regression models were used to examine predictors of OS and PFS. The median follow-up for the entire cohort was 22.86 (0.56-116) months. The actuarial rates for OS were 91%, 86% and 73% at years 1, 2, and 5, respectively. 70.9% (112/158) of patient with abdominal CT prior to starting RT were sarcopenic with a median muscle mass index of 48.2 (range: 30.4-70.9) for males and 35.9 (range: 24.6-53.2) for females. 85.8% (302/352) of patients met with a dietitian during their course of RT and 62.5% of patients who met with dietitian were compliant with the nutritional program. Compliance with the nutritional program resulted in 27% (HR: 0.73, 95% CI: 0.43, 1.26) and 31% (HR: 0.69, 95% CI: 0.50, 0.94) protection from death and disease progression. Lower pretreatment BMI was associated with a higher risk for death (HR: 0.94, 95%CI: 0.90, 0.99) and disease progression (HR: 0.96, 95% CI: 0.93, 0.99). Sarcopenia was not independently predictive for increased risk for overall death and disease progression. Laryngeal and oropharyngeal cancer patients treated with definitive RT who are compliant with an aggressive nutritional program appear to have improved outcomes. Sarcopenia is very common in this patient population and further studies exploring ways to increase compliance with nutritional programs are warranted.

The objective of this study was to examine gene expression patterns from normal upper aerodigestive tract tissues among patients who experienced varying toxicities from radiation treatment for head and neck squamous cell carcinoma with a closer look at mucositis. One hundred seventy-six patients treated with head and neck squamous cell carcinoma had normal tissue adjacent to their tumor sampled at the time of diagnostic biopsy and/or surgery. Ninety of these patients were naïve to prior radiation/surgery and received radiation after sampling. Acute radiation toxicities in these patients were recorded using CTCAE v4.0 criteria and samples were analyzed using gene expression microarrays. The resulting data was processed with GSEA using gene sets from MSigDB. An initial supervised analysis was carried out to identify differentially expressed genes between patients with moderate/severe toxicities (Grade 2 or higher) versus mild/no toxicities (Grade 0-1) including xerostomia, mucositis, and dysphagia, the most common toxicities experienced. One hundred twelve genes were found to be differentially expressed between the two groups when using a threshold of P < .01, 77 of which were upregulated and 35 of which were downregulated in patients with greater toxicities. Promising candidate genes known to be involved in DNA damage response and/or wound healing were identified, including PPARGC1B, RASSF2, MMP3, MMP10, and VEGFC. Additional analysis focusing on mucositis was performed in a smaller cohort after controlling for factors including tumor site, maximum dose, and use of concurrent chemotherapy. Gene sets found to be significantly enriched in the severe group included those associated with dental caries and those associated with an increase in immune surveillance and response. Conversely, gene sets found to be significantly enriched in the non-severe group included those associated with embryonic stem cells and genes involved in mitosis and DNA replication. Our study identified several genes previously shown to be involved in apoptosis, wound healing, and radiosensitivity that were differentially expressed in patients with high versus low grade toxicities from radiation therapy; in addition, we identified several gene sets enriched in patients experiencing mucositis after radiation therapy, including those involved in other oral lesions that can develop independent of radiation therapy (dental caries). We also isolated gene sets enriched in patients with minimal mucositis, including those involved in enhanced cell division/renewal. Studies to validate these markers are ongoing, with the goal of validating biomarkers that may predict radiation toxicity.