Xuefei Jia

Primary Cardiac Sarcoma: 25-Year Cleveland Clinic Experience.

Background:Cardiac sarcomas are rare and have a poor prognosis. The median overall survival remains dismal and has been reported ranging from 6 months to a few years. Primary cardiac sarcoma is the most common malignant tumor comprising approximately 95% of all malignant tumors of the heart. Methods:We conducted a retrospective chart review in a single institution of patients diagnosed between March 1988 and April 2013. A total of 42 patients were identified. The following variables were studied: age at diagnosis, year of diagnosis, sex, stage, site of tumor involvement, tumor histology, grade, treatment modality, type of chemotherapy, and survival outcome. The overall median follow-up time was 49.5 months. Results:The most common histologic type was angiosarcoma. Overall estimated median survival (EMS) was 25 months. Tumors involving the left side of the heart and pericardium demonstrated better survival. Patients who received multimodality treatment (any combination of surgery, radiation therapy, and chemotherapy) had an EMS of 36.5 months compared with 14.1 months for patients treated with surgery, radiation therapy, or chemotherapy only (P=0.05). Conclusions:Cardiac sarcoma is a lethal tumor with an EMS of 25 months. The tumor histology could be a possible predictor of better survival. Although selection bias may have been present, multimodality therapy (surgery, radiation therapy, and chemotherapy) was associated with improved survival.

Impact of the radiosurgery prescription dose on the local control of small (2 cm or smaller) brain metastases

OBJECTIVE The impact of the stereotactic radiosurgery (SRS) prescription dose (PD) on local progression and radiation necrosis for small (≤ 2 cm) brain metastases was evaluated. METHODS An institutional review board-approved retrospective review was performed on 896 patients with brain metastases ≤ 2 cm (3034 tumors) who were treated with 1229 SRS procedures between 2000 and 2012. Local progression and/or radiation necrosis were the primary end points. Each tumor was followed from the date of radiosurgery until one of the end points was reached or the last MRI follow-up. Various criteria were used to differentiate tumor progression and radiation necrosis, including the evaluation of serial MRIs, cerebral blood volume on perfusion MR, FDG-PET scans, and, in some cases, surgical pathology. The median radiographic follow-up per lesion was 6.2 months. RESULTS The median patient age was 56 years, and 56% of the patients were female. The most common primary pathology was non-small cell lung cancer (44%), followed by breast cancer (19%), renal cell carcinoma (14%), melanoma (11%), and small cell lung cancer (5%). The median tumor volume and median largest diameter were 0.16 cm3 and 0.8 cm, respectively. In total, 1018 lesions (34%) were larger than 1 cm in maximum diameter. The PD for 2410 tumors (80%) was 24 Gy, for 408 tumors (13%) it was 19 to 23 Gy, and for 216 tumors (7%) it was 15 to 18 Gy. In total, 87 patients (10%) had local progression of 104 tumors (3%), and 148 patients (17%) had at least radiographic evidence of radiation necrosis involving 199 tumors (7%; 4% were symptomatic). Univariate and multivariate analyses were performed for local progression and radiation necrosis. For local progression, tumors less than 1 cm (subhazard ratio [SHR] 2.32; p < 0.001), PD of 24 Gy (SHR 1.84; p = 0.01), and additional whole-brain radiation therapy (SHR 2.53; p = 0.001) were independently associated with better outcome. For the development of radiographic radiation necrosis, independent prognostic factors included size greater than 1 cm (SHR 2.13; p < 0.001), location in the corpus callosum (SHR 5.72; p < 0.001), and uncommon pathologies (SHR 1.65; p = 0.05). Size (SHR 4.78; p < 0.001) and location (SHR 7.62; p < 0.001)-but not uncommon pathologies-were independent prognostic factors for the subgroup with symptomatic radiation necrosis. CONCLUSIONS A PD of 24 Gy results in significantly better local control of metastases measuring < 2 cm than lower doses. In addition, tumor size is an independent prognostic factor for both local progression and radiation necrosis. Some tumor pathologies and locations may also contribute to an increased risk of radiation necrosis.

Myeloid derived suppressor cell subset accumulation in renal cell carcinoma parenchyma is associated with intratumoral expression of IL-1β, IL-8, CXCL5 and Mip-1α

Purpose: Little is known about the association between myeloid-derived suppressor cell (MDSC) subsets and various chemokines in patients with renal cell carcinoma (RCC) or the factors that draw MDSC into tumor parenchyma. Experimental Design: We analyzed polymorphonuclear MDSC (PMN-MDSC), monocytic MDSC (M-MDSC), and immature MDSC (I-MDSC) from the parenchyma and peripheral blood of 48 patients with RCC, isolated at nephrectomy. We analyzed levels of IL1β, IL8, CXCL5, Mip-1α, MCP-1, and Rantes. Furthermore, we performed experiments in a Renca murine model to assess therapeutic synergy between CXCR2 and anti-PD1 and to elucidate the impact of IL1β blockade on MDSC. Results: Parenchymal PMN-MDSC have a positive correlation with IL1β, IL8, CXCL5, and Mip-1α, and I-MDSC correlate with IL8 and CXCL5. Furthermore, peripheral PMN-MDSC correlate with tumor grade. Given that PMN-MDSC express CXCR2 and parenchymal PMN-MDSC correlated with IL8 and CXCL5, we assessed the response of CXCR2 blockade with or without anti-PD1. Combination therapy reduced tumor weight and enhanced CD4+ and CD8+ T-cell infiltration. In addition, anti-IL1β decreased PMN-MDSC and M-MDSC in the periphery, PMN-MDSC in the tumor, and peripheral CXCL5 and KC. Anti-IL1β also delayed tumor growth. Conclusions: Parenchymal PMN-MDSC have a positive correlation with IL1β, IL8, CXCL5, and Mip-1α, suggesting they may attract PMN-MDSC into the tumor. Peripheral PMN-MDSC correlate with tumor grade, suggesting prognostic significance. Anti-CXCR2 and anti-PD1 synergized to reduce tumor weight and enhanced CD4+ and CD8+ T-cell infiltration in a Renca murine model, suggesting that CXCR2+ PMN-MDSC are important in reducing activity of anti-PD1 antibody. Finally, anti-IL1β decreases MDSC and delayed tumor growth, suggesting a potential target for MDSC inhibition. Clin Cancer Res; 23(9); 2346–55. ©2016 AACR.

Tumor Necrosis Adds Prognostically Significant Information to Grade in Clear Cell Renal Cell Carcinoma: A Study of 842 Consecutive Cases from a Single Institution

Tumor necrosis has been shown to be an independent predictor of adverse outcome in renal cell carcinoma. A modification of the International Society of Urological Pathology (ISUP) grading system for renal cell carcinomas has recently been proposed, which incorporates the presence of tumor necrosis into grade. The investigators proposing this system found that necrosis added significant prognostic information to ISUP grade. We attempted to describe our experience with the effect of tumor necrosis in relationship to nuclear grade by reviewing the slides from a large consecutive series of localized clear cell renal cell carcinomas from our institution and obtaining long-term clinical follow-up information (overall survival). Of the 842 clear cell renal cell carcinomas reviewed, 265 (31.5%) were ISUP grade 1 or 2, 437 (51.9%) were ISUP grade 3, and 140 (16.6%) were ISUP grade 4. Tumor necrosis was present in 177 (21%) cases. Five hundred and forty-seven (64.9%) cases were stage pT1, 83 (9.9%) were stage pT2, 193 (22.9%) were stage pT3a, and 19 (2.3%) were pT3b or higher. Median follow-up was 73.2 months (range 0.12 to 273.6), and 310 (36.8%) patients died. On univariable analysis, there was no significant difference in outcome for tumors of ISUP grades 1 to 3. After adjustment for age, tumor stage, and tumor size, ISUP grade 4 and necrosis were significant predictors of overall survival on multivariable analysis. When the recently proposed modified grading system incorporating tumor necrosis was applied to our data, there was no significant difference in overall survival between patients with modified grade 1 tumors and those with modified grade 2 tumors (P=0.31); however, there was a statistically significant difference between patients with modified grade 1 or 2 tumors and those with modified grade 3 tumors (P=0.04),and a substantial difference in outcome between those with modified grade 3 and modified grade 4 tumors (P<0.001). When a recursive partitioning approach was applied to our data, patients of a given ISUP grade could be further prognostically separated according to the presence or absence of necrosis and could be divided into 3 statistically significant prognostic groups: (1) non-necrotic ISUP grade 1 to 3 tumors, (2) ISUP grade 1 to 3 tumors with necrosis and ISUP grade 4 tumors with <10% necrosis, and (3) ISUP grade 4 tumors with >10% necrosis. In conclusion, our study shows that tumor necrosis adds additional prognostic information to ISUP grade and that quantification of necrosis can further stratify patients with ISUP grade 4 tumors.

Long-Term Outcome Following Stereotactic Radiosurgery for Glomus Jugulare Tumors: A Single Institution Experience of 20 Years

BACKGROUND Glomus jugulare tumors (GJTs) are rare benign tumors, which pose significant treatment challenges due to proximity to critical structures. OBJECTIVE To evaluate the long-term clinical and radiological outcome in patients undergoing stereotactic radiosurgery (SRS) for GJTs through retrospective study. METHODS Forty-two patients with 43 GJTs were treated using Gamma Knife radiosurgery (GKRS; Elekta AB, Stockholm, Sweden) at our institute from 1997 to 2016. Clinical, imaging, and radiosurgery data were collected from an institutional review board approved database. RESULTS Most patients were females (n = 35, 83.3%) and median age was 61 yr (range 23-88 yr). Median tumor volume and diameter were 5 cc and 3 cm, respectively, with a median follow-up of 62.3 mo (3.4-218.6 mo). Overall, 20 patients (47.6%) improved clinically and 14 (33.3%) remained unchanged at last follow-up. New onset or worsening of hearing loss was noted in 6 patients (17.2%) after SRS. The median prescription dose to the tumor margin was 15 Gy (12-18 Gy). Median reduction in tumor volume and maximum tumor diameter at last follow-up was 33.3% and 11.54%, respectively. The 5-yr and 10-yr tumor control rates were 87% ± 6% and 69% ± 13%, respectively. There was no correlation between maximum or mean dose to the internal acoustic canal and post-GK hearing loss (P > .05). CONCLUSION SRS is safe and effective in patients with GJTs and results in durable, long-term control. SRS has lower morbidity than that associated with surgical resection, particularly lower cranial nerve dysfunction, and can be a first-line management option in these patients.

First follow‐up radiographic response is one of the predictors of local tumor progression and radiation necrosis after stereotactic radiosurgery for brain metastases

Local progression (LP) and radiation necrosis (RN) occur in >20% of cases following stereotactic radiosurgery (SRS) for brain metastases (BM). Expected outcomes following SRS for BM include tumor control/shrinkage, local progression and radiation necrosis. 1427 patients with 4283 BM lesions were treated using SRS at Cleveland Clinic from 2000 to 2012. Clinical, imaging and radiosurgery data were collected from the database. Local tumor progression and RN were the primary end points and correlated with patient and tumor‐related variables. 5.7% of lesions developed radiographic RN and 3.6% showed local progression at 6 months. Absence of new extracranial metastasis (P < 0.001), response to SRS at first follow‐up scan (local progression versus stable size (P < 0.001), partial resolution versus complete resolution at first follow up [P = 0.009]), prior SRS to the same lesion (P < 0.001), IDL% (≤55; P < 0.001), maximum tumor diameter (>0.9 cm; P < 0.001) and MD/PD gradient index (≤1.8, P < 0.001) were independent predictors of high risk of local tumor progression. Absence of systemic metastases (P = 0.029), good neurological function at 1st follow‐up (P ≤ 0.001), no prior SRS to other lesion (P = 0.024), low conformity index (≤1.9) (P = 0.009), large maximum target diameter (>0.9 cm) (P = 0.003) and response to SRS (tumor progression vs. stable size following SRS [P < 0.001]) were independent predictors of high risk of radiographic RN. Complete tumor response at first follow‐up, maximum tumor diameter <0.9 cm, tumor volume <2.4 cc and no prior SRS to the index lesion are good prognostic factors with reduced risk of LP following SRS. Complete tumor response to SRS, poor neurological function at first follow‐up, prior SRS to other lesions and high conformity index are favorable factors for not developing RN. Stable or partial response at first follow‐up after SRS have same impact on local progression and RN compared to those with complete resolution or progression.

Accumulation of MDSC subsets in renal cell carcinoma correlates with grade and progression free survival, and is associated with intratumoral expression of IL-1β, IL-8 and CXCL5

Myeloid derived suppressor cells (MDSC, CD33+CD11b+ HLA-DR low/-) play a major role in tumor-mediated immune evasion and are composed of at least 3 subsets PMN (CD15+), monocytic (CD14+) and lineage-negative (CD15-CD14-), and each has been shown to be significantly increased in some human tumor types and to correlate with metastatic burden, clinical cancer stage and outcome. Less in known about the MDSC subsets that accumulate in tumors such as renal cell carcinoma (RCC) and the cytokines/chemokines involved in their recruitment. Flow cytometry analysis of peripheral blood mononuclear cells (PBMC, n = 20) and nephrectomy samples (n = 39, stage 1-4) showed increased levels of total MDSC in RCC patients compared to normal controls (n = 15), with PMN- and Lin- MDSC subsets dominating in the blood and tumor of RCC patients. Blood levels of total MDSC, PMN-MDSC and Lin-MDSC correlated with tumor grade (p = 0.026, p = 0.006 and p = 0.045, respectively), while blood levels of total MDSC and Lin-MDSC correlated with progression free survival (PFS) in patients with limited stage disease (n = 16, stages 1-3) (HR = 1.35, p = 0.03; HR = 1.45, p = 0.02, respectively). In the tumor, higher PMN-MDSC levels were significantly associated with decreased PFS (n = 29, HR = 1.09, p = 0.011). To assess the role of select chemokines (IL-8, CXCL5, Mip-1α, MCP-1 and Rantes) and of the pro-inflammatory cytokine IL-1β in promoting the accumulation of MDSC within the tumor, these proteins were quantitated in tumor lysates by ELISA and correlated to MDSC frequencies (Spearman correlations). We found a direct correlation between the frequency of PMN-MDSC in the parenchyma and the levels of IL-8 (p < 0.001), CXCL-5 (p < 0.001), and IL-1β (p = 0.029). Frequency of parenchymal Lin- MDSC directly correlated with levels of IL-8 (p = 0.033) and CXCL-5 (p = 0.008), but not IL-1β. In circulation, frequency of total MDSCs directly correlated with IL-1β plasma levels (p = 0.003). To further define the role of IL-1β in MDSC accumulation within tumors, we overexpressed IL-1β in RENCA and CT26 tumors and compared them to untransfected tumors. Overexpression of IL-1β resulted in enhanced tumor growth and increased frequency of intratumor PMN-MDSC (10.3X in RENCA and 26X in CT26), with a modest increase in intratumor M-MDSC. A large fraction of tumor infiltrating PMN-MDSC expressed CXCR2 (84% in RENCA and 55% in CT26), which is associated with a significant increase in expression of CXCR2 ligands (KC, CXCL5, and MIP2). These results support the idea that IL-1β-mediated induction of select chemokines promotes the accumulation of MDSC, particularly PMN-MDSC, within tumors, resulting in enhanced immune suppression and angiogenesis.