James S. Babb

Fractionated but Not Single-Dose Radiotherapy Induces an Immune-Mediated Abscopal Effect when Combined with Anti–CTLA-4 Antibody

Purpose: This study tested the hypothesis that the type of dose fractionation regimen determines the ability of radiotherapy to synergize with anti–CTLA-4 antibody. Experimental Design: TSA mouse breast carcinoma cells were injected s.c. into syngeneic mice at two separate sites, defined as a “primary” site that was irradiated and a “secondary” site outside the radiotherapy field. When both tumors were palpable, mice were randomly assigned to eight groups receiving no radiotherapy or three distinct regimens of radiotherapy (20 Gy × 1, 8 Gy × 3, or 6 Gy × 5 fractions in consecutive days) in combination or not with 9H10 monoclonal antibody against CTLA-4. Mice were followed for tumor growth/regression. Similar experiments were conducted in the MCA38 mouse colon carcinoma model. Results: In either of the two models tested, treatment with 9H10 alone had no detectable effect. Each of the radiotherapy regimens caused comparable growth delay of the primary tumors but had no effect on the secondary tumors outside the radiation field. Conversely, the combination of 9H10 and either fractionated radiotherapy regimens achieved enhanced tumor response at the primary site (P < 0.0001). Moreover, an abscopal effect, defined as a significant growth inhibition of the tumor outside the field, occurred only in mice treated with the combination of 9H10 and fractionated radiotherapy (P < 0.01). The frequency of CD8+ T cells showing tumor-specific IFN-γ production was proportional to the inhibition of the secondary tumor. Conclusions: Fractionated but not single-dose radiotherapy induces an abscopal effect when in combination with anti–CTLA-4 antibody in two preclinical carcinoma models. (Clin Cancer Res 2009;15(17):5379–88)

Focal liver lesion detection and characterization with diffusion-weighted MR imaging: Comparison with standard breath-hold T2-weighted imaging

PURPOSE To retrospectively compare diffusion-weighted (DW) magnetic resonance (MR) imaging with standard breath-hold T2-weighted MR imaging for focal liver lesion (FLL) detection and characterization, by using consensus evaluation and other findings as the reference standard. MATERIALS AND METHODS Approval for this retrospective HIPAA-compliant study was obtained from the institutional review board; informed consent was waived. Fifty-three consecutive patients (30 men, 23 women; mean age, 60.7 years) with at least one FLL of 1 cm or greater in diameter were evaluated. Two independent observers reviewed DW (b values of 0, 50, and 500 sec/mm(2)) and T2-weighted images for FLL detection and characterization. Reference standard for diagnosis was obtained from consensus review by the two observers of DW, T2-weighted, and dynamic contrast material-enhanced images, pathologic data, and follow-up imaging results. Apparent diffusion coefficient (ADC) was measured for FLLs identified at consensus review. DW and T2-weighted images were compared for FLL detection and characterization by using a binary logistic regression model. Receiver operating characteristic curve analyses were conducted to evaluate the utility of ADC for diagnosis of malignancy. RESULTS Two hundred eleven FLLs (136 malignant, 75 benign) were detected at consensus review. Overall detection rate (averaged for two observers) was significantly higher for DW (87.7%) versus T2-weighted (70.1%) imaging (P < .001). FLL characterization was not significantly different between DW (89.1%) and T2-weighted (86.8%) imaging (P = .51). ADCs of malignant FLLs were significantly lower than those of benign FLLs (P < .001). The area under the curve for diagnosis of malignancy was 0.839, with sensitivity of 74.2%, specificity of 77.3%, positive predictive value of 85.5%, negative predictive value of 62.3%, and accuracy of 75.3%, by using a threshold ADC of less than 1.60 x 10(-3) mm(2)/sec. CONCLUSION DW MR imaging was better than standard breath-hold T2-weighted imaging for FLL detection and was equal to breath-hold T2-weighted imaging for FLL characterization.

Gliomas: Predicting Time to Progression or Survival with Cerebral Blood Volume Measurements at Dynamic Susceptibility-weighted Contrast-enhanced Perfusion MR Imaging

PURPOSE To retrospectively determine whether relative cerebral blood volume (CBV) measurements can be used to predict clinical outcome in patients with high-grade gliomas (HGGs) and low-grade gliomas (LGGs) and specifically whether patients who have gliomas with a high initial relative CBV have more rapid progression than those who have gliomas with a low relative CBV. MATERIALS AND METHODS Approval for this retrospective HIPAA-compliant study was obtained from the Institutional Board of Research Associates, with waiver of informed consent. One hundred eighty-nine patients (122 male and 67 female patients; median age, 43 years; range, 4-80 years) were examined with dynamic susceptibility-weighted contrast material-enhanced perfusion magnetic resonance (MR) imaging and were followed up clinically with MR imaging (median follow-up, 334 days). Log-rank tests were used to evaluate the association between relative CBV and time to progression by using Kaplan-Meier curves. Binary logistic regression was used to determine whether age, sex, and relative CBV were associated with an adverse event (progressive disease or death). RESULTS Values for the mean relative CBV for patients according to each clinical response were as follows: 1.41 +/- 0.13 (standard deviation) for complete response (n = 4), 2.36 +/- 1.78 for stable disease (n = 41), 4.84 +/- 3.32 for progressive disease (n = 130), and 3.82 +/- 1.93 for death (n = 14). Kaplan-Meier estimates of median time to progression in days indicated that patients with a relative CBV of less than 1.75 had a median time to progression of 3585 days, whereas patients with a relative CBV of more than 1.75 had a time to progression of 265 days. Age and relative CBV were also independent predictors for clinical outcome. CONCLUSION Dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging can be used to predict median time to progression in patients with gliomas, independent of pathologic findings. Patients who have HGGs and LGGs with a high relative CBV (>1.75) have a significantly more rapid time to progression than do patients who have gliomas with a low relative CBV.

Diffusion-weighted MRI for quantification of liver fibrosis : Preliminary experience

OBJECTIVE The purpose of this study was to evaluate our preliminary experience using diffusion-weighted MRI for quantification of liver fibrosis. SUBJECTS AND METHODS Diffusion-weighted MRI with single-shot echo-planar technique at b values of 50, 300, 500, 700, and 1,000 s/mm2 was prospectively performed on 23 patients with chronic hepatitis and on seven healthy volunteers. The apparent diffusion coefficient (ADC) was measured in four locations in the liver. Liver biopsy results (n = 19) were retrospectively reviewed by two hepatopathologists in consensus to determine stage of fibrosis and grade of inflammation. A Mann-Whitney test was used to compare the ADCs between patients classified with respect to having stage 2 or greater versus stage 1 or less fibrosis and stage 3 or greater versus stage or less 2 fibrosis. Receiver operating characteristics analysis was used to assess the performance of ADC in prediction of the presence of stage 2 or greater and stage 3 or greater fibrosis. RESULTS Using a b value of 500 s/mm2 and all combined b values, we found significantly lower hepatic ADCs in stage 2 or greater versus stage 1 or less fibrosis and stage 3 or greater versus stage 2 or less fibrosis. The mean ADCs (x 10(-3) mm2/s) with all b values were 1.47 +/- 0.11 (SD) versus 1.65 +/- 0.10 for stage 2 or greater versus stage 1 or less fibrosis (p < 0.001) and 1.44 +/- 0.07 versus 1.66 +/- 0.10 for stage 3 or greater versus stage 2 or less fibrosis (p <0.001). Hepatic ADC was a significant predictor of stage 2 or greater and stage 3 or greater fibrosis, with areas under the curve of 0.896 and 0.896, sensitivity of 83.3% and 88.9%, and specificity of 83.3% and 80.0% (ADC with all b values, 1.54-1.53 x 10(-3) mm2/s or less). CONCLUSION Diffusion-weighted MRI can be used for prediction of the presence of moderate and advanced liver fibrosis.

Radiation-Induced CXCL16 Release by Breast Cancer Cells Attracts Effector T Cells

Recruitment of effector T cells to inflamed peripheral tissues is regulated by chemokines and their receptors, but the factors regulating recruitment to tumors remain largely undefined. Ionizing radiation (IR) therapy is a common treatment modality for breast and other cancers. Used as a cytocidal agent for proliferating cancer cells, IR in combination with immunotherapy has been shown to promote immune-mediated tumor destruction in preclinical studies. In this study we demonstrate that IR markedly enhanced the secretion by mouse and human breast cancer cells of CXCL16, a chemokine that binds to CXCR6 on Th1 and activated CD8 effector T cells, and plays an important role in their recruitment to sites of inflammation. Using a poorly immunogenic mouse model of breast cancer, we found that irradiation increased the migration of CD8+CXCR6+ activated T cells to tumors in vitro and in vivo. CXCR6-deficient mice showed reduced infiltration of tumors by activated CD8 T cells and impaired tumor regression following treatment with local IR to the tumor and Abs blocking the negative regulator of T cell activation, CTLA-4. These results provide the first evidence that IR can induce the secretion by cancer cells of proinflammatory chemotactic factors that recruit antitumor effector T cells. The ability of IR to convert tumors into “inflamed” peripheral tissues could be exploited to overcome obstacles at the effector phase of the antitumor immune response and improve the therapeutic efficacy of immunotherapy.

Diagnosis of cirrhosis with intravoxel incoherent motion diffusion MRI and dynamic contrast-enhanced MRI alone and in combination: preliminary experience.

To report our preliminary experience with the use of intravoxel incoherent motion (IVIM) diffusion‐weighted magnetic resonance imaging (DW‐MRI) and dynamic contrast‐enhanced (DCE)‐MRI alone and in combination for the diagnosis of liver cirrhosis.

Renal Lesions: Characterization with Diffusion-weighted Imaging versus Contrast-enhanced MR Imaging

PURPOSE To compare the diagnostic performance of diffusion-weighted (DW) magnetic resonance (MR) imaging with that of contrast material-enhanced (CE) MR imaging and to assess the performance of these examinations combined for the characterization of renal lesions, with MR follow-up and histopathologic analysis as the reference standards. MATERIALS AND METHODS The institutional review board waived the requirement of informed patient consent for this retrospective HIPAA-compliant study. One hundred nine renal lesions in 64 patients (46 men, 18 women; mean age, 60.7 years) were evaluated with CE MR imaging and breath-hold DW imaging performed with various b values. Renal lesions were characterized with use of CE MR criteria, and apparent diffusion coefficients (ADCs) were measured. The ADCs of benign and malignant lesions were compared at Mann-Whitney testing. Receiver operating characteristic (ROC) analysis was performed to assess the accuracy of DW imaging and CE MR imaging in the diagnosis of renal cell carcinoma (RCC). RESULTS The 109 renal lesions--81 benign lesions and 28 RCCs--had a mean diameter of 4.2 cm +/- 2.5 (standard deviation). The mean ADC for RCCs (1.41 x 10(-3) mm(2)/sec +/- 0.61) was significantly lower (P < .0001) than that for benign lesions (2.23 x 10(-3) mm(2)/sec +/- 0.87) at DW imaging performed with b values of 0, 400, and 800 sec/mm(2). At a cutoff ADC of less than or equal to 1.92 x 10(-3) mm(2)/sec, the area under the ROC curve (AUC), sensitivity, and specificity of DW imaging for the diagnosis of RCCs (excluding angiomyolipomas) were 0.856, 86%, and 80%, respectively. The corresponding AUC, sensitivity, and specificity of CE MR imaging were 0.944, 100%, and 89%, respectively. Combined DW and CE MR imaging had 96% specificity. The AUC for the DW imaging-based diagnosis of solid RCC versus oncocytoma was 0.854. Papillary RCCs had lower ADCs than nonpapillary RCCs. CONCLUSION DW imaging can be used to characterize renal lesions; however, compared with CE MR imaging, it is less accurate. DW imaging can be used to differentiate solid RCCs from oncocytomas and characterize the histologic subtypes of RCC.

Total brain N-acetylaspartate A new measure of disease load in MS

Objective: To quantitate the extent of neuronal cell loss in MS via the whole brain’s N-acetylaspartate (NAA) concentration (WBNAA). Methods: Because NAA is assumed to be present only in neuronal cell bodies and their axons, we measured WBNAA as a marker for viable neurons in 12 patients (9 women and 3 men, 26 to 53 years of age) suffering from relapsing-remitting (RR) MS for at least 5 years and compared them with 13 age- and sex-matched normal controls. Total brain NAA was determined with proton MR spectroscopy, and WBNAA was obtained by dividing it by the total brain volume, calculated from high resolution MRI. Results: The WBNAA of the RR MS patients was lower than their matched controls (p < 0.005). This difference was greater among older than younger subjects. The linear prediction equations of WBNAA with age indicate a faster, ×10, decline in the patients, ∼0.8% per year of age (p = 0.022). Conclusion: The age-dependent decrease of whole brain N-acetylaspartate (WBNAA) in the patients suggests that progressive neuronal cell loss is a cardinal feature of this disease. WBNAA offers a quick, highly reproducible measure of disease progression and may be an important marker of treatment efficacy in MS as well as other neurodegenerative diseases.

Short-term DTI predictors of cognitive dysfunction in mild traumatic brain injury

Primary objective: To explore whether baseline diffusion tensor imaging (DTI) metrics are predictive of cognitive functioning 6 months post-injury in patients with mild traumatic brain injury (MTBI). Research design: Seventeen patients with MTBI and 29 sex- and age-matched healthy controls were studied. Methods and procedures: Participants underwent an MRI protocol including DTI, at an average of 4.0 (range: 1–10) days post-injury. Mean diffusivity (MD) and fractional anisotropy (FA) were measured in the following white matter (WM) regions: centra semiovale, the genu and the splenium of the corpus callosum and the posterior limb of the internal capsule. Participants underwent neuropsychological (NP) testing at baseline and at 6-month follow-up. Least squares regression analysis was used to evaluate the association of MD and FA with each NP test score at baseline and follow-up. Main outcomes and results: Compared to controls, average MD was significantly higher (p= 0.02) and average FA significantly lower (p= 0.0001) in MTBI patients. At the follow-up, there was a trend toward a significant association between baseline MD and response speed (r= −0.53, p= 0.087) and a positive correlation between baseline FA and Prioritization form B (r= 0.72, p= 0.003). Conclusions: DTI may provide short-term non-invasive predictive markers of cognitive functioning in patients with MTBI.

Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-principle trial

BACKGROUND An abscopal response describes radiotherapy-induced immune-mediated tumour regression at sites distant to the irradiated field. Granulocyte-macrophage colony-stimulating factor is a potent stimulator of dendritic cell maturation. We postulated that the exploitation of the pro-immunogenic effects of radiotherapy with granulocyte-macrophage colony-stimulating factor might result in abscopal responses among patients with metastatic cancer. METHODS Patients with stable or progressing metastatic solid tumours, on single-agent chemotherapy or hormonal therapy, with at least three distinct measurable sites of disease, were treated with concurrent radiotherapy (35 Gy in ten fractions, over 2 weeks) to one metastatic site and granulocyte-macrophage colony-stimulating factor (125 μg/m(2) subcutaneously injected daily for 2 weeks, starting during the second week of radiotherapy). This course was repeated, targeting a second metastatic site. A Simons optimal two-stage design was chosen for this trial: an additional 19 patients could be enrolled in stage 2 only if at least one patient among the first ten had an abscopal response. If no abscopal responses were seen among the first ten patients, the study would be deemed futile and terminated. The primary endpoint was the proportion of patients with an abscopal response (defined as at least a 30% decrease in the longest diameter of the best responding abscopal lesion). Secondary endpoints were safety and survival. Analyses were done based on intention to treat. The trial has concluded accrual, and is registered with ClinicalTrials.gov, number NCT02474186. FINDINGS From April 7, 2003, to April 3, 2012, 41 patients with metastatic cancer were enrolled. In stage 1 of the Simons two-stage design, ten patients were enrolled: four of the first ten patients had abscopal responses. Thus, the trial proceeded to stage 2, as planned, and an additional 19 patients were enrolled. Due to protocol amendments 12 further patients were enrolled. Abscopal responses occurred in eight (27·6%, 95% CI 12·7-47·2) of the first 29 patients, and 11 (26·8%, 95% CI 14·2-42·9) of 41 accrued patients (specifically in four patients with non-small-cell lung cancer, five with breast cancer, and two with thymic cancer). The most common grade 3-4 adverse events were fatigue (six patients) and haematological (ten patients). Additionally, a serious adverse event of grade 4 pulmonary embolism occurred in one patient. INTERPRETATION The combination of radiotherapy with granulocyte-macrophage colony-stimulating factor produced objective abscopal responses in some patients with metastatic solid tumours. This finding represents a promising approach to establish an in-situ anti-tumour vaccine. Further research is warranted in this area. FUNDING New York University School of Medicines Department of Radiation Oncology and Cancer Institute.