Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy.

Nine cancer patients were treated with adoptive cell therapy using autologous anti-MAGE-A3 T-cell receptors (TCR)-engineered T cells. Five patients experienced clinical regression of their cancers including 2 on-going responders. Beginning 1-2 days postinfusion, 3 patients (#'s 5, 7, and 8) experienced mental status changes, and 2 patients (5 and 8) lapsed into comas and subsequently died. Magnetic resonance imagining analysis of patients 5 and 8 demonstrated periventricular leukomalacia, and examination of their brains at autopsy revealed necrotizing leukoencephalopathy with extensive white matter defects associated with infiltration of CD3(+)/CD8(+) T cells. Patient 7, developed Parkinson-like symptoms, which resolved over 4 weeks and fully recovered. Immunohistochemical staining of patient and normal brain samples demonstrated rare positively staining neurons with an antibody that recognizes multiple MAGE-A family members. The TCR used in this study recognized epitopes in MAGE-A3/A9/A12. Molecular assays of human brain samples using real-time quantitative-polymerase chain reaction, Nanostring quantitation, and deep-sequencing indicated that MAGE-A12 was expressed in human brain (and possibly MAGE-A1, MAGE-A8, and MAGE-A9). This previously unrecognized expression of MAGE-A12 in human brain was possibly the initiating event of a TCR-mediated inflammatory response that resulted in neuronal cell destruction and raises caution for clinical applications targeting MAGE-A family members with highly active immunotherapies.

Loss of expression of the cancer stem cell marker aldehyde dehydrogenase 1 correlates with advanced-stage colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) progression is mediated by cancer stem cells (CSCs). We sought to determine if the expression of the CSC marker aldehyde dehydrogenase 1 (ALDH1) in CRC tumors varies by American Joint Committee on Cancer stage or correlates to clinical outcomes. METHODS: Primary and metastatic CRC samples from 96 patients were immunostained with antibodies to ALDH1 and imaged to evaluate marker expression. The percentage of ALDH1(+) cells was correlated to clinical outcomes. RESULTS: ALDH1 was overexpressed in CRC tumors compared with nonneoplastic tissue. Marker expression was highest in nonmetastatic tumors. The loss of expression was associated with advanced stage and metastatic disease. No significant correlation was found between ALDH1 expression and metastasis, recurrence, or survival. CONCLUSIONS: ALDH1 was highly expressed in nonmetastatic CRC, but expression was lost with advancing stage. ALDH1 could be an effective therapeutic target in early CRC but not late-stage disease. No correlation was found between ALDH1 and disease prognosis.

Impact of American College of Surgeons Oncology Group Z0011 and National Surgical Adjuvant Breast and Bowel Project B-32 trial results on surgeon practice in the Pacific Northwest.

BACKGROUND: Recent clinical trials have suggested no survival benefit for completion axillary node dissection (CALND) after sentinel lymph node biopsy (American College of Surgeons Oncology Group Z0011) and no clinically meaningful benefit for the routine use of immunohistochemistry (National Surgical Adjuvant Breast and Bowel Project B-32) in clinically node-negative breast cancer. METHODS: A 12-question electronic survey was distributed to members of 3 Pacific Northwest surgical societies. Surgeons were queried regarding the impact of the trial results on their surgical management of breast cancer. RESULTS: The 181 respondents reported performing fewer CALNDs (63%), fewer intraoperative frozen sections (21%), and no immunohistochemistry (12%) because of trial data. However, 28% of surgeons continued to perform CALND in patients with 1 to 2 positive sentinel lymph nodes undergoing lumpectomy and postoperative radiation. CONCLUSIONS: Recent trial data have impacted the performance of CALNDs and the pathological evaluation of sentinel lymph nodes among Pacific Northwest surgeons. Our results suggest a need for regional surgical societies to disseminate practice-changing trial data to members.

Comparison of pulmonary nodule detection rates between preoperative CT imaging and intraoperative lung palpation.

BACKGROUND: Recent advances in computed tomographic (CT) imaging have improved the detection rate of pulmonary metastasis. The aim of this study was to test the hypothesis that the pulmonary nodule detection rate for preoperative CT imaging and intraoperative palpation are now equivalent. METHODS: A retrospective review of 108 pulmonary metastasectomies in 84 patients was performed. The number of nodules detected on preoperative CT imaging by radiologist report was compared with the number of malignant nodules identified on pathology. Secondary outcome measures were operative approach and primary malignancy. RESULTS: Sarcoma metastases were the most common indication for resection (n = 54 [50%]). Thirty-three percent of metastasectomies were performed using a thoracoscopic approach. When thoracotomy was used, significantly more nodules were palpated and resected than were identified on preoperative CT imaging (3.24 vs 2.12, P < .001). Significantly more of these nodules were confirmed malignant on final pathology (2.40 vs 1.60, P = .01). This difference was not seen for thoracoscopic resections. CONCLUSIONS: Although the sensitivity of CT imaging has improved, a significant number of malignant pulmonary nodules are detected intraoperatively that are not identified on preoperative imaging. Patients undergoing pulmonary metastasectomy require careful intraoperative palpation of lung parenchyma, and therefore open thoracotomy remains the standard of care.

Comparative validation of online nomograms for predicting nonsentinel lymph node status in sentinel lymph node-positive breast cancer.

BACKGROUND: Completion axillary lymph node dissection is recommended for patients with metastases to the sentinel lymph node (SLN) in breast cancer although nonsentinel lymph nodes (NSLN) are often negative for tumor. Online nomograms are available to predict risk of NSLN disease. OBJECTIVE: To compare the accuracy of the Memorial Sloan-Kettering Cancer Center (MSKCC) nomogram (using 9 variables) with the Stanford nomogram (using 3 variables) in predicting NSLN metastasis. SETTING: A single academic center. PATIENTS: Prospectively maintained database of patients with breast cancer who underwent SLN biopsy from October 1, 1999, through January 31, 2008. METHODS: Risk of NSLN metastasis was calculated using each nomogram's online calculator. Results from the axillary lymph node dissection were reviewed for positive NSLNs. Nomograms were evaluated using the area under the receiver operating characteristic curve, false-negative rates, positive predictive value, and calibration plot. MAIN OUTCOME MEASURES: Nomogram scores and axillary lymph node dissection results. RESULTS: Of 579 patients who underwent SLN biopsy, 179 (30.9%) had a positive SLN. For 123 patients who underwent axillary lymph node dissection, the area under the curve for the MSKCC and Stanford nomograms was 0.72 and 0.70, respectively. False-negative rates for nomogram values of 10% or less were low (4.1% for the MSKCC and 7.8% for the Stanford). The positive predictive value for nomogram probabilities of 80% or greater was higher for MSKCC than for Stanford (90.9% vs 61.8%). The Stanford nomogram performed more accurately in low-risk patients with isolated tumor cells or micrometastatic SLN disease; however, the MSKCC nomogram more accurately predicted NSLN outcomes across the entire study population. CONCLUSION: Although the MSKCC and Stanford nomograms performed similarly on the basis of the area under the curve, the MSKCC nomogram was consistently more reliable in predicting actual NSLN outcomes.