Dacian Bonta

CHFR protein expression predicts outcomes to taxane-based first line therapy in metastatic NSCLC

Purpose: Currently, there is no clinically validated test for the prediction of response to tubulin-targeting agents in non–small cell lung cancer (NSCLC). Here, we investigated the significance of nuclear expression of the mitotic checkpoint gene checkpoint with forkhead and ringfinger domains (CHFR) as predictor of response and overall survival with taxane-based first-line chemotherapy in advanced stage NSCLC. Methods: We studied a cohort of 41 patients (median age 63 years) with advanced NSCLC treated at the Atlanta VAMC between 1999 and 2010. CHFR expression by immunohistochemistry (score 0–4) was correlated with clinical outcome using chi-square test and Cox proportional models. A cutoff score of “3” was determined by receiver operator characteristics analysis for “low” CHFR expression. Results were validated in an additional 20 patients who received taxane-based chemotherapy at Emory University Hospital and the Atlanta VAMC. Results: High expression (score = 4) of CHFR is strongly associated with adverse outcomes: the risk for progressive disease after first-line chemotherapy with carboplatin–paclitaxel was 52% in patients with CHFR-high versus only 19% in those with CHFR-low tumors (P = 0.033). Median overall survival was strongly correlated with CHFR expression status (CHFR low: 9.9 months; CHFR high: 6.2 months; P = 0.002). After multivariate adjustment, reduced CHFR expression remained a powerful predictor of improved overall survival (HR = 0.24; 95% CI, 0.1–0.58%; P = 0.002). In the validation set, low CHFR expression was associated with higher likelihood of clinical benefit (P = 0.03) and improved overall survival (P = 0.038). Conclusions: CHFR expression is a novel predictive marker of response and overall survival in NSCLC patients treated with taxane-containing chemotherapy. Clin Cancer Res; 19(6); 1603–11. ©2013 AACR.

Shortening the 4-hour gastric-emptying protocol

Purpose: A standardized 4-hour gastric-emptying protocol has been recommended by a consensus panel. However, a study length of 4 hours may be inconvenient. The purpose of this investigation was to determine if the percent emptying at 2 hours could predict abnormal or normal results at 4 hours. Methods: Our data consist of 2 distinct patient groups, containing 174 and 158 patients, respectively. All patients were given a standardized meal according to the Tougas et al protocol. Percent gastric emptying was measured at 1, 2, 3, and 4 hours (or until gastric emptying was equal to or more than 90%). The sensitivity, specificity, and the likelihood ratios of the 2-hour cutoffs were determined using the 4-hour data as the standard. We have estimated the accuracy and percent of studies stopped at 2 hours, resulting from various “definitely normal” and “definitely abnormal” threshold combinations. Results: Using gastric emptying of less than 35% at 2 hours for diagnosis of delayed gastric emptying, and emptying at 2 hours greater than 55% for a diagnosis of normal gastric emptying yielded accuracies of 0.966 and 0.949 in the 2 datasets, respectively, compared with the Tougas standard values. The observed 2-hour gastric-emptying values would have allowed early termination in 79% and 78% of the studies, respectively. Conclusion: Adopting criteria for the termination of gastric-emptying study at 2 hours in selected patients yields significant reductions in the average length of a gastric-emptying study, while maintaining study accuracy.

Extravasation of a Therapeutic Dose of 131I-Metaiodobenzylguanidine: Prevention, Dosimetry, and Mitigation

After the extravasation of a therapeutic dose of 131I-metaiodobenzylguanidine that produced a radiation burn to a patients forearm, we instituted a catheter placement verification protocol. Methods: Before therapy infusion, proper placement is verified by administering 37 MBq of 99mTc-pertechnetate through the catheter, and monitoring activity at the administration site and on the contralateral extremity. A dosimetric model describing both high-rate and low-rate dose components was developed and predicted that the basal epidermal layer received a radiation dose consistent with the observed moist desquamation radiation skin toxicity. Results: No extravasation incidents have occurred since the verification procedure was instituted. Conclusion: To protect against radiation injury from extravasation of therapeutic radionuclides, test administration of a small 99mTc dose with probe monitoring of comparable sites in both upper extremities appears to be an effective preventive measure.

A variable critical-volume model for normal tissue complication probability

Predicting late-term normal-tissue complication probability (NTCP) after radiotherapy is an important factor in the optimization of conformal radiotherapy. We propose a new NTCP model, based on the properties of the high dose region. The principal assumption of the new model is that a whole-organ complication will occur when the radiation damage to a normal organ volume (a portion of the total organ) exceeds a threshold value. The dose threshold for complications varies with the size of the volume (percent of the total organ). We hypothesize that a complication occurs if the complication threshold is exceeded for any organ volume. We used the average dose to a volume as a measure of radiation damage to that volume. Also, we used the power law to scale the average dose to various organ volumes to a whole-organ equivalent dose, and to identify the volume with the most harmful dose-size combination-the critical volume. We used a logistic distribution to calculate the probability that the patient will develop a complication, given the dose delivered to the critical volume. We used a maximum likelihood fit to estimate the model parameters for late-term rectal complications in a set of patients treated for prostate carcinoma with external photon beam radiotherapy (EBRT). Good correspondence was found between the experimental data and the model predictions.

Clinical Intervention for Quality Improvement of Gastric-Emptying Studies

Prompted by clinical concerns for false-negative tests, we implemented a clinical intervention consisting of a training session and an image-based verification procedure to document homogeneous radioactivity distribution in the radiolabeled meal (egg substitute per the guideline). Methods: A technologist training session emphasized the importance of thorough mixing of 99mTc-sulfur colloid in the egg meal. For 6 mo after training, an image of the prepared mixed egg was acquired before patient ingestion. Consecutive gastric-emptying studies performed 6 mo before and after training were reviewed by 2 experienced physicians. Results: There were 7 abnormal and 44 normal studies before and 15 abnormal and 29 normal studies after training (P < 0.05). Subjective evaluations of images for meal-mixing quality by 2 readers correlated with each other and with an objective measure of expected gastric-emptying physiology (correlation coefficients, 0.54 and 0.38, respectively). Conclusion: The described clinical intervention improved the accuracy of our gastric-emptying studies by decreasing false-negative studies.

Harmonic subtraction for evaluating right ventricle ejection fraction from planar equilibrium radionuclide angiography

We report an initial investigation of a subtraction-based method to estimate right ventricle ejection fraction (RVEF) from ECG-gated planar equilibrium radionuclide angiography (ERNA) data. Twenty-six consecutive patients referred for scintigraphic evaluation of cardiac function prior to chemotherapy had ECG-gated first-pass (FP) imaging and ERNA imaging performed following the same radiotracer injection. RVEF was computed from FP images (RVEFFP) and separately from ERNA images (RVEFERNA). Standard methods for computing ejection fractions were used to obtain RVEFFP values. RVEFERNA values were obtained using harmonic subtraction of the left ventricular contribution from a biventricular region of interest contoured on the equilibrium images acquired in the shallow right anterior oblique projection. Clinically acquired chest CT data were used to derive information regarding the relative position of the left and right ventricle and about the presence of pulmonary artery enlargement. Computation of RVEFERNA was successful for each of the 26 patients. Computation of RVEFFP failed for four patients. For the 22 patients for which RVEF was computed using both methods, the average RVEFFP was 49% and the average RVEFERNA was 51%, with coefficients of variation of 11 and 7.5%, respectively. Low RVEFERNA values were associated with pulmonary artery dilation. Estimation of RVEFERNA, using a harmonic subtraction-based method of computation is clinically feasible and accurate in the patient population studied. The results support further investigation in patients with frank heart failure.