Post-radiotherapy PET/CT for predicting treatment outcomes in head and neck cancer after postoperative radiotherapy.

PURPOSE: The purpose of this study was to retrospectively review the role of post-treatment (post-tx) FDG-PET/CT scans in patients receiving postoperative intensity-modulated radiotherapy (IMRT) for head and neck squamous cell carcinomas (HNSCC). MATERIALS AND METHODS: Eighty-two patients with HNSCC treated with surgery and postoperative IMRT with or without chemotherapy from October 15, 2008 to December 31, 2014 that had post-tx PET/CT within 6 months of completing IMRT were included. PET/CT was considered positive based on multi-disciplinary review integrating clinical information. Survival analysis was performed using the Kaplan-Meier method. Categorical and continuous predictors of positive post-tx PET/CT were evaluated using Fisher's exact test and logistic regression, respectively. Predictors for survival outcomes were evaluated with log-rank testing. A p ≤ 0.05 was considered statistically significant. RESULTS: Median follow-up was 3.88 years. For all patients, 3-year overall survival (OS) and recurrence-free survival (RFS) were 71.8% and 61.3%, respectively. Patients with positive post-tx PET/CT had worse OS compared to those with negative post-tx PET/CT (log rank p < 0.001). For patients with positive post-tx PET/CT, 3-year OS was 11.2% compared to 89.9% for patients with negative post-tx PET/CT. The positive predictive value (PPV) of PET/CT was 100% for local recurrence (LR), regional recurrence (RR) and distant metastasis (DM). The negative predictive values (NPV) for LR, RR and DM were 89.0%, 89.2%, and 85.9%, respectively. Perineural invasion (p = 0.009), p16 status (p = 0.009), non-oropharyngeal primary site (p = 0.002), and the use of chemotherapy (p = 0.01) were independent predictors of positive PET/CT. CONCLUSIONS: Post-tx PET/CT after postoperative radiation is prognostic for survival outcomes. The PPV of post-tx PET for recurrence was excellent, allowing for early detection of recurrent disease. Post-tx PET/CT should be considered after postoperative radiation.

Local radiotherapy versus nonradiotherapy to distant lesions for metastatic nasopharyngeal carcinoma: Retrospective cohort study.

BACKGROUND: To evaluate the efficiency of local radiotherapy to metastatic lesions in patients with metastatic nasopharyngeal carcinoma (mNPC). METHODS: The overall survival was observed and compared for mNPC patients who received local radiotherapy versus nonradiotherapy to metastatic lesions by using the Kaplan-Meier method and Cox analysis. RESULTS: One hundred and nine patients with NPC were involved in this study, with 61 (56.0%) received radiotherapy to metastatic sites and 48 (44.0%) did not receive radiotherapy to metastatic sites. The 2- and 5-year OS for patients who received local radiotherapy to metastatic lesions were 65.8% and 35.7%, and for patients who did not receive radiotherapy to metastatic lesions were 45.3% and 26.2%. The multivariable adjusted hazard radios for local radiotherapy versus nonradiotherapy to metastatic lesions were 0.482 (95% confidence interval is 0.278-0.834, p = 0.009). CONCLUSIONS: Local radiotherapy to metastatic lesions might be a protective factor for patients with mNPC.

Stereotactic body radiotherapy (SBRT) for T2N0 (>3 cm) non-small cell lung cancer: Outcomes and failure patterns.

PURPOSE/OBJECTIVES: Outcomes of T2N0 lung cancer patients treated with stereotactic radiotherapy are not well known. METHODS AND MATERIALS: We conducted a single institution retrospective review of patients with T2N0 NSCLC who were treated with SBRT. The local, regional, distant control rates were calculated from available clinical data. Survival outcomes were determined using the Kaplan Meier method. RESULTS: Fifty-six patients met our selection criteria. The two-year local control rate was 84.2%. The two and 5-year disease-free survival (DFS) and OS were 31.9% and 15.3% and 39.9% and 12.1%, respectively. Centroid BED10 > 150Gy was associated with improved DFS, (p = 0.014), and OS on univariable analysis (p=0.0132). CONCLUSIONS: SBRT provides good local control for T2N0 NSCLC, but systemic failure remains problematic.

Identification of Immune Subtypes of Lung Squamous Cell Carcinoma by Integrative Genome-Scale Analysis.

BACKGROUND: Characterization of the tumor microenvironment is helpful to understand the tumor immune environment of lung cancer and help predict the prognosis. METHODS: First, immune subtypes were identified by consensus subtype among lung squamous carcinoma (LUSC) patients. Immune cell infiltration was evaluated by CIBERSORT and ESTIMATE analyses. Then, based on differentially expressed genes (DEGs) identified, a risk score model was constructed. Finally, gene FPR1 was validated by using YTMLC-90. FINDINGS: LUSC samples were divided into four heterogeneous immune subtypes, with significantly different prognoses with subtype 4 having the poorest overall survival (OS). The immune infiltration score showed that subtype 4 was characterized as immune enriched and fibrotic, while subtype 3 was tumor enriched. DEG analysis showed that upregulated genes in subtype 4 were enriched of neutrophil and exhausted T cell-related biological processes. Based on a univariate Cox regression model, prognostic 7 immune-related genes were combined to construct a risk score model and able to predict OS rates in the validation datasets. Wound healing and transwell assay were conducted to evaluate the invasion property after activating the gene FPR1. INTERPRETATION: The analysis of tumor immune microenvironments among LUSC subtypes may provide new insights into the strategy of immunotherapy.

Digitoxin activates EGR1 and synergizes with paclitaxel on human breast cancer cells.

BACKGROUND: Numerous studies have suggested that digitalis derivatives promise to be superior to existing adjuvant therapy for breast cancer as to effects and side-effects. In the present study, we have used gene expression analysis to determine the molecular action of digitoxin on breast cancer cells and assessed digitoxin's ability to synergize with the chemotherapy agent paclitaxel with respect to inhibition of cell proliferation MATERIALS AND METHODS: We treated (Her2 overexpressing, ER low) MDA-MB-453 human breast cancer cells with digitoxin at four doses {20 ng/ml (26 nM) to 1 µg/ml} and collected RNA at 6 h and 24 h for gene expression analysis. To examine the effects on ER positive cells, we treated MCF7 cells with digitoxin at 1 µg/ml and collected RNA for RT-PCR analysis. In addition, we assayed the growth inhibitory effect of low doses of digitoxin combined with paclitaxel and determined combination index values. RESULTS: To reveal primary effects, we examined digitoxin's effect 6 h post-treatment with the highest dose, 1µg/ml, and found upregulation of the stress response genes EGR-1 and NAB2, lipid biosynthetic genes and the tumor suppressor gene p21, and downregulation of the mitotic cell cycle gene CDC16 and the replication gene PolR3B. RT-PCR analysis validated effects on stress response, apoptotic and cell cycle genes on MDA-MB-453 and MCF7 cells. Western blot analysis confirmed induction of EGR1 protein at 1 h and ATF3 at 24 h. Paclitaxel, as well as digitoxin, inhibited the in vitro activity of the purified Na(+)-K(+)-ATPase; digitoxin enhanced the growth inhibitory effects of paclitaxel on Her2 overexpressing breast cancer cells. CONCLUSIONS: Our studies show the potential of digitoxin to prevent and treat breast cancer and indicate that the combination of digitoxin and paclitaxel is a promising treatment for ER negative breast cancer. These findings are the first to alert physicians to the possible dangers to patients who take a combination of digitoxin and paclitaxel. The potential dangers ensuing when paclitaxel and digitoxin are combined are dependent on the dose of digitoxin.

Ten-Year Treatment Outcomes of Radical Prostatectomy Vs External Beam Radiation Therapy Vs Brachytherapy for 1503 Patients With Intermediate-risk Prostate Cancer.

OBJECTIVE: To compare 10-year oncologic treatment outcomes of radical prostatectomy (RP) vs external beam radiation therapy (EBRT) vs brachytherapy (BT) for patients with intermediate-risk prostate cancer (IRPC). METHODS: A retrospective analysis using propensity score matching was performed on 1503 IRPC patients who underwent treatment from 2004 to 2007. Eight hundred and nineteen underwent RP, 574 underwent EBRT to a median dose of 75.3 Gray, and 110 underwent BT using Iodine-125. Biochemical failure was defined by the American Urological Association definition of failure for RP, and the Phoenix definition for EBRT and BT. RESULTS: Median follow-up was 10.0 years for RP, 9.6 for EBRT, and 9.8 for BT. Neoadjuvant androgen deprivation therapy was given in 0.6% of RP, 58.9% of EBRT, and 12.7% of BT patients, P <.0001. Only 14% of BT received supplemental external radiation. The adjusted 10-year freedom from biochemical failure was 80.2% for BT vs 57.1% for RP vs 57.0% for EBRT, P = .0003. Subset analysis of unfavorable IRPC also showed improved freedom from biochemical failure with BT, P <.0001. There were no significant differences in metastases-free survival or prostate cancer-specific survival after adjusting for age and Charlson comorbidity index. CONCLUSION: BT using Iodine-125, used alone or in combination with supplemental external radiation, is a reasonable treatment option for IRPC patients, yielding equivalent rates of metastases-free survival and prostate cancer-specific survival.

Effect of weight loss by diet or gastric bypass surgery on peptide YY3-36 levels.

OBJECTIVE: To examine the effect of an equivalent weight loss, by gastric bypass surgery (GBP) or by diet, on peptide YY3-36 (PYY3-36), ghrelin, and leptin levels and to determine the effect of diabetes status on PYY3-36 levels. SUMMARY BACKGROUND DATA: The increased PYY3-36 levels after GBP may be involved in the magnitude and the sustainability of weight loss after surgery. METHODS: Of the 30 morbidly obese women who participated in the study, 21 had type 2 diabetes mellitus, and were studied before and after equivalent weight loss of 10 kg by either GBP (n = 11) or by diet (n = 10). RESULTS: : PYY3-36 levels were higher in obese diabetic as compared with nondiabetic individuals (64.1 +/- 34.4 pg/mL vs. 39.9 +/- 21.1 pg/mL; P < 0.05). PYY3-36 levels increased markedly in response to oral glucose after GBP (peak: 72.3 +/- 20.5 pg/mL-132.7 +/- 49.7 pg/mL; P < 0.001; AUC0-180: 51.5 +/- 23.3 pg/mL x min-91.1 +/- 32.2 pg/mL x min P < 0.001), but not after diet (peak: 85.5 +/- 51.9 pg/mL-84.8 +/- 41.13 pg/mL; P = NS; AUC0-180: 68.3 +/- 38.5 pg/mL x min-61.1 +/- 42.2 pg/mL.min P = NS). Fasting ghrelin levels increased after diet (425 +/- 91 pg/mL-519 +/- 105 pg/mL; P < 0.05), but did not change after GBP (506 +/- 121 pg/mL-482 +/- 196 pg/mL; P = NS). CONCLUSIONS: Diabetes status seems to be a determinant of PYY3-36 levels. GBP, but not diet-induced weight loss, resulted in markedly increased glucose-stimulated PYY3-36 levels. The increase in stimulated PYY3-36 levels after GBP is likely a result of the surgery rather than a secondary outcome of weight loss. Changes in PYY3-36 levels and ghrelin could contribute to the success of GBP in sustaining weight loss.

Multi-criteria optimization achieves superior normal tissue sparing in intensity-modulated radiation therapy for oropharyngeal cancer patients.

OBJECTIVES: To evaluate the benefit of intensity-modulated radiation therapy (IMRT) with multi-criteria optimization (MCO) in patients with oropharyngeal cancer (OPC) and compare the dose difference between the MCO plans navigated by physicians and dosimetrists. MATERIALS AND METHODS: The conventional IMRT plans (nonMCO) and MCO IMRT plans navigated by physicians and dosimetrists (MCOp and MCOd) were created for 30patients with OPC. All the plans were reviewed, and the planning time and dose-volume parameters were compared. RESULTS: The difference of D95 among three kinds of plans was not significant (p > 0.05). The maximum dose and D2 of spinal cord, brain stem, the mean dose of bilateral parotids, cochlea, oral cavity and glottic larynx were lower in MCO plans than those in nonMCO plans (p < 0.017). Furthermore, MCOp showed better bilateral parotids, oral cavity and glottic larynx sparing compared to MCOd (p < 0.017), in which the magnitude was related to the overlapping volume of the corresponding organ at risk (OAR) and targets. The active planning time was reduced by a median of 94.3 min (MCOd vs. nonMCO) or 91.6 min (MCOp vs. nonMCO). CONCLUSION: MCO IMRT plans significantly reduced the dose of OARs and the active planning time, without compromising the target coverage in OPC patients; navigations by physicians could be beneficial to the dose sparing of the OARs with high complication rate and those overlapping with targets; the constraints could be the predominant factor affecting the results of optimization in the MCO IMRT planning.

Development of a radiobiological evaluation tool to assess the expected clinical impacts of contouring accuracy between manual and semi-automated segmentation algorithms.

RADEval is a tool developed to assess the expected clinical impact of contouring accuracy when comparing manual contouring and semi-automated segmentation. The RADEval tool, designed to process large scale datasets, imported a total of 2,760 segmentation datasets, along with a Simultaneous Truth and Performance Level Estimation (STAPLE) to act as ground truth tumor segmentations. Virtual dose-maps were created within RADEval and two different tumor control probability (TCP) values using a Logistic and a Poisson TCP models were calculated in RADEval using each STAPLE and each dose-map. RADEval also virtually generated a ring of normal tissue. To evaluate clinical impact, two different uncomplicated TCP (UTCP) values were calculated in RADEval by using two TCP-NTCP correlation parameters (δ = 0 and 1). NTCP values showed that semi-automatic segmentation resulted in lower NTCP with an average 1.5 - 1.6 % regardless of STAPLE design. This was true even though each normal tissue was created from each STAPLE (p <; 0.00001). TCP and UTCP presented no statistically significant differences (p ≥ 0.1884). The intra-operator standard deviations (SDs) for TCP, NTCP and UTCP were significantly lower for the semi-automatic segmentation method regardless of STAPLE design (p <; 0.0331). Both intra-and inter-operator SDs of TCP, NTCP and UTCP were significantly lower for semi-automatic segmentation for the STAPLE 1 design (p <;0.0331). RADEval was able to efficiently process 4,920 datasets of two STAPLE designs and successfully assess the expected clinical impact of contouring accuracy.

Treatment results of brachytherapy vs. external beam radiation therapy for intermediate-risk prostate cancer with 10-year followup.

PURPOSE: To compare 10-year treatment outcomes of brachytherapy vs. external beam radiation therapy for patients with intermediate-risk prostate cancer (IRPC). METHODS AND MATERIALS: Between 2004 and 2007, 93 IRPC patients underwent brachytherapy using iodine-125 to a dose of 145 Gy without supplemental external radiation. A retrospective comparison was performed to a contemporary cohort of 597 patients treated with external beam radiation therapy to a median dose of 75.3 Gy using a propensity score-matched analysis. RESULTS: Median followup was 7.8 years. With brachytherapy, 51.6% had Gleason score 7 vs. 72.0% for external radiation (p < 0.001). Median initial prostate-specific antigen was 8.3 for brachytherapy vs. 9.4 for external radiation (p = 0.01). Neoadjuvant androgen deprivation therapy was given in 59.5% of external radiation vs. 10.8% of brachytherapy patients (p < 0.001). The 10-year freedom from biochemical failure (FFBF) for brachytherapy was 81.7% vs. 54.5% for external radiation (p = 0.002). Unfavorable intermediate-risk patients experienced borderline significant improved FFBF with brachytherapy (p = 0.08). The 10-year freedom from salvage therapy for brachytherapy was 93.2% vs. 72.2% for external radiation (p = 0.006). There were no significant differences in distant metastases-free survival, prostate cancer-specific survival, or overall survival after adjusting for age. Multivariate analysis with propensity score matching showed that brachytherapy remained an independent predictor for improved FFBF (p = 0.007). Grade 1 and 2 late rectal complication rate was 6.5% for brachytherapy vs. 15.2% for external radiation (p = 0.02). CONCLUSIONS: Brachytherapy using iodine-125 without supplemental external radiation is a reasonable treatment option for selected IRPC patients.

Semiautomated segmentation of head and neck cancers in 18F-FDG PET scans: A just-enough-interaction approach.

PURPOSE: The purpose of this work was to develop, validate, and compare a highly computer-aided method for the segmentation of hot lesions in head and neck 18F-FDG PET scans. METHODS: A semiautomated segmentation method was developed, which transforms the segmentation problem into a graph-based optimization problem. For this purpose, a graph structure around a user-provided approximate lesion centerpoint is constructed and a suitable cost function is derived based on local image statistics. To handle frequently occurring situations that are ambiguous (e.g., lesions adjacent to each other versus lesion with inhomogeneous uptake), several segmentation modes are introduced that adapt the behavior of the base algorithm accordingly. In addition, the authors present approaches for the efficient interactive local and global refinement of initial segmentations that are based on the "just-enough-interaction" principle. For method validation, 60 PET/CT scans from 59 different subjects with 230 head and neck lesions were utilized. All patients had squamous cell carcinoma of the head and neck. A detailed comparison with the current clinically relevant standard manual segmentation approach was performed based on 2760 segmentations produced by three experts. RESULTS: Segmentation accuracy measured by the Dice coefficient of the proposed semiautomated and standard manual segmentation approach was 0.766 and 0.764, respectively. This difference was not statistically significant (p = 0.2145). However, the intra- and interoperator standard deviations were significantly lower for the semiautomated method. In addition, the proposed method was found to be significantly faster and resulted in significantly higher intra- and interoperator segmentation agreement when compared to the manual segmentation approach. CONCLUSIONS: Lack of consistency in tumor definition is a critical barrier for radiation treatment targeting as well as for response assessment in clinical trials and in clinical oncology decision-making. The properties of the authors approach make it well suited for applications in image-guided radiation oncology, response assessment, or treatment outcome prediction.

Once Daily High-dose Radiation (≥60 Gy) Treatment in Limited Stage Small Cell Lung Cancer.

BACKGROUND: To investigate outcomes and prognostic factors in patients treated with once daily high-dose (≥60 Gy) radiation therapy (HDRT) and concurrent platinum-based chemotherapy in limited stage small cell lung cancer (LS-SCLC). While we await current phase III trials to determine optimal radiation dose fractionation schemes in LS-SCLC, we report our experience in LS-SCLC with once daily HDRT. We hypothesized that HDRT would achieve similar efficacy and tolerability as twice daily therapy. METHODS: We conducted a single institution retrospective review of all patients with LS-SCLC who underwent curative intent treatment from 2005-2013. Patients treated with HDRT (≥60 Gy) and concurrent chemotherapy (cisplatin or carboplatin and etoposide) were included in our analysis. Clinicopathologic variables assessed include gender, performance status, time to treatment, response to treatment, toxicity, volumetric tumor response at 3 months, and use of prophylactic cranial irradiation (PCI). RESULTS: 42 patients with LS-SCLC who initiated concurrent chemoradiation from 2005 to 2013 were included in the analysis. 38 patients (90%) completed definitive treatment to the lung; 16 (38%) also completed PCI. Median failure free survival (FFS) and overall survival (OS) were 11.9 and 23.1 months, respectively. Two-year and 5-year OS rates were 47% (CI=30-62%) and 21% (CI=7-38%), respectively. On univariate analysis, PCI was associated with improved FFS but this was not significant (p=0.18). Gender was the only co-variate significantly associated with statistical differences in FFS (p=0.03) and OS (p=0.02). Grade 3 and 4 esophagitis were 10.5% and 2.6%, respectively. Pre-HDRT tumor volume and 3-month post-treatment tumor volume were both associated with FFS (p<0.01) but not OS. CONCLUSIONS: In this single institution series, daily HDRT demonstrated a 2-year OS of 47% in LS-SCLC. This compares well to the historical survival of daily fractionation (47%) from INT 0096 reported by Turrisi et. al. Male gender was predictive of significantly worse FFS and OS. Once daily HDRT has similar OS to twice-daily radiation schemes; however, further studies assessing once daily HDRT for LS-SCLC are warranted.

Change of maximum standardized uptake value slope in dynamic triphasic [18F]-fluorodeoxyglucose positron emission tomography/computed tomography distinguishes malignancy from postradiation inflammation in head-and-neck squamous cell carcinoma: a prospective trial.

PURPOSE: To evaluate dynamic [(18)F]-fluorodeoxyglucose (FDG) uptake methodology as a post-radiation therapy (RT) response assessment tool, potentially enabling accurate tumor and therapy-related inflammation differentiation, improving the posttherapy value of FDG-positron emission tomography/computed tomography (FDG-PET/CT). METHODS AND MATERIALS: We prospectively enrolled head-and-neck squamous cell carcinoma patients who completed RT, with scheduled 3-month post-RT FDG-PET/CT. Patients underwent our standard whole-body PET/CT scan at 90 minutes, with the addition of head-and-neck PET/CT scans at 60 and 120 minutes. Maximum standardized uptake values (SUV(max)) of regions of interest were measured at 60, 90, and 120 minutes. The SUV(max) slope between 60 and 120 minutes and change of SUV(max) slope before and after 90 minutes were calculated. Data were analyzed by primary site and nodal site disease status using the Cox regression model and Wilcoxon rank sum test. Outcomes were based on pathologic and clinical follow-up. RESULTS: A total of 84 patients were enrolled, with 79 primary and 43 nodal evaluable sites. Twenty-eight sites were interpreted as positive or equivocal (18 primary, 8 nodal, 2 distant) on 3-month 90-minute FDG-PET/CT. Median follow-up was 13.3 months. All measured SUV endpoints predicted recurrence. Change of SUV(max) slope after 90 minutes more accurately identified nonrecurrence in positive or equivocal sites than our current standard of SUV(max) ≥2.5 (P=.02). CONCLUSIONS: The positive predictive value of post-RT FDG-PET/CT may significantly improve using novel second derivative analysis of dynamic triphasic FDG-PET/CT SUV(max) slope, accurately distinguishing tumor from inflammation on positive and equivocal scans.

High-pressure combinatorial screening of homogeneous catalysts: hydrogenation of carbon dioxide.

A simple method for high-pressure combinatorial catalyst discovery with visual (dye-based) assay is described. With this method, the first highly active catalyst, incorporating metals outside the platinum group, has been identified for CO(2) hydrogenation.