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Purpose Treating critically ill patients in radiation oncology departments poses multiple safety risks. This study describes a method to improve the speed of radiation treatment for patients in the intensive care unit by eliminating the need for computed tomography (CT) simulation or on-table treatment planning using patients’ previously acquired diagnostic CT scans. Methods and Materials Initially, a retrospective planning study was performed to assess the applicability and safety of diagnostic scan-based planning (DSBP) for 3 typical indications for radiation therapy in patients in the intensive care unit: heterotopic ossification (10), spine metastases (cord compression; 10), and obstructive lung lesions (5). After identification of an appropriate diagnostic CT scan, treatment planning was performed using the diagnostic scan data set. These treatment plans were then transferred to the patients’ simulation scans, and a dosimetric comparison was performed between the 2 sets of plans. Additionally, a time study of the first 10 patients treated with DSBP in our department was performed. Results The retrospective analysis demonstrated that DSBP resulted in treatment plans that, when transferred to the CT simulation data sets, provided excellent target coverage, a median D95% of 96% (range, 86%-100%) of the prescription dose with acceptable hot spots, and a median Dmax108% (range, 102%-113%). Subsequently, DSBP has been used for 10 critically ill patients. The patients were treated without CT simulation, and the median time between patient check-in to the department and completion of radiation therapy was 28 minutes (range, 18-47 minutes.) Conclusions This study demonstrates that it is possible to safely use DSBP for the treatment of critically ill patients. This method has the potential to simplify the treatment process and improve the speed and safety of treatment.

Purpose To determine the daily and cumulative dosimetric effects of intrafraction prostate motion on step-and-shoot (SNS) intensity-modulated radiation therapy (IMRT) plans, to evaluate the correlation of dosimetric effect with motion-based metrics, and to compare on a fraction-by-fraction basis the dosimetric effect induced in SNS and helical tomotherapy plans. Methods and Materials Intrafraction prostate motion data from 486 fractions and 15 patients were available. A motion-encoded dose calculation technique was used to determine the variation of the clinical target volume (CTV) D 95% values with respect to the static plan for SNS plans. The motion data were analyzed separately, and the correlation coefficients between various motion-based metrics and the dosimetric effect were determined. The dosimetric impact was compared with that incurred during another IMRT technique to assess correlation across different delivery techniques. Results The mean (±1 standard deviation [SD]) change in D 95% in the CTV over all 486 fractions was 0.2 ± 0.5%. After the delivery of five and 12 fractions, the mean (±1 SD) changes over the 15 patients in CTV D 95% were 0.0 ± 0.2% and 0.1 ± 0.2%, respectively. The correlation coefficients between the CTV D 95% changes and the evaluated motion metrics were, in general, poor and ranged from r = −0.2 to r = −0.39. Dosimetric effects introduced by identical motion in SNS and helical tomotherapy IMRT techniques were poorly correlated with a correlation coefficient of r = 0.32 for the CTV. Conclusions The dosimetric impact of intrafraction prostate motion on the CTV is, in general, small. In only 4% of all fractions did the dosimetric consequence exceed 1% in the CTV. As expected, the cumulative effect was further reduced with fractionation. The poor correlations between the calculated motion parameters and the subsequent dosimetric effect implies that motion-based thresholds are of limited value in predicting the dosimetric impact of intrafraction motion. The dosimetric effects between the two evaluated delivery techniques were poorly correlated.

Purpose: To evaluate two different techniques for whole-breast treatments delivered using the Hi-ART II tomotherapy device. Methods and Materials: Tomotherapy uses the standard rotational helical delivery. Topotherapy uses a stationary gantry while delivering intensity-modulated treatments. CT scans from 5 breast cancer patients were used. The prescription dose was 50.4 Gy. Results: On average, 99% of the target volume received 95% of prescribed dose with either technique. If treatment times are restricted to less than 9 min, the average percentage ipsilateral lung receiving ≥20 Gy was 22% for tomotherapy vs. 10% for topotherapy. The ipsilateral lung receiving ≥50.4 Gy was 4 cc for tomotherapy vs. 27 cc for topotherapy. The percentage of left ventricle receiving ≥30 Gy was 14% with tomotherapy vs. 4% for topotherapy. The average doses to the contralateral breast and lung were 0.6 and 0.8 Gy, respectively, for tomotherapy vs. 0.4 and 0.3 Gy for topotherapy. Conclusions: Tomotherapy provides improved target dose homogeneity and conformality over topotherapy. If delivery times are restricted, topotherapy reduces the amount of heart and ipsilateral lung volumes receiving low doses. For whole-breast treatments, topotherapy is an efficient technique that achieves adequate target uniformity while maintaining low doses to sensitive structures.

We report on our initial experience with daily image guidance for the treatment of a patient with a basal cell carcinoma of the nasal dorsum using bolus electron conformal therapy. We describe our approach to daily alignment using treatment machine‐integrated megavoltage (MV) planar imaging in conjunction with cone beam CT (CBCT) volumetric imaging to ensure the best possible setup reproducibility. Based on MV imaging, beam aperture misalignment with the intended treatment region was as large as 0.5 cm in the coronal plane. Four of the five fractions analyzed show induced shifts when compared to digitally reconstructed radiographs (DRR), in the range of 0.2−0.5 cm. Daily inspection of CBCT images show that the bolus device can have significant tilt in any given direction by as much as 13° with respect to beam axis. In addition, we show that CBCT images reveal air gaps between bolus and skin that vary from day to day, and can potentially degrade surface dose coverage. Retrospective dose calculation on CBCT image sets shows that when daily shifts based on MV imaging are not corrected, geometrical miss of the planning target volume (PTV) can cause an underdosing as large as 14% based on DVH analysis of the dose to the 90% of the PTV volume. PACS number: 87.55.kh

The dosimetric impact of intrafraction prostate motion was investigated for helical tomotherapy treatments. Measured motion tracks were used to calculate the dosimetric impact on delivered target dose distributions. A dynamic dose calculation engine was developed to facilitate this evaluation. It was found that the D95% (minimum dose to 95% of the volume) changes in the prostate were well correlated with D95% changes in the PTV. This means that the dosimetric impact of intrafraction motion is not restricted to the periphery of the target. The amount of motion was not well correlated with the dosimetric impact (measured in target D95% changes) of motion. The relationship between motion and its dosimetric impact is complex and depends on the timing and direction of the movement. These findings have implications for motion management techniques. It appears that the use of target margins is not an effective strategy to protect the prostate from the effects of observed intrafraction motion. The complex relationship between motion and its dosimetric effect renders simple threshold-based intervention schemes inefficient. Monitoring of actual prostate motion would allow the documentation of the dosimetric impact and implementation of corrective action if needed. However, when motion management techniques are evaluated, it should be kept in mind that the dosimetric impact of observed prostate motion is small for the majority of fractions.

Purpose To assess the dosimetric consequence of intrafraction prostate motion on helical tomotherapy plans. Methods and Materials An electromagnetic tracking device was used to measure real-time prostate motion for 515 fractions (16 patients). Motion tracks were used to retrospectively recalculate dose distributions using a four-dimensional calculation engine. The minimum dose (D min ), maximum dose (D max ), and dose to 95% of the volume (D 95% ) were calculated for target volumes and compared with respective values from the treatment plan. The dosimetric effect was evaluated for each fraction. For each patient, the running cumulative effect was assessed throughout the course of treatment. Calculations were repeated assuming a time delay between initial patient setup and start of treatment. Results Averaged over all fractions, the mean change in target D 95% was 95% of up to 20% were seen in individual fractions. Changes in prostate D 95% were similar in frequency and magnitude to D 95% changes in the planning target volume. The cumulative effect on target D 95% was approximately 1% (SD, 1%). The average cumulative effect after five fractions was 1% (SD, 1.5%). Conclusions In general, the dosimetric effect of observed prostate motion on target D 95% was small. Infrequently severe D 95% degradations were observed for individual fractions, but their effect on the cumulative dose distribution was quickly reduced with minimal fractionation.

Background: Human pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the United States. Accumulating studies have witnessed the malfunction of many chemotherapeutic regimens and the current standard-of-care therapy, gemcitabine (GEM), enhances patient survival by only few months. Cucurbitacins, naturally occurring dietary tetracyclic triterpenoid compounds, have shown promising anti-cancer activities. Herein, we investigated the potency and anti-cancer efficacy of a novel analogue of cucurbitacin (Cuc D) in pancreatic cancer cell lines and in a xenograft mouse model. Additionally, we determined efficacy of this analogue on MicroRNAs (miRNAs) which are important regulators of genes that have crucial roles in pancreatic tumorigenesis. Methods: The effect of Cuc D on the growth of pancreatic cancer cells was determined by cell proliferation assay using six pancreatic cancer (MiaPaCa-2, CaPan-1, HPAF-II, Panc-1, BxPC-3 and AsPc-1) cells. Cell growth kinetic assay was carried out at 24, 48, 72 and 96 h. The clonogenic potential of cancer cells was also studied using the colony formation assay. Tumor suppressor miR-145, which is downregulated in pancreatic cancer, directly target MUC13. Thus the effect of Cuc D was also investigated on the expression of miR-145 through qPCR analysis. Immunoblotting techniques were performed to study the known direct targets of miRNA-145 and its associated proteins. The anti-cancer potential of Cuc D in pancreatic cancer was also evaluated in vivo using a xenograft mouse model. Results: Our results demonstrate potent anticancer effects of Cuc D on pancreatic cancer cells. Cuc D induces dose and time dependent inhibition of cell proliferation in a panel of gemcitabine sensitive/resistant pancreatic cancer cell line models at nanomolar concentrations (100-500 nM). It also inhibits colony formation and invasiveness of pancreatic cancer cells. Furthermore, Cuc D blocks the cell cycle progression in G2/M phase and decreases the mitochondrial membrane potential in pancreatic cancer cells. Notably, Cuc D significantly increases the expression of tumor suppressor miR-145 in HPAF-II cells as observed by qPCR. Furthermore, Cuc D decreases the expression of MUC13 and its associated proteins including pAKT and HER2. In addition, it restores the expression of p53 level as studied by immunofluorescence technique. The expression of key oncogenic proteins including NF-κB, STAT3 (Tyr-705) and Mcl-1 were also downregulated. The levels of PTEN and p27 (Kip1) tumor suppressor genes were increased after Cuc D treatment. Additionally, in vivo administration of Cuc D effectively inhibited pancreatic tumor growth in xenograft mouse model. Conclusion: Overall, this study suggests that Cuc D modulates the expression of key oncogenes and tumor suppressors, thus it can be a promising therapeutic modality for pancreatic cancer prevention and treatment. Citation Format: Mohammed Sikander, Sheema Khan, Neeraj Chauhan, Mohd Saif Zaman, Murali Mohan Yallapu, Fathi T. Halaweish, Bhavin Chauhan, Shabnam Malik, Meena Jaggi, Subhash C. Chauhan. Anticancer activity of novel cucurbitacin analogue in pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4468. doi:10.1158/1538-7445.AM2015-4468

Background: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in United States. Tremendous efforts have witnessed the failure of many chemotherapeutic regimens and the current standard-of-care therapy, gemcitabine (GEM), extends patient survival by only a few weeks. Numerous studies implicate the need for the drugs that can target multiple signaling events in pancreatic cancer. Recently, cucurbitacins, tetracyclic triterpenoid compund/molecules, belonging to a family of Cucurbitaceae have shown promising anti-cancer activities such as antiproliferation, cell cycle arrest, and apoptosis induction. Here, we report the anticancer activity of a novel analogue of cucurbitacin (Cuc D) that is able to target important signaling proteins involved in pancreatic cancer cell proliferation, invasion and metastasis. Methods: Herein, we investigated the use of Cuc D for the treatment of pancreatic cancer using a panel of pancreatic cancer cells. The effect of Cuc D on the growth of pancreatic cancer cells was determined by CellTiter 96® AQueous One Solution cell proliferation assay using six pancreatic cancer (MiaPaCa-2, CaPan-1, HPAF-II, Panc-1, BxPC-3 and AsPc-1) cells. Cell growth kinetic assay was carried out at 24, 48, 72 and 96h. The clonogenic potential of cancer cells was also studied using the colony formation assay. microRNA-21 expression levels were investigated through Real-time PCR. Immunoblotting techniques were performed to determine the effects of Cuc D at the molecular level. Results: Our results indicate the anticancer effects of Cuc D in pancreatic cancer cells. Cuc D induces concentration dependent inhibition of cell proliferation in a panel of gemcitabine sensitive/resistant pancreatic cancer cell lines at nano molar concentrations. It also inhibits colony formation and metastasis potential of pancreatic cancer cells in dose and time dependent manner. Importantly, Cuc D targets and inhibits proteins, MUC13, Bcl2 and survivin (inhibitor of apoptosis protein family member: IAP) that are involved in proliferation, metastasis and tumor progression as seen through Western blotting. Additionally, the treatment of Cuc D induces the phosphorylation of p53 (p-p53; ser-15) in pancreatic cancer cells. We also observed that Cuc D effectively inhibits miR-21 levels in pancreatic cancer, HPAF-II cells as seen through Real time PCR analysis. miR-21 is an oncogenic miRNA that is overexpressed in pancreatic cancer. Conclusion: Our findings demonstrate that Cuc D exerts multi-focal action in pancreatic cancer cells targeting multiple signaling events. Overall, this study suggests that Cuc D can be a potential and promising therapeutic modality for pancreatic cancer treatment. Citation Format: Mohammed Sikander, Mohd Saif Zaman, Neeraj Chauhan, Murali M. Yallapu, Sheema Khan, Fathi T. Halaweish, Bhavin Chauhan, Meena Jaggi, Subhash C. Chauhan. A multi-targeted approach for pancreatic cancer treatment by a novel cucurbitacin analogue. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2714. doi:10.1158/1538-7445.AM2014-2714