Gaurav Shukla

Preoperative Intensity Modulated Radiation Therapy and Chemotherapy for Locally Advanced Vulvar Carcinoma: Analysis of Pattern of Relapse

PURPOSE To examine clinical outcomes and relapse patterns in locally advanced vulvar carcinoma treated using preoperative chemotherapy and intensity modulated radiation therapy (IMRT). METHODS AND MATERIALS Forty-two patients with stage I-IVA (stage I, n=3; stage II, n=13; stage III, n=23; stage IVA, n=3) vulvar cancer were treated with chemotherapy and IMRT via a modified Gynecological Oncology Group schema using 5-fluorouracil and cisplatin with twice-daily IMRT during the first and last weeks of treatment or weekly cisplatin with daily radiation therapy. Median dose of radiation was 46.4 Gy. RESULTS Thirty-three patients (78.6%) had surgery for resection of vulva; 13 of these patients also had inguinal lymph node dissection. Complete pathologic response was seen in 48.5% (n=16) of these patients. Of these, 15 had no recurrence at a median time of 26.5 months. Of the 17 patients with partial pathological response, 8 (47.1%) developed recurrence in the vulvar surgical site within a median of 8 (range, 5-34) months. No patient had grade ≥3 chronic gastrointestinal/genitourinary toxicity. Of those having surgery, 8 (24.2%) developed wound infections requiring debridement. CONCLUSIONS Preoperative chemotherapy/IMRT was well tolerated, with good pathologic response and clinical outcome. The most common pattern of recurrence was local in patients with partial response, and strategies to increase pathologic response rate with increasing dose or adding different chemotherapy need to be explored to help further improve outcomes.

Peripherally inserted central catheter placement with the sonic flashlight: initial clinical trial by nurses.

Objective. We describe a case series constituting the first clinical trial by intravenous (IV) team nurses using the sonic flashlight (SF) for ultrasound guidance of peripherally inserted central catheter (PICC) placement. Methods. Two IV team nurses with more than 10 years of experience with placing PICCs and 3 to 6 years of experience with ultrasound attempted to place PICCs under ultrasound guidance in patients requiring long‐term IV access. One of two methods of ultrasound guidance was used: conventional ultrasound (CUS; 60 patients) or a new device called the SF (44 patients). The number of needle punctures required to gain IV access was recorded for each patient. Results. In both methods, 87% of the cases resulted in successful venous access on the first attempt. The average number of needle sticks per patient was 1.18 for SF‐guided procedures compared with 1.20 for CUS‐guided procedures. No significant difference was found in the distribution of the number of attempts between the two methods. Anecdotal comments by the nurses indicated the comparative ease of use of the SF display, although the relatively small scale of the SF image compared with the CUS image was also noted. Conclusions. We have shown that the SF is a safe and effective device for guidance of PICC placement in the hands of experienced IV team nurses. The advantage of placing the ultrasound image at its actual location must be balanced against the relatively small scale of the SF image.

Evaluation of Set-up Uncertainties with Daily Kilovoltage Image Guidance in External Beam Radiation Therapy for Gynaecological Cancers

AIMS To assess the set-up uncertainty for gynaecological cancer patients treated with external beam radiation therapy using daily kilovoltage image guidance and to estimate set-up margins for treatment and factors that would predict higher set-up uncertainty. MATERIALS AND METHODS Alignment data from daily two-dimensional kilovoltage planar images and three-dimensional kilovoltage cone beam images for 52 patients treated on a Varian 2300iX linear accelerator with On Board Imaging (OBI; version 1.4) capability were analysed. The mean displacements of translational shifts, population systematic errors and random errors were calculated. Using van Herks formula, the clinical target volume (CTV) to planning target volume (PTV) margins for set-up uncertainties were calculated. The differences in set-up error were calculated with respect to the type of cancer, imaging type and body mass index (BMI). RESULTS Population systematic and random errors were 1.1 mm, 2.3 mm, 2.3 mm and 3.9 mm, 5.0 mm, 3.5 mm in the anterior-posterior (AP), medial-lateral (ML) and superior-inferior (SI) directions, respectively, for the entire patient population. Using van Herks formula, the CTV to PTV margins for set-up uncertainties were found to be 5.5, 9.1 and 8.3 mm in the AP, ML and SI directions respectively. The mean displacements in the AP, ML and SI directions for BMI ≥ 30 (28 patients) versus <30 (24 patients) were -0.1 mm, 0.9 mm and 1.0 mm versus -0.1 mm, 0.1 mm and 0.4 mm, respectively, (P = 0.02). CONCLUSIONS Daily imaging helps to assess set-up uncertainty. The set-up margin for CTV to PTV was larger for patients with BMI ≥ 30 without image guidance and these patients would benefit more from daily image guidance.

Real-time tomographic reflection in facilitating percutaneous access to the renal collecting system.

BACKGROUND AND PURPOSE Real-time tomographic reflection is a novel technique that uses a geometrically fixed arrangement of a conventional ultrasound transducer, a transducer-incorporated monitor, and a half-silvered mirror. This device, dubbed the Sonic Flashlight, generates a virtual anatomically scaled image, obviating the need for a separate monitor. It may therefore facilitate invasive procedures, such as percutaneous access to the kidney. This proof-of-concept study assesses the feasibility of this technique for renal imaging and concomitant needle puncture guidance. MATERIALS AND METHODS In a swine model with induced hydronephrosis, the Sonic Flashlight was used to visualize and guide needle access to the renal pelvis. Passage of a 7-inch, 18-gauge spinal needle was performed. Entry into the collecting system was confirmed by the aspiration of urine. RESULTS The anechoic renal pelvis and hyperechoic needle tip could be seen with the Sonic Flashlight device. Successful access to the collecting system was obtained twice without dificulty. The sonographic image, appearing to emanate from the tip of the transducer, makes visualization and manipulation more intuitive. Furthermore, by placing the operators eyes and hands in the same field as the sonogram, image-guided procedures are potentially easier to learn. CONCLUSION The relatively shallow depth of penetration of the current device limits its clinical usefulness. A new Sonic Flashlight with a greater depth of penetration is in development.

Pharmacological Inhibition of PD-1 Exacerbates Radiation-Induced Cardiac Toxicity Through Cytotoxic T Cell–Mediated Myocarditis

Pharmacological Inhibition of PD-1 Exacerbates Radiation-Induced Cardiac Toxicity Through Cytotoxic T CelleMediated Myocarditis S. Du, L. Zhou, G. Shukla, N. Wang, L. Yang, X. Ma, Y. Wang, A.P. Dicker, Y. Lu, and B. Lu; Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China, Sidney Kimmel Medical College at Thomas Jefferson University, Sidney Kimmel Cancer Center, Philadelphia, PA, Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, Shanghai Cancer Center, Shanghai, China, Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China

Clinical Investigations Preoperative high dose rate brachytherapy for clinical stage II endometrial carcinoma

Purpose We sought to evaluate pathological response, tolerance, and outcome after preoperative (neoadjuvant) high dose rate brachytherapy in a small series of patients with clinical stage II endometrial carcinoma, and to evaluate a dose and fractionation protocol for this treatment. Material and methods Twelve women diagnosed with clinical stage II endometrial carcinoma from 1999-2010 were treated with preoperative radiation therapy. Their medical charts were retrospectively analyzed for HDR treatment regimen, pathological response, and longitudinal outcomes. Radiation doses were normalized to a biologically equivalent dose of 2 Gy per fraction (EQD2). Results Two patients had complete pathological response to neoadjuvant therapy; five more had only microscopic residual disease at the time of surgery. At a median follow up of 37 months (1-91 months), one patient has developed recurrence at the vaginal apex six months after completing initial therapy, while another developed a lung recurrence at 28 months. Two-year disease-free and cause-specific survivals were 88% and 100%, respectively. Conclusions Our small study shows that the HDR fractionation schedule, as done in our series for preoperative radiation therapy for clinical stage II endometrial cancer, is well tolerated and would be an option for patients treated with neoadjuvant radiation therapy.

Image segmentation using the student's t-test and the divergence of direction on spherical regions

We have developed a new framework for analyzing images called Shells and Spheres (SaS) based on a set of spheres with adjustable radii, with exactly one sphere centered at each image pixel. This set of spheres is considered optimized when each sphere reaches, but does not cross, the nearest boundary of an image object. Statistical calculations at varying scale are performed on populations of pixels within spheres, as well as populations of adjacent spheres, in order to determine the proper radius of each sphere. In the present work, we explore the use of a classical statistical method, the students t-test, within the SaS framework, to compare adjacent spherical populations of pixels. We present results from various techniques based on this approach, including a comparison with classical gradient and variance measures at the boundary. A number of optimization strategies are proposed and tested based on pairs of adjacent spheres whose size are controlled in a methodical manner. A properly positioned sphere pair lies on opposite sides of an object boundary, yielding a direction function from the center of each sphere to the boundary point between them. Finally, we develop a method for extracting medial points based on the divergence of that direction function as it changes across medial ridges, reporting not only the presence of a medial point but also the angle between the directions from that medial point to the two respective boundary points that make it medial. Although demonstrated here only in 2D, these methods are all inherently n-dimensional.

Technical note: a radiomic signature of infiltration in peritumoral edema predicts subsequent recurrence in glioblastoma.

Standard surgical resection of glioblastoma, mainly guided by the enhancement on post-contrast T1-weighted magnetic resonance imaging (MRI), disregards infiltrating tumor within the peritumoral edema region. Subsequent radiotherapy typically delivers uniform radiation to peritumoral FLAIR-hyperintense regions, without attempting to target areas likely to be infiltrated more heavily. Non-invasive in vivo delineation of the areas of tumor infiltration and prediction of early recurrence in peritumoral edema region could assist in targeted intensification of local therapies, thereby potentially delaying recurrence and prolonging survival. This paper presents a method for estimating peritumoral edema infiltration using radiomic signatures determined via machine learning methods, and tests it on 90 patients with de novo glioblastoma. The generalizability of the proposed predictive model was evaluated via cross-validation in a discovery cohort (n=31), and was subsequently evaluated in a replication cohort (n=59). Spatial maps representing the likelihood of tumor infiltration and future early recurrence were compared with regions of recurrence on postresection follow-up studies. The cross-validated accuracy of our predictive infiltration model on the discovery and replication cohorts was 87.51% (odds ratio=10.22, sensitivity=80.65, specificity=87.63) and 89.54% (odds ratio=13.66, sensitivity=97.06, specificity = 76.73), respectively. The radiomic signature of the recurrent tumor region revealed higher vascularity and cellularity when compared with the nonrecurrent region. The proposed model shows evidence that multi-parametric pattern analysis from clinical MRI sequences can assist in in vivo estimation of the spatial extent and pattern of tumor recurrence in peritumoral edema, which may guide supratotal resection and/or intensification of postoperative radiation therapy.

Deriving stable multi-parametric MRI radiomic signatures in the presence of inter-scanner variations: survival prediction of glioblastoma via imaging pattern analysis and machine learning techniques

There is mounting evidence that assessment of multi-parametric magnetic resonance imaging (mpMRI) profiles can noninvasively predict survival in many cancers, including glioblastoma. The clinical adoption of mpMRI as a prognostic biomarker, however, depends on its applicability in a multicenter setting, which is hampered by inter-scanner variations. This concept has not been addressed in existing studies. We developed a comprehensive set of within-patient normalized tumor features such as intensity profile, shape, volume, and tumor location, extracted from multicenter mpMRI of two large (npatients=353) cohorts, comprising the Hospital of the University of Pennsylvania (HUP, npatients=252, nscanners=3) and The Cancer Imaging Archive (TCIA, npatients=101, nscanners=8). Inter-scanner harmonization was conducted by normalizing the tumor intensity profile, with that of the contralateral healthy tissue. The extracted features were integrated by support vector machines to derive survival predictors. The predictors’ generalizability was evaluated within each cohort, by two cross-validation configurations: i) pooled/scanner-agnostic, and ii) across scanners (training in multiple scanners and testing in one). The median survival in each configuration was used as a cut-off to divide patients in long- and short-survivors. Accuracy (ACC) for predicting long- versus short-survivors, for these configurations was ACCpooled=79.06% and ACCpooled=84.7%, ACCacross=73.55% and ACCacross=74.76%, in HUP and TCIA datasets, respectively. The hazard ratio at 95% confidence interval was 3.87 (2.87–5.20, P<0.001) and 6.65 (3.57-12.36, P<0.001) for HUP and TCIA datasets, respectively. Our findings suggest that adequate data normalization coupled with machine learning classification allows robust prediction of survival estimates on mpMRI acquired by multiple scanners.

Dosimetric Impact of a Tumor Treating Fields Device for Glioblastoma Patients Undergoing Simultaneous Radiation Therapy

Purpose A recent randomized phase III clinical trial in patients with glioblastoma demonstrated the efficacy of tumor treating fields (TTFields), in which alternating electric fields are applied via transducer arrays to a patient’s scalp. This treatment, when added to standard of care therapy, was shown to increase overall survival from 16 to 20.9 months. These results have generated significant interest in incorporating the use of TTFields during postoperative concurrent chemoradiation. However, the dosimetric impact of high-density electrodes on the scalp, within the radiation field, is unknown. Methods The dosimetric impact of TTFields electrodes in the radiation field was quantified in two ways: (1) dose calculated in a treatment planning system and (2) physical measurements of surface and deep doses. In the dose calculation comparison, a volumetric-modulated-arc-therapy (VMAT) radiation plan was developed on a CT scan without electrodes and then recalculated with electrodes. For physical measurements, the surface dose underneath TTFields electrodes were measured using a parallel plate ionization chamber and compared to measurements without electrodes for various incident beam angles and for 12 VMAT arc deliveries. Deep dose measurements were conducted for five VMAT plans using Scandidos Delta4 diode array: measured doses on two orthogonal diode arrays were compared. Results In the treatment planning system, the presence of the TTFields device caused mean reduction of PTV dose of 0.5–1%, and a mean increase in scalp dose of 0.5–1 Gy. Physical measurement showed increases of surface dose directly underneath by 30–110% for open fields with varying beam angles and by 70–160% for VMAT deliveries. Deep dose measurement by diode array showed dose decrease of 1–2% in most areas shadowed by the electrodes (max decrease 2.54%). Conclusion The skin dose in patients being treating with cranial irradiation for glioblastoma may increase substantially (130–260%) with the addition of concurrent TTFields electrodes on the scalp. However, the impact of dose attenuation by the electrodes on deep dose during VMAT treatment is of much smaller, but measureable, magnitude (1–2%). Clinical trials exploring concurrent TTFields with cranial irradiation for glioblastoma may utilize scalp-sparing techniques to mitigate any potential increase in skin toxicity.