Keyur J. Mehta

Hyperthermia on immune regulation: A temperature’s story

Over the last decade the linkage between hyperthermia, heat shock proteins and fever with the bodys immune system has been well investigated. The immunomodulatory function of hyperthermia has been found to be quite sensitively regulated by temperature, as different levels of heating can bring different modulatory effect on different sensitive targets. Understanding these intrinsic mechanisms could bring new inspirations on the design of clinical trials combining local tumor hyperthermia with immunotherapy in cancer patients. This review will attempt to tell the story about the effect of temperature on immune regulation, with special emphasis on the clinical application of hyperthermia and the feasibility of combining it with immunotherapy in the clinic.

Bone marrow-derived stromal cell therapy in cirrhosis: clinical evidence, cellular mechanisms, and implications for the treatment of hepatocellular carcinoma.

Current treatment options for hepatocellular carcinoma (HCC) are often limited by the presence of underlying liver disease. In patients with liver cirrhosis, surgery, chemotherapy, and radiation therapy all carry a high risk of hepatic complications, ranging from ascites to fulminant liver failure. For patients receiving radiation therapy, cirrhosis dramatically reduces the already limited radiation tolerance of the liver and represents the most important clinical risk factor for the development of radiation-induced liver disease. Although improvements in conformal radiation delivery techniques have improved our ability to safely irradiate confined areas of the liver to increasingly higher doses with excellent local disease control, patients with moderate-to-severe liver cirrhosis continue to face a shortage of treatment options for HCC. In recent years, evidence has emerged supporting the use of bone marrow-derived stromal cells (BMSCs) as a promising treatment for liver cirrhosis, with several clinical studies demonstrating sustained improvement in clinical parameters of liver function after autologous BMSC infusion. Three predominant populations of BMSCs, namely hematopoietic stem cells, mesenchymal stem cells, and endothelial progenitor cells, seem to have therapeutic potential in liver injury and cirrhosis. Preclinical studies of BMSC transplantation have identified a range of mechanisms through which these cells mediate their therapeutic effects, including hepatocyte transdifferentiation and fusion, paracrine stimulation of hepatocyte proliferation, inhibition of activated hepatic stellate cells, enhancement of fibrolytic matrix metalloproteinase activity, and neovascularization of regenerating liver. By bolstering liver function in patients with underlying Childs B or C cirrhosis, autologous BMSC infusion holds great promise as a therapy to improve the safety, efficacy, and utility of surgery, chemotherapy, and hepatic radiation therapy in the treatment of HCC.

Feasibility study and optimum loading pattern of a multi-ring inflatable intravaginal applicator

Purpose A cylinder applicator is the standard treatment device for intravaginal brachytherapy. However, they are limited in their ability to simultaneously spare the organs at risk (OAR), and reduce the hot spot in the vaginal mucosa, while achieving adequate dose conformality. This study aims to compare the dosimetric characteristics of single and multi-channel cylinders, and utilizes volume point dose optimizations to investigate the feasibility and optimum loading method for a multi-ring inflatable intravaginal applicator. Material and methods Studies were designed to: (1) test the feasibility of multi-ring applicators, (2) compare dose distributions between different multi-channel applicators and loading patterns, (3) test non-uniform prescription depths around the multi-ring cylinder. Results Compared to a cylinder with a single central channel, a cylinder with 6 lumina arranged around the periphery, providing the lumina had adequate distance to the cylinder surface, could reduce dose beyond the prescription depth. However, when the number of outer lumina increased from 6 to 12, no further dose reduction could be achieved and the high dose volume close to the surface of the cylinder increased. Moreover, an additional ring, with lumina further away from the surface, provided increased dose shaping capabilities, allowing for individualized dose distributions. Conclusions Dose could be reduced to normal tissue and the inner mucosa, and better conformity was seen to unique anatomical shapes. A modified peripheral loading pattern provided the optimum dose distribution, yielding good conformity, dose sparing at adjacent organs, and dose reduction in the high dose region of the vaginal mucosa.

Day to day treatment variations of accelerated partial breast brachytherapy using a multi-lumen balloon

Purpose To evaluate the variations of multi-lumen balloon (MLB)-based brachytherapy from simulation day to treatment day and their dosimetric impacts during accelerated partial breast irradiation (APBI). Material and methods A total of 42 CT images scanned from seven patients were evaluated with regards to daily variation due to of: 1) internal uncertainty: size and shape of balloon, seroma volume; 2) geometrical uncertainty-random: length of each catheter was measured for each fraction (total 70); 3) geometrical uncertainty-systematic: virtual systematic errors were tested by offsetting dwell positions. The original plans (as group A) had a mean value of 96.8% on V95 of the PTV_Eval. Plans were rerun (as group B) such that the mean value of the V95 was relaxed to 90.4%. By applying the reference plan to each daily CT image, variations of target coverage under different sources of error were evaluated. Results Shape and size of the balloon had means of < 1 mm decreased in diameter and < 0.4 cm3 decreased in volume; the mean seroma volume increased by 0.2 cm3. This internal variation has a mean of < 1% difference for both V90 and V95. The geometrical uncertainty made a mean deviation of 2.7 mm per root of sum of square. It caused the degradations of V90 and V95 by mean values of 1.0% and 1.2%, respectively. A systematic error of 3 mm and 4 mm would degrade both of V90 and V95 by 4% and 6%, respectively. The degradations on target coverage of the plans in group A were statistically the same as those in group B. Conclusions Overall, APBI treatments with MLB based brachytherapy are precise from day to day. However, minor variation due to daily treatment uncertainties can still degrade tumor bed coverage to an unacceptable coverage when V95 of the original plan is close to 90%.

Progressive transition from pre-planned to intraoperative optimizing seed implant: post implementation analysis.

Purpose To perform a dosimetric comparison between a pre-planned technique and a pre-plan based intraoperative technique in prostate cancer patients treated with I-125 permanent seed implantation. Material and methods Thirty patients were treated with I-125 permanent seed implantation using TRUS guidance. The first 15 of these patients (Arm A) were treated with a pre-planned technique using ultrasound images acquired prior to seed implantation. To evaluate the reproducibility of the prostate volume, ultrasound images were also acquired during the procedure in the operating room (OR). A surface registration was applied to determine the 6D offset between different image sets in arm A. The remaining 15 patients (Arm B) were planned by putting the pre-plan on the intraoperative ultrasound image and then re-optimizing the seed locations with minimal changes to the pre-plan needle locations. Post implant dosimetric analyses included comparisons of V100(prostate), D90(prostate) and V100(rectum). Results In Arm A, the 6D offsets between the two image sets were θx=−1.4±4.3; θy=−1.7±2.6; θz=−0.5±2.6; X=0.5±1.8 mm; Y=−1.3±−3.5 mm; Z=−1.6±2.2 mm. These differences alone degraded V100 by 6.4% and D90 by 9.3% in the pre-plan, respectively. Comparing Arm A with Arm B, the pre-plan based intraoperative optimization of seed locations used in the plans for patients in Arm B improved the V100 and D90 in their post-implant studies by 4.0% and 5.7%, respectively. This was achieved without significantly increasing the rectal dose (V100(rectum)). Conclusions We have progressively moved prostate seed implantation from a pre-planned technique to a pre-plan based intraoperative technique. In addition to reserving the advantage of cost-effective seed ordering and efficient OR implantation, our intraoperative technique demonstrates increased accuracy and precision compared to the pre-planned technique.

Neoadjuvant radiation therapy for the management of myoepithelial carcinoma of the upper extremity: Neoadjuvant radiation therapy

Myoepithelial tumors of the soft tissue are a rare tumor displaying myoepithelial elements and lacking obvious ductal differentiation. The rarity of these precludes any evidence‐based consensus regarding optimal management. Nevertheless, the current approach to these lesions begins with amputation or complete excision. The efficacy of neoadjuvant or adjuvant radiation therapy or chemotherapy has not been established. Here, we present the first report to the authors’ knowledge of neoadjuvant radiation therapy for the treatment of this rare soft tissue neoplasm and review the management and outcomes of published cases of myoepithelial carcinoma. A patient with a soft tissue myoepithelial carcinoma that declined both amputation and chemotherapy was treated with neoadjuvant radiation therapy and wide surgical excision followed by a brachytherapy boost to the resected tumor bed. Neoadjuvant radiation therapy resulted in an excellent response with extensive treatment‐related changes consisting predominantly of fibrosis, hyalinization and hemorrhage and only 10% residual viable myoepithelial carcinoma present in the surgical specimen.

Radiation Recall Dermatitis in Patients Treated with Sorafenib

Introduction Radiation recall dermatitis (RRD) is a phenomenon that occurs in previously irradiated areas shortly after administration of a chemotherapeutic agent. As the use of sorafenib expands, the incidence of radiation recall dermatitis induced by sorafenib will likely increase. Here, we report on a patient who developed RRD and describe his clinical characteristics along with a review of the literature. Case Presentation Our patient was treated with palliative radiation therapy (RT) to a painful metastatic hepatocellular carcinoma lesion in the right forearm. He completed his radiation course with grade 1 dermatitis, which had resolved by the time he was started on sorafenib 400 mg twice daily 7 days afterwards. On the 21st day after RT, he presented with desquamation and erythema in the previously irradiated area of the right forearm, consistent with RRD. The sorafenib was discontinued and his symptoms subsequently resolved with conservative topical management. Conclusions Although the pathophysiologic mechanism of sorafenib-related radiation recall dermatitis remains to be investigated, practitioners should be aware of its presence and management in order to improve clinical outcomes.

Dosimetric Evaluation of a Flexible Dual Balloon-Constructed Applicator in Treating Anorectal Cancer

Background and Purpose: To assess the dosimetric flexibility of a dual balloon brachytherapy applicator developed for the treatment of anorectal lesions. Materials and Methods: Different amounts of water were infused into the inner and outer balloon separately to study the asymmetrical distribution of the catheter, the radial distance of the active source channel to the inner surface of the global target volume , the space between the active source channels, and their dosimetric impact to target tissues and uninvolved rectum. Results: Increasing inner balloon volume directly increased both the space between the active source channels and the radial distance of the active source channel to the inner surface of the global target volume. The space between the active source channels and the percentage of global target volume received 150% or more of the prescribed dose to target had a strong inverse correlation (−0.881/P = .007, −0.976/P = .001, respectively) with the radial distance of the active source channel to the inner surface of the global target volume. Conformity index, dose to 2 cm3 of rectum, and total reference air kerma were strongly correlated with the radial distance of the active source channel to the inner surface of the global target volume, with values of 0.952 (P = .001), 0.833 (P = .015), and 0.922 (P = .002), respectively. Percentage of global target volume received 150% or more of the prescribed dose was significantly correlated with the space between the active source channels (0.81/P = .022), and conformity index was strongly inversely correlated with the space between the active source channels (−0.833/P = .015). Conclusion: The dual balloon-constructed Anorectal Applicator offers a flexible way to adjust the distances of the active source positions to the target in relation to uninvolved rectal wall. This flexibility simplifies planning which results in a highly conformal dose distribution to the target lesion while minimizing dose to normal rectal tissue.

Model assessment of individual tumor control rate and adverse effects in comparing locally advanced cervical cancer treatment using intracavitary with and without interstitial brachytherapy

Purpose This study assessed the modeled probability of tumor control and organ at risk toxicities in locally advanced cervical cancer in patients treated by external beam radiation plus brachytherapy using intracavitary combined with interstitial brachytherapy (IC/IS) vs. intracavitary brachytherapy (IC) alone. Material and methods Twenty cervical cancer patients with a mean HR-CTV volume of 47.4 cm3 and a mean width of 54 mm were planned with both IC/IS and IC brachytherapy alone. A probit model was utilized to model 3-year (3-yr) local control rate (LC), 3-yr cancer specific survival rate (CSS), and the adverse effect (AE) of the organ at risk by using a modeled data set from multiple institutions. Modeling results were used to estimate the LC, CSS, and AE of the treatments in this study. Results Using the IC/IS technique, an EQD2 increase of 12.3 Gy to D90 (from 76.1 Gy to 88.3 Gy) of HR-CTV is expected to increase 3-yr LC and 3-yr CSS by 12.5%, and 11.0%, respectively. Comparing IC/IS to IC alone, the expected G2+ AE were 7.7% vs. 7.9% for the bladder, and 5.9% vs. 6.8% for the rectum. Conclusions The IC/IS technique improved dose coverage to the HR-CTV without significantly increasing dose to 2 cm3 of the organ at risk (OAR) surrounding it. With different regimens of EBRT combined with BT, IC/IS can be used to increase the probability of LC and CSS, or decrease the risk of AE.

Tumor bed variation during multi-lumen balloon-based accelerated partial breast irradiation: implication of surgical clips

HSIANG-CHI KUO, KEYUR J. MEHTA, LESLIE MONTGOMERY, VISWANATHAN SHANKAR, RAVINDRA YAPARPALVI, LINDA HONG, JANA FOX, WOLFGANG A. TOMÉ & SHALOM KALNICKI Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, USA, Department of Surgery, Montefiore Medical Center, Bronx, NY, USA, Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA., and Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.