Radiation-Associated Toxicities in Obese Women with Endometrial Cancer: More Than Just BMI?

PURPOSE: The study characterizes the impact of obesity on postoperative radiation-associated toxicities in women with endometrial cancer (EC). MATERIAL AND METHODS: A retrospective study identified 96 women with EC referred to a large urban institution's radiation oncology practice for postoperative whole pelvic radiotherapy (WPRT) and/or intracavitary vaginal brachytherapy (ICBT). Demographic and clinicopathologic data were obtained. Toxicities were graded according to RTOG Acute Radiation Morbidity Scoring Criteria. Follow-up period ranged from 1 month to 11 years (median 2 years). Data were analyzed by χ(2), logistic regression, and recursive partitioning analyses. RESULTS: 68 EC patients who received WPRT and/or ICBT were analyzed. Median age was 52 years (29-73). The majority were Hispanic (71%). Median BMI at diagnosis was 34.5 kg/m(2) (20.5-56.6 kg/m(2)). BMI was independently associated with radiation-related cutaneous (p = 0.022) and gynecologic-related (p = 0.027) toxicities. Younger women also reported more gynecologic-related toxicities (p = 0.039). Adjuvant radiation technique was associated with increased gastrointestinal- and genitourinary-related toxicities but not gynecologic-related toxicity. CONCLUSIONS: Increasing BMI was associated with increased frequency of gynecologic and cutaneous radiation-associated toxicities. Additional studies to critically evaluate the radiation treatment dosing and treatment fields in obese EC patients are warranted to identify strategies to mitigate the radiation-associated toxicities in these women.

ACR-ARS Practice Parameter for the Performance of Total Body Irradiation.

OBJECTIVES: This practice parameter was revised collaboratively by the American College of Radiology (ACR) and the American Radium Society (ARS). This practice parameter provides updated reference literature regarding both clinical-based conventional total body irradiation and evolving volumetric modulated total body irradiation. METHODS: This practice parameter was developed according to the process described under the heading The Process for Developing ACR Practice Parameters and Technical Standards on the ACR website ( https://www.acr.org/Clinical-Resources/Practice-Parameters-and-Technical-Standards ) by the Committee on Practice Parameters-Radiation Oncology of the ACR Commission on Radiation Oncology in collaboration with the ARS. RESULTS: This practice parameter provides a comprehensive update to the reference literature regarding conventional total body irradiation and modulated total body irradiation. Dependence on dose rate remains an active area of ongoing investigation in both the conventional setting (where instantaneous dose rate can be varied) and in more modern rotational techniques, in which average dose rate is the relevant variable. The role of imaging during patient setup and the role of inhomogeneity corrections due to computer-based treatment planning systems are included as evolving areas of clinical interest notably surrounding the overall dose inhomogeneity. There is increasing emphasis on the importance of evaluating mean lung dose as it relates to toxicity during high-dose total body irradiation regimens. CONCLUSIONS: This practice parameter can be used as an effective tool in designing and evaluating a total body irradiation program that successfully incorporates the close interaction and coordination among the radiation oncologists, medical physicists, dosimetrists, nurses, and radiation therapists.

First-In-Human Pilot PET Immunoimaging Study of 64Cu-Anti-Carcinoembryonic Antigen Monoclonal Antibody (hT84.66-M5A) in Patients with Carcinoembryonic Antigen-Producing Cancers.

Background: PET imaging using radiolabeled immunoconstructs shows promise in cancer detection and in assessing tumor response to therapies. The authors report the first-in-human pilot study evaluating M5A, a humanized anti-carcinoembryonic antigen (CEA) monoclonal antibody (mAb), radiolabeled with 64Cu in patients with CEA-expressing malignancies. The purpose of this pilot study was to identify the preferred patient population for further evaluation of this agent in an expanded trial. Methods: Patients with CEA-expressing primary or metastatic cancer received 64Cu-DOTA-hT84.66-M5A with imaging performed at 1 and 2 days postinfusion. 64Cu-DOTA-hT84.66-M5A PET scan findings were correlated with CT, MRI, and/or FDG PET scans and with histopathologic findings from planned surgery or biopsy performed postscan. Results: Twenty patients received 64Cu-DOTA-hT84.66-M5A. Twelve patients demonstrated positive images, which were confirmed in 10 patients as tumor by standard-of-care (SOC) imaging, biopsy, or surgical findings. Four of the 8 patients with negative imaging were confirmed as true negative, with the remaining 4 patients having disease demonstrated by SOC imaging or surgery. All 5 patients with locally advanced rectal cancer underwent planned biopsy or surgery after 64Cu-DOTA-hT84.66-M5A imaging (4 patients imaged 6-8 weeks after completing neoadjuvant chemotherapy and radiation therapy) and demonstrated a high concordance between biopsy findings and 64Cu-DOTA-hT84.66-M5A PET scan results. Three patients demonstrated positive uptake at the primary site later confirmed by biopsy and at surgery as residual disease. Two patients with negative scans each demonstrated complete pathologic response. In 5 patients with medullary thyroid cancer, 64Cu-DOTA-hT84.66-M5A identified disease not seen on initial CT scans in 3 patients, later confirmed to be disease by subsequent surgery or MRI. Conclusions: 64Cu-DOTA-hT84.66-M5A demonstrates promise in tumor detection, particularly in patients with locally advanced rectal cancer and medullary thyroid cancer. A successor trial in locally advanced rectal cancer has been initiated to further evaluate this agent's ability to define tumor extent before and assess disease response after neoadjuvant chemotherapy and radiotherapy. clinical trial.gov (NCT02293954).

Brentuximab Vedotin Combined With Chemotherapy in Patients With Newly Diagnosed Early-Stage, Unfavorable-Risk Hodgkin Lymphoma.

PURPOSE: To improve curability and limit long-term adverse effects for newly diagnosed early-stage (ES), unfavorable-risk Hodgkin lymphoma. METHODS: In this multicenter study with four sequential cohorts, patients received four cycles of brentuximab vedotin (BV) and doxorubicin, vinblastine, and dacarbazine (AVD). If positron emission tomography (PET)-4-negative, patients received 30-Gy involved-site radiotherapy in cohort 1, 20-Gy involved-site radiotherapy in cohort 2, 30-Gy consolidation-volume radiotherapy in cohort 3, and no radiotherapy in cohort 4. Eligible patients had ES, unfavorable-risk disease. Bulk disease defined by Memorial Sloan Kettering criteria (> 7 cm in maximal transverse or coronal diameter on computed tomography) was not required for cohorts 1 and 2 but was for cohorts 3 and 4. The primary end point was to evaluate safety for cohort 1 and to evaluate complete response rate by PET for cohorts 2-4. RESULTS: Of the 117 patients enrolled, 116 completed chemotherapy, with the median age of 32 years: 50% men, 98% stage II, 86% Memorial Sloan Kettering-defined disease bulk, 27% traditional bulk (> 10 cm), 52% elevated erythrocyte sedimentation rate, 21% extranodal involvement, and 56% > 2 involved lymph node sites. The complete response rate in cohorts 1-4 was 93%, 100%, 93%, and 97%, respectively. With median follow-up of 3.8 years (5.9, 4.5, 2.5, and 2.2 years for cohorts 1-4), the overall 2-year progression-free and overall survival were 94% and 99%, respectively. In cohorts 1-4, the 2-year progression-free survival was 93%, 97%, 90%, and 97%, respectively. Adverse events included neutropenia (44%), febrile neutropenia (8%), and peripheral neuropathy (54%), which was largely reversible. CONCLUSION: BV + AVD × four cycles is a highly active and well-tolerated treatment program for ES, unfavorable-risk Hodgkin lymphoma, including bulky disease. The efficacy of BV + AVD supports the safe reduction or elimination of consolidative radiation among PET-4-negative patients.

Review of Radium-223 and Metastatic Castration-Sensitive Prostate Cancer.

Background: Radium-223 is approved for treatment of bone metastases in metastatic castration-resistant prostate cancer (mCRPC). After the ALSYMPCA trial showed overall survival benefit with the addition of radium-223 to standard of care in mCRPC in 2013, there have been numerous publications and trials using radium-223 in mCRPC. Recently, there has been interest in using radium-223 earlier in the metastatic prostate cancer timeline, in metastatic castrate-sensitive prostate cancer (mCSPC); however, currently, radium-223 in mCSPC treatment is investigational. Aim: A literature search was conducted to review the use of radium-223 in mCSPC treatment from 1980 to 2019. A review of both radium-223 articles and abstracts was performed. Search terms included metastatic prostate cancer and radium-223, mCSPC, hormone-sensitive metastatic prostate cancer, radium-223, and oligometastatic disease. The results were limited to studies involving multiple patients with mCSPC. Conclusion: There are a limited number of studies of radium-223 in mCSPC treatment and the authors report on these studies (two published studies and four ongoing trials). Trials are currently underway to assess if radium-223 could be used in mCSPC as a treatment for bone metastases and micrometastases. Future data from these trials will be informative as to the benefit of radium-223 in mCSPC treatment and may change treatment paradigms for mCSPC. This review will focus on trials assessing the role of radium-223 in mCSPC.

Functional genetic variation in aminopeptidase A (ENPEP): lack of clear association with focal and segmental glomerulosclerosis (FSGS).

The aminopeptidase A (APA) ectopeptidase is an integral membrane-bound zinc metalloprotease that cleaves aspartic and glutamic acidic residues from the N-terminus of a number of protein substrates that includes angiotensin II. Angiotensin II, the most vasoactive component of the renin-angiotensin-aldosterone (RAAS) pathway, can contribute to renal disease by causing an increase in arterial blood pressure leading to glomerular injury and fibrosis. APA is expressed in many organs, including the kidney where it localizes mainly to the podocyte cell membrane and brush borders of the proximal tubule cells. Antibodies directed to the APA peptide can induce an acute massive albuminuria in wild-type BALB/c mice after intravenous injection. We examined whether variants in the APA encoding gene (ENPEP) are more frequent in individuals with the proteinuric disease focal and segmental glomerulosclerosis (FSGS) compared to control individuals. The ENPEP coding sequence was re-sequenced in 188 FSGS patients and 48 controls. Genetic variants were further genotyped in 181 individuals without any known kidney disease. We then examined the effect of the non-synonymous coding variants identified on their cell surface APA activity after transfection in COS-1 cells. Several of these ENPEP variants lead to reproducibly altered APA activity. However, we did not see a clear correlation between the presence of a functional ENPEP variant and FSGS. However, the existence of these variants with marked effect on APA activity suggests that both rare and common variation in ENPEP may contribute to the development of renal and hypertensive disorders and warrants further study.

Measuring health-related quality of life consequences from primary treatment for early-stage prostate cancer.

Radical prostatectomy, external radiation therapy, and brachytherapy are all mainstay treatment options for clinically localized prostate cancer. Over time, each of these treatments has been modified so as to maximize percent cancer-free survival while minimizing health-related risks such as urinary incontinence, bowel incontinence, and sexual dysfunction. With these efforts, there is still not one superior single treatment that is devoid of side effects. Concurrently, efforts have been made to generate validated health-related quality of life (HRQOL) measurement scales to aid in the decision making by both physician and patient. HRQOL measurement scales enable physicians to have informed discussions with patients about potential likelihood of a given set of side effects with the various prostate cancer treatment options. This review will highlight prostate cancer HRQOL outcomes and delineate further areas of study necessary to optimize evidence-based decision making for prostate cancer patients.

Outcomes of medium choroidal melanomas treated with ruthenium brachytherapy guided by three-dimensional pretreatment modeling.

PURPOSE: The Collaborative Ocular Melanoma Study (COMS) established iodine-125 (I-125) plaque brachytherapy for eye preserving treatment of medium-sized choroidal melanomas in the United States. Eye Physics I-125 plaque treatment modeled with Plaque Simulator (PS) software yields similar results to COMS. Herein, we report results from a series of 15 patients treated with ruthenium-106 (Ru-106) plaque brachytherapy using PS pretreatment modeling for plaque localization and dosimetry. METHODS AND MATERIALS: Fifteen patients with medium-sized choroidal melanomas (2.84-5.5 mm in apical height and a basal diameter of 7.8-12.6 mm) treated with ruthenium brachytherapy from 2003 to 2005 were evaluated retrospectively. Baseline and followup data were evaluated for tumor height, best corrected visual acuity, radiation retinopathy, radiation optic neuropathy, postradiation cataract formation, diplopia, and ptosis. Tumor response for both Ru-106 and I-125 plaques planned using the same PS pretreatment modeling was evaluated and compared. RESULTS: Isotope-specific radiation profiles were compared, and rates of local treatment failure (0%), optic neuropathy (6.7%), retinopathy (20%), and cataracts (33%) were evaluated. Five year-treated tumor heights were approximately 0.61 ± 0.29 (I-125, n = 16) and 0.53 ± 0.17 (Ru-106, n = 6) of their heights at diagnosis. CONCLUSIONS: This patient subset had background characteristics very similar to those of the COMS and patients treated at our institution with I-125 plaques. Treatment response was equivalent although radiation complications occurred slightly less frequently in the Ru-106 group compared with those treated with I-125. Image-guided three-dimensional pretreatment modeling for plaque localization and dosimetry seems to work equally as well for Ru as for I-125 plaques and justifies more extensive investigation.

Outcomes of choroidal melanomas treated with eye physics: a 20-year review.

IMPORTANCE: The University of Southern California Eye Physics plaques compare favorably with the Collaborative Ocular Melanoma Study plaques in terms of late adverse effects from radiation, metastasis, and local tumor recurrence. OBJECTIVE: To review the University of Southern California experience using Eye Physics plaques and Plaque Simulator software to treat choroidal melanomas and compare the outcomes with published results of the Collaborative Ocular Melanoma Study. DESIGN, SETTING, AND PARTICIPANTS: A retrospective case series of 82 patients treated for medium-sized choroidal melanoma from January 1, 1990, through December 30, 2010, using iodine 125 plaques and treatment simulation software developed at the University of Southern California. The dosimetric goal was 85 Gy in 7 days to a conformal volume enclosing the apex and a 2-mm margin surrounding the tumor base. Plaque localization was guided by the Plaque Simulator computer modeling system using preoperative imaging studies. MAIN OUTCOMES AND MEASURES: Primary outcome measures were local tumor control, globe preservation, and metastases. Secondary outcome measures were late radiation adverse effects including postoperative vision changes, optic neuropathy, radiation retinopathy, and cataract. RESULTS: The median follow-up for 82 patients was 46.8 months (range, 1-171 months). Globe preservation was achieved in 80 patients (97.6%); 2 patients underwent enucleation for local recurrence. Metastatic disease developed in 9 patients (11.0%). Retinopathy was seen in 31 patients (37.8%), optic neuropathy in 12 (14.6%), and cataracts in 26 (31.7%). Postoperatively, 21 patients (25.6%) lost more than 6 lines of Snellen visual acuity. CONCLUSIONS AND RELEVANCE: When considering rates of local recurrence, metastases, and late radiation adverse effects, the University of Southern California results for medium-sized choroidal melanomas using Eye Physics plaques compared favorably with Collaborative Ocular Melanoma Study data. The Plaque Simulator 3-dimensional tumor-modeling program developed at the University of Southern California is a reliable method for determining plaque positioning preoperatively and for treating this cohort of patients.

HIV- positive anal cancer: an update for the clinician.

Anal cancer used to be a rare cancer traditionally associated with elderly women. There are approximately 5260 cases per year in the U.S. (1). The onslaught of the Human Immunodeficiency Virus (HIV) virus has led to a change in anal cancer demographics. Anal cancer is on the rise in the U.S and the number of anal cases documented has quadrupled in the past 20 yrs correlating with the rise of the HIV epidemic. The incidence of anal cancer is 40 to 80 fold higher in the HIV positive (HIV+) population when compared to the general population (2). With the advent of highly active antiretroviral therapy (HAART), HIV+ patients are living longer as less are progressing to AIDS. As a consequence non AIDS defining cancers such as anal cancer are on the rise. Factors implicated in the etiology of anal cancer in HIV+ patients include (Human papillomavirus) HPV virus status, sexual habits, and a history of smoking. HPV 16 and receptive anal intercourse (RAI) increase the risk of anal cancer by 33% over the general population. In the general population, the rate of anal cancer is approximately 0.9 cases per 100,000. In patients with a history of RAI, the rate approaches 35 cases per 100,000 which is equivalent to the prevalence of cervical cancer (3). Smokers are eight times more likely to develop anal cancer. There has been much discussion about tailoring treatment decisions in HIV+ patients with anal cancer. This review focuses on squamous cell carcinomas of the anal canal which comprise 80 to 90% of all anal cancers diagnosed and highlight key issues in the management of HIV+ anal cancer patients including recent clinical trials.

Alpha-actinin-4 is required for normal podocyte adhesion.

Mutations in the alpha-actinin-4 gene ACTN4 cause an autosomal dominant human kidney disease. Mice deficient in alpha-actinin-4 develop a recessive phenotype characterized by kidney failure, proteinuria, glomerulosclerosis, and retraction of glomerular podocyte foot processes. However, the mechanism by which alpha-actinin-4 deficiency leads to glomerular disease has not been defined. Here, we examined the effect of alpha-actinin-4 deficiency on the adhesive properties of podocytes in vivo and in a cell culture system. In alpha-actinin-4-deficient mice, we observed a decrease in the number of podocytes per glomerulus compared with wild-type mice as well as the presence of podocyte markers in the urine. Podocyte cell lines generated from alpha-actinin-4-deficient mice were less adherent than wild-type cells to glomerular basement membrane (GBM) components collagen IV and laminin 10 and 11. We also observed markedly reduced adhesion of alpha-actinin-4-deficient podocytes under increasing shear stresses. This adhesion deficit was restored by transfecting cells with alpha-actinin-4-GFP. We tested the strength of the integrin receptor-mediated linkages to the cytoskeleton by applying force to microbeads bound to integrin using magnetic pulling cytometry. Beads bound to alpha-actinin-4-deficient podocytes showed greater displacement in response to an applied force than those bound to wild-type cells. Consistent with integrin-dependent alpha-actinin-4-mediated adhesion, phosphorylation of beta1-integrins on alpha-actinin-4-deficient podocytes is reduced. We rescued the phosphorylation deficit by transfecting alpha-actinin-4 into alpha-actinin-4-deficient podocytes. These results suggest that alpha-actinin-4 interacts with integrins and strengthens the podocyte-GBM interaction thereby stabilizing glomerular architecture and preventing disease.