Postmortem study of organ-specific toxicity in glioblastoma patients treated with a combination of temozolomide, irinotecan and bevacizumab.

PURPOSE: Systemic chemotherapy including monotherapy with temozolomide (TMZ) or bevacizumab (BEV); two-drug combinations, such as irinotecan (IRI) and BEV, TMZ and BEV and a three-drug combination with TMZ, IRI and BEV (TIB) have been used in treating patients with progressive high-grade gliomas including glioblastoma (GBM). Most patients tolerated these regimens well with known side effects of hypertension, proteinuria, and reversible clinical myelosuppression (CM). However, organ- or system- specific toxicities from chemotherapy agents have never been examined by postmortem study. This is the largest cohort used to address this issue in glioma patients. METHODS: Postmortem tissues (from all major systems and organs) were prospectively collected and examined by standard institution autopsy and neuropathological procedures from 76 subjects, including gliomas (N = 68, 44/M, and 24/F) and brain metastases (N = 8, 5/M, and 3/F) between 2009 and 2019. Standard hematoxylin and eosin (H&E) were performed on all major organs including brain specimens. Electronic microscopic (EM) study was carried out on 14 selected subject's kidney samples per standard EM protocol. Medical records were reviewed with adverse events (AEs) analyzed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. A swimmer plot was utilized to visualize the timelines of patient history by treatment group. The binary logistic regression models were performed to explore any associations between treatment strategies and incident myelosuppression. RESULTS: Twenty-four glioma subjects were treated with TIB [median: 5.5 (range: 1-25) cycles] at tumor recurrence. Exposure to IRI significantly increased the frequency of CM (p = 0.05). No unexpected adverse events clinically, or permanent end-organ damage during postmortem examination was identified in glioma subjects who had received standard or prolonged duration of BEV, TMZ or TIB regimen-based chemotherapies except rare events of bone marrow suppression. The most common causes of death (COD) were tumor progression (63.2%, N = 43) followed by aspiration pneumonia (48.5%, N = 33) in glioma subjects. No COD was attributed to acute toxicity from TIB. The study also demonstrated that postmortem kidney specimen is unsuitable for studying renal ultrastructural pathological changes due to autolysis. CONCLUSION: There is no organ or system toxicity by postmortem examinations among glioma subjects who received BEV, TMZ or TIB regimen-based chemotherapies regardless of durations except for occasional bone marrow suppression and reversible myelosuppression clinically. IRI, but not the extended use of TMZ, significantly increased CM in recurrent glioma patients. COD most commonly resulted from glioma tumor progression with infiltration to brain stem and aspiration pneumonia.

PSMA-Targeting Imaging and Theranostic Agents-Current Status and Future Perspective.

In the past two decades, extensive efforts have been made to develop agents targeting prostate-specific membrane antigen (PSMA) for prostate cancer imaging and therapy. To date, represented by two recent approvals of [68Ga]Ga-PSMA-11 and [18F]F-DCFPyL by the United States Food and Drug Administration (US-FDA) for positron emission tomography (PET) imaging to identify suspected metastases or recurrence in patients with prostate cancer, PSMA-targeting imaging and theranostic agents derived from small molecule PSMA inhibitors have advanced to clinical practice and trials of prostate cancer. The focus of current development of new PSMA-targeting agents has thus shifted to the improvement of in vivo pharmacokinetics and higher specific binding affinity with the aims to further increase the detection sensitivity and specificity and minimize the toxicity to non-target tissues, particularly the kidneys. The main strategies involve systematic chemical modifications of the linkage between the targeting moiety and imaging/therapy payloads. In addition to a summary of the development history of PSMA-targeting agents, this review provides an overview of current advances and future promise of PSMA-targeted imaging and theranostics with focuses on the structural determinants of the chemical modification towards the next generation of PSMA-targeting agents.

Selection and Characterization of Vimentin-Binding Aptamer Motifs for Ovarian Cancer.

The application of aptamers in biomedicine is emerging as an essential technology in the field of cancer research. As small single-stranded DNA or RNA ligands with high specificity and low immunogenicity for their targets, aptamers provide many advantages in cancer therapeutics over protein-based molecules, such as antibodies. Vimentin is an intermediate filament protein that is overexpressed in endothelial cells of cancerous tissue. High expression levels of vimentin have been associated with increased capacity for migration and invasion of the tumor cells. We have selected and identified thioated aptamers with high specificity for vimentin using human ovarian cancer tissues. Tentative binding motifs were chosen for two vimentin aptamers based on predicted secondary structures. Each of these shorter, tentative binding motifs was synthesized, purified, and characterized via cell binding assays. Two vimentin binding motifs with high fidelity binding were selected and further characterized via cell and tissue binding assays, as well as flow cytometric analysis. The equilibrium binding constants of these small thioated aptamer constructs were also determined. Future applications for the vimentin binding aptamer motifs include conjugation of the aptamers to synthetic dyes for use in targeted imaging and therapy, and ultimately more detailed and precise monitoring of treatment response and tumor progression in ovarian pathology.

Response to COVID-19: Minimizing Risks, Addressing Challenges and Maintaining Operations in a Complex Academic Radiology Department.

The coronavirus disease 2019 (COVID-19) pandemic has necessitated rapid response plans to minimize risks of infection in the workforce while ensuring maintenance of essential functions of radiology departments. Plan adoption is, however, challenged by the need to coordinate with institutional efforts, a rapidly expanding number of patients, and the diversity of clinical and administrative functions in the department. Here, we describe the implementation of a response plan in an academic radiology department, challenges encountered, and tactics used to address these challenges.

A Novel Ultrasound-Guided Technique for Hysteroscopic Adhesiolysis in High-Risk Patients.

Hysteroscopy is a common gynecologic surgical procedure. Certain diagnoses, notably intrauterine adhesions and cervical stenosis, make hysteroscopy more complicated because of an increased likelihood of complications. Three patients, 1 with cervical stenosis and 2 with Asherman syndrome, underwent ultrasound (US)-guided adhesiolysis. Access to the uterine cavity was obtained by either direct balloon-aided dilation or the US-guided Seldinger technique, followed by balloon-aided dilation to enter the endometrial cavity and disrupt intrauterine/intracervical adhesions. In this case series, we describe a novel approach of using US-guided balloon dilation to safely and effectively treat intrauterine adhesions and to decrease the risk of perforation.

Long-Term Percutaneous Nephrostomy Management of Malignant Urinary Obstruction: Estimation of Optimal Exchange Frequency and Estimation of the Financial Impact of Patient Compliance.

PURPOSE: To estimate the least costly routine exchange frequency for percutaneous nephrostomies (PCNs) placed for malignant urinary obstruction, as measured by annual hospital charges, and to estimate the financial impact of patient compliance. MATERIALS AND METHODS: Patients with PCNs placed for malignant urinary obstruction were studied from 2011 to 2013. Exchanges were classified as routine or due to 1 of 3 complication types: mechanical (tube dislodgment), obstruction, or infection. Representative cases were identified, and median representative charges were used as inputs for the model. Accelerated failure time and Markov chain Monte Carlo models were used to estimate distribution of exchange types and annual hospital charges under different routine exchange frequency and compliance scenarios. RESULTS: Long-term PCN management was required in 57 patients, with 87 total exchange encounters. Median representative hospital charges for pyelonephritis and obstruction were 11.8 and 9.3 times greater, respectively, than a routine exchange. The projected proportion of routine exchanges increased and the projected proportion of infection-related exchanges decreased when moving from a 90-day exchange with 50% compliance to a 60-day exchange with 75% compliance, and this was associated with a projected reduction in annual charges. Projected cost reductions resulting from increased compliance were generally greater than reductions resulting from changes in exchange frequency. CONCLUSIONS: This simulation model suggests that the optimal routine exchange interval for PCN exchange in patients with malignant urinary obstruction is approximately 60 days and that the degree of reduction in charges likely depends more on patient compliance than exact exchange interval.

Single-Center Comparison of Overall Survival and Toxicities in Patients with Infiltrative Hepatocellular Carcinoma Treated with Yttrium-90 Radioembolization or Drug-Eluting Embolic Transarterial Chemoembolization.

PURPOSE: To compare overall survival and toxicities after yttrium-90 (90Y) radioembolization and chemoembolization with drug-eluting embolics (DEE) in patients with infiltrative hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Retrospective review of 50 patients with infiltrative HCC without main portal vein invasion who were treated with 90Y radioembolization (n = 26) or DEE chemoembolization (n = 24) between March 2007 and August 2012 was completed. Infiltrative tumors were defined by cross-sectional imaging as masses that lacked well-demarcated boundaries, and treatment allocations were made by a multidisciplinary tumor board. Median age was 63 years; median tumor diameter was 9.0 cm; and there were no significant differences between groups in performance status, severity of liver disease, or HCC stage. Toxicities were graded by Common Terminology Criteria for Adverse Events v4.03. Overall survival from treatment was assessed by Kaplan-Meier analysis, with analysis of potential predictors of survival with log-rank test. RESULTS: There was no difference in the average number of procedures performed in each treatment group (DEE, 1.5 ± 1.1; 90Y, 1.6 ± 0.5; P = .97), and technical success was achieved in all cases. Abdominal pain (73% vs 33%; P = .004) and fever (38% vs 8%; P = .01) were more frequent after DEE chemoembolization. There was no significant difference in median overall survival between treatment groups after treatment (DEE, 9.9 months; 90Y, 8.1 months; P = .11). CONCLUSIONS: 90Y radioembolization and DEE chemoembolization provided similar overall survival in the treatment of infiltrative HCC without main portal vein invasion. Abdominal pain and fever were more frequent after DEE chemoembolization.

Utility of Intravascular US-Guided Portal Vein Access during Transjugular Intrahepatic Portosystemic Shunt Creation: Retrospective Comparison with Conventional Technique in 109 Patients.

PURPOSE: To compare safety and effectiveness of intravascular ultrasound (US)-guided portal vein access during transjugular intrahepatic portosystemic shunt (TIPS) creation with conventional TIPS technique. MATERIALS AND METHODS: In this retrospective study, TIPS creation using intravascular US guidance in 55 patients was compared with conventional TIPS creation in 54 patients by 10 operators over a 3-year period. Operators were classified as experienced if they had performed ≥ 20 TIPS procedures at the beginning of the study period. Time to portal vein access, total radiation dose, and needle pass-related capsular perforation were recorded. RESULTS: Baseline demographic characteristics of patients were similar (P > .05). Mean time to portal venous access was 46 minutes ± 37 for conventional TIPS and 31 minutes ± 19 for intravascular US-guided TIPS (P = .007). Intravascular US guidance allowed significantly shorter times (48 min ± 30 vs 28 min ± 16; P = .01) to portal vein access among operators (n = 5) with limited experience but failed to achieve any significant time savings (44 min ± 43 vs 34 min ± 22; P = .89) among experienced operators (n = 5). Needle pass-related capsular perforation occurred in 17/54 (34%) patients with conventional TIPS and 5/55 (9%) patients with intravascular US-guided TIPS (P = .004). Radiation dose was 2,376 mGy ± 1,816 for conventional TIPS and 1,592 mGy ± 1,263 for intravascular US-guided TIPS (P = .004). CONCLUSIONS: Intravascular US-guided portal vein access during TIPS creation is associated with shorter portal vein access times, decreased needle pass-related capsular perforations, and reduced radiation dose.

Intention toward optimal breastfeeding among expecting mothers in Angul district of Odisha, India.

This paper aims to assess the prenatal breastfeeding intention and its predictors in Odisha, a state in India. Data were collected from 218 rural pregnant women of Angul district of Odisha, India in 2012. About 33% of the women lacked the intention to exclusively breastfeed their babies for 6 months. Prelacteal feeding was intended by one-third of the women while 61.5% of the women intended to feed water during the first 6 months of birth. Women of an older age [odds ratio (OR) = 1.30; 95% confidence interval (CI) = 1.09-1.55], with more education (OR = 1.14; 95% CI = 1.08-1.32), belonging to lower castes [other backward caste (OBC)-OR = 21.33; 95% CI = 4.29-106.0, scheduled caste (SC)-OR = 22.77; 95% CI = 2.47-199.1, scheduled tribe (ST)-OR = 26.16; 95% CI = 4.10-174.8), and lesser number of living sons (OR = 0.59; 95% CI = 0.22-0.94) were more likely to have a higher intention for optimal breastfeeding than those of a lower age, with less education, belonging to a higher caste, and with more number of living sons. Awareness generation programs need to be strengthened to educate pregnant women with appropriate and recommended breastfeeding guidelines to establish optimal breastfeeding practices.

Improving inferior vena cava filter retrieval rates with the define, measure, analyze, improve, control methodology.

PURPOSE: To design a sustainable process to improve optional inferior vena cava (IVC) filter retrieval rates based on the Define, Measure, Analyze, Improve, Control (DMAIC) methodology of the Six Sigma process improvement paradigm. MATERIALS AND METHODS: DMAIC, an acronym for Define, Measure, Analyze, Improve, and Control, was employed to design and implement a quality improvement project to increase IVC filter retrieval rates at a tertiary academic hospital. Retrievable IVC filters were placed in 139 patients over a 2-year period. The baseline IVC filter retrieval rate (n = 51) was reviewed through a retrospective analysis, and two strategies were devised to improve the filter retrieval rate: (a) mailing of letters to clinicians and patients for patients who had filters placed within 8 months of implementation of the project (n = 43) and (b) a prospective automated scheduling of a clinic visit at 4 weeks after filter placement for all new patients (n = 45). The effectiveness of these strategies was assessed by measuring the filter retrieval rates and estimated increase in revenue to interventional radiology. RESULTS: IVC filter retrieval rates increased from a baseline of 8% to 40% with the mailing of letters and to 52% with the automated scheduling of a clinic visit 4 weeks after IVC filter placement. The estimated revenue per 100 IVC filters placed increased from $2,249 to $10,518 with the mailing of letters and to $17,022 with the automated scheduling of a clinic visit. CONCLUSIONS: Using the DMAIC methodology, a simple and sustainable quality improvement intervention was devised that markedly improved IVC filter retrieval rates in eligible patients.

Ureteroarterial fistula: diagnosis and management.

OBJECTIVE: Ureteroarterial fistula (UAF) is an uncommon condition with only approximately 150 cases reported in the literature. Patients typically present with hematuria in the setting of prolonged ureteral stenting, prior pelvic surgery, malignancy, or radiation. Presentation can vary from intermittent hematuria to life-threatening hemorrhagic shock. CONCLUSION: Recognizing this condition in a prototypical patient is essential for accurate diagnosis and management. Angiography yields the highest diagnostic benefit, and arterial stent-graft placement is the treatment of choice.

ACR Appropriateness Criteria® Screening for Abdominal Aortic Aneurysm.

Abdominal aortic aneurysm (AAA) is a significant vascular disease found in 4% to 8% of the screening population. If ruptured, its mortality rate is between 75% and 90%, and it accounts for up to 5% of sudden deaths in the United States. Therefore, screening of AAA while asymptomatic has been a crucial portion of preventive health care worldwide. Ultrasound of the abdominal aorta is the primary imaging modality for screening of AAA recommended for asymptomatic adults regardless of their family history or smoking history. Alternatively, duplex ultrasound and CT abdomen and pelvis without contrast may be appropriate for screening. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

ACR Appropriateness Criteria® Pulmonary Arteriovenous Malformation (PAVM): 2023 Update.

Pulmonary arteriovenous malformations (PAVMs) occur in 30% to 50% of patients with hereditary hemorrhagic telangiectasia. Clinical presentations vary from asymptomatic disease to complications resulting from the right to left shunting of blood through the PAVM such as paradoxical stroke, brain abscesses, hypoxemia, and cardiac failure. Radiology plays an important role both in the diagnosis and treatment of PAVM. Based on different clinical scenarios, the appropriate imaging study has been reviewed and is presented in this document. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

The phosphatidylserine targeting antibody bavituximab plus pembrolizumab in unresectable hepatocellular carcinoma: a phase 2 trial.

Immune checkpoint inhibitors targeting PD-1/L1 have modest efficacy in hepatocellular carcinoma as single agents. Targeting membranous phosphatidylserine may induce pro-inflammatory and -immune stimulating effects that enhance immunotherapy activity. This hypothesis was tested in a single-arm phase 2 trial evaluating frontline bavituximab, a phosphatidylserine targeting antibody, plus pembrolizumab (anti-PD-1) in patients with unresectable hepatocellular carcinoma (NCT03519997). The primary endpoint was investigator-assessed objective response rate among evaluable patients, and secondary end points included progression-free survival, incidence of adverse events, overall survival, and duration of response. Among 28 evaluable patients, the confirmed response rate was 32.1%, which met the pre-specified endpoint, and the median progression-free survival was 6.3 months (95% CI, 1.3-11.3 months). Treatment related-adverse events of any grade occurred in 45.7% of patients, with grade 3 or greater adverse events in 14.3% of patients. Adverse events of any cause were observed in 33 patients (94.3%), with grade 3 or greater adverse events in 11 patients (31.4%). Prespecified exploratory analyses of baseline tumor specimens showed that a depletion of B cells, and the presence of fibrotic tissue and expression of immune checkpoints in stroma was associated with tumor response. These results suggest that targeting phosphatidylserine may lead to synergistic effects with PD-1 blockade without increasing toxicity rates, and future studies on this therapeutic strategy may be guided by biomarkers characterizing the pre-treatment tumor microenvironment.

Diagnostic performance of the adrenal vein to inferior vena cava aldosterone ratio in classifying the subtype of primary aldosteronism.

Adrenal vein sampling (AVS) is the standard procedure for distinguishing unilateral primary aldosteronism (PA) from bilateral PA. In cases where only one adrenal vein is successfully cannulated, it has been suggested that subtype classification can be determined based on the ratio of the concentration of aldosterone between the adrenal vein and the inferior vena cava (AV/IVC index). However, diagnostic performance of the ipsilateral versus contralateral AV/IVC index in predicting lateralization has not been directly compared. In a retrospective cohort of 133 patients with confirmed PA who underwent successful AVS, the performance of the AV/IVC index to predict laterality was evaluated and the area under the receiver operating characteristic (AUROC) curves was calculated. In detecting left unilateral PA (n = 47), the AUROC of the right AV/IVC index (RAV/IVC) was significantly higher than the AUROC of the left AV/IVC (LAV/IVC) index (0.967 vs. 0.871, p = 0.008). In detecting right unilateral PA (n = 30), the AUROC of the LAV/IVC index tended to be higher than that of the RAV/IVC index, but the difference did not reach statistical significance (0.966 vs. 0.906, p = 0.08). In detecting left unilateral PA, the sensitivities of the RAV/IVC and LAV/IVC indices were 83% and 46%, respectively, while the specificities of both were above 90%. In detecting right unilateral PA, the sensitivities of the LAV/IVC and RAV/IVC indices were 80% and 43%, respectively, while the specificities of both were above 90%. The AV/IVC index has superior diagnostic performance in detecting contralateral unilateral PA compared to ipsilateral unilateral PA.

Occupational stress and social support in naval personnel.

BACKGROUND: Data show that naval personnel have a high incidence of stress related disorders. A high prevalence of occupational stress was seen in a previous survey carried out on Indian Naval personnel. However, the role of social support in reducing occupational stress was not studied. To study occupational stress in Indian Naval personnel and to study the effect of social support on occupational stress. METHODS: 5077 naval personnel were surveyed using study questionnaires which included Occupational Stress Inventory, Multidimensional Scale of Perceived Social Support, and the General Health Questionnaire (GHQ)-12 item version as a measure of psychological health. The data was statistically analysed using chi square test and other non-parametric tests. RESULTS: High occupational stress was seen in personnel serving afloat (66.47%) as compared to those serving ashore (51.55%) and on submarines (53.72%). Among personnel serving afloat, occupational stress was highest among Junior Sailors as compared to Senior Sailors and Officers. Occupational stress was linked to poor psychological health as measured by the GHQ and younger age. Perceived social support was effective in reducing occupational stress in Officers and Senior Sailors but not in Junior Sailors where paradoxically it seemed to lead to greater occupational stress. CONCLUSIONS: High occupational stress was seen in more than half the service personnel studied. Occupational stress is mitigated by social support in Officers and Senior Sailors but not in Junior Sailors.