Evaluation of the VioOne HIV profile supplemental assay.

HIV is an ongoing global epidemic with estimates of more than a million new infections occurring annually. To combat viral spread, continuous innovations in areas including testing and treatment are necessary. In the United States, the Centers for Disease Control and Prevention recommend that laboratories follow an HIV testing algorithm that first uses a US Food and Drug Administration approved immunoassay to detect antibodies to HIV-1 or HIV-2 as well as HIV-1 p24 antigen in serum or plasma samples. An initially reactive specimen is tested by a supplemental assay for confirmation and to differentiate antibodies to HIV-1 or HIV-2. There are few Food and Drug Administration (FDA)-approved supplemental differentiation tests currently available. A multicenter investigation was conducted to determine the clinical performance for two independent versions of the Avioq VioOne HIV Profile Supplemental Assay (Avioq, Inc., Research Triangle Park, NC). The performance of both assay versions compared favorably with the performance parameters for the Geenius HIV 1/2 Supplemental Assay as published in that assay package insert (Bio-Rad Laboratories, Hercules, CA), the current gold standard for HIV supplemental testing. When comparing the two VioOne assays, version 2 (lacking HIV-2 p27 antibody detection) demonstrated improved reproducibility, specificity, and sensitivity as compared to its predecessor. IMPORTANCE We evaluated the reproducibility, sensitivity, and specificity data for two versions of the VioOne HIV Profile Supplemental Assay and compared these results back to similar results for the Geenius HIV 1/2 Supplemental Assay that are publicly available. Our study concluded that the VioOne HIV Profile Supplemental Assay compared favorably with the Geenius HIV 1/2 Supplemental Assay, thus providing an additional option for clinical laboratories to improve and expand their HIV testing capabilities.

Synthesis and antiproliferative activity of a tetrahydrofuran analog of FR901464.

FR901464 is a natural product that exhibits antiproliferative activity at single-digit nanomolar concentrations in cancer cells. Its tetrahydropyran-spiroepoxide covalently binds the spliceosome. Through our medicinal chemistry campaign, we serendipitously discovered that a bromoetherification formed a tetrahydrofuran. The tetrahydrofuran analog was three orders of magnitude less potent than the corresponding tetrahydropyran analogs. This study shows the significance of the tetrahydropyran ring that presents the epoxide toward the spliceosome.

Patient Access of Their Radiology Reports Before and After Implementation of 21st Century Cures Act Information-Blocking Provisions at a Large Multicampus Health System.

BACKGROUND. To implement provisions of the 21st Century Cures Act that address information blocking, federal regulations mandated that health systems provide patients with immediate access to elements of their electronic health information, including imaging results. OBJECTIVE. The purpose of this study was to compare patient access of radiology reports before and after implementation of the information-blocking provisions of the 21st Century Cures Act. METHODS. This retrospective study included patients who underwent outpatient imaging examinations from January 1, 2021, through December 31, 2022, at three campuses within a large health system. The system implemented policies to comply with the Cures Act information-blocking provisions on January 1, 2022. Imaging results were released in patient portals after a 36-hour embargo period before implementation versus being released immediately after report finalization after implementation. Data regarding patient report access in the portal and report acknowledgment by the ordering provider in the EMR were extracted and compared between periods. RESULTS. The study included reports for 1,188,692 examinations in 388,921 patients (mean age, 58.5 ± 16.6 [SD] years; 209,589 women, 179,290 men, eight nonbinary individuals, and 34 individuals for whom sex information was missing). A total of 77.5% of reports were accessed by the patient before implementation versus 80.4% after implementation. The median time from report finalization to report release in the patient portal was 36.0 hours before implementation versus 0.4 hours after implementation. The median time from report release to first patient access of the report in the portal was 8.7 hours before implementation versus 3.0 hours after implementation. The median time from report finalization to first patient access was 45.0 hours before implementation versus 5.5 hours after implementation. Before implementation, a total of 18.5% of reports were first accessed by the patient before being accessed by the ordering provider versus 44.0% after implementation. After implementation, the median time from report release to first patient access was 1.8 hours for patients with age younger than 60 years old versus 4.3 hours for patients 60 years old or older. CONCLUSION. After implementation of institutional policies to comply with 21st Century Cures Act information-blocking provisions, the length of time until patients accessed imaging results decreased, and the proportion of patients who accessed their reports before the ordering provider increased. CLINICAL IMPACT. Radiologists should consider mechanisms to ensure timely and appropriate communication of important findings to ordering providers.

Update on Percutaneous Ablation for Sarcoma.

PURPOSE OF REVIEW: To provide an update on the current state of percutaneous thermal ablation in the treatment of sarcoma. RECENT FINDINGS: Data continue to accrue in support of ablation for local control and palliation of specific sarcoma subtypes such as extra-abdominal desmoid fibromatosis and for broader indications such as the treatment of oligometastatic disease. The synergistic possibilities of various combination therapies such as cryoablation and immunotherapy represent intriguing areas of active investigation. Histotripsy is an emerging non-invasive, non-thermal ablative modality that may further expand the therapeutic arsenal for sarcoma treatment. Percutaneous thermal ablation is a valuable tool in the multidisciplinary management of sarcoma, offering a minimally invasive adjunct to surgery and radiation therapy. Although there remains a paucity of high-level evidence specific to sarcomas, ablation techniques are demonstrably safe and effective for achieving local tumor control and providing pain relief in select patients and are of particular benefit in those with metastatic disease or requiring palliative care.

Scutellaria baicalensis enhances 5-fluorouracil-based chemotherapy via inhibition of proliferative signaling pathways.

Fluoropyridine-based chemotherapy remains the most widely used treatment for colorectal cancer (CRC). In this study, we investigated the mechanism by which the natural product Scutellaria baicalensis (Huang Qin; HQ) and one of its main components baicalin enhanced 5-fluorouracil (5-FU) antitumor activity against CRC. Cell proliferation assays, cell cycle analysis, reverse-phase protein array (RPPA) analysis, immunoblot analysis, and qRT-PCR were performed to investigate the mechanism(s) of action of HQ and its active components on growth of CRC cells. HQ exhibited in vitro antiproliferative activity against drug resistant human CRC cells, against human and mouse CRC cells with different genetic backgrounds and normal human colon epithelial cells. In vivo animal models were used to document the antitumor activity of HQ and baicalin. The mechanism of growth inhibitory activity of HQ is due to inhibition of proliferative signaling pathways including the CDK-RB pathway. In addition, HQ enhanced the antitumor effects of 5-FU and capecitabine in vivo. Furthermore, we identified baicalin as an active component of HQ. The combination of baicalin and 5-FU demonstrated synergistic activity against 5-FU-resistant RKO-R10 cells. The combination significantly inhibited in vivo tumor growth greater than each treatment alone. RPPA results showed that the signaling pathway alterations in CRC cells were similar following HQ and baicalin treatment. Together, these results indicate that HQ and its component baicalin enhance the effect of 5-fluorouracil-based chemotherapy via inhibition of CDK-RB pathway. These findings may provide the rational basis for developing agents that can overcome the development of cellular drug resistance. Video Abstract.

Percutaneous Cryoablation of Plasmacytomas: Oncologic Effectiveness and Adverse Events.

PURPOSE: To evaluate the oncologic outcomes and adverse events associated with cryoablation of plasmacytomas. MATERIALS AND METHODS: Retrospective review of an institutional percutaneous ablation database showed that 43 patients underwent 46 percutaneous cryoablation procedures for treatment of 44 plasmacytomas between May 2004 and March 2021. The treatment of 25 (25 of 44, 56.8%) tumors was augmented with bone consolidation/cementoplasty. The median patient age was 64 years (interquartile range [IQR], 54-69), and 30 of 43 (69.8%) patients were men. The median maximum plasmacytoma diameter was 5.0 cm (IQR, 3.1-7.0). Thirty of 44 (68.2%) tumors were periacetabular, vertebral, or located in the iliac wing. Twenty-nine of 44 (65.9%) cryoablated plasmacytomas were recurrent tumors after prior external beam radiation therapy (EBRT). Survival analyses were performed using the Kaplan-Meier method. Adverse events were graded using Society of Interventional Radiology criteria. RESULTS: The 5-year estimated local tumor recurrence-free survival was 85.3% (95% CI, 74.1%-98.1%), the 5-year estimated new plasmacytoma-free survival was 49.9% (95% CI, 33.9%-73.4%), and the 5-year estimated overall survival was 70.4% (95% CI, 56.9%-87.1%). Nine of 46 (19.6%) major adverse events occurred in 8 patients, including 3 of 46 (6.5%) new or progressive pathologic fractures at the ablation site requiring surgical intervention, 3 of 46 (6.5%) nerve injuries, 1 of 46 (2.2%) avascular necrosis and femoral head collapse, 1 of 46 (2.2%) septic arthritis, and 1 of 46 (2.2%) acute renal failure caused by rhabdomyolysis. CONCLUSIONS: Percutaneous cryoablation is a viable treatment option for patients with plasmacytomas, including those with recurrent plasmacytomas after EBRT. Postcryoablation adverse events are relatively common.

Radiofrequency Ablation of Benign and Malignant Thyroid Nodules.

Thyroid nodule treatment has significantly evolved over recent years with attempts to individualize treatment on the basis of the cause of the nodule and patient performance status. The risks and complications associated with surgery and radioactive iodine have promoted interest in additional therapies such as radiofrequency ablation (RFA). RFA creates an electrical current through a target tissue (thyroid nodule) with resultant tissue heating causing coagulative necrosis. National and international groups are beginning to recognize the role of RFA as a viable therapeutic option in the treatment of thyroid nodules. Based on numerous guidelines, RFA is indicated in the treatment of symptomatic benign nodules and autonomously functioning nodules when surgery is refused or when the patient would not tolerate surgery. The treatment of thyroid malignancy with RFA is controversial, with some groups advocating for its use in the treatment of small papillary thyroid cancers in specific scenarios. The most important aspect of RFA is the preprocedural workup and adequate patient selection. Procedural technique varies among centers. However, RFA is typically performed as a single-day-admission outpatient procedure. Methods such as hydrodissection and a moving shot technique are employed to ensure adequate coverage of the nodule without overtreating the peripheries and damaging sensitive structures. As a result, the procedure is well tolerated, and major complications such as recurrent laryngeal nerve injury and nodule rupture are very rare. In the proper patient cohort, thyroid RFA offers an efficacious and safe option in the management of thyroid nodules. An invited commentary by Filippiadis and Vrachliotis is available online. ©RSNA, 2022.

American Association of Clinical Endocrinology Disease State Clinical Review: The Clinical Utility of Minimally Invasive Interventional Procedures in the Management of Benign and Malignant Thyroid Lesions.

OBJECTIVE: The objective of this disease state clinical review is to provide clinicians with a summary of the nonsurgical, minimally invasive approaches to managing thyroid nodules/malignancy, including their indications, efficacy, side effects, and outcomes. METHODS: A literature search was conducted using PubMed and appropriate key words. Relevant publications on minimally invasive thyroid techniques were used to create this clinical review. RESULTS: Minimally invasive thyroid techniques are effective and safe when performed by experienced centers. To date, percutaneous ethanol injection therapy is recommended for recurrent benign thyroid cysts. Both ultrasound-guided laser and radiofrequency ablation can be safely used for symptomatic solid nodules, both toxic and nontoxic. Microwave ablation and high-intensity focused ultrasound are newer approaches that need further clinical evaluation. Despite limited data, encouraging results suggest that minimally invasive techniques can also be used in small-size primary and locally recurrent thyroid cancer. CONCLUSION: Surgery and radioiodine treatment remain the conventional and established treatments for nodular goiters. However, the new image-guided minimally invasive approaches appear safe and effective alternatives when used appropriately and by trained professionals to treat symptomatic or enlarging thyroid masses.

Prevention of Allergic-like Reactions at Repeat CT: Steroid Pretreatment versus Contrast Material Substitution.

Background It is unclear whether steroid premedication is an effective means of preventing repeat allergic-like reactions in high-risk patients with a previous allergic-like reaction to iodinated contrast material (ICM). Purpose To compare the effectiveness of ICM substitution (ie, using iohexol in a patient with a previous iopromide reaction) with 12- and 2-hour steroid premedication for preventing repeat acute allergic-like reactions in high-risk patients. Materials and Methods This retrospective study identified all high-risk (ie, having a previous allergic-like reaction) adult and pediatric patients who underwent a contrast-enhanced CT examination at the institution from June 1, 2009, to May 9, 2017. Prophylactic treatments and repeat reactions were identified using chart review. The effectiveness of prophylactic treatments on repeat reaction rates was examined with multivariable regression models that used generalized estimating equations. Results A total of 1973 high-risk patients who underwent 4360 subsequent ICM-enhanced CT examinations were included. Of the 4360 examinations, a total of 280 allergic-like reactions occurred (6%) in 224 of the 1973 patients (11% of patients), with only 19 of 280 reactions (7%) that were more severe than the previous reaction being demonstrated. After adjustment, patients who received a different ICM with and without steroid premedication had a significantly lower rate of repeat reactions than did patients who received steroid premedication and the same ICM (same ICM and steroid premedication: 80 of 423 examinations [19%]; different ICM and no steroid premedication: 10 of 322 examinations [3%]; odds ratio [OR], 0.14 [95% CI: 0.06, 0.33]; P < .001; different ICM and steroid premedication: five of 166 patients [3%]; OR, 0.12 [95% CI: 0.04, 0.36]; P < .001). When examining the first scan only, patients who received the same ICM had a similar risk of repeat reactions regardless of whether they received steroid premedication (steroid premedication: 44 of 172 patients [26%] vs no premedication: 73 of 298 patients [25%]; OR, 1.00 [95% CI: 0.64, 1.57]; P = .99). Conclusion In this cohort, using an iodinated contrast material (ICM) substitution was more effective for preventing repeat allergic-like reactions than using steroid premedication and the same ICM that caused the previous reaction. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Davenport and Weinstein in this issue.

Indeterminate QuantiFERON Gold Plus Results Reveal Deficient Interferon Gamma Responses in Severely Ill COVID-19 Patients.

SARS-CoV-2 is a novel positive-sense single-stranded RNA virus that has caused a recent pandemic. Most patients have a mild disease course, while approximately 20% have moderate to severe disease, often requiring hospitalization and, in some cases, care in the intensive care unit. By investigating a perceived increased rate of indeterminate QuantiFERON-TB Gold Plus results in hospitalized COVID patients, we demonstrate that severely ill COVID-19 patients have at least a 6-fold reduction of interferon gamma (IFN-γ) levels compared to control patients. What is more, over 60% of these severely ill COVID-19 patients' peripheral T cells were found to be unable to produce measurable IFN-γ when stimulated with phytohemagglutinin (PHA), a potent IFN-γ mitogen, reflected by an indeterminate QuantiFERON-TB Gold Plus result. This defect of IFN-γ production was independent of absolute lymphocyte counts and immunosuppressive therapy. It was associated with increased levels of interleukin-6 (IL-6), which was a predictor of patient outcomes for our cohort when measured early in the course of disease. Finally, in a subset of COVID-19 patients, we found elevated IL-10 levels in addition to IL-6 elevation. In addition to finding a significant limitation of interferon-gamma release assay (IGRA) testing in severely ill COVID-19 patients, these data provide evidence that many of these patients demonstrate a focused Th2 immune response with inhibition of IFN-γ signaling and, in many cases, significant elevations of IL-6.

Image-guided tumor ablation in gynecologic oncology: Review of interventional oncology techniques and case examples highlighting a collaborative, multidisciplinary program.

As interventional oncology services within radiology mature, image-guided ablation techniques are increasingly applied to recurrent gynecologic malignancies. Ablation may be performed using thermal techniques like cryoablation, microwave ablation, or radiofrequency ablation, as well as non-thermal ones, such as focused ultrasound or irreversible electroporation. Feasibility and approach depend on tumor type, size, number, anatomic location, proximity of critical structures, and goals of therapy. Current indications include local control of limited metastatic disease or palliation of painful bone metastases refractory or unsuitable to conventional therapies. Technical aspects of these procedures, including methods to protect nearby critical structures are presented through illustrative examples. Cases amenable to image-guided ablation include, but are not limited to, hepatic or pulmonary metastases, musculoskeletal metastases, retroperitoneal nodal metastases, pelvic side wall disease, abdominal wall disease, and vaginal or vulvar tumors. Protective maneuvers, such as hydro-displacement of bowel, neuromonitoring, and retrograde pyeloperfusion through ureteral stents, permit safe ablation despite close proximity to vulnerable nerves or organs. Image-guided ablation offers an alternative modality to achieve local tumor control without the risks associated with surgery or systemic treatment in appropriately selected patients. A multidisciplinary approach to use of image-guided ablation includes collaboration between gynecologic oncology, interventional radiology, anesthesia, urology and radiation oncology teams allowing for appropriate patient-centered case selection. Long-term follow up and additional studies are needed to determine the oncologic benefits of such techniques.

Preservation of Renal Function after Major Bleeding Events due to Ultrasound-Guided Parenchymal Renal Biopsy.

The clinical outcomes of major bleeding events following ultrasound-guided native and allograft parenchymal renal biopsy were evaluated. Forty-eight bleeding complications after biopsy (Society of Interventional Radiology adverse event grade ≥ 2) from 2002 to 2018 were identified. The primary outcome assessed was renal function. The clinical outcomes and interventions performed, including blood transfusion, angiography with or without embolization, nephrostomy tube placement, surgery, nephrectomy, hospitalization, intensive care unit admission, dialysis, and survival, were noted. Renal function may be moderately diminished in the short-term periprocedural setting. None of the patients studied died or required nephrectomy or the initiation of dialysis as a result of a major bleeding complication after the renal biopsy.

Percutaneous Image-Guided Core Needle Biopsy of Neuroendocrine Tumors: How Common Is Intraprocedural Carcinoid Crisis?

PURPOSE: To retrospectively evaluate the incidence of carcinoid crisis, other complications, and physiologic disturbances during percutaneous image-guided core needle biopsy of neuroendocrine tumors (NETs) in the lung and the liver. MATERIALS AND METHODS: Between January 2010 and January 2020, 106 computed tomography (CT) or ultrasound (US)-guided core needle biopsies of lung and liver NETs were performed in 95 consecutive adult patients. The mean age was 64 ± 13 years, and 48% were female. The small bowel was the most common primary site (33%, 31/95), and 32 (34%) patients had pre-existing symptoms of carcinoid syndrome. The mean tumor size was 3.2 ± 2.6 cm, and mean number of passes was 3.4 ± 1.6. A 17/18-gauge needle was used in 91% (96/106) of the biopsies. Thirteen (12%) patients received either outpatient or prophylactic octreotide. RESULTS: No patients experienced carcinoid crisis or needed octreotide, inotropes, vasopressors, or resuscitation. A single biopsy procedure (0.9%, 1/106) was complicated by bleeding that required angiographic hepatic artery embolization. Changes in pre-biopsy- versus post-biopsy systolic blood pressure and heart rate were -1.6 mm Hg (P = .390) and 0.6 beat/min (P = .431), respectively. Tumor functional status, overall tumor burden, and the elevation of neuroendocrine markers were not associated with intraprocedural physiologic disturbances. There were 4 minor complications (0.4%, 4/106) associated with the biopsy procedure that were not attributed to hormone excretion from tumor manipulation. CONCLUSIONS: Percutaneous image-guided core biopsy of NETs is safe, with low complication rate and no definite carcinoid crisis in the current cohort.

A Single-Institution Experience in Percutaneous Image-Guided Cryoablation of Lymph Node Metastases.

OBJECTIVE. The purpose of this study was to assess the feasibility, safety, and efficacy of percutaneous cryoablation for the treatment of lymph node metastases. MATERIALS AND METHODS. In this single-institution retrospective study 55 patients were identified who underwent CT-guided cryoablation of metastatic lymph nodes between November 2006 and September 2019. Patient demographics, disease characteristics, and procedural details were recorded. The primary endpoints were technical success and major complications. The secondary endpoints were time to local and time to distant progression. Complications were graded according to the Society of Interventional Radiology consensus guidelines. RESULTS. The study sample comprised 55 patients (42 men, 13 women; mean age 64 ± 12 years) who underwent 61 cryoablation procedures to treat 65 lymph node metastases. Targeted nodes measured 1.7 ± 1.2 cm in mean short-axis diameter. Technical success was achieved in 60 of 61 cryoablation procedures (98%). Adjunctive maneuvers performed to protect adjacent structures included hydrodissection (n = 40), ureteral stenting (n = 3), and neural monitoring (n = 3). There were two Society of Interventional Radiology major complications (3%): pneumothorax (n = 1) and bleeding (n = 1). Local tumor control was achieved in treatment of 53 of 65 (82%) nodal metastases within a median of 25 months (range, 1-121 months) of follow-up. Local progression occurred in 12 of 65 cases (18%); the median time to recurrence was 11 months. CONCLUSION. Percutaneous cryoablation of nodal metastases is feasible and safe. Further investigation is warranted to assess the long-term efficacy of this technique and to define its role in oncologic care.

Acute Reactions to Gadolinium-Based Contrast Agents in a Pediatric Cohort: A Retrospective Study of 16,237 Injections.

BACKGROUND. Incidences and risk factors for acute reactions to gadolinium-based contrast agents (GBCAs) are not fully understood, particularly in pediatric patients. OBJECTIVE. The purpose of this study was to retrospectively examine allergiclike and physiologic acute reactions in pediatric patients who receive GBCAs for MRI examinations. METHODS. The study cohort consisted of all pediatric patients (age < 18 years old) who underwent an MRI examination with a GBCA at our institution from June 1, 2009, to May 9, 2017. Acute reactions were identified by medical record review and classified by severity using the American College of Radiology guidelines. Potential risk factors for reactions were examined using generalized estimating equation methods accounting for rare events. RESULTS. A total of 16,237 GBCA injections (10,141 gadodiamide injections, 4880 gadobutrol injections, and 1216 gadobenate dimeglumine injections) were administered to a study cohort of 10,190 patients (49% [7982/16,237] girls and 51% [8255/16,237] boys). Incidences of 0.10% (17/16,237) for allergiclike and 0.14% (23/16,237) for physiologic reactions were observed. No severe reactions occurred. Allergiclike reaction incidences were significantly higher with gadobenate compared with gadodiamide (0.49% vs 0.04%; p < .001) and in patients who underwent abdominal or pelvic MRI examinations (0.38%) or cardiac examinations (0.55%) compared with head examinations (0.05%; p < .001 and p = .006, respectively). Physiologic reaction incidences were significantly higher in older patients (0.25% in patients 12-17 years old vs 0.03% in patients 2 to < 12 years old; p < .001) and in patients who underwent abdominal or pelvic examinations compared with head examinations (0.38% vs 0.10%; p = .002). Of 16 MRI examinations performed in patients with a prior allergiclike reaction to GBCAs, only one resulted in a repeat reaction. CONCLUSION. In this pediatric cohort, GBCA type, patient age, and MRI type were risk factors for acute reactions. Repeat reactions were rare. CLINICAL IMPACT. Providers must weigh the risks and benefits when choosing a particular GBCA to use in their practices and must consider multiple, potentially disparate risks associated with each GBCA.

Expanding Access to Biospecimens for Lyme Disease Test Development.

The laboratory diagnosis of Lyme disease relies upon serologic testing. A standard or modified two-tiered testing algorithm is used to enhance the accuracy of antibody detection. However, this approach suffers from a lack of sensitivity in early Lyme disease. Ongoing efforts to develop more sensitive antibody detection technologies and other diagnostic approaches are dependent upon the availability of quality-assured biospecimens linked to reliable clinical data. In this issue of the Journal of Clinical Microbiology, Horn et al. (E. J. Horn, G. Dempsey, A. M. Schotthoefer, U. L. Prisco, et al., J Clin Microbiol 58:e00032-20, 2020, https://doi.org/10.1128/JCM.00032-20) described the development of the Lyme Disease Biobank. Clinically categorized case patients with early Lyme disease and healthy controls were identified (without laboratory diagnostic testing) from three sites where Lyme disease is endemic. Subjects provided whole blood and urine, which were processed and stored at a central biorepository. Whole blood, serum, and urine aliquots were prepared and are available to investigators developing laboratory diagnostics for Lyme disease. After obtaining samples, extensive laboratory testing was performed, including serologic and nucleic acid amplification testing for B. burgdorferi and other tick-borne pathogens. Direct detection methods yielded few positive results. Relative to the findings for another commonly used biorepository cohort, the results of this testing demonstrated a low seropositive rate, as determined by standard two-tiered testing. Additionally, relatively few subjects demonstrated seroconversion with testing of convalescent-phase samples. This clinical and serologically defined cohort of samples from Lyme disease and control cases from areas of Lyme disease endemicity offers an additional valuable resource for novel test development that includes alternate specimen types.

Safety and Efficacy of Retrograde Pyeloperfusion for Ureteral Protection during Renal Tumor Cryoablation.

PURPOSE: To determine safety and efficacy of retrograde pyeloperfusion for ureteral protection during cryoablation of adjacent renal tumors. MATERIALS AND METHODS: Retrospective review of 155 patients treated with renal cryoablation, including adjunctive retrograde pyeloperfusion, from 2005 to 2019 was performed. Ice contacted the ureter in 67 of the 155 patients who represented the study cohort. Median patient age was 68 years old (interquartile range [61, 74]), 52 patients (78%) were male, and 37 tumors (55%) were clear cell histology. Mean tumor size was 3.4 ± 1.3 cm, and 42 tumors (63%) were located at the lower pole. Treatment-related complication and oncologic outcomes were recorded based on a review of post-procedural images and chart review. RESULTS: Technical success of cryoablation was attained in 67 cases (100%), and technical success of pyeloperfusion was attained in 66 cases (99%). A total of 13 patients (19.4%) experienced SIR major C or D complications related to the procedure, including hemorrhage (n = 4), urine leak (n = 3), transient urinary obstruction (n = 2), pulmonary embolism (n = 1), hypertensive urgency (n = 1), acute respiratory failure (n = 1), and ureteropelvic junction (UPJ) stricture (n = 1). No complications were attributable to pyeloperfusion. Three of 45 patients with biopsy-proven renal cell carcinoma experienced local recurrence resulting in local recurrence-free survival of 92% (95% confidence interval, 81.5%-100%) 3 years after ablation. CONCLUSIONS: Retrograde pyeloperfusion of the renal collecting system is a relatively safe and efficacious option for ureteral protection during renal tumor cryoablation. This adjunctive procedure should be considered for patients in whom cryoablation of a renal mass could potentially involve the ureter.

Discovery of [1,2,4]triazolo[4,3-a]pyridines as potent Smoothened inhibitors targeting the Hedgehog pathway with improved antitumor activity in vivo.

Triple-negative breast cancer (TNBC), a subset of breast cancers, have poorer survival than other breast cancer types. Recent studies have demonstrated that the abnormal Hedgehog (Hh) pathway is activated in TNBC and that these treatment-resistant cancers are sensitive to inhibition of the Hh pathway. Smoothened (Smo) protein is a vital constituent in Hh signaling and an attractive drug target. Vismodegib (VIS) is one of the most widely studied Smo inhibitors. But the clinical application of Smo inhibitors is limited to adult patients with BCC and AML, with many side effects. Therefore, it's necessary to develop novel Smo inhibitor with better profiles. Twenty [1,2,4]triazolo[4,3-a]pyridines were designed, synthesized and screened as Smo inhibitors. Four of these novel compounds showed directly bound to Smo protein with stronger binding affinity than VIS. The new compounds showed broad anti-proliferative activity against cancer cell lines in vitro, especially triple-negative breast cancer cells. Mechanistic studies demonstrated that TPB15 markedly induced cell cycle arrest and apoptosis in MDA-MB-468 cells. TPB15 blocked Smo translocation into the cilia and reduced Smo protein and mRNA expression. Furthermore, the expression of the downstream regulatory factor glioma-associated oncogene 1 (Gli1) was significantly inhibited. Finally, TPB15 demonstrated greater anti-tumor activity in our animal models than VIS with lower toxicity. Hence, these results support further optimization of this novel scaffold to develop improved Smo antagonists.

Influence of Germline Genetics on Tacrolimus Pharmacokinetics and Pharmacodynamics in Allogeneic Hematopoietic Stem Cell Transplant Patients.

Tacrolimus exhibits high inter-patient pharmacokinetics (PK) variability, as well as a narrow therapeutic index, and therefore requires therapeutic drug monitoring. Germline mutations in cytochrome P450 isoforms 4 and 5 genes (CYP3A4/5) and the ATP-binding cassette B1 gene (ABCB1) may contribute to interindividual tacrolimus PK variability, which may impact clinical outcomes among allogeneic hematopoietic stem cell transplantation (HSCT) patients. In this study, 252 adult patients who received tacrolimus for acute graft versus host disease (aGVHD) prophylaxis after allogeneic HSCT were genotyped to evaluate if germline genetic variants associated with tacrolimus PK and pharmacodynamic (PD) variability. Significant associations were detected between germline variants in CYP3A4/5 and ABCB1 and PK endpoints (e.g., median steady-state tacrolimus concentrations and time to goal tacrolimus concentration). However, significant associations were not observed between CYP3A4/5 or ABCB1 germline variants and PD endpoints (e.g., aGVHD and treatment-emergent nephrotoxicity). Decreased age and CYP3A5*1/*1 genotype were independently associated with subtherapeutic tacrolimus trough concentrations while CYP3A5*1*3 or CYP3A5*3/*3 genotypes, myeloablative allogeneic HSCT conditioning regimen (MAC) and increased weight were independently associated with supratherapeutic tacrolimus trough concentrations. Future lines of prospective research inquiry are warranted to use both germline genetic and clinical data to develop precision dosing tools that will optimize both tacrolimus dosing and clinical outcomes among adult HSCT patients.

Acute Adverse Events Following Gadolinium-based Contrast Agent Administration: A Single-Center Retrospective Study of 281 945 Injections.

Background Acute allergic-like and physiologic reactions occur following administration of gadolinium-based contrast agents (GBCAs) for MRI examinations. Because these reactions are uncommon, it is challenging to compare reaction rates between GBCAs and to determine risk factors. Purpose To compare reaction rates between the four GBCAs gadodiamide, gadobutrol, gadobenate dimeglumine, and gadoterate meglumine, and to determine potential risk factors for reactions. Materials and Methods This retrospective study identified all intravenous GBCA injections for MRI examinations performed at a single institution from June 1, 2009, to May 9, 2017. Reactions were identified by reviewing records from the MRI technologist, MRI nursing staff, radiologist, emergency department, and provider. Reactions were classified as allergic-like or physiologic and as mild, moderate, or severe by using American College of Radiology criteria. GBCA reaction rates and other potential risk factors were examined by using multivariable regression models with generalized estimating equations. Results Analysis included a total of 158 100 patients (median age, 55 years [interquartile range, 40-67 years], 51% women) who received a total of 281 945 GBCA injections (140 645 gadodiamide, 94 109 gadobutrol, 39 138 gadobenate, and 8053 gadoterate). At multivariate analysis, gadobenate or gadobutrol had higher rates of allergic-like reactions compared with gadodiamide (gadobenate: odds ratio [OR], 3.9 [95% confidence interval {CI}: 3.0, 5.1]; P < .001; gadobutrol: OR, 2.3 [95% CI: 1.8, 2.9]; P < .001) or gadoterate (gadobenate: OR, 4.8 [95% CI: 1.0, 23]; P = .049; gadobutrol: OR, 2.8 [95% CI: 0.6, 14]; P = .20). Physiologic reactions were more frequently observed with gadoterate (OR, 7.7 [95% CI: 2.3, 25; P = .001), gadobenate (OR, 1.8 [95% CI: 1.3, 2.5; P < .001), and gadobutrol (OR, 1.6 [95% CI: 1.3, 2.1; P < .001) administration compared with gadodiamide. Six severe allergic-like reactions (three gadobutrol, three gadobenate) occurred requiring hospitalization. Patient age (P values .025 to < .001), sex (P < .001), location (P = .006), and MRI type (P = .003 and P = .006) were associated with acute reactions. Conclusion Gadobenate and gadobutrol are associated with higher rates of allergic-like reactions compared with gadodiamide or gadoterate, and gadoterate, gadobenate, and gadobutrol are associated with higher rates of physiologic reactions compared with gadodiamide. Patient sex, age, location, and MRI type correlate with acute reaction rates. © RSNA, 2019 Online supplemental material is available for this article.