Preclinical assessment of a mathematical model for ablation zone prediction in thyroid laser ablation.

To develop and validate a 3D simulation model to calculate laser ablation (LA) zone size and estimate the volume of treated tissue for thyroid applications, a model was developed, taking into account dynamic optical and thermal properties of tissue change. For validation, ten Yorkshire swines were equally divided into two cohorts and underwent thyroid LA at 3 W/1,400 J and 3 W/1,800 J respectively with a 1064-nm multi-source laser (Echolaser X4 with Orblaze™ technology; ElEn SpA, Calenzano, Italy). The dataset was analyzed employing key statistical measures such as mean and standard deviation (SD). Model simulation data were compared with animal gross histology. Experimental data for longitudinal length, width (transverse length), ablation volume and sphericity were 11.0 mm, 10.0 mm, 0.6 mL and 0.91, respectively at 1,400 J and 14.6 mm, 12.4 mm, 1.12 mL and 0.83, respectively at 1,800 J. Gross histology data showed excellent reproducibility of the ablation zone among same laser settings; for both 1,400 J and 1,800 J, the SD of the in vivo parameters was ≤ 0.7 mm, except for width at 1,800 J, for which the SD was 1.1 mm. Simulated data for longitudinal length, width, ablation volume and sphericity were 11.6 mm, 10.0 mm, 0.62 mL and 0.88, respectively at 1,400 J and 14.2 mm, 12.0 mm, 1.06 mL and 0.84, respectively at 1,800 J. Experimental data for ablation volume, sphericity coefficient, and longitudinal and transverse lengths of thermal damaged area showed good agreement with the simulation data. Simulation datasets were successfully incorporated into proprietary planning software (Echolaser Smart Interface, Elesta SpA, Calenzano, Italy) to provide guidance for LA of papillary thyroid microcarcinomas. Our mathematical model showed good predictability of coagulative necrosis when compared with data from in vivo animal experiments.

Breast imaging with an ultra-low field MRI scanner: a pilot study.

Breast cancer screening is necessary to reduce mortality due to undetected breast cancer. Current methods have limitations, and as a result many women forego regular screening. Magnetic resonance imaging (MRI) can overcome most of these limitations, but access to conventional MRI is not widely available for routine annual screening. Here, we used an MRI scanner operating at ultra-low field (ULF) to image the left breasts of 11 women (mean age, 35 years ±13 years) in the prone position. Three breast radiologists reviewed the imaging and were able to discern the breast outline and distinguish fibroglandular tissue (FGT) from intramammary adipose tissue. Additionally, the expert readers agreed on their assessment of the breast tissue pattern including fatty, scattered FGT, heterogeneous FGT, and extreme FGT. This preliminary work demonstrates that ULF breast MRI is feasible and may be a potential option for comfortable, widely deployable, and low-cost breast cancer diagnosis and screening.

Antiviral activity of copper contact surfaces against MS2 coliphage and hepatitis a virus.

AIMS: Viral diseases can be indirectly transmitted by contaminated non-food contact surfaces to final food products by cross-contamination. The interaction of metal surfaces and viruses, MS2 coliphage and hepatitis A virus (HAV), was investigated for strategy development in decreasing this transmission risk. METHODS AND RESULTS: MS2 deposited onto stainless-steel surface was stable but inactivated at 0.95 log10 PFU min-1 on 99.9% copper surfaces. Greater copper-inactivation of MS2 was observed in (a) simple media (phosphate buffered saline, PBS) than protein-rich media (beef extract buffer), and (b) acidic than pH ≥ 6.8 environments. Among food matrices (strawberry juices and beef broth), the greatest MS2 inactivation by copper occurred in filtered strawberry juice at pH 3.5. At a reduction of 0.17 log10 PFU min-1, HAV survived longer than MS2 on copper by FRhK-4 cell infectivity assay. CONCLUSIONS: The inactivation of virus on copper surfaces was greater in acidic viral surrounding environments and in simple PBS medium. In the same 99% PBS medium, MS2 may not be an appropriate surrogate for HAV when assessing viral inactivation on copper surfaces.

Functional Imaging of Hypoxia: PET and MRI.

Molecular and functional imaging have critical roles in cancer care. Existing evidence suggests that noninvasive detection of hypoxia within a particular type of cancer can provide new information regarding the relationship between hypoxia, cancer aggressiveness and altered therapeutic responses. Following the identification of hypoxia inducible factor (HIF), significant progress in understanding the regulation of hypoxia-induced genes has been made. These advances have provided the ability to therapeutically target HIF and tumor-associated hypoxia. Therefore, by utilizing the molecular basis of hypoxia, hypoxia-based theranostic strategies are in the process of being developed which will further personalize care for cancer patients. The aim of this review is to provide an overview of the significance of tumor hypoxia and its relevance in cancer management as well as to lay out the role of imaging in detecting hypoxia within the context of cancer.

A comparison of lymphatic embolization and sclerotherapy in the management of iatrogenic abdominopelvic lymphoceles following oncological surgery.

PURPOSE: To compare the safety and efficacy of sclerotherapy and lymphatic embolization (LE) in the treatment of symptomatic iatrogenic lymphoceles following the placement of a percutaneous drainage catheter. METHODS: This is a retrospective study of 46 patients who underwent sclerotherapy (17 patients) or LE (29 patients) for the management of symptomatic iatrogenic lymphoceles following percutaneous drain placement between January 2017 and December 2021. The demographic characteristics, time between surgery and lymphatic intervention, clinical presentation, number of procedures, drain output pre- and post-intervention, time from intervention to drain removal, and adverse events were collected and compared for both groups. The clinical success rate, defined as the successful removal of the drain after one procedure, was calculated. Adverse events were reported according to the Society of Interventional Radiology classification. A statistical analysis was conducted using SPSS, and the P value for statistical significance was set at 0.05. The Mann-Whitney U test was used to compare differences in the scale variables, and Fisher's exact test was used to compare the categorical and ordinal variables between both groups. RESULTS: A total of 46 patients with 49 lymphoceles met the inclusion criteria of the study. Of these patients, 17 patients (19 lymphoceles) underwent sclerotherapy, and 29 patients (30 lymphoceles) underwent LE as their initial procedures. The clinical success after one procedure was significantly higher (83% vs. 47%, P = 0.011), and the median time between the first intervention and drain removal was significantly shorter in the LE group (median duration of 6 vs. 13 days, P = 0.018) compared with the sclerotherapy group. No statistically significant difference in adverse events was noted between both groups (0.26 vs. 0.10, P = 0.11). CONCLUSION: This study found that LE had a higher clinical success rate after the first procedure and a shorter time to drain removal compared with sclerotherapy. There was no difference in the rate of adverse events between both groups. Although LE is a safe and promising technique, a prospective study is needed to further compare the efficacy of both treatment modalities.

Primary and Metastatic Lung Cancer: Rationale, Indications, and Outcomes of Thermal Ablation.

The widespread use of imaging as well as the efforts conducted through screening campaigns has dramatically increased the early detection rate of lung cancer. Historically, the management of lung cancer has heavily relied on surgery. However, the increased proportion of patients with comorbidities has given significance to less invasive therapeutic options like minimally invasive surgery and image-guided thermal ablation, which could precisely target the tumor without requiring general anesthesia or a thoracotomy. Thermal ablation is considered low-risk for lung tumors smaller than 3 cm that are located in peripheral lung and do not involve major blood vessels or airways. The rationale for ablative therapies relies on the fact that focused delivery of energy induces cell death and pathologic necrosis. Image-guided percutaneous thermal ablation therapies are established techniques in the local treatment of hepatic, renal, bone, thyroid and uterine lesions. In the lung, and specifically in the setting of metastatic disease, the 3 main indications for lung ablation are to serve as (1) curative intent, (2) as a strategy to achieve a chemo-holiday in oligometastatic disease, and (3) in oligoprogressive disease. Following these premises, the current paper aims to review the rationale, indications, and outcomes of thermal ablation as a form of local therapy in the treatment of primary and metastatic lung disease.

Image-Guided Percutaneous and Transarterial Therapies for Primary and Metastatic Lung Cancer.

Lung cancer is the leading cause of cancer mortality in the world. A significant proportion of patients with lung cancer are not candidates for surgery and must resort to other treatment alternatives. Rapid technological advancements in fields like interventional radiology have paved the way for valid treatment modalities like image-guided percutaneous and transarterial therapies for treatment of both primary and metastatic lung cancer. The rationale of ablative therapies relies on the fact that focused delivery of energy induces tumor destruction and pathological necrosis. Image-guided percutaneous thermal ablation therapies are established techniques in the local treatment of hepatic, renal, bone, thyroid, or uterine lesions. In the lung, the 3 main indications for lung ablation include local curative intent, a strategy to achieve a chemoholiday in oligometastatic disease, and recently, oligoprogressive disease. Transarterial therapies include a set of catheter-based treatments that involve delivering embolic and/or chemotherapeutic agents directed into the target tumor via the supplying arteries. This article provides a comprehensive review of the various techniques available and discusses their applications and associated complications in primary and metastatic lung cancer.

Artificial Intelligence for Breast US.

US is a widely available, commonly used, and indispensable imaging modality for breast evaluation. It is often the primary imaging modality for the detection and diagnosis of breast cancer in low-resource settings. In addition, it is frequently employed as a supplemental screening tool via either whole breast handheld US or automated breast US among women with dense breasts. In recent years, a variety of artificial intelligence systems have been developed to assist radiologists with the detection and diagnosis of breast lesions on US. This article reviews the background and evidence supporting the use of artificial intelligence tools for breast US, describes implementation strategies and impact on clinical workflow, and discusses potential emerging roles and future directions.

Interventional Management of Portal Hypertension in Cancer Patients.

PURPOSE OF REVIEW: To provide an overview of the classifications and clinical hallmarks of common cancer-related conditions that contribute to the high incidence of portal hypertension in this population and provide an update on currently available interventional radiology therapeutic approaches. RECENT FINDINGS: In the last few decades, there have been significant advancements in understanding the pathophysiology of portal hypertension. This knowledge has led to the development of safer and more effective minimally invasive approaches. The main objective is to provide alternatives to prevent life-threatening complications from clinically significant portal hypertension and to allow the continuation of cancer treatment interventions that would otherwise be stopped. Clinicians involved in cancer care should be aware of risk factors, associated complications, and management of portal hypertension in cancer patients. Interventional radiology offers minimally invasive alternatives that play a central role in improving clinical outcomes and survival of these patients, allowing the continuation of cancer treatments.

Intraarterial Therapies for the Management of Hepatocellular Carcinoma.

Image-guided locoregional therapies play a crucial role in the management of patients with hepatocellular carcinoma (HCC). Transarterial therapies consist of a group of catheter-based treatments where embolic agents are delivered directly into the tumor via their supplying arteries. Some of the transarterial therapies available include bland embolization (TAE), transarterial chemoembolization (TACE), drug-eluting beads-transarterial chemoembolization (DEB-TACE), selective internal radioembolization therapy (SIRT), and hepatic artery infusion (HAI). This article provides a review of pre-procedural, intra-procedural, and post-procedural aspects of each therapy, along with a review of the literature. Newer embolotherapy options and future directions are also briefly discussed.

Image-Guided Percutaneous Ablation for Primary and Metastatic Tumors.

Image-guided percutaneous ablation methods have been further developed during the recent two decades and have transformed the minimally invasive and precision features of treatment options targeting primary and metastatic tumors. They work by percutaneously introducing applicators to precisely destroy a tumor and offer much lower risks than conventional methods. There are usually shorter recovery periods, less bleeding, and more preservation of organ parenchyma, expanding the treatment options of patients with cancer who may not be eligible for resection. Image-guided ablation techniques are currently utilized for the treatment of primary and metastatic tumors in various organs including the liver, pancreas, kidneys, thyroid and parathyroid, prostate, lung, bone, and soft tissue. This article provides a brief review of the various imaging modalities and available ablation techniques and discusses their applications and associated complications in various organs.

Optimizing 90Y Particle Density Improves Outcomes After Radioembolization.

PURPOSE: To determine how particle density affects dose distribution and outcomes after lobar radioembolization. METHODS: Matched pairs of patients, treated with glass versus resin microspheres, were selected by propensity score matching (114 patients), in this single-institution retrospective study. For each patient, tumor and liver particle density (particles/cm3) and dose (Gy) were determined. Tumor-to-normal ratio was measured on both 99mTc-MAA SPECT/CT and post-90Y bremsstrahlung SPECT/CT. Microdosimetry simulations were used to calculate first percentile dose, which is the dose in the cold spots between microspheres. Local progression-free survival (LPFS) and overall survival were analyzed. RESULTS: As more particles were delivered, doses on 90Y SPECT/CT became more uniform throughout the treatment volume: tumor and liver doses became more similar (p = 0.04), and microscopic cold spots between particles disappeared. For hypervascular tumors (tumor-to-normal ratio ≥ 2.6 on MAA scan), delivering fewer particles (< 6000 particles/cm3 treatment volume) was associated with better LPFS (p = 0.03). For less vascular tumors (tumor-to-normal ratio < 2.6), delivering more particles (≥ 6000 particles/cm3) was associated with better LPFS (p = 0.02). In matched pairs of patients, using the optimal particle density resulted in improved overall survival (11.5 vs. 6.8 months, p = 0.047), compared to using suboptimal particle density. Microdosimetry resulted in better predictions of LPFS (p = 0.03), and overall survival (p = 0.02), compared to conventional dosimetry. CONCLUSION: The number of particles delivered can be chosen to maximize the tumor dose and minimize the liver dose, based on tumor vascularity. Optimizing the particle density resulted in improved LPFS and overall survival.

Management of Architectural Distortion on Digital Breast Tomosynthesis With Nonmalignant Pathology at Biopsy.

BACKGROUND. Digital breast tomosynthesis (DBT) has led to increased detection and biopsy of architectural distortion, which may yield malignancy, radial scar, or other benign pathologies. Management of nonmalignant architectural distortion on DBT remains controversial. OBJECTIVE. The purpose of this study was to determine upgrade rates of architectural distortion on DBT from nonmalignant pathology at biopsy to malignancy at surgery. METHODS. This retrospective study included cases of mammographically detected architectural distortion from July 1, 2016, to June 30, 2019, that were nonmalignant at image-guided needle biopsy and underwent surgical excision. Mammographic examinations included digital 2D mammography and DBT. Imaging data were extracted from radiology reports. Upgrade rates were summarized using descriptive statistics. Features of upgraded and nonupgraded cases were compared using Pearson chi-square test and Wilcoxon signed rank test. RESULTS. The study included 129 cases of architectural distortion with nonmalignant pathology at biopsy that underwent excision in 125 women (mean age, 54 years; range, 23-90 years). At biopsy, 92 (71.3%) were radial scars and 37 (28.7%) were other nonmalignant pathologies. Of 66 radial scars without atypia at biopsy, one (1.5%) was upgraded to ductal carcinoma in situ (DCIS) at surgery and none to invasive cancer. Of 24 benign pathologies without atypia at biopsy, one was considered discordant. Of the 23 remaining concordant cases, one (4.3%) was upgraded to DCIS at surgery and none to invasive cancer. The overall upgrade rate to cancer of architectural distortion with concordant nonmalignant pathology at biopsy was 10.2% (13/128). The upgrade rate to cancer of architectural distortion without atypia was 2.2% (2/89) and with atypia was 28.2% (11/39). Explored features (age, personal or family breast cancer history, presentation by screening vs diagnostic mammography, breast density, associated mammographic findings, presence and size of ultrasound correlate, biopsy modality) showed no signifi-cant associations with upgrade risk (p > .05). CONCLUSION. Architectural distortion on DBT with concordant nonmalignant pathology at biopsy has an overall upgrade rate to malignancy at surgery of 10.2%. Architectural distortion without atypia has a low upgrade rate of 2.2%. CLINICAL IMPACT. Imaging surveillance can be considered for architectural distortion on DBT yielding radial scar without atypia or other concordant benign pathologies without atypia at biopsy.

Percutaneous liver venous deprivation: outcomes in heavily pretreated metastatic colorectal cancer patients.

BACKGROUND: To evaluate liver venous deprivation (LVD) outcomes in patients with colorectal liver metastasis (CRLM) heavily pretreated with systemic and hepatic arterial infusion pump (HAIP) chemotherapies that had an anticipated insufficient future liver remnant (FLR) hypertrophy after portal vein embolization (PVE). METHODS: PVE was performed with liquid embolics using a transsplenic or ipsilateral transhepatic approach. Simultaneously and via a trans-jugular approach, the right hepatic vein was embolized with vascular plugs. Liver volumetry was assessed on computed tomography before and 3-6 weeks after LVD. RESULTS: Twelve consecutive CRLM patients that underwent LVD before right hepatectomy or trisectionectomy were included, all previously treated with systemic chemotherapy for a mean of 11.9 months. Six patients had additional HAIP. After embolization, FLR ratio increased from 28.7% ± 5.9 to 42.2% ± 9.0 (P < 0.01). Mean kinetic growth rate (KGR) was 3.56%/week ± 2.3, with a degree of hypertrophy (DH) of 13.8% ± 7.1. In the HAIP subgroup, mean KGR and DH were respectively 3.58%/week ± 2.8 and 14.3% ± 8.7. No severe complications occurred. Ten patients reached surgery after 39 days ± 7.5. CONCLUSION: In heavily pretreated patients, LVD safely stimulated a rapid and effective FLR hypertrophy, with a resultant high rate of resection.

Immunofluorescence Assay of Ablated Colorectal Liver Metastases: The Frozen Section of Image-Guided Tumor Ablation?

PURPOSE: To validate an immunofluorescence assay (IFA) detecting residual viable tumor (VT) as intraprocedural thermal ablation (TA) zone assessment and demonstrate its prognostic value for local tumor progression (LTP) after colorectal liver metastasis (CLM) TA. MATERIALS AND METHODS: This prospective study, approved by the institutional review board, included 99 patients with 155 CLMs ablated between November 2009 and January 2019. Tissue samples from the ablation zone (AZ) center and minimal margin underwent immunofluorescent microscopic examination interrogating cellular morphology and mitochondrial viability (IFA) within 30 minutes after ablation. The same tissue samples were subsequently evaluated with standard morphologic and immunohistochemical methods. The sensitivity, specificity, and overall accuracy of IFA versus standard morphologic and immunohistochemical examination were calculated. The LTP-free survival rates were evaluated for the 12-month follow-up period. RESULTS: Of the 311 tissue samples stained, 304 (98%) were deemed evaluable. Of these specimens, 27% (81/304) were considered positive for the presence of VT. The accuracy of IFA was 94% (286/304). The sensitivity and specificity were 100% (63/63) and 93% (223/241), respectively. The 18 false-positive IFA assessments corresponded to samples that included viable cholangiocytes. The 12-month LTP-free survival was 59% versus 78% for IFA positive versus negative for VT AZs, respectively (P < .001). There was no difference in LTP between margin positive only and central AZ-positive tumors (25% vs 31%, P = 1). CONCLUSIONS: The IFA assessment of the AZ can be completed intraprocedurally and serve as a valid real-time biomarker of complete tumor eradication or detect residual VT after TA. This method could improve tumor control by TA.

Treatment of Malignant Bile Duct Obstruction: What the Interventional Radiologist Needs to Know.

Management of malignant bile duct obstruction is both a clinically important and technically challenging aspect of caring for patients with advanced malignancy. Bile duct obstruction can be caused by extrinsic compression, intrinsic tumor/stone/debris, or by biliary ischemia, inflammation, and sclerosis. Common indications for biliary intervention include lowering the serum bilirubin level for chemotherapy, ameliorating pruritus, treating cholangitis or bile leak, and providing access for bile duct biopsy or other adjuvant therapies. In some institutions, biliary drainage may also be considered prior to hepatic or pancreatic resection. Prior to undertaking biliary intervention, it is essential to have high-quality cross-sectional imaging to determine the level of obstruction, the presence of filling defects or atrophy, and status of the portal vein. High bile duct obstruction, which we consider to be obstruction above, at, or just below the confluence (Bismuth classifications IV, III, II, and some I), is optimally managed percutaneously rather than endoscopically because interventional radiologists can target specific ducts for drainage and can typically avoid introducing enteric contents into isolated undrained bile ducts. Options for biliary drainage include external or internal/external catheters and stents. In the setting of high obstruction, placement of a catheter or stent above the ampulla, preserving the function of the sphincter of Oddi, may lower the risk of future cholangitis by preventing enteric contamination of the biliary tree. Placement of a primary suprapapillary stent without a catheter, when possible, is the procedure most likely to keep the biliary tree sterile.

Percutaneous Lymphatic Embolization as Primary Management of Pelvic and Retroperitoneal Iatrogenic Lymphoceles.

PURPOSE: To evaluate the efficacy of lymphatic embolization (LE) in decreasing catheter output and dwell time in iatrogenic lymphoceles after percutaneous catheter drainage. MATERIALS AND METHODS: Retrospective review of patients who underwent intranodal lymphangiography (INL) with or without LE for management of iatrogenic lymphoceles between January 2017 and November 2020 was performed. Twenty consecutive patients (16 men and 4 women; median age, 60.5 years) underwent a total of 22 INLs and 18 LEs for 15 pelvic and 5 retroperitoneal lymphoceles. Lymphatic leaks were identified in 19/22 (86.4%) of the INLs. Three patients underwent INL only because a leak was not identified or was identified into an asymptomatic lymphocele. One patient underwent repeat INL and LE after persistent high catheter output, and 1 patient underwent repeat INL with LE after the initial INL did not identify a leak. Catheter output was assessed until catheter removal, and changes in output before and after the procedure were reported. The patients were followed up for 2-30 months, and procedural complications were reported. RESULTS: The median catheter output before the procedure was 210 mL/day (50-1,200 mL/day), which decreased to a median of 20 mL/day (0-520 mL/day) 3 days after the procedure, with a median output decrease of 160 mL (0-900 mL). The median time between INL with LE and catheter removal was 6 days, with no recurrence requiring redrainage. Four patients experienced minor complications of low-grade fever (n = 2) and lower limb edema (n = 2). CONCLUSIONS: Lymphangiogram and LE are safe and effective methods for the management of lymphoceles.

Ultrasound-Guided Percutaneous Laser Ablation of the Thyroid Gland in a Swine Model: Comparison of Ablation Parameters and Ablation Zone Dimensions.

BACKGROUND: To compare laser ablation (LA) zone dimensions at two predetermined energy parameters to cover a theoretical 10 mm zone + 2 mm margin in a thyroid swine model. METHODS: Approval of the Institutional Animal Care and Use Committee was obtained. After hydrodissection, an ultrasound-guided LA (Elesta Echolaser X4 with Orblaze technology, 1064 nm) was performed in the periphery of the thyroid in 10 swine. Two cohorts were established to ablate a region of 10mm diameter with 2mm margin based on manufacturer's ex vivo data (n= 5 at 3W/1400J and n= 5 at 3W/1800J). The ablation zone was measured on contrast-enhanced computed tomography (CT) and compared to the pathological specimen. Euthanasia was performed 48 hours following ablation. RESULTS: All ablations in the 3W/1800J group achieved a diameter of 12 mm ± 1 mm in three dimensions. In the 3W/1400J group, 1 ablation reached 12 mm ± 1 mm in 2 dimensions and 4 ablations reached this size in one dimension. Maximum diameter was higher in the 3W/1800J compared to the 3W/1400J group, both on histology (1.46 cm ± 0.05 vs. 1.1 cm ± 0.0, p< 0.01) and CT (1.52 cm ± 0.04 vs. 1.18 cm ± 0.04, p< 0.01). Similar results were obtained regarding volumes, both on histology (1.12 mL ± 0.13 vs. 0.57 mL ± 0.06, p< 0.01) and CT (1.24 mL ± 0.13 vs. 0.59 mL ± 0.07, p< 0.01). Histology showed coagulation necrosis and correlated well with CT measurements. CONCLUSION: Optimal parameters to obtain a LA zone of 10 mm with 2 mm margin utilizing a single needle are 3W/1800J.

Microwave Ablation in Primary Lung Malignancies.

Lung cancer is the leading cause of cancer-related mortality worldwide. Eighty-five percent of cases correspond to non-small cell lung cancer (NSCLC) and pivotal nonsurgical options for early-stage disease include percutaneous ablation and stereotactic body radiation therapy (SBRT). Microwave Ablation (MWA) is a locoregional treatment option that has many advantages over radiofrequency ablation and has been able to overcome the limitations of this technique in the treatment of early-stage NSCLC. In this review article, we highlight the current evidence supporting the use of MWA in patients with early-stage NSCLC and discuss the technical considerations of the procedure, including optimal patient selection and planning strategies, as well as the potential complications and reported outcomes. Finally, we mention future trends involving ablation in NSCLC, including its role in combination with SBRT in central tumors, management of post-SBRT local recurrence, and its potential as an adjuvant treatment option for patients with resistance to systemic therapy or in combination with checkpoint inhibitors.