Short-Term Out-of-Pocket and Total Costs of Care After Ablation, Resection, or Transplant for Early-Stage Hepatocellular Carcinoma: A National SEER-Medicare Cost Comparison.

Background: Differences in survival and morbidity among treatment options (ablation, surgical resection, and transplant) for early-stage hepatocellular carcinoma (HCC) have been well-studied. Additional understanding of the costs of such care would help to identify drivers of high costs and potential barriers to care delivery. Objective: To quantify total and patient out-of-pocket costs for ablation, surgical resection, and transplant in the management of early-stage HCC and to identify factors predictive of these costs. Methods: This retrospective U.S. population-based study used the SEER-Medicare linked dataset to identify a sample of 1067 Medicare beneficiaries (mean age, 73 years; 674 men, 393 women) diagnosed with early-stage HCC (size ≤5 cm) treated with ablation (N=623), resection (N=201), or transplant (N=243) between January 2009 and December 2016. Total costs and patient out-of-pocket costs for the index procedure as well as for any care within 30 days and 90 days post-procedure were identified and stratified by treatment modality. Additional comparisons were performed among propensity-score matched subgroups of patients treated by ablation or resection (each N=172). Multivariable linear regression models were used to identify factors predictive of total costs and out-of-pocket costs for index procedures as well as for 30-day and 90-day post-procedure periods. Results: For ablation, resection, and transplant, median index-procedure total cost was $6689, $25,614, and $66,034; index-procedure out-of-pocket cost was $1235, $1650, and $1317; 30-day total cost was $9456, $29,754, and $69,856; 30-day out-of-pocket cost was $1646, $2208, and $3198; 90-day total cost was $14,572, $34,984, and $88,103; and 90-day out-of-pocket cost was $2138, $2462, and $3876, respectively (all p<.001). In propensity-matched subgroups, ablation and resection had median index-procedure, 30-day, and 90-day total costs of $6690 and $25,716, $9995 and $30,365, and $15,851 and $34,455, respectively. In multivariable analysis adjusting for socioeconomic factors, comorbidities, and liver-disease prognostic indicators, surgical treatment (resection or transplant) was predictive of significantly greater costs compared with ablation at all time points. Conclusion: Total and out-of-pocket costs for index procedures as well as for 30-day and 90-day post-procedure periods were lowest for ablation, followed by resection and then transplant. Clinical Impact: This comprehensive cost analysis could help inform future cost-effectiveness analyses.

Predictors for Early Liver Cancer Survival After Ablation and Surgical Resection: A Surveillance, Epidemiology, and End Results Program-Medicare Study.

OBJECTIVE: To identify independent predictors of all-cause and cancer-specific mortality after ablation or surgical resection (SR) for small hepatocellular carcinomas (HCCs), after adjusting for key confounders. METHODS: Using Surveillance, Epidemiology, and End Results Program-Medicare, HCCs less than 5 cm treated with ablation or SR in 2009 to 2016 (n = 956) were identified. Univariate and multivariable Cox regression models for all-cause and cancer-specific mortality were performed including demographics, clinical factors (tumor size, medical comorbidities, and liver disease factors), social determinants of health, and treatment characteristics. We also determined the most influential predictors of survival using a random forest analysis. RESULTS: Larger tumor size (3-5 cm) is predictive of all-cause (hazard ratio [HR] 1.31, P = .002) and cancer-specific mortality (HR 1.59, P < .001). Furthermore, chronic kidney disease is predictive of all-cause mortality (HR 1.43, P = .013), though it is not predictive of cancer-specific death. Multiple liver disease factors are predictive of all-cause and cancer-specific mortality including portal hypertension and esophageal varices (HRs > 1, P < .05). Though Asian race is protective in univariate models, in fully adjusted, multivariable models, Asian race is not a significant protective factor. Likewise, other social determinants of health are not significantly predictive of all-cause or cancer-specific mortality. Finally, treatment with SR, in later procedure years or at high-volume centers, is protective for all-cause and cancer-specific mortality. In machine learning models, year procedure was performed, ascites, portal hypertension, and treatment choice were the most influential factors. DISCUSSION: Treatment characteristics, liver disease factors, and tumor size are more important predictors of all-cause and cancer-specific death than social determinants of health for small HCCs.

Demonstrating the Value of Interventional Radiology.

While national healthcare expenditures per capita in the United States exceed those in all other Organisation for Economic Co-operation and Development (OECD) countries, measures of health outcomes in the United States lag behind those in peer nations. This combination of high healthcare spending and relatively poor health has led to attempts to identify high- and low-value healthcare services and to develop mechanisms to reimburse health care providers based on the value of the care delivered. This article investigates the meaning of value in healthcare and identifies specific services delivered by interventional radiologists that have accrued evidence that they meet criteria for high-value services. Recognizing the shift in reimbursement to high-value care, it is imperative that interventional radiology (IR) develop the evidence needed to articulate to all relevant stakeholders how IR contributes value to the system.

Beyond Survival: Adverse Events and Care Delivery Outcomes after Early Liver Cancer Treatment in a Nationally Representative Cohort.

PURPOSE: To compare secondary outcomes after ablation (AB), surgical resection (SR), and liver transplant (LT) for small hepatocellular carcinomas (HCCs), including resource utilization and adverse event (AE) rates. MATERIALS AND METHODS: Using Surveillance, Epidemiology, and End Results Program (SEER)-Medicare, HCCs <5 cm that were treated with AB, SR, or LT in 2009-2016 (n = 1,067) were identified using Healthcare Common Procedure Coding System codes through Medicare claims. Index procedure length of stay, need for intensive care unit (ICU) level care, readmission rates, and AE rates at 30 and 90 days were compared using chi-square tests or Fisher exact tests. Examined AEs included hemorrhage, abscess formation, biliary injury, pneumonia, sepsis, liver disease-related AEs, liver failure, and anesthesia-related AEs, identified by International Classification of Diseases, Ninth/10th Revision, codes. RESULTS: The median length of stay for initial treatment was 1 day, 6 days, and 7 days for AB, SR, and LT, respectively (P < .001). During initial hospital stay, 5.0%, 40.8%, and 63.4% of AB, SR, and LT cohorts, respectively, received ICU-level care (P < .001). By 30 and 90 days, there were significant differences among the AB, SR, and LT cohorts in the rate of postprocedural hemorrhage, abscess formation, biliary injury, pneumonia, sepsis, liver disease-related AEs, and anesthesia-related AEs (P < .05). By 90 days, the readmission rates after AB, SR, and LT were 18.6%, 28.2%, and 40.6% (P < .001), respectively. CONCLUSIONS: AB results in significantly less healthcare utilization during the initial 90 days after procedure compared with that after SR and LT due to shorter length of stay, lower intensity care, fewer readmissions, and fewer AEs.

Prediction of Lung Shunt Fraction for Yttrium-90 Treatment of Hepatic Tumors Using Dynamic Contrast Enhanced MRI with Quantitative Perfusion Processing.

There is no noninvasive method to estimate lung shunting fraction (LSF) in patients with liver tumors undergoing Yttrium-90 (Y90) therapy. We propose to predict LSF from noninvasive dynamic contrast enhanced (DCE) MRI using perfusion quantification. Two perfusion quantification methods were used to process DCE MRI in 25 liver tumor patients: Kety's tracer kinetic modeling with a delay-fitted global arterial input function (AIF) and quantitative transport mapping (QTM) based on the inversion of transport equation using spatial deconvolution without AIF. LSF was measured on SPECT following Tc-99m macroaggregated albumin (MAA) administration via hepatic arterial catheter. The patient cohort was partitioned into a low-risk group (LSF ≤ 10%) and a high-risk group (LSF > 10%). Results: In this patient cohort, LSF was positively correlated with QTM velocity |u| (r = 0.61, F = 14.0363, p = 0.0021), and no significant correlation was observed with Kety's parameters, tumor volume, patient age and gender. Between the low LSF and high LSF groups, there was a significant difference for QTM |u| (0.0760 ± 0.0440 vs. 0.1822 ± 0.1225 mm/s, p = 0.0011), and Kety's Ktrans (0.0401 ± 0.0360 vs 0.1198 ± 0.3048, p = 0.0471) and Ve (0.0900 ± 0.0307 vs. 0.1495 ± 0.0485, p = 0.0114). The area under the curve (AUC) for distinguishing between low LSF and high LSF was 0.87 for |u|, 0.80 for Ve and 0.74 for Ktrans. Noninvasive prediction of LSF is feasible from DCE MRI with QTM velocity postprocessing.

Long-Term Survival After Surgery Versus Ablation for Early Liver Cancer in a Large, Nationally Representative Cohort.

OBJECTIVE: To compare survival outcomes (all-cause, cancer-specific, and disease-free) for small hepatocellular carcinomas (HCCs), less than or equal to 5 cm, after ablation (AB) and surgical resection (SR) after adjusting for key confounders. Secondarily, to understand differential survival outcomes of liver transplant (TR) compared with SR and AB. METHODS: Using Surveillance, Epidemiology, and End Results Program-Medicare, HCCs less than 5 cm that were treated with AB, SR, or TR in 2009 to 2016 (n = 1,215) were identified using Healthcare Common Procedure Coding System codes through Medicare claims. The TR group was subdivided into two groups: TR with prior treatment and TR without prior treatment. All-cause survival, cancer-specific survival, and disease-free survival were analyzed using Kaplan-Meier curves and compared between groups using log-rank tests and Cox regression analyses. Propensity score-matched comparison of AB and SR groups was performed, with groups matched on demographics, social determinants of health, medical comorbidities, and liver disease severity prognostic indicators. RESULTS: Median study follow-up time was 2.71 years (interquartile range 1.25-3.83). Unadjusted 1-, 3-, and 5-year cancer-specific survivals were 85.9%, 67.6%, and 56.3% for the AB group; 91.7%, 82.6%, and 81.7% for the SR group; 93.5%, 88.7%, and 79.4% for TR without prior treatment group; and 96.4%, 93.2%, and 93.2% for TR with prior treatment group (P < .0001). With SR as the reference group, the propensity-matched hazard ratios for AB were 2.04 (95% confidence interval: 1.51-2.77) for all-cause mortality, 2.44 (95% confidence interval: 1.56-3.80) for cancer-specific mortality, and 2.12 (95% confidence interval: 1.61-2.78) for disease recurrence. DISCUSSION: SR is superior to AB for small HCCs in a large, nationally representative, modern cohort, and in secondary analysis TR was superior to both.

Conventional Hepatic Volumetry May Lead to Inaccurate Segmental Yttrium-90 Radiation Dosimetry.

OBJECTIVE: To compare radioembolization treatment zone volumes from mapping cone beam CT (CBCT) versus planning CT/MRI and to model their impact on dosimetry. METHODS: Y90 cases were retrospectively identified in which intra-procedural CBCT angiograms were performed. Segmental and lobar treatment zone volumes were calculated with semi-automated contouring using Couinaud venous anatomy (planning CT/MRI) or tumor angiosome enhancement (CBCT). Differences were compared with a Wilcoxon signed-rank test. Treatment zone-specific differences in segmental volumes by volumetric method were also calculated and used to model differences in delivered dose using medical internal radiation dosimetry (MIRD) at 200 and 120 Gy targets. Anatomic, pathologic, and technical factors likely affecting segmental volumes by volumetric method were evaluated. RESULTS: Forty segmental and 48 lobar CBCT angiograms and corresponding planning CT/MRI scans were included. Median Couinaud- and CBCT-derived segmental volumes were 281 and 243 mL, respectively (p = 0.005). Differences between Couinaud and CBCT lobar volumes (right, left) were not significant (p = 0.24, p = 0.07). Couinaud overestimated segmental volumes in 28 cases by a median of 98 mL (83%) and underestimated in 12 cases by median 69 mL (20%). At a 200 Gy dose target, Couinaud estimates produced median delivered doses of 367 and 160 Gy in these 28 and 12 cases. At a 120 Gy target, Couinaud produced doses of 220 and 96 Gy. Proximal vs. distal microcatheter positioning, variant arterial anatomy, and tumor location on or near segmental watersheds were leading factors linked to volumetric differences. CONCLUSION: Use of CBCT-based volumetry may allow more accurate, personalized dosimetry for segmental Y90 radioembolization.

Role of interventional radiology in the treatment of COVID-19 patients: Early experience from an epicenter.

OBJECTIVE: To highlight the role of interventional radiology (IR) in the treatment of patients hospitalized with coronavirus disease 2019 (COVID-19). METHODS: Retrospective review of hospitalized patients who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and had one or more IR procedures at a tertiary referral hospital in New York City during a 6-week period in April and May of 2020. RESULTS: Of the 724 patients admitted with COVID-19, 92 (12.7%) underwent 124 interventional radiology procedures (79.8% in IR suite, 20.2% at bedside). The median age of IR patients was 63 years (range 24-86 years); 39.1% were female; 35.9% in the intensive care unit. The most commonly performed IR procedures were central venous catheter placement (31.5%), inferior vena cava filter placement (9.7%), angiography/embolization (4.8%), gastrostomy tube placement (9.7%), image-guided biopsy (10.5%), abscess drainage (9.7%), and cholecystostomy tube placement (6.5%). Thoracentesis/chest tube placement and nephrostomy tube placement were also performed as well as catheter-directed thrombolysis of massive pulmonary embolism and thrombectomy of deep vein thrombosis. General anesthesia (10.5%), monitored anesthesia care (18.5%), moderate sedation (29.8%), or local anesthetic (41.1%) was utilized. There were 3 (2.4%) minor complications (SIR adverse event class B), 1 (0.8%) major complication (class C), and no procedure-related death. With a median follow-up of 4.3 months, 1.1% of patients remain hospitalized, 16.3% died, and 82.6% were discharged. CONCLUSION: Interventional radiology participated in the care of hospitalized COVID-19 patients by performing a wide variety of necessary procedures.

Radiation Segmentectomy and Radiation Lobectomy: A Practical Review of Techniques.

The radiation segmentectomy technique may be defined as the administration of transarterial radioembolization delivered to 1 or 2 hepatic segments with the intention of segmental tissue ablation. Since first being described in 2011, radiation segmentectomy has quickly gained acceptance as a safe, effective, and potentially curative outpatient treatment for selected lower stage hepatocellular carcinomas. We describe our recommended techniques for radiation segmentectomy with glass or resin radiomicrospheres, including patient selection, dosimetry, microcatheter techniques, and clinical and imaging follow-up, accompanied by a brief review of the radiation segmentectomy literature. Radiation lobectomy, defined as the ablation of an entire hepatic lobe via transarterial radioembolization, is an area of growing interest in many centers. We also review the existing radiation lobectomy literature and suggest which patient and tumor factors may be associated with higher likelihood of successful treatment.

Percutaneous Ablation Versus Partial and Radical Nephrectomy for T1a Renal Cancer: A Population-Based Analysis.

Background: Stage T1a renal cell carcinoma (RCC) (tumors <4 cm) is usually curable. Nephron-sparing partial nephrectomy (PN) has replaced radical nephrectomy (RN) as the standard of care for these tumors. Radical nephrectomy remains the first alternative treatment option, whereas percutaneous ablation (PA), a newer, nonsurgical treatment, is recommended less strongly because of the relative paucity of comparative PA data. Objective: To compare PA, PN, and RN outcomes. Design: Observational cohort analysis using inverse probability of treatment-weighted propensity scores. Setting: Population-based SEER (Surveillance, Epidemiology, and End Results) cancer registry data linked to Medicare claims. Patients: Persons aged 66 years or older who received treatment for T1a RCC between 2006 and 2011. Interventions: PA versus PN and RN. Measurements: RCC-specific and overall survival, 30- and 365-day postintervention complications. Results: 4310 patients were followed for a median of 52 months for overall survival and 42 months for RCC-specific survival. After PA versus PN, the 5-year RCC-specific survival rate was 95% (95% CI, 93% to 98%) versus 98% (CI, 96% to 99%); after PA versus RN, 96% (CI, 94% to 98%) versus 95% (CI, 93% to 96%). After PA versus PN, the 5-year overall survival rate was 77% (CI, 74% to 81%) versus 86% (CI, 84% to 88%); after PA versus RN, 74% (CI, 71% to 78%) versus 75% (CI, 73% to 77%). Cumulative rates of renal insufficiency 31 to 365 days after PA, PN, and RN were 11% (CI, 8% to 14%), 9% (CI, 8% to 10%), and 18% (CI, 17% to 20%), respectively. Rates of nonurologic complications within 30 days after PA, PN, and RN were 6% (CI, 4% to 9%), 29% (CI, 27% to 30%), and 30% (CI, 28% to 32%), respectively. Ten percent of patients in the PN group had intraoperative conversion to RN. Seven percent of patients in the PA group received additional PA within 1 year of treatment. Limitations: Analysis of observational data may have been affected by residual confounding by provider or from selection bias toward younger, healthier patients in the PN group. Findings from this older study population are probably less applicable to younger patients. Use of SEER-Medicare linked files prevented analysis of patients who received treatment after 2011, possibly reducing generalizability to the newest PA, PN, and RN techniques. Conclusion: For well-selected older adults with T1a RCC, PA may result in oncologic outcomes similar to those of RN, but with less long-term renal insufficiency and markedly fewer periprocedural complications. Compared with PN, PA may be associated with slightly shorter RCC-specific survival but fewer periprocedural complications. Primary Funding Source: Association of University Radiologists GE Radiology Research Academic Fellowship and Society of Interventional Radiology Foundation.

Bone biopsy protocol for advanced prostate cancer in the era of precision medicine.

BACKGROUND: Metastatic biopsies are increasingly being performed in patients with advanced prostate cancer to search for actionable targets and/or to identify emerging resistance mechanisms. Due to a predominance of bone metastases and their sclerotic nature, obtaining sufficient tissue for clinical and genomic studies is challenging. METHODS: Patients with prostate cancer bone metastases were enrolled between February 2013 and March 2017 on an institutional review board-approved protocol for prospective image-guided bone biopsy. Bone biopsies and blood clots were collected fresh. Compact bone was subjected to formalin with a decalcifying agent for diagnosis; bone marrow and blood clots were frozen in optimum cutting temperature formulation for next-generation sequencing. Frozen slides were cut from optimum cutting temperature cryomolds and evaluated for tumor histology and purity. Tissue was macrodissected for DNA and RNA extraction, and whole-exome sequencing and RNA sequencing were performed. RESULTS: Seventy bone biopsies from 64 patients were performed. Diagnostic material confirming prostate cancer was successful in 60 of 70 cases (85.7%). The median DNA/RNA yield was 25.5 ng/µL and 16.2 ng/µL, respectively. Whole-exome sequencing was performed successfully in 49 of 60 cases (81.7%), with additional RNA sequencing performed in 20 of 60 cases (33.3%). Recurrent alterations were as expected, including those involving the AR, PTEN, TP53, BRCA2, and SPOP genes. CONCLUSIONS: This prostate cancer bone biopsy protocol ensures a valuable source for high-quality DNA and RNA for tumor sequencing and may be used to detect actionable alterations and resistance mechanisms in patients with bone metastases. Cancer 2018;124:1008-15. © 2017 American Cancer Society.

The Top Three Health Care Developments Impacting the Practice of Interventional Radiology in the Next Decade.

OBJECTIVE: We discuss three health care trends that will have a profound impact on interventional radiology (IR) in the next decade. CONCLUSION: Precision medicine, representing the next frontier of medicine, will bring opportunities and challenges to the field. Significant changes in payment models may prove beneficial to the subspecialty if proactive steps are taken by its members. Finally, shifts in population demographics are predicted to increase demand for services while intensifying the need to cultivate a complementary workforce.

Yttrium-90 microsphere radioembolotherapy in a patient with spontaneously ruptured hepatocellular carcinoma.

Spontaneous rupture of hepatocellular carcinoma (HCC) is a potentially fatal presentation of the disease. Although many options for treatment exist, Yttrium-90 transcatheter arterial radioembolization has not previously been reported. We report a case of a 92-year-old woman found to have a ruptured HCC treated with radioembolization that showed no viable tumor and no extrahepatic disease at 2 years. While further studies are warranted, this patient's clinical course may suggest that radioembolization may be an additional palliative treatment option in these patients.

Characterization of in vivo ablation zones following percutaneous microwave ablation of the liver with two commercially available devices: are manufacturer published reference values useful?

PURPOSE: To analyze in vivo ablation properties of microwave ablation antennae in tumor-bearing human livers by performing retrospective analysis of ablation zones following treatment with two microwave ablation systems. MATERIALS AND METHODS: Percutaneous microwave ablations performed in the liver between February 2011 and February 2013 with use of the AMICA and Certus PR ablation antennae were included. Immediate postablation computed tomography images were evaluated retrospectively for ablation length, diameter, and volume. Ablation length, diameter, and volume indices were calculated and compared between in vivo results and references provided from each device manufacturer. The two microwave antenna models were then also compared versus each other. RESULTS: Twenty-five ablations were performed in 20 patients with the AMICA antenna, and 11 ablations were performed in eight patients with the Certus PR antenna. The AMICA and Certus PR antennae showed significant differences in ablation length (P = .013 and P = .009), diameter (P = .001 and P = .009), and volume (P = .003 and P = .009). The AMICA ablation indices were significantly higher than the Certus PR ablation indices in length (P = .026) and volume (P = .002), but there was no significant difference in ablation diameter indices (P = .110). CONCLUSIONS: In vivo ablation indices of human tumors are significantly smaller than reference ex vivo ablation indices, and there are significant differences in ablation indices and sphericity between devices.

Interventional radiologic techniques for screening, diagnosis and treatment of patients with renal artery stenosis.

Renal artery stenosis resulting in renovascular hypertension or renal ischemia is a potentially treatable condition that results in increased morbidity and mortality, especially among older individuals. Sophisticated imaging techniques are used for screening and identification of affected patients to guide therapy. Treatment guidelines recommend intervention in patients with significant renal artery stenosis, although recent evidence has questioned the benefit of intervention in certain populations. Current research focuses on improving the specificity of imaging techniques and determining which imaging modalities best identify patients who will benefit from intervention.

Transarterial therapies for primary liver tumors.

Over the last decade, transarterial therapies have gained worldwide acceptance as standard of care for inoperable primary liver cancer. Survival times after transarterial chemoembolization (TACE) continue to improve as the technique and selection criteria are refined. Transarterial treatments, frequently provided in an outpatient setting, are now safely and effectively being applied to patients with even advanced malignancy or partially decompensated cirrhosis. In the coming years, newer transarterial therapies such as radiation segmentectomy, boosted-transarterial radioembolzation, combined TACE-ablation, TACE-portal vein embolization, and transarterial infusion of cancer-specific metabolic inhibitors promise to continue improving survival and quality of life.

Thermal ablation matches sublobar resection outcomes in older patients with early-stage non-small cell lung cancer.

PURPOSE: To compare survival outcomes of sublobar resection and thermal ablation for early-stage non-small cell lung cancer (NSCLC) in older patients. MATERIALS AND METHODS: SEER-Medicare linked data for patients with a diagnosis of lung cancer from 2007-2009 were used. Patients ≥ 65 years old with stage IA or IB NSCLC who were treated with sublobar resection or thermal ablation were identified. Primary outcome was overall survival (OS), and secondary outcome was lung cancer-specific survival (LCSS). Demographic and clinical variables were compared. Unadjusted OS and LCSS curves were estimated using the Kaplan-Meier method, and multivariate analysis was performed using the Cox model. OS and LCSS curves for propensity score matched groups were also compared. RESULTS: The final unmatched study population comprised 1,897 patients. Patients who underwent sublobar resection were significantly younger (P = .006) and significantly less likely to have a comorbidity index > 1 (P = .036), a diagnosis of chronic obstructive pulmonary disease (P = .017), or adjuvant radiation therapy (P < .0001) compared with patients treated with thermal ablation. Unadjusted survival curves of unmatched groups demonstrated significantly better OS (P = .028) and LCSS (P = .0006) in the resection group. Multivariate Cox model adjusting for demographic and clinical variables found no significant difference in OS between the treatment groups (P = .555); a difference in LCSS (hazard ratio = 1.185, P = .026) persisted. Survival curves for matched groups found no significant difference in OS (P = .695) or LCSS (P = .819) between treatment groups. CONCLUSIONS: After controlling for selection bias, this study found no difference in OS between patients treated with sublobar resection and thermal ablation.

Update on portal vein embolization: evidence-based outcomes, controversies, and novel strategies.

Portal vein embolization (PVE) is an established therapy used to redirect portal blood flow away from the tumor-bearing liver to the anticipated future liver remnant (FLR) and usually results in FLR hypertrophy. PVE is indicated when the FLR is considered too small before surgery to support essential function after surgery. When appropriately applied, PVE reduces postoperative morbidity and increases the number of patients eligible for curative hepatic resection. PVE also has been combined with other therapies to improve patient outcomes. This article assesses more recent outcomes data regarding PVE, reviews the existing controversies, and reports on novel strategies currently being investigated.