Interventional Liver-Directed Therapy for Neuroendocrine Metastases: Current Status and Future Directions.

OPINION STATEMENT: Liver-directed therapy should be considered for patients with unresectable liver metastases from neuroendocrine tumor if symptomatic or progressing despite medical management. Our experience and current literature shows that the bland embolization, chemoembolization, and radioembolization are very effective in controlling symptoms and disease burden in the liver, and that these embolization modalities are similar in terms of efficacy and radiologic response. Their safety profiles differ, however, with recent studies suggesting an increase in biliary toxicity with drug-eluting bead chemoembolization over conventional chemoembolization, and a risk of long-term hepatotoxicity with radioembolization. For this reason, we tailor the type of embolotherapy to each patient according to their clinical status, symptoms, degree of tumor burden, histologic grade, and life expectancy. We do not recommend a "one-size-fits-all" approach. Our general strategy is to use bland embolization as first-line embolotherapy, and radioembolization for patients with high-grade tumors or who have failed other embolotherapy.

Loss of the adipokine lipocalin-2 impairs satellite cell activation and skeletal muscle regeneration.

Lipocalin-2 (LCN2) is an adipokine previously described for its contribution to numerous processes, including innate immunity and energy metabolism. LCN2 has also been demonstrated to be an extracellular matrix (ECM) regulator through its association with the ECM protease matrix metalloproteinase-9 (MMP-9). With the global rise in obesity and the associated comorbidities related to increasing adiposity, it is imperative to gain an understanding of the cross talk between adipose tissue and other metabolic tissues, such as skeletal muscle. Given the function of LCN2 on the ECM in other tissues and the importance of matrix remodeling in skeletal muscle regeneration, we examined the localization and expression of LCN2 in uninjured and regenerating wild-type skeletal muscle and assessed the impact of LCN2 deletion (LCN2-/-) on skeletal muscle repair following cardiotoxin injury. Though LCN2 was minimally present in uninjured skeletal muscle, its expression was increased significantly at 1 and 2 days postinjury, with expression present in Pax7-positive satellite cells. Although satellite cell content was unchanged, the ability of quiescent satellite cells to become activated was significantly impaired in LCN2-/- skeletal muscles. Skeletal muscle regeneration was also significantly compromised as evidenced by decreased embryonic myosin heavy chain expression and smaller regenerating myofiber areas. Consistent with a role for LCN2 in MMP-9 regulation, regenerating muscle also displayed a significant increase in fibrosis and lower ( P = 0.07) MMP-9 activity in LCN2-/- mice at 2 days postinjury. These data highlight a novel role for LCN2 in muscle regeneration and suggest that changes in adipokine expression can significantly impact skeletal muscle repair.

Activation of autophagy by globular adiponectin is required for muscle differentiation.

Regulated autophagy is a critical component for a healthy skeletal muscle mass, such that dysregulation of the autophagic processes correlates with severe myopathies. Thus, defining the biological molecules involved in the autophagic processes within skeletal muscle is of great importance. Here we demonstrate that globular adiponectin (gAd) activates autophagy in skeletal muscle myoblasts via an AMPK-dependent mechanism. Activation of autophagy through gAd promotes myoblast survival and apoptosis inhibition during serum starvation and the gAd-activated autophagy orchestrates the myogenic properties of the hormone. Consistent with this conclusion, inhibition of gAd-activated autophagy by both a pharmacological (chloroquine) or siRNA approach greatly inhibited muscle differentiation, as demonstrated by reductions in myosin heavy chain expression and myotube formation. Further support for the role of adiponectin in autophagy comes from the skeletal muscles of adiponectin KO mice which display decreased LC3 II expression and a myopathic phenotype (heterogeneous fiber sizes, numerous central nuclei). Overall, these findings demonstrate that gAd activates autophagy in myoblasts and that gAd-activated autophagy drives the myogenic properties of this hormone.

The NLRP3 inflammasome contributes to sarcopenia and lower muscle glycolytic potential in old mice.

The mechanisms underpinning decreased skeletal muscle strength and slowing of movement during aging are ill-defined. "Inflammaging," increased inflammation with advancing age, may contribute to aspects of sarcopenia, but little is known about the participatory immune components. We discovered that aging was associated with increased caspase-1 activity in mouse skeletal muscle. We hypothesized that the caspase-1-containing NLRP3 inflammasome contributes to sarcopenia in mice. Male C57BL/6J wild-type (WT) and NLRP3-/- mice were aged to 10 (adult) and 24 mo (old). NLRP3-/- mice were protected from decreased muscle mass (relative to body mass) and decreased size of type IIB and IIA myofibers, which occurred between 10 and 24 mo of age in WT mice. Old NLRP3-/- mice also had increased relative muscle strength and endurance and were protected from age-related increases in the number of myopathic fibers. We found no evidence of age-related or NLRP3-dependent changes in markers of systemic inflammation. Increased caspase-1 activity was associated with GAPDH proteolysis and reduced GAPDH enzymatic activity in skeletal muscles from old WT mice. Aging did not alter caspase-1 activity, GAPDH proteolysis, or GAPDH activity in skeletal muscles of NLRP3-/- mice. Our results show that the NLRP3 inflammasome participates in age-related loss of muscle glycolytic potential. Deletion of NLRP3 mitigates both the decline in glycolytic myofiber size and the reduced activity of glycolytic enzymes in muscle during aging. We propose that the etiology of sarcopenia involves direct communication between immune responses and metabolic flux in skeletal muscle.

Therapeutic Response of Metastatic Colorectal Cancer Harboring a KRAS Missense Mutation After Combination Chemotherapy With the EGFR Inhibitor Panitumumab.

Over the past decade, subset analyses of retrospective and prospective clinical studies have determined that KRAS-mutated metastatic colorectal cancers do not respond effectively to inhibition of epidermal growth factor receptor (EGFR) with the EGFR-targeting monoclonal antibodies cetuximab or panitumumab. Within the past few years, the scope of tested variants in the KRAS oncogene has expanded significantly, and testing of all RAS family genes has become more widely available in clinical laboratories. Expert consensus guidelines have recommended not using EGFR inhibitors in patients with KRAS-mutated tumors. However, with increasing identification of low-prevalence variants, it is conceivable that some RAS mutations do not provide equivalent resistance to EGFR inhibition compared with the most prevalent mutations at codons 12, 13, and 61. This report describes a case of a patient with metastatic colon cancer harboring the p.A59T variant of KRAS, with objective radiographic response (36% decrease per RECIST 1.1) and carcinoembryonic antigen biomarker response to panitumumab therapy given with FOLFIRI chemotherapy. We propose that A59T represents one potential exception to the guidelines that KRAS mutant tumors fail to respond to therapy with EGFR inhibitors, altering the paradigm of using this generalized approach.

The Use of Latex Catheters to Close Enterocutaneous Fistulas: An Institutional Protocol and Retrospective Review.

OBJECTIVE: The objective of our study was to retrospectively review an institutional protocol that uses latex catheters for the treatment of enterocutaneous fistulas (ECFs) that are resistant to simple drainage. MATERIALS AND METHODS: Forty-six consecutive patients with ECFs that did not close with simple abscess drainage were treated with latex catheters. These patients' charts were retrospectively reviewed to determine treatment success rates and the relationship of treatment success to clinical characteristics. RESULTS: ECFs in 26 of the 46 (56.5%) patients were treated successfully with latex catheters. On univariate analysis, the fistulas that originated from the stomach were statistically less likely to close (p = 0.03), whereas those originating from the small bowel were more likely to close (p = 0.01). The duration of treatment was significantly longer in patients for whom the treatment failed than in those who were successfully treated (p = 0.003). After a total treatment time of more than 116 days (odds ratio [OR], 9.8 [95% CI, 2.5-38.4]; p = 0.001) or latex catheter treatment time of more than 74 days (OR, 8.9 [95% CI, 2.2-35.0]; p = 0.002), the chance of ECF closure decreased significantly. CONCLUSION: Treatment of ECFs that are resistant to simple abscess cavity drainage with a latex catheter is possible and decreases the need for surgery.

Effect of MRI Versus MDCT on Milan Criteria Scores and Liver Transplantation Eligibility.

OBJECTIVE: The Milan criteria for the selection of patients with hepatocellular carcinoma (HCC) for liver transplantation were originally based on the findings of contrast-enhanced CT examinations. Studies have shown improvement in HCC detection of using contrast-enhanced MRI instead of CT, but they have provided little information on the potential downstream effect on patient management that might result from discrepant imaging findings. We sought to assess the effect of discrepant imaging findings on patient eligibility to undergo liver transplantation. MATERIALS AND METHODS: From 2006 to 2013, patients with a diagnosis of HCC who underwent both MDCT and MRI examinations within a 40-day period were studied retrospectively. All examinations were independently reviewed by two abdominal radiologists who recorded the number, diameter, and location of each lesion. Secondary confirmation of the lesions was made on the basis of histopathologic findings, diffusion restriction on DWI, increased T2 signal intensity, lesion growth, presence of fat, uptake of ethiodized oil, or a combination of these findings. RESULTS: Sixty-four patients (48 men and 16 women; mean age, 62 years) met the criteria for inclusion in the study. Of the 129 lesions identified by MRI, only 102 of these lesions (79%) were identified by MDCT. This discrepancy led to a difference in the Milan criteria scoring for nine patients (14%). There was no statistically significant difference in the mean (± SD) greatest lesion diameter measured using the two modalities, with measurements of 3.52 ± 2.8 cm and 3.46 ± 2.8 cm noted on MDCT and MRI, respectively (p = 0.8). Lesions missed on MDCT studies tended to be smaller, with a mean diameter of 2.7 cm. Of the 129 lesions identified by MRI, 112 (87%) had available histopathologic findings or other confirmatory diagnostic evidence. CONCLUSION: MDCT missed one-fifth of the HCC lesions detected by MRI. Had MDCT been the only imaging examination performed, failure to identify these lesions would have led to a different management plan for 14% of patients.

Muscle-specific AMPK ß1ß2-null mice display a myopathy due to loss of capillary density in nonpostural muscles.

AMP-activated protein kinase (AMPK) is a master regulator of metabolism. While muscle-specific AMPK ß1ß2 double-knockout (ß1ß2M-KO) mice display alterations in metabolic and mitochondrial capacity, their severe exercise intolerance suggested a secondary contributor to the observed phenotype. We find that tibialis anterior (TA), but not soleus, muscles of sedentary ß1ß2M-KO mice display a significant myopathy (decreased myofiber areas, increased split and necrotic myofibers, and increased centrally nucleated myofibers. A mitochondrial- and fiber-type-specific etiology to the myopathy was ruled out. However, ß1ß2M-KO TA muscles displayed significant (P<0.05) increases in platelet aggregation and apoptosis within myofibers and surrounding interstitium (P<0.05). These changes correlated with a 45% decrease in capillary density (P<0.05). We hypothesized that the ß1ß2M-KO myopathy in resting muscle resulted from impaired AMPK-nNOSµ signaling, causing increased platelet aggregation, impaired vasodilation, and, ultimately, ischemic injury. Consistent with this hypothesis, AMPK-specific phosphorylation (Ser1446) of nNOSµ was decreased in ß1ß2M-KO compared to wild-type (WT) mice. The AMPK-nNOSµ relationship was further demonstrated by administration of 5-aminoimidazole-4-carboxamide 1-ß-D-ribofuranoside (AICAR) to ß1ß2-MKO muscles and C2C12 myotubes. AICAR significantly increased nNOSµ phosphorylation and nitric oxide production (P<0.05) within minutes of administration in WT muscles and C2C12 myotubes but not in ß1ß2M-KO muscles. These findings highlight the importance of the AMPK-nNOSµ pathway in resting skeletal muscle.

Conservative Management of Invasive Placenta Using Combined Prophylactic Internal Iliac Artery Balloon Occlusion and Immediate Postoperative Uterine Artery Embolization.

PURPOSE: The objective of the study was to evaluate the efficacy and safety of combined prophylactic intraoperative internal iliac artery balloon occlusion and postoperative uterine artery embolization in the conservative management (uterine preservation) of women with invasive placenta undergoing scheduled caesarean delivery. METHODS: Ten women (mean age 35 years) with invasive placenta choosing caesarean delivery without hysterectomy had preoperative insertion of internal iliac artery occlusion balloons, intraoperative inflation of the balloons, and immediate postoperative uterine artery embolization with absorbable gelatin sponge. A retrospective review was performed with institutional review board approval. Outcome measures were intraoperative blood loss, transfusion requirement, hysterectomy rate, endovascular complications, surgical complications, and postoperative morbidity. RESULTS: All women had placenta increta or percreta, and concomitant complete placenta previa. Mean gestational age at delivery was 36 weeks. In 6 women the placenta was left undisturbed in the uterus, 2 had partial removal of the placenta, and 2 had piecemeal removal of the whole placenta. Mean estimated blood loss during caesarean delivery was 1.2 L. Only 2 patients (20%) required blood transfusion. There were no intraoperative surgical complications, endovascular complications, maternal deaths, or perinatal deaths. Three women developed postpartum complications necessitating postpartum hysterectomy; the hysterectomy rate was therefore 30% and uterine preservation was successful in 70%. CONCLUSION: Combined bilateral internal iliac artery balloon occlusion and uterine artery embolization may be an effective strategy to control intraoperative blood loss and preserve the uterus in patients with invasive placenta undergoing caesarean delivery.

Practical Considerations When Choosing Chemoembolization versus Radioembolization for Hepatocellular Carcinoma.

Transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) are common liver-directed therapies (LDTs) for unresectable HCC. While both deliver intra-arterial treatment directly to the site of the tumor, they differ in mechanisms of action and side effects. Several studies have compared their side effect profile, time to progression, and overall survival data, but often these lack practical considerations when choosing which treatment modality to use. Many factors can impact operator's choice for treatment, and the choice depends on treatment availability, cost, insurance coverage, operator's comfort level, patient-specific factors, tumor location, tumor biology, and disease stage. This review discusses survival data, time to progression data, as well as more practical patient and tumor characteristics for personalized LDT with TACE or TARE.

Lung shunt fraction calculations before Y-90 transarterial radioembolization: Comparison of accuracy and clinical significance of planar scintigraphy and SPECT/CT.

PURPOSE: To determine the accuracy and clinical significance of planar scintigraphy lung shunt fraction (PLSF) and single-photon emission computerized tomography (SPECT) computed tomography (CT) lung shunt fraction (SLSF) before Y-90 transarterial radioembolization. MATERIALS AND METHODS: Seventy patients (46 men, 24 women; mean age, 64 ± 9.5 [SD] years) who underwent 83 treatments with Y-90 transarterial radioembolization for primary or secondary malignancies of the liver with a PLSF ≥ 7.5% were retrospectively evaluated. The patients mapping technetium 99 m (Tc-99 m) macroaggregated albumin (MAA) PLSF and SLSF were calculated and compared to the post Y-90 delivery SLSF. A model using modern dose thresholds was created to identify patients who would require dose reduction due to a lung dose ≥ 30 Gy, with patients who required >50% dose reduction considered to be delivery cancelations. RESULTS: A significant difference was found between mean PLSF (14.7 ± 11.6 [SD]%; range: 7.5-84.1%) and mean SLSF (8.7 ± 8.5 [SD]%; range: 1.7-73.5) (P < 0.001). The mean realized LSF (7.1 ± 3 [SD]%; range:1.5-17.6) was significantly less than the PLSF (P <0.001) but not the SLSF (P = 0.07). PLSF significantly overestimated the realized LSF by more than the SLSF (8.5 ± 5.3 [SD] % [range: -0.1-21.7] vs. 0.8 ± 3.6 [SD] % [range: -5-13.2], respectively) (P < 0.001). Based on the clinical significance model, 20 patients (20/83, 24.1%) would have required dose reduction or cancelation when using PLSF but would not require even a dose reduction when using the SLSF. Significantly more deliveries would have been be canceled if PLSF was used as compared to SLSF (22/83 [26.5%] vs. 6/83 [7.2%], respectively) (P < 0.001). CONCLUSION: SLSF is significantly more accurate at predicting realized LSF than PLSF and this difference is of clinical significance in a number of patients with a PLSF ≥ 7.5%.

Evaluation of Inflammatory Scores in Metastatic Colorectal Cancer Patients Undergoing Transarterial Radioembolization.

PURPOSE: To evaluate the correlation of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), aspartate aminotransferase-to-lymphocyte ratio (ALRI), systemic inflammation index (SII), and lymphocyte count to oncologic outcomes in metastatic colorectal cancer (mCRC) patients undergoing transarterial radioembolization (TARE). MATERIALS AND METHODS: All patients undergoing TARE for mCRC were retrospectively reviewed at a single academic institution. A receiver operating characteristics (ROC) curve analysis was performed using a landmark survival point of 12 months, with an area under the curve (AUC) calculated. A cutoff point was determined by Youden's index and used to separate patients for OS and PFS analysis. Cox proportional-hazards models which included pertinent clinical factors were also created to evaluate PFS and OS. RESULTS: In total, 41 patients who underwent 66 TARE treatments were included. A correlation was seen between post-treatment ALRI < 45 (HR: 0.38 (95%CI: 0.17-0.86), p = 0.02) and PFS. Patients with a pretreatment ALRI score < 20 had a significantly longer OS (HR: 0.49 (95%CI: 0.19-0.88), p = 0.02) as did those with a post-treatment lymphocyte count > 1.1 109/L (HR: 0.27 (95%CI: 0.11-0.68), p = 0.005). In multivariate analysis of PFS, post-treatment lymphocyte count (HR: 8.46 (95%CI: 1.14-62.89), p = 0.044) was the only significantly associated inflammatory marker and presence of extrahepatic disease (HR:8.46 (95%CI: 1.14-62.89, p = 0.044) also correlated. Multivariate analysis of OS showed that pretreatment PLR (HR:1.01 (95%CI:1.-1.03), p = 0.02) and post-treatment NLR (HR:0.33 (95%CI:0.14-0.76), p = 0.009), PLR (HR:0.98 (95%CI:0.97-1), p = 0.046), SII (HR:1.04 (95%CI:1.01-1.08), p = 0.014), and lymphocyte count (HR:0.07 (95%CI:0.01-0.16), p = 0.003) were significantly associated. CONCLUSION: Inflammatory markers may be associated with OS and PFS in mCRC patients undergoing TARE.

Intrahepatic cholangiocarcinoma: a dose threshold evaluation in those undergoing transarterial radioembolization.

Background: Intrahepatic cholangiocarcinoma (ICC) is a rare primary hepatic malignancy. One of the treatment strategies which has shown some promise is transarterial radioembolization (TARE). However, data on dose thresholds, arguably the most important aspect of the procedure itself, is still limited. The study aims to evaluate the relationship between dose to tumor and radiologic response in intrahepatic cholangiocarcinoma patients undergoing transarterial radioembolization. Methods: Twenty-patients who underwent treatment for 26 tumors were retrospectively reviewed. Radiologic response at 3-month was evaluated and post yttrium-90 bremsstrahlung single photon emission computerized tomography computed tomography was evaluated to determine tumor dose. Other factors such as particle load and activity per particle were evaluated. Results: The mean tumor dose for those with progressive disease or stable disease, partial response, and complete response (CR) by European Association for the Study of Liver (EASL) criteria for the glass cohort was 294±0, 465.4±292.4 and 951.8±666.5 Gy respectively (P=0.039). A receiver operating characteristic (ROC) curve analysis of tumor dose demonstrated an area under the curve (AUC) of 0.738 (P=0.038) with Youden-index analysis demonstrated a cutoff point of >541.7 Gy (sensitivity: 55.56%; specificity: 92.86%) for the glass cohort. Significantly longer survival was noted in those who achieved a CR [HR: 4.79 (95% CI: 1.41-16.25)] and those treated with glass as compared to resin [HR: 5.02 (95% CI: 1.23-20.55), P=0.025]. Of the 17 treatments in 13 patients which were done concomitantly with chemotherapy 7/17 (41.2%) required a delay in chemotherapy, however all patients reinitiated chemotherapy after a delay. Conclusions: There appears to be a relationship between tumor dose and radiologic response, with this study suggesting a target of ≥541.7 Gy being warranted in patients receiving treatment with glass microspheres.

Thermal Ablation in the Liver: Heat versus Cold-What Is the Role of Cryoablation?

Cryoablation is commonly used in the kidney, lung, breast, and soft tissue, but is an uncommon choice in the liver where radiofrequency ablation (RFA) and microwave ablation (MWA) predominate. This is in part for historical reasons due to serious complications that occurred with open hepatic cryoablation using early technology. More current technology combined with image-guided percutaneous approaches has ameliorated these issues and allowed cryoablation to become a safe and effective thermal ablation modality for treating liver tumors. Cryoablation has several advantages over RFA and MWA including the ability to visualize the ice ball, minimal procedural pain, and strong immunomodulatory effects. This article will review the current literature on cryoablation of primary and secondary liver tumors, with a focus on efficacy, safety, and immunogenic potential. Clinical scenarios when it may be more beneficial to use cryoablation over heat-based ablation in the liver, as well as directions for future research, will also be discussed.

Radiation induces long-term muscle fibrosis and promotes a fibrotic phenotype in fibro-adipogenic progenitors.

BACKGROUND: Radiation-induced muscle pathology, characterized by muscle atrophy and fibrotic tissue accumulation, is the most common debilitating late effect of therapeutic radiation exposure particularly in juvenile cancer survivors. In healthy muscle, fibro/adipogenic progenitors (FAPs) are required for muscle maintenance and regeneration, while in muscle pathology FAPs are precursors for exacerbated extracellular matrix deposition. However, the role of FAPs in radiation-induced muscle pathology has not previously been explored. METHODS: Four-week-old Male CBA or C57Bl/6J mice received a single dose (16 Gy) of irradiation (IR) to a single hindlimb with the shielded contralateral limb (CLTR) serving as a non-IR control. Mice were sacrificed 3, 7, 14 (acute IR response), and 56 days post-IR (long-term IR response). Changes in skeletal muscle morphology, myofibre composition, muscle niche cellular dynamics, DNA damage, proliferation, mitochondrial respiration, and metabolism and changes in progenitor cell fate where assessed. RESULTS: Juvenile radiation exposure resulted in smaller myofibre cross-sectional area, particularly in type I and IIA myofibres (P < 0.05) and reduced the proportion of type I myofibres (P < 0.05). Skeletal muscle fibrosis (P < 0.05) was evident at 56 days post-IR. The IR-limb had fewer endothelial cells (P < 0.05) and fibro-adipogenic progenitors (FAPs) (P < 0.05) at 56 days post-IR. Fewer muscle satellite (stem) cells were detected at 3 and 56 days in the IR-limb (P < 0.05). IR induced FAP senescence (P < 0.05), increased their fibrogenic differentiation (P < 0.01), and promoted their glycolytic metabolism. Further, IR altered the FAP secretome in a manner that impaired muscle satellite (stem) cell differentiation (P < 0.05) and fusion (P < 0.05). CONCLUSIONS: Our study suggests that following juvenile radiation exposure, FAPs contribute to long-term skeletal muscle atrophy and fibrosis. These findings provide rationale for investigating FAP-targeted therapies to ameliorate the negative late effects of radiation exposure in skeletal muscle.

mRNA stability as a function of striated muscle oxidative capacity.

A change in mRNA stability alters the abundance of mRNA available for translation and is emerging as a critical pathway influencing gene expression. Variations in the stability of functional and regulatory mitochondrial proteins may contribute to the divergent mitochondrial densities observed in striated muscle. Thus we hypothesized that the stability of mRNAs encoding for regulatory nuclear and mitochondrial transcription factors would be inversely proportional to muscle oxidative capacity and would be facilitated by the activity of RNA binding proteins (RBPs). The stability of mitochondrial transcription factor A (Tfam), peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), and nuclear respiratory factor 2α (NRF-2α) mRNA was assessed in striated muscles with distinct oxidative capacities using in vitro decay assays. All three mitochondrial regulators were rapidly degraded in cardiac and slow-twitch red (STR) muscle, resulting in a ∼60-65% lower (P < 0.05) mRNA half-life (t(1/2)) compared with fast-twitch white (FTW) fibers. This accelerated rate of Tfam mRNA decay was matched by a 2.5-fold increase in Tfam transcription in slow- compared with fast-twitch muscle (P = 0.05). Protein expression of four unique RBPs [AU-rich binding factor 1 (AUF1), human antigen R (HuR), KH-homology splicing regulatory protein (KSRP), and CUG binding protein 1 (CUGBP1)] believed to modulate mRNA stability was elevated in cardiac and STR muscles (P < 0.05) and was moderately associated with the decay of Tfam, PGC-1α, and NRF-2α mRNA. Variable rates of transcript degradation were apparent when comparing all transcripts within the same muscle type. Thus the distribution of RBPs appears to follow a fiber-type specific pattern and subsequently functions to alter the stability of specific mitochondrial regulators in a transcript- and tissue-specific fashion.

Lung shunt fraction quantification methods in radioembolization: What you need to know.

In some patients undergoing radioembolization, lung toxicity is a limiting factor when calculating their dose. At the same time, it is known that the lung shunt fraction (LSF) is overestimated by the mapping exam. Furthermore, there are multiple methods to measure LSF. Planar measurement is both the most commonly utilized and easiest to perform, however new dosimetry software provides the ability to use more advanced 3D techniques. This paper reviews the different LSF calculation methods and elucidates the available data comparing the techniques, clinical relevance, and dose calculation.

Inflammatory Scores: Correlation with Clinical Outcomes in Hepatocellular Carcinoma Patients Undergoing Transarterial Radioembolization.

PURPOSE: To evaluate the ability of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), aspartate aminotransferase-to-lymphocyte ratio (ALRI) and systemic-inflammation index (SII) to predict clinical outcomes in hepatocellular carcinoma (HCC) patients undergoing transarterial radioembolization (TARE). MATERIALS AND METHODS: One hundred forty-five patients who underwent treatment of 167 HCCs had their pretreatment and 1 month post treatment laboratory values evaluated. Overall survival (OS), progression-free survival (PFS) and local PFS models were performed with patients separated by median inflammatory scores. RESULTS: The median pretreatment NLR, PLR, ALRI and SII were 3.0 (range: 0.5-176), 104.4 (range: 25-830), 55.7 (range: 7.5-2090) and 360.2 (range: 51.1-7207.8), respectively. While the median post treatment NLR, PLR, ALRI and SII were 6.2 (range: 0.4-176), 180 (range: 35-2100), 125 (range: 15.9-5710) and 596.8 (range: 28.9-19,320), respectively. OS models showed significant differences when separating the groups by median post treatment NLR (p = 0.003) and SII (p = 0.003). Multivariate Cox regression models for OS with all pre and post treatment inflammatory markers (log-scale) as well as tumor size, AFP and Child-Pugh score showed significant pretreatment NLR [HR: 0.22 (95% CI:0.06-0.75), p = 0.016] and SII [3.52 (95% CI: 1.01-12.3), p = 0.048], as well as post treatment NLR [6.54 (95% CI: 1.57-27.2), p = 0.010] and SII [0.20 (95% CI: 0.05-0.82), p = 0.025] association. The post treatment ALRI (p = 0.010) correlated with PFS while, post treatment NLR (p < 0.001), ALRI (p = 0.024) and SII (p = 0.005) correlated with local PFS. CONCLUSION: Pretreatment and post treatment NLR and SII may be associated with OS and post treatment ALRI may be associated with both PFS and local PFS in HCC patients undergoing TARE.

Dynamic Lymphocyte Changes Following Transarterial Radioembolization: Association with Normal Liver Dose and Effect on Overall Survival.

OBJECTIVE: To evaluate the dynamic changes of lymphocytes following transarterial radioembolization (TARE) for hepatocellular carcinoma (HCC) and their relationship to normal liver dose (NLD). MATERIALS AND METHODS: A total of 93 patients who underwent 102 treatments were retrospectively reviewed. Absolute lymphocyte counts pretreatment and at 1, 3, 6, and 12 months were evaluated. Kaplan-Meier, Spearman correlation, receiver operating characteristic (ROC) curve, and area under the curve (AUC) analyses were performed. RESULTS: The mean absolute lymphocyte count at baseline was 1.25 ± 0.79 103/µL which was significantly greater than 1 (0.71 ± 0.47 103/µL, p<0.0001), 3 (0.79 ± 0.77 103/µL, p=0.0003), and 6 (0.81 ± 0.44 103/µL, p=0.0001) months, but not significantly different than 12 (0.92 ± 0.8 103/µL, p=0.12) months post treatment. There was a modest negative correlation between NLD and lymphocyte count at 1 month (rho= -0.216, p=0.03), which strengthened at 3 months post treatment (rho= -0.342, p=0.008). AUC of ROC analysis between absolute lymphocyte count ≤1 103/µL or >1 103/µL at 1, 3, 6, and 12 months post treatment was 0.625, 0.676, 0.560, and 0.794, respectively. Univariate analysis of overall survival when separating patients by a lymphocyte count of ≤1 103/µL and >1 103/µL demonstrated a significant difference at 1 (HR: 0.56, 95% CI: 0.33-0.95, p=0.03), 3 (HR: 0.41, 95% CI: 0.18-0.94, p=0.035) and 6 (HR: 0.36, 95% CI: 0.17-0.77, p=0.008) months post treatment, but not pretreatment or at 12 months. CONCLUSION: NLD may correlate with lymphocyte depression at 1 and 3 months and lymphopenia may portend a worse overall survival in the post treatment setting.

Local recurrence following complete radiologic response in patients treated with transarterial chemoembolization for hepatocellular carcinoma.

PURPOSE: The purpose of this study was to determine the local progression rate and identify factors that may predict local progression, in patients who achieve a complete response (CR) radiologically after undergoing transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: One-hundred-forty-seven patients, who achieved CR of 224 HCCs after TACE, were retrospectively reviewed. There were 109 men and 38 women with a mean age of 61.6 ± 6.8 (SD) years (range: 45.4-86.9 years). Logistic mixed-effects and Cox regression models were used to evaluate associations between clinical factors and local progression. RESULTS: A total of 75 patients (75/147; 51%) and 99 (99/224,44.2%) lesions showed local progression at a median of 289.5 days (Q1: 125, Q3: 452; range: 51-2245 days). Pre-treatment, international normalization ratio (INR) (1.17 ± 0.15 [SD] vs. 1.25 ± 0.16 [SD]; P <0.001), model for end-stage liver disease (9.4 ± 2.6 [SD] vs. 10.6 ± 3.2 [SD]; P = 0.010) and Child-Pugh score (6 ± 1 [SD] vs. 6.4 ± 1.3 [SD]; P = 0.012) were significantly lower while albumin serum level (3.4 ± 0.62 [SD] vs. 3.22 ± 0.52 [SD]; P = 0.033) was significantly greater in those who showed local progression as compared to those who did not. In terms of local-recurrence free survival, the number of TACE treatments (hazard ratio [HR]: 2.05 [95% CI: 1.57-2.67]; P<0.001), INR (HR: 0.13 [95% CI: 0.03-0.61]; P = 0.010) and type of TACE (P = 0.003) were significant. Patients with local progression on any tumor did not differ from those who did in terms of overall survival (P = 0.072), however, were less likely to be transplanted (20/75, 26.7%) than those who did not (33/72; 36.1%) (P = 0.016). CONCLUSION: A significant number of patients who achieve CR of HCC after TACE have local progression. This emphasizes the importance of long-term follow up.