Safety and feasibility of initiating a hepatic artery infusion pump chemotherapy program for unresectable colorectal liver metastases: A multicenter, retrospective cohort study.

INTRODUCTION: Hepatic artery infusion pump (HAIP) chemotherapy is a specialized therapy for patients with unresectable colorectal liver metastases (uCRLM). Its effectiveness was demonstrated from a high volume center, with uncertainty regarding the feasibility and safety at other centers. Therefore, we sought to assess the safety and feasibility of HAIP for the management of uCRLM at other centers. METHODS: We conducted a multicenter retrospective cohort study of patients with uCRLM treated with HAIP from January 2003 to December 2017 at six North American centers initiating the HAIP program. Outcomes included the safety and feasibility of HAIP chemotherapy. RESULTS: We identified 154 patients with HAIP insertion and the median age of 54 (48-61) years. The burden of disease was >10 intra-hepatic metastatic foci in 59 (38.3%) patients. Patients received at least one cycle of systemic chemotherapy before HAIP insertion. Major complications occurred in 7 (4.6%) patients during their hospitalization and 13 (8.4%) patients developed biliary sclerosis during follow-up. A total of 148 patients (96.1%) received at least one-dose of HAIP chemotherapy with a median of 5 (4-7) cycles. 78 patients (56.5%) had a complete or partial response and 12 (7.8%) received a curative liver resection. CONCLUSION: HAIP programs can be safely and effectively initiated in previously inexperienced centers with good response.

Does graft hemodynamics affect the risk of hepatocellular carcinoma recurrence after liver transplantation?

Although experimental studies have reported that hepatic ischemia-reperfusion injury promotes tumor growth and metastases, the impact of graft hemodynamics on the recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is unclear. To investigate the association between graft hemodynamics and HCC recurrence after LT, we conducted a retrospective analysis of 279 patients who underwent LT for HCC. Graft hemodynamics including portal vein flow (PVF), hepatic artery flow (HAF), and total hepatic flow (THF) was analyzed as a predictor of HCC recurrence, using competing risk regression analyses. The cutoff values of PVF, HAF, and THF were set at the lower quartile of distribution. A cumulative recurrence curve demonstrated that low THF (<1511 mL/min, P = .005) was significantly associated with increased recurrence, whereas neither low PVF (<1230 mL/min, P = .150) nor low HAF (<164 mL/min, P = .110) was significant. On multivariate analysis, outside Milan criteria (sub-hazard ratio [SHR] = 3.742; P < .001), microvascular invasion (SHR = 3.698; P < .001), and low THF (SHR = 2.359; P = .010) were independently associated with increased HCC recurrence. In conclusion, our findings suggest that graft hemodynamics may play an important role in HCC recurrence after LT.

A comparison of indocyanine green fluorescence and laparoscopic ultrasound for detection of liver tumors.

BACKGROUND: Indocyanine green (ICG) fluorescence imaging (ICG-FI) has been suggested for intraoperative identification of liver tumors. We aim to compare the intraoperative diagnostic utility of this imaging modality with laparoscopic ultrasound (LUS). METHODS: This is an IRB-approved prospective study. ICG was administered intravenously 1-2 days before surgery. The findings on ICG-FI were compared to those on preoperative cross-sectional imaging (POCSI), LUS, diagnostic laparoscopy (DL). RESULTS: A total of 144 lesions (62 superficial [visible on DL] and 82 deep) were detected in the study patients. POCSI identified 74%, LUS identified 92%, and ICG-FI identified 43%. ICG-FI detection rate was higher for superficial (95%) versus deep lesions (4%). 3% (4/144) of all lesions were seen only on ICG-FI. However, all of these lesions were small and superficial lesions that were apparent on DL. CONCLUSION: Although ICG-FI allowed detection of small superficial lesions that were not identifiable by POCSI or LUS, these lesions were apparent on DL even before ICG-FI. Therefore, its utility as an intraoperative diagnostic modality is limited at the dosage and timing used in the study. We believe that rather than a diagnostic tool, it has more potential for a dynamic use in guiding the resection of superficial lesions and delineating segmental/lobar anatomy.

Impact of temperature on the magnitude and duration of relief after lumbar facets medial branch nerves radiofrequency ablation: a randomized double-blinded study.

INTRODUCTION: There are numerous studies appraising the variables that may influence the clinical outcomes after lumbar thermal radiofrequency ablation (RFA). Expanding the lesion size may increase the likelihood of capturing the target nerves in the lesion, thereby increasing the technical success rate of RFA. However, our literature search has failed to identify a consensus on the optimal target temperature. A retrospective study demonstrated that there seems to be significant functional improvement associated with the temperature of 90°C compared with 80°C. The authors prospectively studied the subject in a double-blinded randomized fashion. METHODS: Patients undergoing RFA for lumbar facetogenic pain were randomized in two cohorts (80°C and 90°C). Physicians and patients were blinded to the temperature used. The primary outcome was self-reported pain scores up to 12 months. Secondary outcomes included: self-reported functional improvement, duration of relief as measured by the time before repeat ablation of the same medial branches nerves, opioids' consumption, and patient satisfaction. RESULTS: Both groups reported pain improvement in all follow-up time points. Overall, both groups achieved statistically significant pain reduction (p<0.05). The median time to repeat RFA in the 80°C group was 112 (49-252) days, while it was 217 (198-348) days in the 90°C group (p<0.04). The univariate analysis emphasized that the RFA temperature is a statistically significant factor for pain improvement of more than 50%, OR 2.7 (1.1 to 6.6) p value=0.031. CONCLUSION: RFA has been demonstrated as an effective therapeutic modality for lumbar facetogenic back pain. Yet, the several factors involved in determining a favorable outcome of this procedure require further research and optimization. This prospective double-blinded randomized trial demonstrated that RFA at both temperatures (80°C, 90°C) provided significance at all the time periods examined. However, RFA at 90°C was superior to 80°C in regard to the duration of relief.

Salivary miRNAs as non-invasive biomarkers of hepatocellular carcinoma: a pilot study.

BACKGROUND: Improved detection of hepatocellular carcinoma (HCC) is needed, as current detection methods, such as alpha fetoprotein (AFP) and ultrasound, suffer from poor sensitivity. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate many cellular functions and impact cancer development and progression. Notably, miRNAs are detectable in saliva and have shown potential as non-invasive biomarkers for a number of cancers including breast, oral, and lung cancers. Here, we present, to our knowledge, the first report of salivary miRNAs in HCC and compare these findings to patients with cirrhosis, a high-risk cohort for HCC. METHODS: We performed small RNA sequencing in 20 patients with HCC and 19 with cirrhosis. Eleven patients with HCC had chronic liver disease, and analyses were performed with these samples combined and stratified by the presence of chronic liver disease. P values were adjusted for multiple comparisons using a false discovery rate (FDR) approach and miRNA with FDR P < 0.05 were considered statistically significant. Differential expression of salivary miRNAs was compared to a previously published report of miRNAs in liver tissue of patients with HCC vs cirrhosis. Support vector machines and leave-one-out cross-validation were performed to determine if salivary miRNAs have predictive potential for detecting HCC. RESULTS: A total of 4,565 precursor and mature miRNAs were detected in saliva and 365 were significantly different between those with HCC compared to cirrhosis (FDR P < 0.05). Interestingly, 283 of these miRNAs were significantly downregulated in patients with HCC. Machine-learning identified a combination of 10 miRNAs and covariates that accurately classified patients with HCC (AUC = 0.87). In addition, we identified three miRNAs that were differentially expressed in HCC saliva samples and in a previously published study of miRNAs in HCC tissue compared to cirrhotic liver tissue. CONCLUSIONS: This study demonstrates, for the first time, that miRNAs relevant to HCC are detectable in saliva, that salivary miRNA signatures show potential to be highly sensitive and specific non-invasive biomarkers of HCC, and that additional studies utilizing larger cohorts are needed.

Salivary Metabolites are Promising Non-Invasive Biomarkers of Hepatocellular Carcinoma and Chronic Liver Disease.

BACKGROUND: Hepatocellular carcinoma (HCC) is a leading causes of cancer mortality worldwide. Improved tools are needed for detecting HCC so that treatment can begin as early as possible. Current diagnostic approaches and existing biomarkers, such as alpha-fetoprotein (AFP) lack sensitivity, resulting in too many false negative diagnoses. Machine-learning may be able to identify combinations of biomarkers that provide more robust predictions and improve sensitivity for detecting HCC. We sought to evaluate whether metabolites in patient saliva could distinguish those with HCC, cirrhosis, and those with no documented liver disease. METHODS AND RESULTS: We tested 125 salivary metabolites from 110 individuals (43 healthy, 37 HCC, 30 cirrhosis) and identified 4 metabolites that displayed significantly different abundance between groups (FDR P <.2). We also developed four tree-based, machine-learning models, optimized to include different numbers of metabolites, that were trained using cross-validation on 99 patients and validated on a withheld test set of 11 patients. A model using 12 metabolites -octadecanol, acetophenone, lauric acid, 1-monopalmitin, dodecanol, salicylaldehyde, glycyl-proline, 1-monostearin, creatinine, glutamine, serine and 4-hydroxybutyric acid- had a cross-validated sensitivity of 84.8%, specificity of 92.4% and correctly classified 90% of the HCC patients in the test cohort. This model outperformed previously reported sensitivities and specificities for AFP (20-100ng/ml) (61%, 86%) and AFP plus ultrasound (62%, 88%). CONCLUSIONS AND IMPACT: Metabolites detectable in saliva may represent products of disease pathology or a breakdown in liver function. Notably, combinations of salivary metabolites derived from machine-learning may serve as promising non-invasive biomarkers for the detection of HCC.

Lateral transorbital canthopexy using a silicone tube in patients with paralytic ectropion.

PURPOSE: We describe the efficacy of lateral transorbital canthopexy using a silicone tube in managing severe paralytic ectropion. METHODS: Patients with paralytic ectropion involving at least two-third of lower eyelid length and scleral exposure of 3 mm or more were considered. A silicone prosthetic was inserted during canthopexy. RESULTS: Lateral transorbital canthopexy using a silicone tube was performed on 10 eyelids in nine patients. All patients had corneal surface abnormalities. Scleral exposure resolved completely in three cases. At 8-month follow-up, residual scleral exposure of 1 mm and 2 mm persisted in n = 6 and n = 1 cases, respectively. CONCLUSIONS: Lateral transorbital canthopexy using a silicone tube is an effective therapeutic option for paralytic ectropion, facilitating both functional and cosmetic results that proved durable over time.

Breath Metabolomics Provides an Accurate and Noninvasive Approach for Screening Cirrhosis, Primary, and Secondary Liver Tumors.

Hepatocellular carcinoma (HCC) and secondary liver tumors, such as colorectal cancer liver metastases are significant contributors to the overall burden of cancer-related morality. Current biomarkers, such as alpha-fetoprotein (AFP) for HCC, result in too many false negatives, necessitating noninvasive approaches with improved sensitivity. Volatile organic compounds (VOCs) detected in the breath of patients can provide valuable insight into disease processes and can differentiate patients by disease status. Here, we investigate whether 22 VOCs from the breath of 296 patients can distinguish those with no liver disease (n = 54), cirrhosis (n = 30), HCC (n = 112), pulmonary hypertension (n = 49), or colorectal cancer liver metastases (n = 51). This work extends previous studies by evaluating the ability for VOC signatures to differentiate multiple diseases in a large cohort of patients. Pairwise disease comparisons demonstrated that most of the VOCs tested are present in significantly different relative abundances (false discovery rate P < 0.1), indicating broad impacts on the breath metabolome across diseases. A predictive model developed using random forest machine learning and cross validation classified patients with 85% classification accuracy and 75% balanced accuracy. Importantly, the model detected HCC with 73% sensitivity compared with 53% for AFP in the same cohort. An added value of this approach is that influential VOCs in the predictive model may provide insight into disease etiology. Acetaldehyde and acetone, both of which have roles in tumor promotion, were considered important VOCs for differentiating disease groups in the predictive model and were increased in patients with cirrhosis and HCC compared to patients with no liver disease (false discovery rate P < 0.1). Conclusion: The use of machine learning and breath VOCs shows promise as an approach to develop improved, noninvasive screening tools for chronic liver disease and primary and secondary liver tumors.

Hepatobiliary malignancies have distinct peripheral myeloid-derived suppressor cell signatures and tumor myeloid cell profiles.

Myeloid-derived suppressor cells (MDSCs) are immunosuppressive cells that are increased in patients with numerous malignancies including viral-derived hepatocellular carcinoma (HCC). Here, we report an elevation of MDSCs in the peripheral blood of patients with other hepatobiliary malignancies including non-viral HCC, neuroendocrine tumors (NET), and colorectal carcinoma with liver metastases (CRLM), but not cholangiocarcinoma (CCA). The investigation of myeloid cell infiltration in HCC, NET and intrahepatic CCA tumors further established that the frequency of antigen-presenting cells was limited compared to benign lesions, suggesting that primary and metastatic hepatobiliary cancers have distinct peripheral and tumoral myeloid signatures. Bioinformatics analysis of The Cancer Genome Atlas dataset demonstrated that a high MDSC score in HCC patients is associated with poor disease outcome. Given our observation that MDSCs are increased in non-CCA malignant liver cancers, these cells may represent suitable targets for effective immunotherapy approaches.

Thoracic spine disc degeneration, translation, and angular motion: An analysis using thoracic spine kinematic MRI (kMRI).

The aim of this study was to evaluate disc degeneration and kinematic changes in translation and angular motion of the thoracic spine using kinematic MRI (kMRI). 105 thoracic spine kMRI were analyzed from T4-5 to T11-12 using MRAnalyzer3. Translational and angular motion were evaluated in neutral, flexion, and extension positions. Thoracic disc height and disc degeneration grading were measured in the neutral position. Intraclass Correlation Coefficients were used to analyze agreement among three observers. The Friedman's test was used to analyze the difference in disc height, disc degeneration, translational motion, and angular motion. The Wilcoxon-signed rank test was used for post-hoc analysis with a Bonferroni correction. A p-value of 0.00625 was used to establish a statistically significant difference. Analysis using the Friedman's test revealed that translational motion, disc height, and disc degeneration were significantly different from T4-5 to T11-12 (p < 0.001). The T4-5 level showed the least translational motion, while the T10-11 showed the most translational motion. The lower thoracic level (T8-12) showed significantly more translational motion, more advanced disc degeneration, and greater disc height than the upper thoracic level (T4-8, p < 0.001). T11-12 showed the most advanced disc degeneration. There was a significant negative correlation between disc degeneration and translational motion at the upper thoracic level (p = 0.013). The lower thoracic region (below T8) had significantly more translational motion, more advanced disc degeneration, and greater disc height. This information is crucial in further understanding thoracic spinal kinematics and may contribute to determining the stopping level in fusion surgeries involving the thoracic spine.

Kinematic analysis of the space available for cord and disc bulging of the thoracic spine using kinematic magnetic resonance imaging (kMRI).

BACKGROUND CONTEXT: The thoracic spine was previously known as a relatively stable region in human spine. Several studies reported that the motion of the thoracic spine and changes in the cross-sectional area of the spinal cord changed with positions in the sagittal plane. The kinematic relationship between the thoracic disc and the space available for cord (SAC) with the positional change is still not well investigated. PURPOSE: The objective of this study was to evaluate the kinematic change of the intervertebral disc and space available for the spinal cord of the thoracic spine using kinematic magnetic resonance imaging (kMRI). STUDY DESIGN: This is a retrospective study. PATIENT SAMPLE: The patient sample included 105 patients who underwent thoracic spine kMRI. OUTCOME MEASUREMENT: Disc bulging and the SAC were evaluated from T4-T5 to T11-T12 in flexion, neutral, and extension positions. METHODS: MRAnalyzer3 (TrueMRI Corporation, Bellflower, CA, USA) was used to analyze disc bulging and SAC from T4-T5 to T11-T12. The Friedman test was used to analyze the differences in disc bulging and SAC between neutral, flexion, and extension positions at each segment. The Wilcoxon signed-rank test was used for post hoc analysis for the significant levels from the Friedman test. RESULTS: The mean value of the thoracic intervertebral disc area from T4-T5 to T11-T12 tended to be larger in flexion than in extension. Initial analysis with the Friedman test revealed a significant difference in disc bulging at T8-T9, T9-T10, and T11-T12 among the three positions (p<.05). Post hoc analysis showed that disc bulging was only significant at T8-T9 between flexion and extension (p<.001), at T9-T10 between neutral and flexion (0.003), and at T9-T10 between flexion and extension (p=.004). The SAC from T4-T5 to T11-T12 tended to be widest in extension and narrowest in flexion. Only T5-T6 exhibited a statistically significant difference in SAC between flexion and extension (p=.002). CONCLUSIONS: The thoracic discs and the SAC from T4-T5 to T11-T12 showed kinematic changes from flexion to extension. The thoracic spinal canal tended to be narrowest in flexion and widest in the extension. Thus, kyphotic deformities could be one of the etiologies for neurogenic deterioration in patients with thoracic myelopathy.