Differential Effects of HDAC6 Inhibition Versus Knockout During Hepatic Ischemia-reperfusion Injury Highlight Importance of HDAC6 C-terminal Zinc-finger Ubiquitin-binding Domain.

BACKGROUND: Ischemia-reperfusion injury (IRI) causes significant morbidity in liver transplantation among other medical conditions. IRI following liver transplantation contributes to poor outcomes and early graft loss. Histone/protein deacetylases (HDACs) regulate diverse cellular processes, play a role in mediating tissue responses to IRI, and may represent a novel therapeutic target in preventing IRI in liver transplantation. METHODS: Using a previously described standardized model of murine liver warm IRI, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were assessed at 24 and 48 h after reperfusion to determine the effect of different HDAC inhibitors. RESULTS: Broad HDAC inhibition with trichostatin-A (TSA) was protective against hepatocellular damage (P < 0.01 for AST and P < 0.05 for ALT). Although HDAC class I inhibition with MS-275 provided statistically insignificant benefit, tubastatin-A (TubA), an HDAC6 inhibitor with additional activity against HDAC10, provided significant protection against liver IRI (P < 0.01 for AST and P < 0.001 for ALT). Surprisingly genetic deletion of HDAC6 or -10 did not replicate the protective effects of HDAC6 inhibition with TubA, whereas treatment with an HDAC6 BUZ-domain inhibitor, LakZnFD, eliminated the protective effect of TubA treatment in liver ischemia (P < 0.01 for AST and P < 0.01 for ALT). CONCLUSIONS: Our findings suggest TubA, a class IIb HDAC inhibitor, can mitigate hepatic IRI in a manner distinct from previously described class I HDAC inhibition and requires the HDAC6 BUZ-domain activity. Our data corroborate previous findings that HDAC targets for therapeutic intervention of IRI may be tissue-specific, and identify HDAC6 inhibition as a possible target in the treatment of liver IRI.

Circulating Tumor DNA (ctDNA) Clearance May Predict Treatment Response in Neoadjuvant Colorectal Cancer Management.

Background: Circulating tumor DNA (ctDNA) is extracellular DNA released by tumors and has been proposed as a marker of residual disease as well as a predictor of disease recurrence in the adjuvant setting. However, data are lacking on the utility of this biomarker in the neoadjuvant setting. Methods: We performed a retrospective study of stage III and IV colorectal cancer patients receiving neoadjuvant treatment at a single institution. Results: Seventeen patients converted from a positive pre-neoadjuvant ctDNA to a negative ctDNA prior to surgery. Five patients remained persistently positive despite systemic treatment. ctDNA conversion was found to be associated with a higher incidence of favorable treatment effect scores on final surgical pathology. There was no difference in recurrence-free survival in this small population. Furthermore, no added benefit was identified for patients receiving additional neoadjuvant therapy after the time of positive to negative ctDNA conversion. Conclusions: This study highlights the potential utility of ctDNA and the need for prospective trials in the neoadjuvant setting to monitor treatment response and guide decisions on treatment duration.

HDAC2 targeting stabilizes the CoREST complex in renal tubular cells and protects against renal ischemia/reperfusion injury.

Histone/protein deacetylases (HDAC) 1 and 2 are typically viewed as structurally and functionally similar enzymes present within various co-regulatory complexes. We tested differential effects of these isoforms in renal ischemia reperfusion injury (IRI) using inducible knockout mice and found no significant change in ischemic tolerance with HDAC1 deletion, but mitigation of ischemic injury with HDAC2 deletion. Restriction of HDAC2 deletion to the kidney via transplantation or PAX8-controlled proximal renal tubule-specific Cre resulted in renal IRI protection. Pharmacologic inhibition of HDAC2 increased histone acetylation in the kidney but did not extend renal protection. Protein analysis demonstrated increased HDAC1-associated CoREST protein in HDAC2-/- versus WT cells, suggesting that in the absence of HDAC2, increased CoREST complex occupancy of HDAC1 can stabilize this complex. In vivo administration of a CoREST inhibitor exacerbated renal injury in WT mice and eliminated the benefit of HDAC2 deletion. Gene expression analysis of endothelin showed decreased endothelin levels in HDAC2 deletion. These data demonstrate that contrasting effects of HDAC1 and 2 on CoREST complex stability within renal tubules can affect outcomes of renal IRI and implicate endothelin as a potential downstream mediator.

The volume-outcome relationship in robotic protectectomy: does center volume matter? Results of a national cohort study.

BACKGROUND: Utilization of robotic proctectomy (RP) for rectal cancer has steadily increased since the inception of robotic surgery in 2002. Randomized control trials evaluating the safety of RP are in process to better understand the role of robotic assistance in proctectomy. This study aimed to characterize the trends in the use of RP for rectal cancer, and to compare oncologic outcomes with center-level RP volume. MATERIALS AND METHODS: 8107 patients with rectal adenocarcinoma who underwent RP were identified in the National Cancer Database (2010-2015). Logistic regression was used to evaluate associations between center-level volume and conversion to open proctectomy, margin status, lymph node yield, 30- and 90-day post-operative mortality, and overall survival. RESULTS: The utilization of RP increased from 2010 to 2015. On multivariate regression, lower center-level volume of RP was associated with significantly higher rates of conversion to open, positive margins, inadequate lymph node harvest (≥ 12), and lower overall survival. The present study was limited by its retrospective design and lack of information regarding disease-specific survival. CONCLUSIONS: This series suggests a volume-outcome relationship association; patients who have robot-assisted proctectomies performed at low-volume centers are more likely to have poorer overall survival, positive margins, inadequate lymph node harvest, and require conversion to open surgery. While these data demonstrate the increased adoption of robot-assisted proctectomy, an understanding of the appropriateness of this intervention is still lacking. As with any new intervention, further information from ongoing randomized controlled trials is needed to better clarify the role of RP in order to optimize patient outcomes.

Ostomy-Related Complications.

Ileostomy or colostomy formation is an important component of many surgical procedures performed for a wide range of disorders of the gastrointestinal tract. Despite the frequency with which intestinal stomas are created, stoma-related complications remain common and are associated with significant morbidity as well as cost. Some of the most prevalent complications of stoma formation which will be detailed in this article include peristomal skin complications, retraction, stomal necrosis, stomal stenosis, prolapse, bleeding, dehydration from high ostomy output, and parastomal hernia. The authors will review these common complications, detail means to avoid or prevent them, and outline recommendations for management.

Impact of prolonged dialysis prior to renal transplantation.

INTRODUCTION: The new kidney allocation system (KAS) prioritizes patients based on date of dialysis initiation or waitlisting, whichever is earlier. We hypothesized that this change would increase transplant rates for patients with prolonged pretransplant dialysis times (DT) and aimed to assess the impact of prolonged DT on post-transplant outcomes. METHODS: We used United Network for Organ Sharing registry data to assess outcomes for patients added to the renal transplant waitlist from January 1, 1998 to December 31, 2010 and patients transplanted from January 1, 1998 to December 3, 2012. RESULTS: Compared with patients transplanted pre-emptively, patients with <5 years, 5-9 years, and ≥10 years DT had progressively decreased graft and patient survival (P < .001). The rates of short-term complications including delayed graft function, graft loss within 30 days, and patient death within 30 days were significantly higher in cohorts with ≥10 years DT than in cohorts with less DT (P < .001). CONCLUSIONS: Patients with pretransplant DT of ≥10 years had worse outcomes than patients pre-emptively transplanted or transplanted with shorter DT. Durations of dialysis dependence beyond 10 years were associated with further deterioration in short-term but not long-term post-transplant outcomes.

Incidence of Occult Intrahepatic Metastasis in Hepatocellular Carcinoma Treated With Transplantation Corresponds to Early Recurrence Rates After Partial Hepatectomy.

OBJECTIVE: This study aimed to compare the incidence of radiologically unrecognized (occult) hepatocellular carcinoma (HCC) lesions in explant hepatectomy specimens from orthotopic liver transplants (OLTs) performed for HCC with rates of HCC intrahepatic recurrence after resection. SUMMARY OF BACKGROUND DATA: Resection of HCC is associated with high rates of intrahepatic HCC recurrence. However, it is unclear whether these recurrences represent incomplete resection of unrecognized metastatic lesions from the primary tumor or subsequent de novo tumor formation due to inherent biological proclivity for HCC formation. METHODS: We collected patient, tumor, and pathology data on HCC patients treated surgically from 3696 OLTs in the Organ Procurement and Transplantation (OPTN) national database, 299 OLTs at a single transplant center, and 232 partial hepatectomies from a hepatobiliary cancer center. RESULTS: In the OPTN and high-volume transplant center cohorts, 37% and 42% of patients had occult HCC lesions on explant pathology, respectively. Among cancer center patients, the 2-year recurrence rate was 46%, and 74% of patients who recurred presented with liver only recurrence. CONCLUSION: Although the transplant and resection populations differ, occult multifocality is common in transplant explants and similar to the 46% early recurrence rate following partial hepatectomy. These data suggest that noncurative resection often results from occult intrahepatic multifocality present at the time of resection rather than a malignant predisposition of the remnant liver with de novo tumorigenesis.

Same policy, different impact: Center-level effects of share 35 liver allocation.

Early studies of national data suggest that the Share 35 allocation policy increased liver transplants without compromising posttransplant outcomes. Changes in center-specific volumes and practice patterns in response to the national policy change are not well characterized. Understanding center-level responses to Share 35 is crucial for optimizing the policy and constructing effective future policy revisions. Data from the United Network for Organ Sharing were analyzed to compare center-level volumes of allocation-Model for End-Stage Liver Disease (aMELD) ≥ 35 transplants before and after policy implementation. There was significant center-level variation in the number and proportion of aMELD ≥ 35 transplants performed from the pre- to post-Share 35 period; 8 centers accounted for 33.7% of the total national increase in aMELD ≥ 35 transplants performed in the 2.5-year post-Share 35 period, whereas 25 centers accounted for 65.0% of the national increase. This trend correlated with increased listing at these centers of patients with Model for End-Stage Liver Disease (MELD) ≥ 35 at the time of initial listing. These centers did not overrepresent the total national volume of liver transplants. Comparison of post-Share 35 aMELD to calculated time-of-transplant (TOT) laboratory MELD scores showed that only 69.6% of patients transplanted with aMELD ≥ 35 maintained a calculated laboratory MELD ≥ 35 at the TOT. In conclusion, Share 35 increased transplantation of aMELD ≥ 35 recipients on a national level, but the policy asymmetrically impacted practice patterns and volumes of a subset of centers. Longer-term data are necessary to assess outcomes at centers with markedly increased volumes of high-MELD transplants after Share 35. Liver Transplantation 23 741-750 2017 AASLD.

Improved renal ischemia tolerance in females influences kidney transplantation outcomes.

Experimentally, females show an improved ability to recover from ischemia-reperfusion injury (IRI) compared with males; however, this sex-dependent response is less established in humans. Here, we developed a series of murine renal ischemia and transplant models to investigate sex-specific effects on recovery after IRI. We found that IRI tolerance is profoundly increased in female mice compared with that observed in male mice and discovered an intermediate phenotype after neutering of either sex. Transplantation of adult kidneys from either sex into a recipient of the opposite sex followed by ischemia at a remote time resulted in ischemia recovery that reflected the sex of the recipient, not the donor, revealing that the host sex determines recovery. Likewise, renal IRI was exacerbated in female estrogen receptor α-KO mice, while female mice receiving supplemental estrogen before ischemia were protected. We examined data from the United Network for Organ Sharing (UNOS) to determine whether there is an association between sex and delayed graft function (DGF) in patients who received deceased donor renal transplants. A multivariable logistic regression analysis determined that there was a greater association with DGF in male recipients than in female recipients. Together, our results demonstrate that sex affects renal IRI tolerance in mice and humans and indicate that estrogen administration has potential as a therapeutic intervention to clinically improve ischemia tolerance.

Radiographic assessment of splenic injury without contrast: is contrast truly needed?

INTRODUCTION: Computed tomography (CT) has become an essential tool in the assessment of the stable trauma patient. Intravenous (i.v.) contrast is commonly relied upon to provide superior image quality, particularly for solid-organ injury. However, a substantial proportion of injured patients have contraindications to i.v. contrast. Little information exists concerning the repercussions of CT imaging without i.v. contrast, specifically for splenic injury. METHODS: We performed a retrospective analysis using data from our trauma registry and chart review as part of a quality improvement project at our institution. All patients with splenic injury, during a 3-year period (2008-2010), where a CT of the abdomen without i.v. contrast (DRY) early during their admission were selected. All splenic injuries had to have been verified with abdominal CT imaging with i.v. contrast (CONTRAST) or via intraoperative findings. DRY images were independently read by a single, blinded, radiologist and assessed for parenchymal injury or "suspicious" splenic injury findings and compared with CONTRAST imaging results or intraoperative findings. RESULTS: During the time period of the study, 319 patients had documented splenic injury with 44 (14%) patients undergoing DRY imaging, which was also verified by CONTRAST imaging or operative findings. Splenic parenchymal injury was only visualized in 38% of patients DRY patients. "Suspicious" splenic injury radiographic findings were common. When these less-specific findings for splenic injury were incorporated in the radiographic assessment, DRY imaging had more than 93% sensitivity for detecting splenic injury. CONCLUSION: DRY imaging is increasingly being performed after injury and has a low sensitivity in detecting splenic parenchymal injury. However, less-specific radiographic findings suspicious for splenic injury in combination provide high sensitivity for the detection of splenic injury. These results suggest CONTRAST imaging is preferred to detect splenic injury; however, in those patients who have contraindications to i.v. contrast, DRY imagining may be able to select those who require close monitoring or intervention.

Autopsy as a quality control measure for radiology, and vice versa.

OBJECTIVE: Radiologic studies are anatomic studies lacking the natural full-color, 3D, and microscopic-level examination of autopsies, suggesting that autopsies might be able to serve as quality control for radiology. MATERIALS AND METHODS: Cases in which complete or near-complete autopsies were performed at a university hospital in 2008 were reviewed, and antemortem radiologic diagnoses were compared with corresponding autopsy findings. Discrepancies between antemortem radiologic diagnoses and autopsy findings were categorized. RESULTS: For 729 of the 828 diagnoses reviewed in the study, the pathologic condition in question was thought to be present at the time that a radiologic study of the relevant anatomic region was performed. Of these 729 radiologic diagnoses, 201 (27.6%) were determined to be discrepant from the corresponding autopsy diagnoses (i.e., autopsy deemed correct), but many of these radiologic discrepancies were not of clinical significance. The radiologic error rate considers only the clinically relevant discrepancies categorized as "missed diagnosis" or "misinterpretation"; it was calculated to be 3.3%. Interestingly, 32 autopsy discrepancies (i.e., radiology deemed correct) were also identified in the study. CONCLUSION: The results of this study suggest that even in 2008 patients sometimes died with undiagnosed or misdiagnosed diseases. Radiologic diagnoses discrepant from autopsy findings were consistently identified in this study and show that autopsies can help radiologists sharpen their skills in interpreting radiologic studies and can perhaps serve as quality control for radiology. The results also suggest that radiology can serve as quality control for autopsy.