Intrahepatic Site Research Articles

Early versus Late Recurrence of Hepatocellular Carcinoma after Surgical Resection Based on Post-recurrence Survival: An International Multi-institutional Analysis

Introduction: To define early versus late recurrence based on post-recurrence survival (PRS) among patients undergoing curative resection for hepatocellular carcinoma (HCC). Method: Patients who underwent curative-intent resection for HCC between 2000 and 2017 were identified from an international multi-institutional database. The optimal cut-off time point to discriminate early versus late recurrence was determined relative to PRS. Results: Among 1,004 patients, 443 (44.1%) patients experienced recurrence with a median recurrence-free survival time of 12 months. A cut-off time point of 8 months was defined as the optimal threshold based on sensitivity analyses relative to PRS for early (n=165, 37.2%) versus late relapse (n=278, 62.8%)(p=0.008). Early recurrence was associated with worse PRS (median PRS, 27.0 vs. 43.0 months, p=0.019), as well as Overall survival (OS) (median OS, 32.0 versus 74.0 months, p< 0.001) versus late recurrence. In addition, patients who recurred early were more likely to recur at extra- ± intrahepatic (35.5% vs. 19.8%, p=0.003) sites. Patients undergoing curative re-treatment of late recurrence had a comparable OS with patients who had no recurrence (median OS, 139.0 vs. 140.0 months); patients with early recurrence had inferior OS after curative re-treatment versus patients with no recurrence (median OS, 69.0 vs. 140.0 months, p=0.036), yet still better than patients who received palliative treatment for early recurrence (median OS, 69.0 vs. 21.0 months, p< 0.001). Conclusions: Eight months was identified as the cut-off value to differentiate early versus late recurrence. Curative-intent treatment for recurrent intrahepatic tumors was associated with reasonable long-term outcomes.

Insight into the distinctive paradigm of Human Cytomegalovirus associated intrahepatic and extrahepatic cholestasis in neonates

Human Cytomegalovirus has been implicated as a probable cause for the development of hepatic cholestasis among neonates. Our study tried to ascertain the exact demographic, biochemical and immunological markers to differentially diagnose patients with HCMV associated intrahepatic and extrahepatic cholestasis and also decipher the phylogenetic variability among the viral strains infecting the two groups. A total of 110 neonates collected over a span of 2 years were selected for the study classified into four different groups based on the presence of hepatic cholestasis and active HCMV infection. Our analysis predicted that total Cholesterol, GGT, ALP and TNFα were the only significant biological markers with exact cut-off scores, capable of distinguishing between HCMV associated intrahepatic and extrahepatic cholestasis. We confirmed that in patients belonging to both of these groups, the inflammasome is activated and the extent of this activation is more or less same except for the initial activators NLRP3 and AIM2 respectively. When we performed two separate phylogenetic analyses with HCMV gM and gN gene sequences, we found that in both cases the sequences from the IHC and EHC groups formed almost separate phylogenetic clusters. Our study has shown that the HCMV clinical strains infecting at intrahepatic and extrahepatic sites are phylogenetically segregated as distinct clusters. These two separate groups show different physiological as well as immunological modulations while infecting a similar host.

Preliminary results in unresectable cholangiocarcinoma treated by CT percutaneous irreversible electroporation: feasibility, safety and efficacy.

Cholangiocarcinoma (CC) accounts for about 3% of the gastrointestinal and 10-25% of all hepatobiliary malignancies. It arises from the epithelium of the bile duct and it can be classified in intrahaepatic (ICC), perihilar (PCC) and distal (DCC) cholangiocarcinoma, depending on the anatomical location. About 50-60% of the cases are PCC. Early detection is very difficult for the lack of symptoms, and most of the patients are not resectable at the time of diagnosis. IRE is a non-thermal ablation technique that determines cellular apoptosis by electrical impulses without involving extracellular matrix like MW or RF ablation (MWA and RFA). The aim of our study is to demonstrate the safety, feasibility and efficacy of this procedure in the treatment of cholangiocarcinoma according to our experience. From 2015 to 2019, fifteen patients with unre-sectable perhilar and intrahepatic colangiocarcinoma (7 female and 8 male, mean age 69.2) were referred to our department to be enrolled in our prospective study that was approved by local Ethical Committee. Eight lesions were defined iCC and seven of them pCC. Six patients had biliary STENT and four external percutaneous transhepatic biliary drainage (PTBD). The IRE procedure was performed to expert radiologist (G.B.) under CT guidance using the Nanoknife IRE device (Angiodynamics, Queensbury, NY). The data before and after treatment were compared using Wilcoxon Rank Test and the survival outcome was evaluated using Kaplan Meyer Test. All procedures performed under CT guidance have been successfully completed. Treated lesions were located seven perhilar and eight intrahepatic sites and showed a mean volume 66.3 (SD 70.9; IC ranged from 5.57 to 267.20 cm3). No major complications were observed. From 30 to 90days, the mortality rate was around 0%. Progression of the disease in all cases were not observed. Only one patient was reported increase of the Ca19-9 without sign of pancreatitis and bile obstruction. The imaging follow-up showed the local disease control with a decrease of the entire volume of the lesion and a further reduction of the densitometric values. From the comparison between the mean volumes for each group (before and after treatment), the Wilcoxon Rank test demonstrated the statistical significant difference with a p value < 0.01. On the contrary, it is believed that this results encouraging in considering the IRE procedure the safe, feasible and effective method in the treatment of the CC.

Early Versus Late Recurrence of Hepatocellular Carcinoma After Surgical Resection Based on Post-recurrence Survival: an International Multi-institutional Analysis

BackgroundTo define early versus late recurrence based on post-recurrence survival (PRS) among patients undergoing curative resection for hepatocellular carcinoma (HCC). MethodsPatients who underwent curative-intent resection for HCC between 2000 and 2017 were identified from an international multi-institutional database. The optimal cut-off time point to discriminate early versus late recurrence was determined relative to PRS. ResultsAmong 1004 patients, 443 (44.1%) patients experienced recurrence with a median recurrence-free survival time of 12 months. A cut-off time point of 8 months was defined as the optimal threshold based on sensitivity analyses relative to PRS for early (n = 165, 37.2%) versus late relapse (n = 278, 62.8%) (p = 0.008). Early recurrence was associated with worse PRS (median PRS, 27.0 vs. 43.0 months, p = 0.019), as well as overall survival (OS) (median OS, 32.0 versus 74.0 months, p < 0.001) versus late recurrence. In addition, patients who recurred early were more likely to recur at extra- ± intrahepatic (35.5% vs. 19.8%, p = 0.003) sites and were less likely to have the recurrence treated with curative intent (33.8% vs. 45.7%, p = 0.08). Patients undergoing curative re-treatment of late recurrence had a comparable OS with patients who had no recurrence (median OS, 139.0 vs. 140.0 months); patients with early recurrence had inferior OS after curative re-treatment versus patients with no recurrence (median OS, 69.0 vs. 140.0 months, p = 0.036), yet still better than patients who received palliative treatment for early recurrence (median OS, 69.0 vs. 21.0 months, p < 0.001). ConclusionsEight months was identified as the cut-off value to differentiate early versus late recurrence. Curative-intent treatment for recurrent intrahepatic tumors was associated with reasonable long-term outcomes.

VEGF-Modified PVA/Silicone Nanofibers Enhance Islet Function Transplanted in Subcutaneous Site Followed by Device-Less Procedure.

IntroductionAs heterologous islets or islet-like stem cells become optional sources for islet transplantation, the subcutaneous site appears to be an acceptable replacement of the intrahepatic site due to its graft retrievability. The device-less (DL) procedure improves the feasibility; however, some limitations such as fibrotic overgrowth or immunodeficiency still exist. Nanofibers could mimic the extracellular matrix to improve the vitality of transplanted islets. Therefore, we designed a vascular endothelial growth factor (VEGF)-modified polyvinyl alcohol (PVA)/silicone nanofiber (SiO2-VEGF) to optimize the DL procedure.MethodsSiO2-VEGF nanofibers were designed by nano-spinning and characterized the physical-chemical properties before subcutaneous islet transplantation. Cell viability, vessel formation, and glucose-stimulated insulin secretion were tested in vitro to ensure biocompatibility; and blood glucose level (BGL), transplanted islet function, and epithelial–mesenchymal transition (EMT)-related biomarker expression were analyzed in vivo.ResultsThe intensity of inflammatory reaction induced by SiO2 nanofibers was between nylon and silicone, which did not bring out excessive fibrosis. The vascularization could be enhanced by VEGF functionalization both in vitro and in vivo. The BGL control was better in the DL combined with SiO2-VEGF group. The percentage of recipients that achieved normoglycemia was higher and earlier (71% at day 57), and the intraperitoneal glucose tolerance test (IPGTT) also confirmed better islet function. The expressions of vimentin, α-SMA, and twist-1 were upregulated, which indicated that SiO2-VEGF nanofibers might promote islet function by regulating the EMT pathway.DiscussionIn summary, our new SiO2-VEGF combined with DL procedure might improve the feasibility of subcutaneous islet transplantation for clinical application.

Evaluating Safety and Dosimetry of SBRT following 90Y for Hepatocellular Carcinoma

Liver directed therapy is fundamental in the treatment of HCC. SBRT is the only non-invasive local therapy characterized by precise target delineation and accurate, quantifiable dosimetry. Often, SBRT is utilized following interventional therapy; however, there is a lack of data reporting safety and outcomes of patients receiving liver SBRT after yttrium-90 (90Y). We performed a safety and dosimetric evaluation in our series of HCC patients who received SBRT after 90Y by compiling post 90Y PET imaging fusions with SBRT treatment plans for accurate quantification of liver exposed to both SBRT and 90Y. An institutional review board-approved liver SBRT registry of 197 patients was used for data collection. All patients had post-90Y PET (measuring Bremsstrahlung component of 90Y) fused to SBRT treatment planning CT creating composite plans for dosimetric analysis. Volume of ablated liver was estimated using the sharp gradient edge of post-90Y PET, and the 30 Gy isodose line for SBRT (V30). Clinical and laboratory follow up 3 months post SBRT were used to evaluate safety. Changes in chemistry and hematology related to hepatic function, using CTCAE v4.0, were analyzed. Sixteen patients with non-metastatic HCC and prior 90Y were treated with SBRT to 18 intrahepatic sites. Patients received 23 prior 90Y administrations; six patients were treated twice and one patient treated three times. Child-Pugh (CP) category at SBRT was A in 12, and two each of B and C. SBRT dose was 35-50 Gy in 3-5 fractions (median 50 Gy/5). Median time between 90Y and SBRT was 4.6 months (range 1.3-34.8). Mean follow up was 14 months, and 11 patients were alive at analysis. Treatment intent was definitive for 13 patients and downstaging in 3. Mean total liver volume was 2,000 cc (range 986-3304), SBRT PTV 209 cc (range 26-494), and individual 90Y treatment volume 308 cc (range 36-1477). Liver ablative results summarized in Table 1.Abstract SU_13_2123; Table 1Mean valueMean %RangeV30 liver (SBRT)273 cc13.7%36-739 cc (3-34.8%)90Y volume (sum)436 cc22.6%95-1512 cc (3.5-52.6%)V30 volume within prior 90Y93 cc33.2%0-306 cc (0-75%) Open table in a new tab Laboratory data was available for 75% of patients. At 3 months post SBRT there were no new grade ≥2 changes from baseline in bilirubin, hemoglobin, INR, AST, ALT, and albumin in CP-A/B patients. The two CP-C patients, who had higher 90Y volumes and more overlap of 90Y with V30, demonstrated clinically significant hepatic decompensation. Although toxicity was noted, both patients were successfully down-staged within Milan then rescued with transplant 10 and 15 weeks post SBRT. This is the first series to incorporate PET delineation of 90Y ablation distribution in a composite plan with SBRT. Our experience of CP-A /B patients demonstrates minimal toxicity, but notable decompensation in CP-C patients. SBRT can be an effective tool to downstage within Milan but extra caution is warranted in this group, such that risk matches treatment intent, especially in patients that may not be rescued with transplant.

Posttransplant oxygen inhalation improves the outcome of subcutaneous islet transplantation: A promising clinical alternative to the conventional intrahepatic site.

Subcutaneous tissue is a promising site for islet transplantation, due to its large area and accessibility, which allows minimally invasive procedures for transplantation, graft monitoring, and removal of malignancies as needed. However, relative to the conventional intrahepatic transplantation site, the subcutaneous site requires a large number of islets to achieve engraftment success and diabetes reversal, due to hypoxia and low vascularity. We report that the efficiency of subcutaneous islet transplantation in a Lewis rat model is significantly improved by treating recipients with inhaled 50% oxygen, in conjunction with prevascularization of the graft bed by agarose-basic fibroblast growth factor. Administration of 50% oxygen increased oxygen tension in the subcutaneous site to 140mmHg, compared to 45mmHg under ambient air. In vitro, islets cultured under 140mmHg oxygen showed reduced central necrosis and increased insulin release, compared to those maintained in 45mmHg oxygen. Six hundred syngeneic islets subcutaneously transplanted into the prevascularized graft bed reversed diabetes when combined with postoperative 50% oxygen inhalation for 3days, a number comparable to that required for intrahepatic transplantation; in the absence of oxygen treatment, diabetes was not reversed. Thus, we show oxygen inhalation to be a simple and promising approach to successfully establishing subcutaneous islet transplantation.

Long term responders to palliative chemotherapy for advanced biliary tract cancer.

Patients with advanced biliary tract cancer (BTC) are often treated with palliative chemotherapy (PC). Standard PC since 2010 is a cisplatin/gemcitabine doublet, with median overall survival (OS) of 11.7 months from the ABC-02 trial. Prior to this, our institutional standard was gemcitabine and fluoropyrimidine. The ABC-02 study used 8 cycles of PC as standard with treatment stopped even in the absence of disease progression, but some patients may benefit from continuing PC longer than 8 cycles. Patients treated with at least 2 cycles of PC for advanced BTC in Princess Margaret Cancer Centre between 1987 and 2015 were included, and divided into 2 groups for analysis-long-term responders (LTR) who received 9 or more cycles, and controls (2-8 cycles). Data was collected on demographics, clinicopathological features, PC regimen, toxicities, and survival. The primary outcome measure was OS, with secondary analyses including progression-free survival (PFS) and toxicity rates between groups. A total of 382 patients were identified, 123 who met the criteria for LTR and 259 who were included as controls. The baseline demographic and clinical characteristics were similar, although more patients in the control group had gallbladder cancer or extrahepatic cholangiocarcinoma than LTR (P=0.024), and more patients in the LTR group were treated with combination chemotherapy regimens (93% vs. 82% in controls, P=0.003). The LTR patients had significantly longer PFS (median 13.3 vs. 4.1 months, P<0.001) and longer OS than controls (median 22.1 vs. 9.2 months, P<0.001). In LTR patients, 15% had a break from chemotherapy of 3 months or more and restarted the same regimen. The LTR patients reported higher rates of nausea, cutaneous and hematologic toxicity, but also more frequently went on to receive second-line chemotherapy (47% vs. 33%, P=0.007). In multivariable analysis of OS, LTR, good performance status and intrahepatic site of cancer were associated with better survival. From this institutional dataset, a significant proportion of patients continued chemotherapy past 8 cycles, and appeared to derive benefit from longer duration of treatment. Toxicity rates were higher in this group, but manageable as evidenced by second-line treatment rates. Discontinuation of chemotherapy for reasons other than toxicity or progression may result in loss of disease control and impact survival in this population; these data suggest the use of continued chemotherapy to disease progression in patients with advanced BTC is a favorable option.

The effect of hypoxia on free and encapsulated adult porcine islets-an in vitro study.

Adult porcine islets (APIs) constitute a promising alternative to human islets in treating type 1 diabetes. The intrahepatic site has been used in preclinical primate studies of API xenografts; however, an estimated two-thirds of donor islets are destroyed after intraportal infusion due to a number of factors, including the instant blood-mediated inflammatory reaction (IBMIR), immunosuppressant toxicity, and poor reestablishment of extracellular matrix connections. Intraperitoneal (ip) transplantation of non-vascularized encapsulated islets offers several advantages over intrahepatic transplantation of free islets, including avoidance of IBMIR, immunoprotection, accommodation of a larger graft volume, and reduced risk of hemorrhage. However, there exists evidence that the peritoneal site is hypoxic, which likely impedes islet function. We tested the effect of hypoxia (2%-5% oxygen or pO2 : 15.2-38.0mmHg) on free and encapsulated APIs over a period of 6days in culture. Free and encapsulated APIs under normoxia served as controls. Islet viability was evaluated with a viability/cytotoxicity assay using calcein AM and ethidium bromide on days 1, 3, and 6 of culture. Alamar blue assay was used to measure the metabolic activity on days 1 and 6. Insulin in spent medium was assayed by ELISA on days 1 and 6. Viability staining indicated that free islet clusters lost their integrity and underwent severe necrosis under hypoxia; encapsulated islets remained intact, even when they began to undergo necrosis. Under hypoxia, the metabolic activity and insulin secretion (normalized to metabolic activity) of both free and encapsulated islets decreased relative to islets cultured under normoxic conditions. Hypoxia (2%-5% oxygen or pO2 : 15.2-38.0mmHg) affects the viability, metabolic activity, and insulin secretion of both free and encapsulated APIs over a six-day culture period. Encapsulation augments islet integrity under hypoxia, but it does not prevent loss of viability, metabolic activity, or insulin secretion.

A multicenter registry to evaluate indications and outcomes for PDT in bronchogenic and esofageal cancers

Cholangiocarcinomas (CC) can be sub-divided into intrahepatic (IHCC) or extrahepatic (EHCC). Hilar or ‘Klatskin’ tumours are anatomically extrahepatic. Most international studies, also from the UK, report increasing IHCC and decreasing EHCC incidence. The second edition of the International Classification of Diseases for Oncology (ICD-O-2) assigned ‘Klatskin’ tumours a unique histology code (8162/3), but this was cross-referenced to the topography code for intrahepatic (IHBD) rather than extrahepatic bile duct tumours (EHBD). Under the third ICD-O edition, ‘Klatskin’ tumours are cross-referenced to either IHBD or EHBD. New editions of the ICD-O classification are adopted at different time points by different countries. We investigated the impact of changing ICD-O classifications and the potential misclassification of hilar/’Klatskin’ tumours on bile duct tumour and CC incidence rates in England and Wales and the US. We also examined whether coding practices by cancer registries in England and Wales could be influencing these rates.We analysed age-standardised incidence rates (ASIR) in England and Wales for IHBD and EHBD tumours between 1990 and 2008, then transferred all ‘Klatskin’ tumours from IHBD to EHBD and reanalysed rates from 1995, when ICD-O-2 was introduced in the UK. We also compared trends in IHBD, EHBD, and ‘Klatskin’ tumours in England and Wales with those in the USSEER (Surveillance, Epidemiology and End Results) database. Coding practice at Cancer registry level in England and Wales was investigated via a questionnaire completed by all national cancer registries.In England and Wales, 1990–2008, ASIR of IHBD cancers rose (0.43–1.84/100,000 population in males; 0.27–1.51 in females) but fell for EHBD (0.78–0.51/100,000 population in males; 0.62–0.39 in females). After transferring all ‘Klatskin’ tumours from IHBD to EHBD, there remained a marked increase in ASIR of IHBD cancers and a decrease in ASIR for EHBD, as only 1% of CC were reportedly ‘Klatskin’. The US SEER data showed that ASIR for IHBD gradually rose from 0.59/100,000 population in 1990 to 0.91 in 2001, then sharply fell before plateauing at 0.60 by 2007. ASIR for EHBD remained relatively stable at around 0.80/100,000 population until 2001, then began increasing, to 0.97 by 2007. Annually, between 1995 and 2008, the vast majority of ‘Klatskin’ tumours in England and Wales were coded as IHBD. This was also the case in the SEER data until 2001, when the situation was reversed and subsequently most ‘Klatskin’ tumours were coded as EHBD. US trends coincide with a switch from ICD-O2 to ICD-O-3 in 2001. In the UK, the switch to ICD-O-3 only occurred in 2008. On questioning, cancer registries in England and Wales stated they would not code a CC described as ‘hilar’ with the designated ‘Klatskin’ histology code. If the tumour site is unspecified, most registries classify CC as intrahepatic.Changes in ICD-classification may be influencing observed changes in IHBD and EHBD incidence rates. Coding misclassification is likely to have been skewing CC registration to an intrahepatic site, thereby contributing to the previously reported rise in intrahepatic tumours.

Therapy response of Chinese herbal medicine in primary liver cancer.

488 Background: Aiming at starting the ball rolling and contributing humble effort to promote Chinese traditional medicine, we report successful cases of Chinese herbal decoction for primary liver cancer. Methods: Conventional therapy of surgical resection and artery catheterization chemotherapy was applied in cases reported. In the meantime, we administered Chinese medicine (Gan Decoction, mixed with a variety of effective herbal components) to help them to recover from poor condition. Results: After taking the Chinese herbal decoction for months, the tumour marker (AFP, CA19-9) level dramatically decreased to the normal range. Most residual intrahepatic metastatic sites reduced according to ultrasonography/CT imaging, and the patient felt free from the complaint of abdominal discomfort. The quality of life has been greatly improved, we managed to have prolonged the PFS (Progression-Free-Survival) and TTP (Time-to-Progression) from the onset to date. Conclusions: Chinese medicine considers human body as a dynamic platform in which all organs are correlative and bind each other. Each case showed distinguished liver cancer progression and heterogeneity with individual therapy response. Our report suggested that Chinese herbs might be an additional choice with its better benefits and tolerability in the treatment of primary liver cancer.

Defective Glucagon Secretion During Hypoglycemia After Intrahepatic But Not Nonhepatic Islet Autotransplantation

Defective glucagon secretion during hypoglycemia after islet transplantation has been reported in animals and humans with type 1 diabetes. To ascertain whether this is true of islets from nondiabetic humans, subjects with autoislet transplantation in the intrahepatic site only (TP/IAT-H) or in intrahepatic plus nonhepatic (TP/IAT-H+NH) sites were studied. Glucagon responses were examined during stepped hypoglycemic clamps. Glucagon and symptom responses during hypoglycemia were virtually absent in subjects who received islets in the hepatic site only (glucagon increment over baseline = 1 ± 6, pg/mL, mean ± SE, n = 9, p = ns; symptom score = 1 ± 1, p = ns). When islets were transplanted in both intrahepatic + nonhepatic sites, glucagon and symptom responses were not significantly different than Control Subjects (TP/IAT-H + NH: glucagon increment = 54 ± 14, n = 5; symptom score = 7 ± 3; control glucagon increment = 67 ± 15, n = 5; symptom score = 8 ± 1). In contrast, glucagon responses to intravenous arginine were present in TP/IAT-H recipients (TP/IAT: glucagon response = 37 ± 8, n = 7). Transplantation of a portion of the islets into a nonhepatic site should be seriously considered in TP/IAT to avoid posttransplant abnormalities in glucagon and symptom responses to hypoglycemia.

Telaprevir-based treatment effects on hepatitis C virus in liver and blood.

Understanding hepatitis C virus (HCV) replication has been limited by access to serial samples of liver, the primary site of viral replication. Our understanding of how HCV replicates and develops drug-resistant variants in the liver is limited. We studied 15 patients chronically infected with genotype 1 HCV treated with telaprevir (TVR)/pegylated-interferon alpha/ribavirin. Hepatic fine needle aspiration was performed before treatment and at hour 10, days 4 and 15, and week 8 after initiation of antiviral therapy. We measured viral kinetics, resistance patterns, TVR concentrations, and host transcription profiles. All patients completed all protocol-defined procedures that were generally well tolerated. First-phase HCV decline (baseline/treatment day 4) was significantly slower in liver than in plasma (slope plasma: -0.29; liver, -0.009; P < 0.001), whereas second-phase decline (posttreatment days 4-15) did not differ between the two body compartments (-0.11 and -0.15, respectively; P = 0.1). TVR-resistant variants were detected in plasma, but not in liver (where only wild-type virus was detected). Based upon nonstructural protein 3 sequence analysis, no compartmentalization of viral populations was observed between plasma and liver compartments. Gene expression profiling revealed strong tissue-specific expression signatures. Human intrahepatic TVR concentration, measured for the first time, was lower, compared to plasma, on a gram per milliliter basis. We found moderate heterogeneity between HCV RNA levels from different intrahepatic sites, indicating differences in hepatic microenvironments. These data support an integrated model for HCV replication wherein the host hepatic milieu and innate immunity control the level of viral replication, and the early antiviral response observed in the plasma is predominantly driven by inhibition of hepatic high-level HCV replication sites.

The Effects of Intermittent Energy Restriction on Indices of Cardiometabolic Health

Intermittent energy restriction (IER) has become the subject of considerable scientific interest as a potential dietary approach for weight-loss and improving cardiometabolic health. This approach involves intermittent periods of total or partial energy restriction (ER) alternated with non-restricted intake, and has been studied in rodent and human populations. This review aims to provide an overview of the IER literature to date, with a specific focus on its effects on cardiometabolic health indices in rodents and humans. Current evidence from studies in rodents and humans suggests that IER is capable of promoting weight-loss and/or favourably influencing an array of cardiometabolic health indices, with equal or greater efficacy than conventional continuous ER approaches. Putative mechanisms include the effects of IER on adipose tissue physiology, stress resistance and fat distribution within visceral and intra-hepatic sites. However, a large proportion of this mechanistic evidence is limited to indirect observations and/or has come from rodent studies requiring translation into humans. Furthermore, whilst there is some indication that total IER and the array of partial IER protocols which have been developed may elicit distinct biological effects, our knowledge around this is limited as only a small number of rodent studies have directly addressed this. Ultimately, whilst much remains to be learned about IER, including its mechanisms of action and long-term efficacy, the positive findings to date serve to highlight promising avenues for future research.

Clinical outcomes and toxicity using Stereotactic Body Radiotherapy (SBRT) for advanced cholangiocarcinoma

BackgroundTo report single-institutional clinical outcomes and toxicity with SBRT for cholangiocarcinoma.MethodsFrom March 2009 to July 2011, 10 patients with 12 unresectable primary (n = 6) or recurrent (n = 6) cholangiocarcinoma lesions underwent abdominal SBRT. Sites treated included liver (n = 10), abdominal lymph nodes (n = 1), and adrenal gland (n = 1). SBRT was delivered in three (n = 2) or five (n = 10) consecutive daily fractions over one week. The median prescription dose was 55 Gy (range, 45–60). Treatment response was graded by RECIST v.1.1, and toxicities were scored by CTCAE v.4.0. Data was analyzed using the Kaplan-Meier method to determine rates of local control (LC), freedom from distant progression (FFDM) and overall survival (OS).ResultsThe median follow-up was 14 months (range, 2–26 months). LC, defined as freedom from progression within the SBRT field, was 100%, but four patients treated to intrahepatic sites experienced progression elsewhere in the liver. Estimates for FFDM at 6 and 12 months were 73% and 31%, respectively. Sites of disease relapse included liver (n = 3), liver and lymph nodes (n = 1), liver and lungs (n = 1), lymph nodes (n = 1), and mesentery (n = 1). OS estimates for the cohort at 6 and 12 months were 83% and 73%, respectively. The most common Grade ≥2 early toxicities were Grade 2 nausea and vomiting (n = 5) and gastrointestinal pain (n = 2). Late ≥2 toxicities included Grade 2 gastrointestinal pain (n = 3), Grade 3 biliary stenosis (n = 1), and Grade 5 liver failure (n = 1).ConclusionsSBRT shows promise as an effective local therapy for properly-selected patients with cholangiocarcinoma. Further follow-up is needed to better quantify the risk of late complications associated with SBRT.

Macro- or microencapsulation of pig islets to cure type 1 diabetes

Although allogeneic islet transplantation can successfully cure type 1 diabetes, it has limited applicability. For example, organs are in short supply; several human pancreas donors are often needed to treat one diabetic recipient; the intrahepatic site may not be the most appropriate site for islet implantation; and immunosuppressive regimens, which are associated with side effects, are often required to prolong survival of the islet graft. An alternative source of insulin-producing cells would therefore be of major interest. Pigs represent a possible alternative source of beta cells. Grafting of pig islets may appear difficult because of the immunologic species barrier, but pig islets have been shown to function in primates for at least 6 mo with clinically incompatible immunosuppression. Therefore, a bioartificial pancreas made of encapsulated pig islets may resolve issues associated with islet allotransplantation. Although several groups have shown that encapsulated pig islets are functional in small-animal models, less is known about the use of bioartificial pancreases in large-animal models. In this review, we summarize current knowledge of encapsulated pig islets, to determine obstacles to implantation in humans and possible solutions to overcome these obstacles.

Rising trends in cholangiocarcinoma: Is the ICD classification system misleading us?

Cholangiocarcinomas (CC) can be sub-divided into intrahepatic (IHCC) or extrahepatic (EHCC). Hilar or 'Klatskin' tumours are anatomically extrahepatic. Most international studies, also from the UK, report increasing IHCC and decreasing EHCC incidence. The second edition of the International Classification of Diseases for Oncology (ICD-O-2) assigned 'Klatskin' tumours a unique histology code (8162/3), but this was cross-referenced to the topography code for intrahepatic (IHBD) rather than extrahepatic bile duct tumours (EHBD). Under the third ICD-O edition, 'Klatskin' tumours are cross-referenced to either IHBD or EHBD. New editions of the ICD-O classification are adopted at different time points by different countries. We investigated the impact of changing ICD-O classifications and the potential misclassification of hilar/'Klatskin' tumours on bile duct tumour and CC incidence rates in England and Wales and the US. We also examined whether coding practices by cancer registries in England and Wales could be influencing these rates. We analysed age-standardised incidence rates (ASIR) in England and Wales for IHBD and EHBD tumours between 1990 and 2008, then transferred all 'Klatskin' tumours from IHBD to EHBD and reanalysed rates from 1995, when ICD-O-2 was introduced in the UK. We also compared trends in IHBD, EHBD, and 'Klatskin' tumours in England and Wales with those in the USSEER (Surveillance, Epidemiology and End Results) database. Coding practice at Cancer registry level in England and Wales was investigated via a questionnaire completed by all national cancer registries. In England and Wales, 1990-2008, ASIR of IHBD cancers rose (0.43-1.84/100,000 population in males; 0.27-1.51 in females) but fell for EHBD (0.78-0.51/100,000 population in males; 0.62-0.39 in females). After transferring all 'Klatskin' tumours from IHBD to EHBD, there remained a marked increase in ASIR of IHBD cancers and a decrease in ASIR for EHBD, as only 1% of CC were reportedly 'Klatskin'. The US SEER data showed that ASIR for IHBD gradually rose from 0.59/100,000 population in 1990 to 0.91 in 2001, then sharply fell before plateauing at 0.60 by 2007. ASIR for EHBD remained relatively stable at around 0.80/100,000 population until 2001, then began increasing, to 0.97 by 2007. Annually, between 1995 and 2008, the vast majority of 'Klatskin' tumours in England and Wales were coded as IHBD. This was also the case in the SEER data until 2001, when the situation was reversed and subsequently most 'Klatskin' tumours were coded as EHBD. US trends coincide with a switch from ICD-O2 to ICD-O-3 in 2001. In the UK, the switch to ICD-O-3 only occurred in 2008. On questioning, cancer registries in England and Wales stated they would not code a CC described as 'hilar' with the designated 'Klatskin' histology code. If the tumour site is unspecified, most registries classify CC as intrahepatic. Changes in ICD-classification may be influencing observed changes in IHBD and EHBD incidence rates. Coding misclassification is likely to have been skewing CC registration to an intrahepatic site, thereby contributing to the previously reported rise in intrahepatic tumours.

Pig islet for xenotransplantation in human: structural and physiological compatibility for human clinical application

Allogeneic islet transplantation has proven difficult because organ shortages are recurrent, several pancreas donors are often needed to treat one diabetic recipient, and the intrahepatic site of islet implantation may not be the most appropriate site. Thus, another source of insulin-producing cells would be beneficial; and pigs represent a possible and viable source for obtaining such cells. Although the use of pig islet grafts appears to be difficult because of the species barrier, recent reports demonstrated that pig islet xenotransplantation can overcome the immunological barrier following strong immunosuppression and function successfully in primates for at least 6 months. Before becoming clinically applicable, however, pig islet xenotransplantation must still overcome the structural and physiological incompatibility between pig donor and human recipient. Researchers agree that it is necessary to produce more preclinical data in the pig-to-primate model before any pig-to-human transplantation of islets can be considered. Therefore, in this review, we provide a summary of the present state of knowledge about pig and human islet compatibility.

Extrahepatic islet transplantation with microporous polymer scaffolds in syngeneic mouse and allogeneic porcine models

Intraportal transplantation of islets has successfully treated select patients with type 1 diabetes. However, intravascular infusion and the intrahepatic site contribute to significant early and late islet loss, yet a clinical alternative has remained elusive. We investigated non-encapsulating, porous, biodegradable polymer scaffolds as a vehicle for islet transplantation into extrahepatic sites, using syngeneic mouse and allogeneic porcine models. Scaffold architecture was modified to enhance cell infiltration leading to revascularization of the islets with minimal inflammatory response. In the diabetic mouse model, 125 islets seeded on scaffolds implanted into the epididymal fat pad restored normoglycemia within an average of 1.95 days and transplantation of only 75 islets required 12.1 days. Increasing the pore size to increase islet–islet interactions did not significantly impact islet function. The porcine model was used to investigate early islet engraftment. Increasing the islet seeding density led to a greater mass of engrafted islets, though the efficiency of islet survival decreased. Transplantation into the porcine omentum provided greater islet engraftment than the gastric submucosa. These results demonstrate scaffolds support murine islet transplantation with high efficiency, and feasibility studies in large animals support continued pre-clinical studies with scaffolds as a platform to control the transplant microenvironment.

High Vascular Density and Oxygenation of Pancreatic Islets Transplanted in Clusters into Striated Muscle

Pancreatic islet transplantation is presently almost exclusively performed using the intraportal route for transplantation into the liver. However, islets at this site are poorly revascularized and, when also considering the poor long-term results of clinical islet transplantation, there has in recent years emerged an increased interest to evaluate alternative sites for islet transplantation. Striated muscle is easily accessible and has for decades been used for autotransplantation of parathyroid glands. Moreover, it is almost the only tissue in the adult where physiological angiogenesis occurs. The present study tested the hypothesis that striated muscle would provide good conditions for revascularization and oxygenation of transplanted islets. Because we previously have observed similar revascularization of islets implanted to the renal subcapsular site and intraportally into the liver, islets grafted to the kidney were for simplicity besides native islets used for comparison. Islets grafted into muscle were found to have three times more blood vessels than corresponding islets at the renal subcapsular site at 2 month follow-up, but still less vascular numbers than native islets. The oxygen tension in 2-month-old intramuscular islet grafts was sixfold higher than in corresponding renal subcapsular grafts, and 70% of that in native islets. However, the oxygenation of surrounding muscle was only 50% of that in renal cortex, and connective tissue constituted a larger proportion of the intramuscular than the renal subcapsular grafts, suggesting exaggerated early islet cell death at the former site. We conclude that the intramuscular site provides excellent conditions for vascular engraftment, but that interventions to improve early islet survival likely are needed before clinical application. Such could include bioengineered matrices that not only spatially disperse the islet, but also could provide local supply of oxygen carriers, growth and survival factors, strategies that are much more easily applied at the intramuscular than the intrahepatic site.