Hepatocellular carcinoma radiation segmentectomy treatment intensification prior to liver transplantation increases rates of complete pathologic necrosis: an explant analysis of 75 tumors.

PURPOSE: To verify the correlation between yttrium-90 glass microsphere radiation segmentectomy treatment intensification of hepatocellular carcinoma (HCC) and complete pathologic necrosis (CPN) at liver transplantation. METHODS: A retrospective, single center, analysis of patients with HCC who received radiation segmentectomy prior to liver transplantation from 2016 to 2021 was performed. The tumor treatment intensification cohort (n = 38) was prescribed radiation segmentectomy as per response recommendations identified in a previously published baseline cohort study (n = 37). Treatment intensification and baseline cohort treatment parameters were compared for rates of CPN. Both cohorts were then combined for an overall analysis of treatment parameter correlation with CPN. RESULTS: Sixty-three patients with a combined 75 tumors were analyzed. Specific activity, dose, and treatment activity were significantly higher in the treatment intensification cohort (all p < 0.01), while particles per cubic centimeter of treated liver were not. CPN was achieved in 76% (n = 29) of tumors in the treatment intensification cohort compared to 49% (n = 18) in the baseline cohort (p = 0.013). The combined cohort CPN rate was 63% (n = 47). ROC analysis showed that specific activity ≥ 327 Bq (AUC 0.75, p < 0.001), dose ≥ 446 Gy (AUC 0.69, p = 0.005), and treatment activity ≥ 2.55 Gbq (AUC 0.71, p = 0.002) were predictive of CPN. Multivariate logistic regression demonstrated that a specific activity ≥ 327 Bq was the sole independent predictor of CPN (p = 0.013). CONCLUSION: Radiation segmentectomy treatment intensification for patients with HCC prior to liver transplantation increases rates of CPN. While dose strongly correlated with pathologic response, specific activity was the most significant independent radiation segmentectomy treatment parameter associated with CPN.

Radiation Segmentectomy for the Treatment of Solitary Hepatocellular Carcinoma: Outcomes Compared with Those of Surgical Resection.

PURPOSE: To investigate the outcomes of radiation segmentectomy (RS) versus standard-of-care surgical resection (SR). MATERIALS AND METHODS: A multisite, retrospective analysis of treatment-naïve patients who underwent either RS or SR was performed. The inclusion criteria were solitary hepatocellular carcinoma ≤8 cm in size, Eastern Cooperative Oncology Cohort performance status of 0-1, and absence of macrovascular invasion or extrahepatic disease. Target tumor and overall progression, time to progression (TTP), and overall survival rates were assessed. Outcomes were censored for liver transplantation. RESULTS: A total of 123 patients were included (RS, 57; SR, 66). Tumor size, Child-Pugh class, albumin-bilirubin score, platelet count, and fibrosis stage were significantly different between cohorts (P ≤ .01). Major adverse events (AEs), defined as grade ≥3 per the Clavien-Dindo classification, occurred in 0 patients in the RS cohort vs 13 (20%) patients in the SR cohort (P < .001). Target tumor progression occurred in 3 (5%) patients who underwent RS and 5 (8%) patients who underwent SR. Overall progression occurred in 19 (33%) patients who underwent RS and 21 (32%) patients who underwent SR. The median overall TTP was 21.9 and 29.4 months after RS and SR, respectively (95% confidence interval [CI], 15.5-28.2 and 18.5-40.3, respectively; P = .03). Overall TTP subgroup analyses showed no difference between treatment cohorts with fibrosis stages 3-4 (P = .26) and a platelet count of <150 × 109/L (P = .29). The overall progression hazard ratio for RS versus SR was not significant per the multivariate Cox regression analysis (1.16; 95% CI, 0.51-2.63; P = .71). The median overall survival was not reached for either of the cohorts. Propensity scores were calculated but were too dissimilar for analysis. CONCLUSIONS: RS and SR were performed in different patient populations, which limits comparison. RS approached SR outcomes, with a lower incidence of major AEs, in patients who were not eligible for hepatectomy.

Natural History of Incidental Enhancing Nodules on Cone-Beam Computed Tomography during Transarterial Therapy of Hepatocellular Carcinoma.

PURPOSE: To evaluate the natural history of incidental enhancing nodules (IENs) on contrast-enhanced cone-beam computed tomography (CT) during transarterial treatment of hepatocellular carcinoma (HCC). MATERIAL AND METHODS: A single-center retrospective analysis of 100 patients with HCC who underwent contrast-enhanced cone-beam CT prior to transarterial treatment from August 2015 to June 2019 was performed. Inclusion criteria were patients with segmental distribution sublobar HCC, contrast-enhanced cone-beam CT of the target lesion and nontarget liver parenchyma, and follow-up cross-sectional imaging. Patients with IENs ≥3 mm that did not meet imaging criteria for HCC were analyzed. Exclusion criteria included biphenotypic tumors and IEN present inside the treated area of the liver. RESULTS: Fifty-six patients demonstrated 154 IENs on contrast-enhanced cone-beam CT, of which 13 IENs (8.5%) progressed to HCC. The mean primary tumor size was 29 mm (range: 10.2-189 mm). Ten patients had ≥4 IENs, and 46 patients had 1-3 IENs. The mean IEN size was 6.8 mm (range: 3.0-16.3 mm). The median follow-up interval after contrast-enhanced cone-beam CT was 282 days (interquartile range: 143-522). Increased alpha-fetoprotein before treatment (≥15.5 ng/mL, P = .035), having ≥4 IENs (P = .020), and hepatitis C virus (P = .015) were significantly correlated with IEN progression to HCC. No statistically significant differences were identified in baseline neutrophil-to-lymphocyte ratio, targeted HCC characteristics (size, macrovascular invasion, infiltrative pattern, enhancement pattern, and satellite lesions), and IEN size between those with IEN progression to HCC and those without. CONCLUSIONS: Most IENs of ≥3 mm on contrast-enhanced cone-beam CT in patients with segmental distribution sublobar HCC do not progress to HCC. Patients with segmental distribution sublobar HCC with ≥4 IENs, alpha-fetoprotein elevation (≥15.5 ng/mL), or hepatitis C virus have an increased risk of IEN progression to HCC.

Percutaneous direct pancreatic duct intervention in management of pancreatic fistulas: a primary treatment or temporizing therapy to prepare for elective surgery.

BACKGROUND: This study evaluates preliminary results of image-guided percutaneous direct pancreatic duct intervention in the management of pancreatic fistula after surgery or pancreatitis when initially ineligible for surgical or endoscopic therapy. METHODS: Between 2001 and 2018 the medical records of all patients that underwent percutaneous pancreatic duct intervention for radiographically confirmed pancreatic fistula initially ineligible for surgical or endoscopic repair were reviewed for demographics, clinical history, procedure details, adverse events, procedure related imaging and laboratory results, ability to directly catheterized the main pancreatic duct, and whether desired clinical objectives were met. RESULTS: In 10 of 11patients (6 male and 5 female with mean age 60.5, range 39-89) percutaneous pancreatic duct cannulation was possible. The 10 duct interventions included direct ductal suction drainage in 7, percutaneous duct closure in 3 and stent placement in 1. Pancreatic fistulas closed in 7 of 10, 2 were temporized until elective surgery, and 1 palliated until death from malignancy. The single patient with failed duct cannulation resolved the fistula with prolonged catheter drainage of the peri-pancreatic cavity. There were no major adverse events related to intervention. CONCLUSION: In patients with pancreatic fistulas initially ineligible for endoscopic therapy or elective surgery, direct percutaneous pancreatic duct interventions are possible, can achieve improvement without major morbidity or mortality, and can improve and maintain the medical condition of patients in preparation for definitive surgery.

Toilet hygiene-review and research needs.

The goal of good toilet hygiene is minimizing the potential for pathogen transmission. Control of odours is also socially important and believed to be a societal measure of cleanliness. Understanding the need for good cleaning and disinfecting is even more important today considering the potential spread of emerging pathogens such as SARS-CoV-2 virus. While the flush toilet was a major advancement in achieving these objectives, exposure to pathogens can occur from failure to clean and disinfect areas within a restroom, as well as poor hand hygiene. The build-up of biofilm within a toilet bowl/urinal including sink can result in the persistence of pathogens and odours. During flushing, pathogens can be ejected from the toilet bowl/urinal/sink and be transmitted by inhalation and contaminated fomites. Use of automatic toilet bowl cleaners can reduce the number of microorganisms ejected during a flush. Salmonella bacteria can colonize the underside of the rim of toilets and persist up to 50 days. Pathogenic enteric bacteria appear in greater numbers in the biofilm found in toilets than in the water. Source tracking of bacteria in homes has demonstrated that during cleaning enteric bacteria are transferred from the toilet to the bathroom sinks and that these same bacteria colonize cleaning tools used in the restroom. Quantitative microbial risk assessment has shown that significant risks exist from both aerosols and fomites in restrooms. Cleaning with soaps and detergents without the use of disinfectants in public restrooms may spread bacteria and viruses throughout the restroom. Odours in restrooms are largely controlled by ventilation and flushing volume in toilet/urinals. However, this results in increased energy and water usage. Contamination of both the air and surfaces in restrooms is well documented. Better quantification of the risks of infection are needed as this will help determine what interventions will minimize these risks.

Increasing Yttrium-90 Dose Conformality Using Proximal Radioembolization Enabled by Distal Angiosomal Truncation for the Treatment of Hepatic Malignancy.

PURPOSE: To evaluate safety and feasibility of improving radiation dose conformality via proximal radioembolization enabled by distal angiosomal truncation where selective administration was not practical. MATERIALS AND METHODS: Hepatic malignancies treated via angiosomal truncation between January 2017 and March 2019 were retrospectively evaluated. Thirty-three patients (8 women, 25 men; mean age, 62.2 y; range, 36-78 y) underwent 39 treatments. Of treatments, 74.3% (n = 29) were for hepatocellular carcinomas, 10.2% (n = 4) were for cholangiocarcinomas, and 15.4% (n = 6) were for metastatic tumors (1 colorectal adenocarcinoma, 1 pancreatic adenocarcinoma, 3 melanomas, and 1 endometroid carcinoma). Truncation was achieved using temporary embolic devices including a microvascular plug, detachable coil, gelatin slurry, and balloon microcatheter, after which proximal radioembolization was performed. Range of treatment activity was 0.47-5.75 GBq. Technetium-99m macroaggregated albumin and bremsstrahlung single photon emission computed tomography (CT)/CT threshold analysis was conducted to delineate and compare distribution of activity within the treatment angiosome before and after radioembolization. RESULTS: Dosimetric analysis of 14 patients demonstrated a significant reduction in nontarget liver radiation exposure at 5, 20, and 40% thresholds (P = .002, P = .001, and P = .008, respectively). There were no grade 3 or higher adverse events. There was no significant change in Albumin-Bilirubin grade and Eastern Cooperative Oncology Group Performance Status (P = .09 and P = .74) before and 3 months after the procedure. Truncated arteries were patent on subsequent angiography in 11 cases and on MR angiography or CT angiography in 38 of 39 cases. CONCLUSIONS: Proximal radioembolization enabled by distal angiosomal truncation is safe and decreases nontarget parenchymal radioembolization dose in cases not amenable to selective administration.

Therapeutic efficacy of intra-articular delivery of encapsulated human mesenchymal stem cells on early stage osteoarthritis.

Mesenchymal stem cells (MSCs) represent a great therapeutic promise in pre-clinical models of osteoarthritis (OA), but many questions remain as to their therapeutic mechanism of action: engraftment versus paracrine action. Encapsulation of human MSCs (hMSCs) in sodium alginate microspheres allowed for the paracrine signaling properties of these cells to be isolated and studied independently of direct cellular engraftment. The objective of the present study was to quantitatively assess the efficacy of encapsulated hMSCs as a disease-modifying therapeutic for OA, using a medial meniscal tear (MMT) rat model. It was hypothesized that encapsulated hMSCs would have a therapeutic effect, through paracrine-mediated action, on early OA development. Lewis rats underwent MMT surgery to induce OA. 1 d post-surgery, rats received intra-articular injections of encapsulated hMSCs or controls (i.e., saline, empty capsules, non-encapsulated hMSCs). Microstructural changes in the knee joint were quantified using equilibrium partitioning of a ionic contrast agent based micro-computed tomography (EPIC-µCT) at 3 weeks post-surgery, an established time point for early OA. Encapsulated hMSCs significantly attenuated MMT-induced increases in articular cartilage swelling and surface roughness and augmented cartilaginous and mineralized osteophyte volumes. Cellular encapsulation allowed to isolate the hMSC paracrine signaling effects and demonstrated that hMSCs could exert a chondroprotective therapeutic role on early stage OA through paracrine signaling alone. In addition to this chondroprotective role, encapsulated hMSCs augmented the compensatory increases in osteophyte formation. The latter should be taken into strong consideration as many clinical trials using MSCs for OA are currently ongoing.

Percutaneous Retrograde Transhepatic Arterial Puncture to Regain Access in the True Lumen of the Dissected and Acutely Occluded Transplant Hepatic Artery.

Iatrogenic hepatic artery dissection is a serious complication that can progress to complete hepatic artery occlusion and graft loss. Restoration of arterial flow to the graft is urgent, but the severity and extent of the dissection may interfere with endovascular techniques. The authors describe a technique of percutaneous retrograde transhepatic arterial puncture to regain access into the true lumen of the dissected hepatic artery to restore in-line flow to the liver graft.

Single-institution experience of radioembolization with yttrium-90 microspheres for unresectable metastatic neuroendocrine liver tumors.

BACKGROUND AND AIM: The aim of this study was to assess the effectiveness of yttrium-90 (90 Y) microspheres for the treatment of unresectable metastatic liver neuroendocrine tumors (NET). METHODS: From February 2006 to September 2015, 36 patients (19 male and 17 female, age 63.6 ± 9.4 years) who underwent 90 Y therapy for unresectable liver metastases of NET were included and analyzed retrospectively. All patients received a variety of treatments before 90 Y therapy. The radiological response, symptoms improvement of carcinoid syndrome, tumor marker changes, complications, side effects/toxicity, survival, and factors related to survival were evaluated and analyzed. RESULTS: Of the 36 patients, the mean delivered dose of 90 Y was 1.8 ± 0.7 GBq with a total of 40 treatments. Overall disease control rate was 88.9% (32/36) at 3 months following therapy. In 16 patients with carcinoid syndrome, 15 (93.8%) patients had symptomatic improvement. Tumor marker response (5-hydroxyindoleacetic acid [n = 7] and chromogranin A [n = 13]) at 3 months after treatment were as follows: none (n = 0, 4), partial (n = 6, 7), and complete (n = 1, 2). Radiation-induced gastrointestinal ulcers (n = 2, 5.6%) were identified. Side effects included fatigue (n = 31, 86.1%), anorexia (n = 26, 72.2%), nausea (n = 15, 41.7%), vomiting (n = 14, 38.9%), abdominal pain (n = 10, 27.8%), and fever (n = 8, 22.2%). The mean follow-up was 27.0 ± 16.4 months, with a median survival of 41.0 months. Child-Pugh classification (P = 0.008) and lymph node metastases (P = 0.045) had statistically significant influence on overall survival. CONCLUSIONS: Yttrium-90 radioembolization can be effective in the treatment of unresectable liver metastases of NET who failed to respond to other treatments.

Selective method for identification and quantification of Bifidobacterium animalis subspecies lactis BB-12 (BB-12) from the gastrointestinal tract of healthy volunteers ingesting a combination probiotic of BB-12 and Lactobacillus rhamnosus GG.

AIM: To develop a novel validated method for the isolation of Bifidobacterium animalis ssp. lactis BB-12 (BB-12) from faecal specimens and apply it to studies of BB-12 and Lactobacillus rhamnosus GG (LGG) recovered from the healthy human gastrointestinal (GI) tract. METHODS AND RESULTS: A novel method for isolating and enumerating BB-12 was developed based on its morphologic features of growth on tetracycline-containing agar. The method identified BB-12 correctly from spiked stool close to 100% of the time as validated by PCR confirmation of identity, and resulted in 97-104% recovery of BB-12. The method was then applied in a study of the recovery of BB-12 and LGG from the GI tract of healthy humans consuming ProNutrients® Probiotic powder sachet containing BB-12 and LGG. Viable BB-12 and LGG were recovered from stool after 21 days of probiotic ingestion compared to baseline. In contrast, no organisms were recovered 21 days after baseline in the nonsupplemented control group. CONCLUSIONS: We demonstrated recovery of viable BB-12, using a validated novel method specific for the isolation of BB-12, and LGG from the GI tract of healthy humans who consumed the probiotic supplement. SIGNIFICANCE AND IMPACT OF THE STUDY: This method will enable more detailed and specific studies of BB-12 in probiotic supplements, including when in combination with LGG.

Abrupt occlusion of right gastroepiploic artery as an angiographic evidence of gastrointestinal hemorrhage.

Angiography plays an important role in both diagnosis and treatment of gastrointestinal (GI) bleeding; however, the sensitivity is low for diagnosis. We report a case of a 38-year-old woman who presented with recurrent upper GI bleeding following central pancreatectomy. Multiple selective arteriograms failed to reveal any active bleeding or other common signs of bleeding. There was an abrupt occlusion of the right gastroepiploic artery initially interpreted to be a surgical ligation. Upon direct superselective injection near the occlusion, an area of frank contrast extravasation was demonstrated immediately beyond the occlusion. The underlying vessel was embolized with n-butyl cyanoacrylate without recurrent bleeding up to 3-month follow-up.

Caval Penetration by Inferior Vena Cava Filters: A Systematic Literature Review of Clinical Significance and Management.

BACKGROUND: Limited penetration into the caval wall is an important securing mechanism for inferior vena cava (IVC) filters; however, caval penetration can also cause unintentional complications. The aim of this study was to assess the incidence, severity, clinical consequences, and management of filter penetration across a range of commercially available IVC filters. METHODS AND RESULTS: The MEDLINE database was searched for all studies (1970-2014) related to IVC filters. A total of 88 clinical studies and 112 case reports qualified for analysis; these studies included 9002 patients and 15 types of IVC filters. Overall, penetration was reported in 19% of patients (1699 of 9002), and 19% of those penetrations (322 of 1699) showed evidence of organ/structure involvement. Among patients with penetration, 8% were symptomatic, 45% were asymptomatic, and 47% had unknown symptomatology. The most frequently reported symptom was pain (77%, 108 of 140). Major complications were reported in 83 patients (5%). These complications required interventions including surgical removal of the IVC filter (n=63), endovascular stent placement or embolization (n=11), endovascular retrieval of the permanent filter (n=4), and percutaneous nephrostomy or ureteral stent placement (n=3). Complications led to death in 2 patients. A total of 87% of patients (127 of 146) underwent premature filter retrieval or interventions for underlying symptoms or penetration-related complications. CONCLUSIONS: Caval penetration is a frequent but clinically underrecognized complication of IVC filter placement. Symptomatic patients accounted for nearly 1/10th of all penetrations; most of these cases had organ/structure involvement. Interventions with endovascular retrieval and surgery were required in most of these symptomatic patients.

Long-term results of aortouniiliac stent grafts for the endovascular repair of abdominal aortic aneurysms.

BACKGROUND: Long-term follow-up of patients with aortouniiliac (AUI) grafts is lacking in the current literature. The purpose of this study was to review the outcomes of endovascular aneurysm repair (EVAR) using commercially available AUI devices with femorofemoral bypass in patients whose aortoiliac anatomy was unfavorable for bifurcated repair. METHODS: A retrospective review of 35 patients from September 2000 to February 2012, who underwent EVAR with commercially manufactured AUI devices, was performed. These comprised 35 of 372 (9.4%) patients who underwent EVAR during that period. Patient records were reviewed to determine morbidity, mortality, and survival after AUI repair. Patients were followed at 1-, 3-, 6-, and 12-month intervals with computed tomography (CT) scans during each visit. Median follow-up was 40 months (range: 2-135 months). RESULTS: Median age at surgery was 76 years (range: 60-93). The median preoperative aneurysm diameter was 57 mm (range: 45-71) and the median postoperative diameter was 53 mm (range: 29-80). Two type II endoleaks occurred on 1-month CT, whereas 10 endoleaks (type I [3], II [6], and III [1]) occurred during follow-up after 1 month. Migration of the stent graft occurred in 9% (n=3). Secondary procedures were required in 26% (n=9), whereas tertiary procedures were required in 3% (n=1). One patient required treatment for thrombosis of the iliac extension and 2 required treatment for thrombosis of the femorofemoral component. Mortality over the follow-up period was 34% (n=12) with no deaths occurring within 30 days. CONCLUSIONS: High-risk patients who present with aortoiliac anatomy unsuitable for bifurcated stent graft placement should be offered AUI graft placement as a potential alternative to open repair.

Histologic Findings of Sinusoidal Dilatation and Congestion in Liver Grafts Do Not Correlate with Hepatic Venous Anastomotic Gradients.

PURPOSE: Hepatic venous transplant anastomotic pressure gradient measurement and transjugular liver biopsy are commonly used in clinical decision-making in patients with suspected anastomotic hepatic venous outflow obstruction. This investigation aimed to determine if sinusoidal dilatation and congestion on histology are predictive of hepatic venous anastomotic outflow obstruction, and if it can help select patients for hepatic vein anastomosis stenting. MATERIALS AND METHODS: This is a single-center retrospective study of 166 transjugular liver biopsies in 139 patients obtained concurrently with transplant venous anastomotic pressure gradient measurement. Demographic characteristics, laboratory parameters, procedure and clinical data, and histology of time-zero allograft biopsies were analyzed. RESULTS: No relationship was found between transplant venous anastomotic pressure gradient and sinusoidal dilatation and congestion (P = 0.92). Logistic regression analysis for sinusoidal dilatation and congestion confirmed a significant relationship with reperfusion/preservation injury and/or necrosis of the allograft at time-zero biopsy (OR 6.6 [1.3-33.1], P = 0.02). CONCLUSION: There is no relationship between histologic sinusoidal dilatation and congestion and liver transplant hepatic vein anastomotic gradient. In this study group, sinusoidal dilatation and congestion is a nonspecific histopathologic finding that is not a reliable criterion to select patients for venous anastomosis stenting.

Radiation Segmentectomy for the Treatment of Primary Hepatic Malignancies of the Caudate Lobe: A Case Series.

PURPOSE: Tumors involving the caudate lobe present a unique therapeutic challenge due to their complex anatomy and the safety and efficacy of locoregional therapy can be variable. The purpose of this study is to analyze the outcomes of radiation segmentectomy for primary caudate lobe tumors. MATERIALS AND METHODS: Eight patients [5 women and 3 men; median age = 69 y (range 50-79)] that underwent transarterial radioembolization (TARE) using yttrium-90 (Y90) glass microspheres for primary caudate lobe tumors (hepatocellular carcinoma = 6, intrahepatic cholangiocarcinoma = 2) from August 2017 to March 2021 were retrospectively analyzed. Descriptive statistics, treatment parameters, tumor response (using modified response evaluation criteria in solid tumors), adverse events [using common terminology criteria for adverse events (CTCAE)], and survival outcomes were evaluated. RESULTS: Eight primary caudate lobe tumors with a median size of 2.2 cm [interquartile range (IQR), 1.7-3.3] and Child-Pugh class A liver function underwent TARE of the caudate lobe. The median radiation dose was 596 Gy (IQR 356-1585), median total activity was 0.84 GBq (IQR 0.56-1.31), median specific activity was 473 Bq/sphere (IQR 226-671), and the median number of Y90 microspheres used was 1.4 million (IQR 1.2-3.4). All complications were CTCAE grade 1, and no clinically significant hilar plate complications were observed. In targeted tumors, complete response was seen in all patients.  At a median follow-up period of 16.6 months (IQR 6.6-21.6) 75% (6/8) of patients were alive with no in-field progression. CONCLUSION: Radiation segmentectomy of primary caudate lobe tumors appears effective and is well tolerated in this limited case series within the described treatment parameters. LEVEL OF EVIDENCE: Level 4, Case Series.

Acute and long-term effects of peroxisome proliferator-activated receptor-γ activation on the function and insulin secretory responsiveness of clonal beta-cells.

Thiazolidinediones (TZDs) are used as antidiabetic therapy. The purpose of the present study was to examine whether the TZD rosiglitazone has direct actions on pancreatic beta-cells that contribute to its overall effects. Effects of acute and prolonged (48 h) exposure to rosiglitazone, as a model glitazone compound, were assessed in clonal pancreatic BRIN-BD11 beta-cells maintained in standard, glucotoxic and lipotoxic cultures. In acute 20-min incubations, rosiglitazone (0.2-100 µM) did not alter basal or glucose-stimulated insulin secretion. However, rosiglitazone (6.25 µM) enhanced (p<0.001) the acute insulinotropic action of GLP-1. Prolonged exposure to 6.25 µM rosiglitazone in standard media had no effect on cell viability or cellular insulin content, but slightly reduced the insulin secretory response to glucose and alanine (p<0.05). Prolonged (48 h) exposure to glucotoxic or lipotoxic conditions reduced beta-cell viability (p<0.05), cellular insulin content (p<0.001 and p<0.05, respectively), and insulin release in response to glucose and a range of secretagogues. The adverse effect of lipotoxicity on beta-cell viability was prevented by concomitant exposure to 6.25 µM rosiglitazone. Culture with 6.25 µM rosiglitazone further decreased acute insulin release under glucotoxic conditions. However, when insulin secretion was expressed as percentage cellular insulin content, rosiglitazone (6.25 µM) significantly improved many of the adverse effects of gluco- and lipotoxic conditions on insulin secretory responsiveness. The results suggest that despite decrease in cellular insulin content TZDs exert direct beneficial effects on beta-cell viability and function during gluco- or lipotoxicity.

In vivo veritas: the search for TB drug targets goes live.

The term 'microbial persistence' describes a phenomenon whereby microorganisms which are drug-susceptible when tested outside the body are nevertheless capable of surviving within the body despite intensive therapy with the appropriate antimicrobial drug. In clinical practice this phenomenon obviously has to do with the post-treatment 'carrier state' and with post-treatment relapse. In short, it is this phenomenon which is responsible for our inability to eradicate an infection from a person or a community by the use of drugs. - Walsh McDermott, The Yale Journal of Biology and Medicine 30, 257 (1958).

Biochemical Safety of Ablative Yttrium-90 Radioembolization for Hepatocellular Carcinoma as a Function of Percent Liver Treated.

PURPOSE: Transarterial radioembolization can serve as an ablative therapy for early-stage hepatocellular carcinoma (HCC). Given the volumetric variability of liver segments, this study aimed to characterize the safety of ablative radioembolization by determining percent liver treated (%LT) thresholds associated with biochemical toxicity. PATIENTS AND METHODS: Patients with HCC receiving a single ablative radioembolization treatment using glass microspheres from 2017 through 2020 were reviewed. %LT was calculated as treatment angiosome volume divided by whole liver volume. Biochemical toxicities were defined as increases in Albumin-Bilirubin (ALBI) grade or Child-Pugh (CP) class compared to baseline and albumin or bilirubin adverse events (AEs) per the Common Terminology Criteria for Adverse Events. Receiver operating characteristic curves and multivariate logistic regression analyses were performed to assess the impact of %LT on toxicities. RESULTS: Of 141 patients analyzed, 53% (n=75) were ALBI 1, 45% (n=64) ALBI 2, 79% (n=111) CP-A, and 21% (n=30) CP-B. A %LT ≥14.5% was associated with grade/class increases in ALBI 2 (p≤0.01) and CP-B patients (p=0.026). In multivariate analysis, a %LT ≥14.5% was an independent predictor of increases in the ALBI 2 and CP-B groups (p<0.01). No significant %LT threshold was found for ALBI 1 and CP-A patients. No grade 3/4 albumin or bilirubin AEs were reported, while grade 2 AEs were related to an initial whole liver volume <1.3 L (p≤0.01). CONCLUSION: Patients with ALBI 2 and CP-B liver function are less likely to have an increase in their respective grade/class when treating <14.5% of the liver using glass microspheres. ALBI 1 and CP-A patients showed no definitive %LT threshold for biochemical toxicity within the range of this study.

Effects of metformin on BRIN-BD11 beta-cell insulin secretory desensitization induced by prolonged exposure to sulphonylureas.

AIMS: Prolonged exposure of pancreatic beta-cells in vitro to the sulphonylureas tolbutamide and glibenclamide induces subsequent desensitization of insulinotropic pathways. Clinically, the insulin-sensitizing biguanide drug metformin is often administered alongside sulphonylurea as antidiabetic therapy. The present study examines the functional effects of metformin (200 µM) on tolbutamide- and glibenclamide-induced desensitisation. METHODS: Acute and prolonged (18 h) effects of exposure to tolbutamide and glibenclamide alone, or in the presence of metformin, were examined in insulin-secreting BRIN-BD11 cells. RESULTS: In acute 20 min incubations at 1.1 mM glucose, metformin increased (1.2-1.7-fold; p < 0.001) the insulin-releasing actions of tolbutamide and glibenclamide. At 16.7 mM glucose, metformin significantly enhanced glibenclamide-induced insulin release at all concentrations (50-400 µM) examined, but tolbutamide-stimulated insulin secretion was only augmented at higher concentrations (300-400 µM). Exposure for 18 h to 100 µM tolbutamide or glibenclamide significantly impaired insulin release in response to glucose and a broad range of insulin secretagogues. Concomitant culture with metformin (200 µM) prevented or partially reversed many of the adverse effects on K(ATP) channel dependent and independent insulinotropic pathways. Beneficial effects of metformin were also observed in cells exposed to glibenclamide for 18 h with significant improvements in the insulin secretory responsiveness to alanine, GLP-1 and sulphonylureas. The decrease of viable cell numbers observed with glibenclamide was reversed by co-culture with metformin, but cellular insulin content was depressed. CONCLUSIONS: The results suggest that metformin can prevent the aspects of sulphonylurea-induced beta-cell desensitization.