Artemisinin-induced cholestatic liver injury and intrahepatic ductopenia.

Artemisinin, an ancient Chinese herbal remedy known colloquially as "Qinghao", is now used as treatment for malaria as recommended by the World Health Organisation. There have been few reports of artemisinin-induced liver injury. Most of these instances of hepatotoxicity are reportedly due to prolonged use of herbal remedies containing artemisinin. To our knowledge, we report the first case of intrahepatic ductopenia in a patient with cholestatic liver injury after artemisinin use.

An Unusual Case of Large Cell Neuroendocrine Cancer of the Gallbladder With Mixed Adenocarcinoma Component in a Patient With Pancreatobiliary Maljunction.

Gallbladder neuroendocrine tumors (GB-NETs) and gallbladder neuroendocrine carcinomas (GB-NECs) are rare forms of neuroendocrine neoplasms (NENs). Most GB-NENs present as incidental findings or as gallbladder polyps in the course of investigation of nonspecific symptoms such as upper abdominal pain and nausea. Given the rarity of GB-NENs, only a few small case series are currently available describing this entity, and even fewer guiding consensus on standard treatment and the role of adjuvant therapy.  We present the case of a 65-year-old South American female referred for a chronic history of intermittent post-prandial epigastric pain, bloating, nausea, and occasional diarrhea. Pancreaticobiliary maljunction with dilation was present and she was diagnosed with primary gallbladder large cell neuroendocrine carcinoma (GB-LCNEC) mixed with a minor component of gallbladder adenocarcinoma.

Effect of obesity on post-operative outcomes following colorectal cancer surgery.

BACKGROUND: Colorectal cancer (CRC) resection is currently being undertaken in an increasing number of obese patients. Existing studies have yet to reach a consensus as to whether obesity affects post-operative outcomes following CRC surgery. AIM: To evaluate the post-operative outcomes of obese patients following CRC resection, as well as to determine the post-operative outcomes of obese patients in the subgroup undergoing laparoscopic surgery. METHODS: Six-hundred and fifteen CRC patients who underwent surgery at the Prince Charles Hospital between January 2010 and December 2020 were categorized into two groups based on body mass index (BMI): Obese [BMI ≥ 30, n = 182 (29.6%)] and non-obese [BMI < 30, n = 433 (70.4%)]. Demographics, comorbidities, surgical features, and post-operative outcomes were compared between both groups. Post-operative outcomes were also compared between both groups in the subgroup of patients undergoing laparoscopic surgery [n = 472: BMI ≥ 30, n = 136 (28.8%); BMI < 30, n = 336 (71.2%)]. RESULTS: Obese patients had a higher burden of cardiac (73.1% vs 56.8%; P < 0.001) and respiratory comorbidities (37.4% vs 26.8%; P = 0.01). Obese patients were also more likely to undergo conversion to an open procedure (12.8% vs 5.1%; P = 0.002), but did not experience more post-operative complications (51.6% vs 44.1%; P = 0.06) or high-grade complications (19.2% vs 14.1%; P = 0.11). In the laparoscopic subgroup, however, obesity was associated with a higher prevalence of post-operative complications (47.8% vs 39.3%; P = 0.05) but not high-grade complications (17.6% vs 11.0%; P = 0.07). CONCLUSION: Surgical resection of CRC in obese individuals is safe. A higher prevalence of post-operative complications in obese patients appears to only be in the context of laparoscopic surgery.

Absence of microglia promotes diverse pathologies and early lethality in Alzheimer's disease mice.

Microglia are strongly implicated in the development and progression of Alzheimer's disease (AD), yet their impact on pathology and lifespan remains unclear. Here we utilize a CSF1R hypomorphic mouse to generate a model of AD that genetically lacks microglia. The resulting microglial-deficient mice exhibit a profound shift from parenchymal amyloid plaques to cerebral amyloid angiopathy (CAA), which is accompanied by numerous transcriptional changes, greatly increased brain calcification and hemorrhages, and premature lethality. Remarkably, a single injection of wild-type microglia into adult mice repopulates the microglial niche and prevents each of these pathological changes. Taken together, these results indicate the protective functions of microglia in reducing CAA, blood-brain barrier dysfunction, and brain calcification. To further understand the clinical implications of these findings, human AD tissue and iPSC-microglia were examined, providing evidence that microglia phagocytose calcium crystals, and this process is impaired by loss of the AD risk gene, TREM2.

Double trouble: synchronous extrahepatic cholangiocarcinoma and gallbladder cancer in a Caucasian woman with no pancreaticobiliary maljunction.

Synchronous malignancies of the bile duct and the gallbladder are rare. These cases are often associated with pancreaticobiliary maljunction which is characterized by a long common shared pancreatobiliary channel leading to the Sphincter of Oddi. This predisposes the biliary epithelium to pancreatic enzyme reflux and makes the development of neoplasia more likely. We describe the case of a 64-year-old Caucasian female who presented with new jaundice and severe cholecystitis secondary to an impacted gallstone which was seen on ultrasound. Magnetic resonance cholangiopancreatography was organized with suspicion of a possible Mirizzi syndrome. This revealed a mid-distal bile duct cancer in addition to cholecystitis from an impacted gallstone. She was treated with intravenous antibiotics for her cholecystitis and underwent an urgent endoscopic retrograde cholangiopancreatography procedure for biliary decompression and stenting for her obstructive jaundice. The patient proceeded to pancreaticoduodenectomy with final histopathology revealing a synchronous primary gallbladder malignancy in addition to the known bile duct cancer.

Quality of Life in Children with Hearing Impairment: Systematic Review and Meta-analysis.

OBJECTIVE: To determine the impact of pediatric hearing loss (HL) on quality of life (QOL). DATA SOURCES: A qualified medical librarian conducted a literature search for relevant publications that evaluate QOL in school-aged children with HL. REVIEW METHODS: Studies were assessed independently by 2 reviewers for inclusion in the systematic review and meta-analysis. RESULTS: From 979 abstracts, 69 were identified as relevant; ultimately, 40 articles were included in the systematic review. This review revealed that children with HL generally report a lower QOL than their normal-hearing peers and that QOL improves after interventions. The extent of these differences is variable among studies and depends on the QOL measure. Four studies using the Pediatric Quality of Life Inventory (PedsQL) had sufficient data for inclusion in a meta-analysis. After studies were pooled, statistically and clinically significant differences in PedsQL scores were found between children with normal hearing and those with HL, specifically in the social and school domains. Statistically significant differences were also noted in total scores for children with unilateral HL and in the physical domain for children with bilateral HL as compared with those having normal hearing; however, these differences were not clinically meaningful. CONCLUSIONS: Our analysis reveals that decreased QOL in children with HL is detected in distinct domains of the PedsQL. These domains-school activities and social interactions-are especially important for development and learning. Future work should focus on these aspects of QOL when assessing HL in the pediatric population.

Genotyping and Resolution of a Case of Osteomyelitis in a 16-Month-Old Boy of Hispanic/African American Ethnicity.

Most cases of osteomyelitis in children are caused by Staphylococcus aureus, although Kingella kingae, various streptococci, and Salmonella species also underlie this condition. Organisms such as Mycobacterium, Histoplasma, and Cryptococcus are much less commonly identified as etiologic agents in osteomyelitis. This case report describes a 16-month-old boy of Hispanic/African American ethnicity who had extensive inflammation of and discharge from his right ankle. Imaging studies supported a diagnosis of osteomyelitis. Acid-fast bacillus (AFB) and routine wound cultures were ordered on the wound discharge. The AFB culture yielded a positive result for Mycobacterium bovis, and molecular diagnostic testing further genotyped the microorganism as Mycobacterium bovis, Bacillus Calmette-Guerin (BCG). Herein, we report a rare case of osteomyelitis that we believe resulted from a BCG vaccine that the patient had received outside the United States.

A blinded comparison of the safety and efficacy of hot biopsy forceps electrocauterization and conventional snare polypectomy for diminutive colonic polypectomy in a porcine model.

BACKGROUND: Although linked with perforation, serositis, delayed bleeding, and incomplete resection, hot biopsy forceps electrocauterization (HBF) is still widely used for diminutive colonic polypectomy. OBJECTIVE: To evaluate the safety and efficacy of HBF in comparison with conventional snare polypectomy (CSP). DESIGN: Randomized, blinded, controlled trial. SETTING: Academic endoscopy unit. SUBJECTS: Ten swine. INTERVENTION: Eighty-two paired polypectomies (41 HBF, 41 CSP) of small, minimally elevated, artificial lesions. Standardized technique using coagulating current at 25 W. HBF: the tissue was avulsed after 1 to 2 seconds of current caused blanching of the artificial pedicle. CSP: the polyp was removed by snare diathermy. MAIN OUTCOME MEASUREMENTS: Histopathology of resected specimens and polypectomy sites in colectomy specimens at necropsy (lateral mucosal and depth of ulceration, necrosis and inflammation). RESULTS: Some (21%) of the HBF specimens were ablated and uninterpretable. All CSP specimens yielded interpretable specimens. Mucosal necrosis adjacent to HBF resection sites varied widely, between 1.5 and 9 mm (mean 5.7 mm, standard deviation ± 2). There was visible mucosa under the HBF ulcer in 14% of cases. The depth of necrosis in the colon wall was significantly different between the two techniques, with partial muscularis propria (MP) necrosis in 14 of 41 lesions (34%) with HBF, compared with 1 of 41 (2%) of CSP (P < .001), and full-thickness MP necrosis in 9 of 41 lesions (22%) with HBF, compared with 1 of 41 (2%) of CSP (P = .014). There was full-thickness MP inflammation in 13 of 41 lesions (32%) with HBF compared with 5 of 41 (12%) of CSP (P = .06). Transmural subserosal inflammation was seen in 13 of 41 lesions (32%) with HBF compared with 4 of 41 (10%) of CSP (P = .027). There was no relationship between visible lateral mucosal injury and depth of injury (rs = -0.07). LIMITATIONS: Animal study. CONCLUSION: Despite use of the standardized HBF technique, there is a wide range of lateral mucosal and deep thermal injury as well as residual target mucosa. HBF also results in a significantly greater depth of tissue injury, with a high proportion of transmural necrosis. Ensuring minimal blanching of the mucosa during the procedure does not protect from deep injury. In comparison to conventional snare polypectomy, HBF is imprecise, potentially ineffective, and hazardous.

Beyond the snare: technically accessible large en bloc colonic resection in the West: an animal study.

BACKGROUND: Endoscopic submucosal dissection (ESD) and circumferential submucosal incision endoscopic mucosal resection (CSI-EMR) are techniques for en bloc excision of large sessile colonic lesions. Our aims were to compare the efficacy, safety and learning curve of colonic hybrid knife (HK) ESD versus CSI-EMR for en bloc excision of 50 mm diameter hemi-circumferential artificial lesions in a porcine model. PATIENTS AND METHODS: Two separate 50 mm diameter areas of normal recto-sigmoid mucosa were marked out in each of ten pigs. One was excised with HK-ESD using succinylated gelatin (SG) submucosal injection. The other was isolated with CSI with the Insulated Tip Knife 2 followed by SG submucosal injection then EMR with a large snare. Euthanasia and colectomy was performed at 72 h followed by blinded histopathology assessment. RESULTS: En bloc excision rates were: HK-ESD 100% versus CSI-EMR 20% (P = 0.008). The mean number of resections per lesion was HK-ESD 1 versus CSI-EMR 3 (P = 0.001). The mean dimensions of the largest specimen per technique were HK-ESD 63 × 54 mm versus CSI-EMR 49 × 41 mm (P = 0.005). Procedure duration mean was HK-ESD 54 min versus CSI-EMR 22 min (P < 0.001). When procedure duration was adjusted for the size of the resected en bloc specimen, a statistically significant and accelerated learning effect was noted for HK-ESD (r = -0.83, P = 0.003). There were no perforations and no significant bleeding. CONCLUSIONS: HK-ESD with SG submucosal injection is superior to CSI-EMR for en bloc excision of 50 mm diameter lesions in a porcine model. The technique is rapidly learnt. This novel approach may lower the barrier to colonic ESD for Western endoscopists.

Hepatitis C virus induces the cannabinoid receptor 1.

BACKGROUND: Activation of hepatic CB(1) receptors (CB(1)) is associated with steatosis and fibrosis in experimental forms of liver disease. However, CB(1) expression has not been assessed in patients with chronic hepatitis C (CHC), a disease associated with insulin resistance, steatosis and metabolic disturbance. We aimed to determine the importance and explore the associations of CB(1) expression in CHC. METHODS: CB(1) receptor mRNA was measured by real time quantitative PCR on extracted liver tissue from 88 patients with CHC (genotypes 1 and 3), 12 controls and 10 patients with chronic hepatitis B (CHB). The Huh7/JFH1 Hepatitis C virus (HCV) cell culture model was used to validate results. PRINCIPAL FINDINGS: CB(1) was expressed in all patients with CHC and levels were 6-fold higher than in controls (P<0.001). CB(1) expression increased with fibrosis stage, with cirrhotics having up to a 2 fold up-regulation compared to those with low fibrosis stage (p<0.05). Even in mild CHC with no steatosis (F0-1), CB(1) levels remained substantially greater than in controls (p<0.001) and in those with mild CHB (F0-1; p<0.001). Huh7 cells infected with JFH-1 HCV showed an 8-fold upregulation of CB(1), and CB(1) expression directly correlated with the percentage of cells infected over time, suggesting that CB(1) is an HCV inducible gene. While HCV structural proteins appear essential for CB(1) induction, there was no core genotype specific difference in CB(1) expression. CB(1) significantly increased with steatosis grade, primarily driven by patients with genotype 3 CHC. In genotype 3 patients, CB(1) correlated with SREBP-1c and its downstream target FASN (SREBP-1c; R=0.37, FASN; R=0.39, p<0.05 for both). CONCLUSIONS/SIGNIFICANCE: CB(1) is up-regulated in CHC and is associated with increased steatosis in genotype 3. It is induced by the hepatitis C virus.

Succinylated gelatin substantially increases en bloc resection size in colonic EMR: a randomized, blinded trial in a porcine model.

BACKGROUND: Succinylated gelatin (SG) is an inexpensive colloid that may combine ease of use with the advantages of a colloid to potentially increase EMR specimen size, leading to a higher rate of en bloc resection. OBJECTIVE: To evaluate the safety, efficacy, and impact on EMR specimen size of SG as a submucosal (s.m.) injectant in comparison with normal saline solution (NS). DESIGN: Randomized, blinded, controlled trial conducted with Animal Ethics Committee approval. SETTING: Academic hospital. SUBJECTS: Ten swine. INTERVENTIONS: Sixty EMRs (30 using SG vs 30 using NS as 3 paired experiments per animal) of the largest possible en bloc snare resection of normal colonic mucosa after s.m. injection of a fixed volume of either SG or NS. MAIN OUTCOME MEASUREMENTS: EMR specimen size, duration of s.m. cushion, duration of procedure, ratio of vertical elevation to lateral spread of injectant, ease of resection, adverse effects, perforation, histopathology of EMR sites in colectomy specimens at necropsy (for inflammatory cell content, depth of ulceration, and vascular or ischemic changes). RESULTS: The mean subject weight was 53 kg. The mean EMR specimen dimensions and surface area were significantly larger with SG (length 37 vs 31 mm, P = .031; width 32 vs 26 mm, P = .022; surface area 9.5 cm(2) vs 6.7 cm(2), P = .044, respectively). The median s.m. cushion duration was 60 minutes with SG versus 15 minutes with NS (P = .005). The median procedure duration with SG was 2.6 minutes vs 2.5 minutes with NS (P = .515). The ratio of vertical elevation to lateral spread of injectant (mean score on a 3-point scale) was 3 with SG versus 2 with NS (P = .228). Ease of resection score (mean score on a 10-point scale) was 8 with SG versus 7 with NS (P = .216). There were no systemic adverse effects, hypersensitivity reactions, or bleeding episodes. There were 2 perforations (treated with clips) with SG and 1 with NS (P = 1.0). Blinded histopathologist assessment of necropsy colectomy specimens did not identify any significant differences between SG and NS EMR sites. LIMITATIONS: Animal study. CONCLUSIONS: SG is safe and results in a 42% increased surface area for en bloc EMR. Given its other favorable properties, it represents a significant step toward defining the ideal EMR solution.

Endoscopic resection for Barrett's high-grade dysplasia and early esophageal adenocarcinoma: an essential staging procedure with long-term therapeutic benefit.

OBJECTIVES: Patients with Barrett's high-grade dysplasia (HGD) or early esophageal adenocarcinoma (EAC) that is shown on biopsy alone continue to undergo esophagectomy without more definitive histological staging. Endoscopic resection (ER) may provide more accurate histological grading and local tumor (T) staging, definitive therapy, and complete Barrett's excision (CBE); however, long-term outcome data are limited. Our objective was to demonstrate the effect on histological grade or local T stage, efficacy, safety and long-term outcome of ER for Barrett's HGD/EAC and of CBE in suitable patients. METHODS: This prospective study at two Australian academic hospitals involved 75 consecutive patients over 7 years undergoing ER for biopsy-proven HGD or EAC, using multiband mucosectomy or cap technique. In addition, CBE by 2-3-stage radical mucosectomy was attempted for all Barrett's segments

A multicenter blinded study to evaluate KRAS mutation testing methodologies in the clinical setting.

Evidence that activating mutations of the KRAS oncogene abolish the response to anti-epidermal growth factor receptor therapy has revolutionized the treatment of advanced colorectal cancer. This has resulted in the urgent demand for KRAS mutation testing in the clinical setting to aid choice of therapy. The aim of this study was to evaluate six different KRAS mutation detection methodologies on two series of primary colorectal cancer samples. Two series of 80 frozen and 74 formalin-fixed paraffin-embedded tissue samples were sourced and DNA was extracted at a central site before distribution to seven different testing sites. KRAS mutations in codons 12 and 13 were assessed by using single strand conformation polymorphism analysis, pyrosequencing, high resolution melting analysis, dideoxy sequencing, or the commercially available TIB Molbiol (Berlin, Germany) or DxS Diagnostic Innovations (Manchester, UK) kits. In frozen tissue samples, concordance in KRAS status (defined as consensus in at least five assays) was observed in 66/80 (83%) cases. In paraffin tissue, concordance was 46/74 (63%) if all assays were considered or 71/74 (96%) using the five best performing assays. These results demonstrate that a variety of detection methodologies are suitable and provide comparable results for KRAS mutation analysis of clinical samples.

Targeted high-resolution ultrasound is not an effective substitute for sentinel lymph node biopsy in patients with primary cutaneous melanoma.

PURPOSE: To reassess traditional ultrasound descriptors of sentinel lymph node (SLN) metastases, to determine the minimum cross-sectional area (CSA) of an SLN metastasis detectable by ultrasound (US), and to establish whether targeted, high-resolution US of SLNs identified by lymphoscintigraphy before initial melanoma surgery can be used as a substitute for excisional SLN biopsy. METHODS: US was performed on SLNs identified in 871 lymph node fields in 716 patients. SLN biopsy was performed within 24 hours of lymphoscintigraphy and US examination. The CSA of each SLN metastatic deposit was determined sonographically and histologically. RESULTS: The sensitivity of targeted US in the detection of positive SLNs was 24.3% (95% CI, 19.5% to 28.7%), and the specificity was 96.8% (95% CI, 95.9% to 97.7%). The sensitivity was highest for neck SLNs (45.8%) and improved with greater Breslow thickness. The median histologic CSA of the SLN metastatic deposits was 0.39 mm(2) (12.75 mm(2) for US true-positive results and 0.22 mm(2) for US false-negative results). True-positive, US-detected SLNs had significantly greater CSAs (t test P < .001) than undetected SLN metastases and were more likely to be spherical in cross-section. More than two sonographic descriptors of SLN metastases or rounding of the node alone were factors highly suggestive of a melanoma deposit. CONCLUSION: US is not an appropriate substitute for SLN biopsy, but it is of value in preoperative SLN assessment and postoperative monitoring.

En-bloc resection of multiple type 1 gastric carcinoid tumors by endoscopic multi-band mucosectomy.

BACKGROUND AND AIM: Gastric carcinoid tumors are rare but increasing in incidence. Current recommendations suggest endoscopic resection for type I carcinoids found in the stomach, however reports of incomplete resection have led to difficulty planning future management. Our purpose was to describe the application of the endoscopic multi-band mucosectomy (MBM) device to achieve en-bloc resection of multiple gastric carcinoid tumors. METHODS: Over a 30-month period (June 2006-January 2009) eight patients attending for endoscopic assessment of gastric carcinoid tumors were identified at two tertiary referral centers. Patients underwent endoscopic resection of the carcinoids with an MBM device. En-bloc specimens underwent histological evaluation for identification and tumor resection margins. Patients with type I carcinoids were subsequently enrolled in an endoscopic follow-up program. RESULTS: A total of 34 gastric carcinoid tumors were removed from eight patients. On histological analyses seven out of eight patients were diagnosed with type I tumors. In the remaining patient a single, sporadic (type III) gastric carcinoid was diagnosed. No complications of severe bleeding or perforation occurred. All specimens were shown to have clear deep and peripheral histological resection margins. CONCLUSION: Complete 'en-bloc' endoscopic resection of multiple 'type I' gastric carcinoid tumors can be safely and easily performed with an MBM technique.

p27KIP-1, cyclin A and cyclin D1 protein expression in ductal carcinoma in situ of the breast: p27KIP-1 correlates with hormone receptor status but not with local recurrence.

Using whole sections of formalin-fixed paraffin-embedded material the expression of p27(KIP-1), cyclin A and cyclin D1 was examined in 60 cases of ductal carcinoma in situ (DCIS) using routine immunohistochemistry with a median follow up of 95 months (range 10-139 months) to identify any association with disease recurrence. Fifty-six patients were treated by local excision and radiotherapy and four by mastectomy without radiotherapy. There was a highly significant positive association between p27(KIP-1) and estrogen receptor/progesterone receptor (ER/PR) status (P = 0.002, P = 0.02) and with p27(KIP-1) and cyclin D1 expression (P = 0.002). A trend between cyclin A and PR status (P = 0.08) was also identified. These findings mirror those described in invasive ductal carcinoma, but there were no associations of any biomarker with histological parameters such as nuclear grade or with local recurrence on univariate analysis, which was present in four of the 56 locally excised group (7.1%). Further examination of a larger cohort may be worthwhile to explore the possible role as adjunctive predictive markers to aid clinical decision making.