Clinical Outcomes After Endoscopic Management of Low-Risk and High-Risk T1a Esophageal Adenocarcinoma: A Multicenter Study.

INTRODUCTION: Endoscopic eradication therapy (EET) is standard of care for T1a esophageal adenocarcinoma (EAC). However, data on outcomes in high-risk T1a EAC are limited. We assessed and compared outcomes after EET of low-risk and high-risk T1a EAC, including intraluminal EAC recurrence, extraesophageal metastases, and overall survival. METHODS: Patients who underwent EET for T1a EAC at 3 referral Barrett's esophagus endotherapy units between 1996 and 2022 were included. Patients with submucosal invasion, positive deep margins, or metastases at initial diagnosis were excluded. High-risk T1a EAC was defined as T1a EAC with poor differentiation and/or lymphovascular invasion, with low-risk disease being defined without these features. All pathology was systematically assessed by expert gastrointestinal pathologists. Baseline and follow-up endoscopy and pathology data were abstracted. Time-to-event analyses were performed to compare outcomes between groups. RESULTS: One hundred eighty-eight patients with T1a EAC were included (high risk, n = 45; low risk, n = 143) with a median age of 70 years, and 84% were men. Groups were comparable for age, sex, Barrett's esophagus length, lesion size, and EET technique. Rates of delayed extraesophageal metastases (11.1% vs 1.4%) were significantly higher in the high-risk group ( P = 0.02). There was no significant difference in the rates of intraluminal EAC recurrence ( P = 0.79) and overall survival ( P = 0.73) between the 2 groups. DISCUSSION: Patients with high-risk T1a EAC undergoing successful EET had a substantially higher rate of extraesophageal metastases compared with those with low-risk T1a EAC on long-term follow-up. These data should be factored into discussions with patients while selecting treatment approaches. Additional prospective data in this area are critical.

Lymphocytic Esophagitis: Assessing Risk Factors and Clinical Outcomes.

BACKGROUND: Lymphocytic esophagitis is a rare esophageal condition. Our knowledge of potential risk factors and treatment outcomes of lymphocytic esophagitis is limited. AIM: To investigate potential risk factors associated with the development of lymphocytic esophagitis and compare clinical characteristics and treatment outcomes of patients diagnosed with lymphocytic esophagitis to patients diagnosed with eosinophilic esophagitis. METHODS: This is a multicenter retrospective study. Lymphocytic esophagitis patients were identified based on pathology results between 1997 and 2019. Control groups consisted of patients with normal esophageal biopsies and patients diagnosed with eosinophilic esophagitis. Thirteen potential risk factors for lymphocytic esophagitis were analyzed using univariate and multivariate models including IBD, achalasia, hyperlipidemia, hypothyroidism, celiac sprue, CVID, H. pylori, thymoma, aspirin, opioids, ACE-I, metformin, and statin use. Comparative statistics were performed. RESULTS: Ninety-four adult patients with lymphocytic esophagitis, 344 with eosinophilic esophagitis, and 5202 control patients with normal esophageal biopsies were analyzed. Age older than 60 [adjusted odd ratio (AOR) 1.03, 95% CI 1.02-1.05, p = 0.001], aspirin use (2.7, 95% CI 1.4-4.9, p = 0.001), statin use (2.2, 95% CI 1.2-4.2, p = 0.01), or a diagnosis of achalasia (2.4, 95% 1.08-5.67, p = 0.03) were associated with lymphocytic esophagitis. Compared to eosinophilic esophagitis, lymphocytic esophagitis patients were more likely to respond to medical treatment (95% CI 2.54-12.8, p = 0.0001). CONCLUSIONS: Our data suggests that lymphocytic esophagitis is more likely to be found in older female patients and is significantly associated with achalasia, statin, and aspirin use. Compared to eosinophilic esophagitis, lymphocytic esophagitis is more likely to respond to treatment with medical therapy.

Volumetric laser endomicroscopy in the biliary and pancreatic ducts: a feasibility study with histological correlation.

BACKGROUND: Volumetric laser endomicroscopy (VLE) provides circumferential images 3 mm into the biliary and pancreatic ducts. We aimed to correlate VLE images with the normal and abnormal microstructure of these ducts. METHODS: Samples from patients undergoing hepatic or pancreatic resection were evaluated. VLE images were collected using a low-profile VLE catheter inserted manually into the biliary and pancreatic ducts ex vivo. Histological correlation was assessed by two unblinded investigators. RESULTS: 25 patients (20 liver and 5 pancreatic samples) and 111 images were analyzed. VLE revealed three histological layers: epithelium, connective tissue, and parenchyma. It identified distinctive patterns for primary sclerosing cholangitis (PSC), pancreatic cysts, neuroendocrine tumor, and adenocarcinoma adjacent to the pancreatic duct or ampulla. VLE failed to identify dysplasia in a dominant stricture and inflammatory infiltrates in PSC. Reflectivity measurements of the liver parenchyma diagnosed liver cirrhosis with high sensitivity. CONCLUSIONS: VLE can identify histological changes in the biliary and pancreatic ducts allowing real-time diagnosis. Further studies are needed to measure the accuracy of VLE in a larger sample and to validate our findings in vivo.

Predictors of Progression in Barrett's Esophagus with Low-Grade Dysplasia: Results from a Multicenter Prospective BE Registry.

OBJECTIVES: Low-grade dysplasia (LGD) is a risk factor for progression in Barrett's esophagus (BE). Progression estimates however vary and predictors of progression are not well established. We aimed to assess predictors of progression in a multicenter BE-LGD cohort. METHODS: All subjects with LGD (diagnosed by a GI pathologist) in a prospective BE registry were identified. Progression was defined development of HGD/EAC more than 12 months after index date of LGD diagnosis. Clinical, endoscopic factors and impact of histologic review by an independent panel of two GI pathologists were assessed as predictors of progression. Cox proportional hazard models were used to assess their association with risk of progression. RESULTS: 244 BE-LGD subjects met inclusion criteria. Their mean age was 63.2 years. 205 (84%) were males. The median follow up was 4.8 years. Fifty six patients were diagnosed with HGD/EAC in less than 12 months, while 14 progressed to HGD/EAC after 12 months, with an overall annual risk of progression of 1.2%. 29% of LGD subjects were downgraded to non-dysplastic and the remaining re-confirmed as LGD or indefinite dysplasia. The risk of progression in the reconfirmed LGD group was eight fold higher (hazards ratio: 7.6, 95% CI: 1.5-139.4) in a propensity score stratified model. CONCLUSIONS: In this large BE-LGD cohort, progression risk increased substantially when an additional panel of two expert GI pathologists re-confirmed a LGD diagnosis. These BE subjects may be candidates for endoscopic therapy. LGD was a marker of prevalent HGD/EAC in 18% of patients.

Impact of an Endoscopic Quality Improvement Program Focused on Adenoma Detection on Sessile Serrated Adenoma/Polyp Detection.

BACKGROUND: Sessile serrated adenomas/polyps (SSA/P) are an under-recognized disease with a unique malignant pathway. Improved endoscopic recognition and pathological interpretation is needed. AIMS: To determine whether an educational intervention that improved adenoma detection rate (ADR) could improve SSA/P detection rate after reclassification of previously termed "hyperplastic" polyps. METHODS: We reanalyzed data from a prospective randomized trial of an educational intervention aimed at increasing ADR. All hyperplastic polyps ≥6 mm reported in a previously published study were rereviewed and reclassified using standardized criteria for serrated lesions. Detection rates of sessile serrated adenomas/polyps and other clinically relevant serrated polyps were calculated in the baseline and post-training phases of the original study. RESULTS: Of 263 available for rereview, 33 (12.5%) were reclassified as SSA/P (N = 32) or traditional serrated adenoma (TSA) (N = 1). Reclassification was more common in the right colon (18 vs. 8%, p = 0.02). Baseline SSA/P detection rate was 0.7% in the untrained group and 1.3% in the trained group. Post-training, the SSA/P detection rate increased to 2.1 and 1.5%, respectively. The clinically relevant serrated polyp detection rate at baseline was 14.2% in the untrained group and 11.3% in the trained group. After the educational intervention, the clinically relevant serrated polyp detection rates increased to 16.5 and 14.8% in the untrained and trained groups, respectively. The estimated odds of an endoscopist detecting either a SSA/P or other clinically relevant serrated polyp during colonoscopy increased by only 3% with the educational intervention (OR 1.03, 95% CI 0.61-1.74, p = 0.91). CONCLUSIONS: Pathological re-interpretation of larger serrated polyps resulted in the reclassification of 12.5% of lesions. Quality improvement methods focused on adenoma detection did not impact SSA/P detection, and thus specific methods for serrated polyp detection are needed.

Novel patient-derived xenograft mouse model for pancreatic acinar cell carcinoma demonstrates single agent activity of oxaliplatin.

BACKGROUND: Pancreatic acinar cell carcinoma (PACC) is a rare malignancy, accounting for <1 % of all pancreatic neoplasms. Very few retrospective studies are available to help guide management. We previously reported the case of a patient with metastatic PACC who achieved prolonged survival following doxorubicin treatment. Personalized treatment was based on molecular and in vitro data collected from primary cells developed from their liver metastasis. We now report the characterization of a patient derived tumor xenograft (PDTX) mouse model that originated from this patient's PACC liver metastasis. METHODS: Fragments of biopsy tissue (5 mm(3)) from PACC liver metastasis were implanted into athymic nude mice. Tumors were grown and passaged from the host mice into new mice to be tested for therapeutic response. Immuno-histochemical (IHC) biomarkers were used to confirm that the PDTX model represents human PACC. The antitumor activities of multiple drugs (5-FU, irinotecan, oxaliplatin, gemcitabine, bevacizumab, erlotinib, doxorubicin and imatinib) were tested. Tumor size was measured over 74 days or until they reached an endpoint volume of ~800 mm(3). Tests to measure serum lipase levels and histological analyses of tumor tissues were also conducted to assess PACC progression and re-differentiation. RESULTS: The model presented here expresses the same IHC markers found in human PACC. In the chemotherapy study, oxaliplatin produced a prolonged durable growth response associated with increased apoptosis, decreased serum lipase levels and increased healthy acinar cells. Bevacizumab also produced a significant growth response, but the effect was not prolonged as demonstrated by oxaliplatin treatment. The other chemotherapies had moderate to little effect, particularly after treatment ceased. Mutations in DNA repair genes are common in PACC and increase tumor susceptibility to oxaliplatin. To explore this we performed IHC and found no nuclear expression of BRCA2 in our model, indicating a mutation affecting nuclear localization. Gene sequencing confirms BRCA2 has a homozygous gene deletion on Exon 10, which frequently causes a protein truncation. CONCLUSIONS: In summary, we report the development and characterization of the first and only preclinical PACC PDTX model. Here we show sustained anti-tumor activity of single agent oxaliplatin, a compound that is more effective in tumors that harbor mutations in DNA repair genes. Our data shows that BRCA2 is mutated in our PACC model, which could contribute to the oxaliplatin sensitivity observed. Further studies on this rare PACC model can serve to elucidate other novel therapies, biomarkers, and molecular mechanisms of signaling and drug resistance.

Characterization of a porcine model for associating liver partition and portal vein ligation for a staged hepatectomy.

BACKGROUND: Publications using the ALPPS (associating liver partition and portal vein ligation for a staged hepatectomy) procedure have demonstrated a future liver remnant growth of 40-160% in only 6-9 days. The present study aimed to develop and describe the first large animal model of ALPPS that can be used for future studies. METHODS: A total of 13 female domestic pigs underwent ALPPS stage 1 (portal vein division and parenchymal transection) followed by ALPPS stage 2 (completion left-extended hepatectomy) 7 days later. An abdominal computed tomography (CT) scan was performed immediately prior to ALPPS stage 1 surgery and again 7 days later to assess hypertrophy immediately prior to ALPPS stage 2 surgery. Blood samples, as well as tissue analysis for Ki-67, were performed. RESULTS: On CT volumetric analysis, the mean size of the future liver remnant (FLR) prior to ALPPS stage 1 was 21 ± 2% and 40 ± 6% prior to ALPPS stage 2. The median degree of growth was 75% with a mean kinetic growth rate of 11% per day. Liver weights at autopsy correlated well with CT volumetric analysis (r = 0.87). There was no significant difference in mean lab values [asparate aminotransferase (AST), alanine aminotransferase (ALT), ammonia, International Normalized Ratio (INR) or bilirubin] from baseline until immediately prior to ALPPS stage 2. Post ALPPS stage 2 there was a significant increase in INR from baseline 1.1 to 1.6 (P = 0.012). No post-operative deaths secondary to liver failure were observed. CONCLUSION: The present study describes the first reproducible large animal model of the ALPPS procedure. The degree of liver growth and the kinetic rate of growth were similar to that which has been demonstrated in human publications. This model will be valuable as future laboratory studies are performed.

Gastric adenomas in familial adenomatous polyposis are common, but subtle, and have a benign course.

BACKGROUND: Patients with familial adenomatous polyposis (FAP) are known to have an increased risk for gastric adenomas. The clinical features of gastric adenomas in FAP have not been well characterized, and there is a lack of standardized approaches to the management of these lesions. AIMS: To study the endoscopic appearance, risk factors, clinical course, and response to therapy of gastric adenomas in patients with FAP. METHODS: We retrospectively reviewed the records of 97 patients with FAP who underwent esophagogastroduodenoscopy (EGD) at Mayo Clinic (Florida, Rochester and Arizona) between 2004 and 2013. RESULTS: Nine patients (9%) had biopsy-proven gastric adenomas. Adenomas were located in the antrum (five patients), in the body and fundus in the setting of background fundic gland polyps (FGP) (three patients), and in the body not associated with FGP (one patient). Adenoma size was 3-40 mm and the number of adenomas per patient ranged from one to 20. Adenomas in the antrum were flat and subtle, whereas those in the gastric body or fundus were polypoid and difficult to differentiate from the cystic FGPs seen in patients with FAP. The performing endoscopists reported difficulty with identifying adenomas, and six patients had at least one EGD within the previous three years where gastric adenomas were not reported. Adenomas were classified as tubular in eight patients and tubulovillous in one patient. High grade dysplasia was noted in one patient. After a median follow-up of 63 months (interquartile range: 20-149 months), no patient in our entire cohort (with or without gastric adenomas) developed gastric cancer. The patients in whom gastric adenoma developed, compared to those without gastric adenoma, were more likely to be younger [36 ± 12 vs. 48 ± 15 years, p = 0.02], have concomitant chronic gastritis [22% vs. 0%, p = 0.008], and have desmoid tumors [5 (56%) vs. 19 (22%), p = 0.04]. CONCLUSIONS: Gastric adenomas are not uncommon in patients with FAP and are often difficult to identify endoscopically. Endoscopists should have a high degree of suspicion for gastric adenomas in these patients and a low threshold to biopsy. Given the benign clinical course, recommended initial management is conservative with endoscopic therapy and periodic surveillance.

Submucosal Epstein-Barr Virus Positive Polymorphic B-cell Lymphoproliferative Disorder of the Larynx: A Case Report.

Epstein-Barr virus (EBV) belongs to the group of human herpes virus and can cause clinical and subclinical infections. Although EBV-related disease presentations are similar, they can lead to oncogenic transformation with various clinical manifestations. A thorough workup with morphology, immunohistochemistry, and molecular studies is crucial for the diagnosis of EBV-positive polymorphic B-cell lymphoproliferative disorder, not otherwise specified (NOS), which is a new entity introduced by International Consensus Classification in 2022. We describe an interesting presentation of EBV-positive polymorphic B-cell lymphoproliferative disorder with laryngeal involvement to bring awareness to this entity and we would like to address the need for more accessible treatment options.

Classification criteria for advanced adenomas of the colon by using probe-based confocal laser endomicroscopy: a preliminary study.

BACKGROUND: Probe-based confocal laser endomicroscopy may allow a strategy of "diagnose, resect, and discard" for small nonadvanced adenomas, but there are concerns about discarding polyps with advanced histology. OBJECTIVE: The aim of this study was to evaluate the potential use of probe-based confocal laser endomicroscopy to aid in distinguishing low-grade from advanced colon adenomas. DESIGN: Six observers, blinded to histopathology, scored 5 adenoma features and an overall diagnosis and confidence level for the diagnosis. SETTING: This study was conducted at single, tertiary care referral center. PATIENTS: Patients undergoing screening and surveillance colonoscopies and for whom an adenomatous polyp was removed were included. INTERVENTIONS: A sample of 27 advanced adenomas and 120 nonadvanced adenomas were used in the study. An initial classification system was created with 10 advanced and 10 nonadvanced adenomas. The remaining 127 adenomas were scored by each observer in the validation portion of the study. MAIN OUTCOME MEASURES: The primary outcome measured was the accurate classification of advanced and nonadvanced adenomas. RESULTS: Overall, across all 6 observers, the sensitivity in correctly classifying advanced adenomas was 43%, the negative predictive value was 89%, the specificity was 71%, and the positive predictive value was 19%. No single feature or combination of features as seen with probe-based confocal laser endomicroscopy consistently identified advanced adenomas. LIMITATIONS: Classification criteria were developed subjectively, and there was limited observer experience with probe-based confocal laser endomicroscopy use. CONCLUSIONS: Our initial attempt at creating classification criteria for probe-based confocal laser endomicroscopy did not consistently distinguish advanced from nonadvanced adenomas and, therefore, is not useful in applying a "diagnose, resect, and discard" strategy. However, further refinement of our probe-based confocal laser endomicroscopy classification scheme in future studies has potential to accurately detect advanced histology in colorectal polyps.

Screening for Muir-Torre syndrome using mismatch repair protein immunohistochemistry of sebaceous neoplasms.

Screening for the Muir-Torre variant of Lynch Syndrome (LS) using Mismatch Repair (MMR) gene immunohistochemistry (IHC) on sebaceous neoplasms (SNs) is technically feasible. To date, research into the clinical utility of MMR IHC for this indication is limited. We conducted a retrospective chart review of 90 patients with MMR IHC completed on at least one SN from January 2005 to May 2010. SNs included were adenomas, epitheliomas, carcinomas and basal and squamous cell carcinomas with sebaceous differentiation. Of the 90 patients, 13 (14 %) had genetically confirmed or fulfilled clinical criteria for a diagnosis of MTS and 51 patients (57 %) presented with an abnormal MMR IHC result (loss of one or more MMR proteins) on at least one SN. Abnormal IHC had a sensitivity of 85 %, specificity of 48 %, positive predictive value (PPV) of 22 % and negative predictive value (NPV) of 95 % when evaluating for MTS. When personal or family history of colorectal cancer (≥2 family members with a history of colorectal cancer) was taken into consideration, ignoring IHC results, sensitivity was 92 %, specificity was 99 %, PPV was 92 % and NPV was 99 %. MMR IHC on SNs when used to screen for MTS has poor diagnostic utility. We recommend that MMR IHC not be performed routinely on SNs when the patient does not have either personal or family history of colorectal cancer.

Iatrogenic Acute Ascending Aortic Dissection During Combined Heart/Liver Transplant for Amyloidosis.

We report a case of iatrogenic acute type A aortic dissection (ATAAD) during a combined heart-liver transplant in a patient with amyloid-associated cardiac and hepatic failure. The patient developed ATAAD of the recipient's aorta during the heart transplantation. Because there was no sign of malperfusion or proximal extension into the donor aorta, we proceeded with the liver transplantation and continued medical management for ATAAD. The patient was discharged uneventfully 30 days after the transplant, and computed tomography coronary angiogram after 4 months showed stable dissection. During a heart transplant, ATAAD of the native aorta without malperfusion syndrome can be managed conservatively with close progress monitoring.

Diagnostic accuracy of probe-based confocal laser endomicroscopy and narrow band imaging for small colorectal polyps: a feasibility study.

OBJECTIVES: Probe-based confocal laser endomicroscopy (pCLE) allows real-time in-vivo microscopic imaging of tissue. Narrow band imaging (NBI) can also classify colorectal lesions. Both systems may allow accurate optical diagnosis of small (6-9 mm) and diminutive (1-5 mm) polyps without histopathology. This study assesses the accuracy of pCLE and NBI for prediction of histology. METHODS: Participants underwent high-definition colonoscopy. The surface pit pattern of all polyps (1-9 mm) was determined in vivo using NBI. Confocal videos were obtained after administration of IV fluorescein. Recorded videos were subsequently analyzed offline, blinded to endoscopic characteristics, and histopathology. Confocal images were classified as neoplastic and non-neoplastic according to the Miami classification system. RESULTS: A total of 130 polyps (58 neoplastic, 72 non-neoplastic, mean size 4.6 mm) from 65 patients were assessed. Assuming histopathology as gold standard, pCLE had higher sensitivity than NBI (86% vs. 64%, P=0.008), with lower specificity (78% vs. 92%, p=0.027) and similar overall accuracy (82% vs. 79%, P=0.59). When 65 high-confidence cases were analyzed (polyps diagnosed identically with pCLE and NBI and with high-quality confocal videos), sensitivity and specificity were 94 and 97%. CONCLUSIONS: pCLE demonstrated higher sensitivity in predicting histology of small polyps compared with NBI, whereas NBI had higher specificity. When used in combination, the accuracy of pCLE and NBI was extremely high, approaching the accuracy of histopathology. Together, they may reduce the need for histological examination. However, further studies are warranted to evaluate the role of these techniques, especially in the population-based colon cancer screening.

Diagnostic accuracy of probe-based confocal laser endomicroscopy and narrow band imaging in detection of dysplasia in duodenal polyps.

GOALS: To estimate the accuracy of probe-based confocal laser endomicroscopy (pCLE) and narrow band imaging (NBI), individually and in combination, for classification of duodenal polyps. BACKGROUND: Ex vivo pathologic diagnosis of duodenal polyps causes time delay, requiring separate procedures for diagnosis and therapy. It also involves small risk of pancreatitis in ampullary adenomas and can make subsequent endoscopic mucosal resection more difficult by "tacking down" mucosa. In vivo diagnosis with pCLE and NBI may avoid these complications and may guide immediate therapy. STUDY: During high-definition white light endoscopy, 1 endoscopist (M.B.W.) performed NBI and then, pCLE of duodenal sites. Matched tissue sampling or endoscopic mucosal resection was performed. Confocal videos were recorded, de-identified, and reviewed by same endoscopist, blinded to histopathology, 1 month later. Confocal features of dysplasia in Barrett esophagus were applied for detection of duodenal dysplasia. RESULTS: Of 65 sites from 36 participants, 24 lesions showed dysplasia, whereas 41 polyps and control sites were nondysplastic on histopathology, used as standard reference. The accuracy, sensitivity, and specificity of pCLE were 83%, 92%, and 78%, whereas that of NBI were 80%, 83%, and 78%, respectively. In subset of 49 lesions with similar pCLE and NBI diagnosis, the accuracy, sensitivity, and specificity, improved significantly and was found to be 92%, 95%, and 90%, respectively. CONCLUSIONS: Our study suggests that pCLE has superior sensitivity as compared with NBI for detection of dysplasia in duodenal polyps. Combined accuracy of pCLE and NBI approaches that of ex vivo pathology, which may help in avoiding biopsy sampling.

Attribution of the discrepancy between ELISA and LC-MS/MS assay results of a PEGylated scaffold protein in post-dose monkey plasma samples due to the presence of anti-drug antibodies.

High-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) and enzyme-linked immunosorbent assay (ELISA) methods were developed for the quantification of a PEGylated scaffold protein drug in monkey plasma samples. The LC-MS/MS method was based on the extraction of the therapeutic protein with a water-miscible organic solvent and the subsequent trypsin digestion of the extract followed by the detection of a surrogate peptide. The assay was linear over a range of 10-3,000 ng/mL. The ELISA method utilized a therapeutic target-binding format in which the recombinant target antigen was used to capture the drug in the sample, followed by detection with an anti-PEG monoclonal antibody. The assay range was 30-2,000 ng/mL. A correlation study between the two methods was performed by measuring the drug concentrations in plasma samples from a single-dose pharmacokinetic (PK) study in cynomolgus monkeys following a 5-mg/kg subcutaneous administration (n = 4). In the early time points of the PK profile, the drug concentrations obtained by the LC-MS/MS method agreed very well with those obtained by the ELISA method. However, at later time points, the drug concentrations measured by the LC-MS/MS method were consistently higher than those measured by the ELISA method. The PK parameters calculated based on the concentration data showed that the two methods gave equivalent peak exposure (C(max)) at 24-48 h. However, the LC-MS/MS results exhibited about 1.53-fold higher total exposure (AUC(tot)) than the ELISA results. The discrepancy between the LC-MS/MS and ELISA results was investigated by conducting immunogenicity testing, anti-drug antibody (ADA) epitope mapping, and Western blot analysis of the drug concentrations coupled with Protein G separation. The results demonstrated the presence of ADA specific to the engineered antigen-binding region of the scaffold protein drug that interfered with the ability of the drug to bind to the target antigen used in the ELISA method. In the presence of the ADAs, the ELISA method measured only the active circulating drug (target-binding), while the LC-MS/MS method measured the total circulating drug. The work presented here indicates that the bioanalysis of protein drugs may be complicated owing to the presence of drug-binding endogenous components or ADAs in the post-dose (incurred) samples. The clear understanding of the behavior of different bioanalytical techniques vis-à-vis the potentially interfering components found in incurred samples is critical in selecting bioanalytical strategies for measuring protein drugs.

Prkci Regulates Autophagy and Pancreatic Tumorigenesis in Mice.

Protein kinase C iota (PKCι) functions as a bonafide human oncogene in lung and ovarian cancer and is required for KrasG12D-mediated lung cancer initiation and progression. PKCι expression is required for pancreatic cancer cell growth and maintenance of the transformed phenotype; however, nothing is known about the role of PKCι in pancreas development or pancreatic tumorigenesis. In this study, we investigated the effect of pancreas-specific ablation of PKCι expression on pancreatic cellular homeostasis, susceptibility to pancreatitis, and KrasG12D-mediated pancreatic cancer development. Knockout of pancreatic Prkci significantly increased pancreatic immune cell infiltration, acinar cell DNA damage, and apoptosis, but reduced sensitivity to caerulein-induced pancreatitis. Prkci-ablated pancreatic acinar cells exhibited P62 aggregation and a loss of autophagic vesicles. Loss of pancreatic Prkci promoted KrasG12D-mediated pancreatic intraepithelial neoplasia formation but blocked progression to adenocarcinoma, consistent with disruption of autophagy. Our results reveal a novel promotive role for PKCι in pancreatic epithelial cell autophagy and pancreatic cancer progression.

Pyomyositis presenting as myonecrosis secondary to methicillin-resistant Staphylococcus aureus bacteremia in chronic lymphocytic leukemia.

The incidence of pyomyositis in immunocompromised patients with HIV, diabetes, myelodysplastic syndromes, and acute lymphocytic leukemia is well documented. However, there are only a few reports of pyomyositis and myonecrosis in patients with chronic lymphocytic leukemia (CLL). We present a rare case of pyomyositis presenting as myonecrosis secondary to methicillin-resistant Staphylococcus aureus bacteremia in a 72-year-old patient with CLL. Pyomyositis, although rare, warrants increased provider awareness and management, especially among CLL patients who pose diagnostic and treatment challenges.

Comparison of probe-based confocal laser endomicroscopy with virtual chromoendoscopy for classification of colon polyps.

BACKGROUND & AIMS: Probe-based confocal laser endomicroscopy (pCLE) allows in vivo imaging of tissue at micron resolution. Virtual chromoendoscopy systems, such as Fujinon intelligent color enhancement and narrow band imaging, also have potential to differentiate neoplastic colorectal lesions. The accuracy of these systems in clinical practice is, however, unknown. Our primary aim was to compare sensitivity and specificity of pCLE to virtual chromoendoscopy for classification of colorectal polyps using histopathology as a gold standard. A secondary aim was to compare sensitivity and specificity of pCLE to virtual chromoendoscopy using a modified gold standard that assumed that all polyps >/=10 mm had malignant potential and were considered neoplastic or high risk. METHODS: Patients underwent colonoscopy using high-resolution colonoscopes. The surface pit pattern was determined with NBI or FICE in all patients. Confocal images were recorded and subsequently analyzed offline, blinded to the endoscopic characteristics and histopathology. Each polyp was diagnosed as benign or neoplastic based on confocal features according to modified Mainz criteria. RESULTS: A total of 119 polyps (81 neoplastic, 38 hyperplastic) from 75 patients was assessed. The pCLE had higher sensitivity compared to virtual chromoendoscopy when considering histopathology as gold standard (91% vs 77%; P = .010) and modified gold standard (88% vs 76%; P = .037). There was no statistically significant difference in specificity between pCLE and virtual chromoendoscopy when considering histopathology or modified gold standard. CONCLUSIONS: Confocal endomicroscopy demonstrated higher sensitivity with similar specificity in classification of colorectal polyps. These new methods may replace the need for ex vivo histological confirmation of small polyps, but further studies are warranted.