Common Deficiencies of <Emphasis Type="Italic">in vitro</Emphasis> Binding Bioequivalence (BE) Studies Submitted in Abbreviated New Drug Applications (ANDAs)

There are several drug products that bind phosphate or bile acid in the gastrointestinal (GI) tract to exert their therapeutic efficacy. In vitro binding studies are used to assess bioequivalence (BE) of these products. The objective of this study is to identify the common deficiencies in Abbreviated New Drug Applications (ANDAs) for these products. Deficiencies were compiled from ANDAs containing in vitro binding BE studies. The deficiencies were classified into eight categories: Pre-Study Method Validation, During-Study Sample Analysis, Study Design, Study Procedure, Dissolution/Disintegration, Analytical Site Inspection, Data Submission, and Formulations. Within each category, additional subcategories were defined to characterize the deficiencies. A total of 712 deficiencies from 95 ANDAs for 11 drug products were identified and included in the analysis. The four categories with the most deficiencies were During-Study Sample Analysis (27.8%), Pre-Study Method Validation (17.3%), Data Submission (16.7%), and Study Design (15.7%). For the During-Study Sample Analysis category, failure to submit complete raw data or analytical runs ranked as the top deficiency (32.8%). For the Study Design category, using an unacceptable alternate study design (26.8%) was the most common deficiency. Within this category, other commonly occurring deficiencies included incorrect/insufficient number of absorbent concentrations, failure to pre-treat drug product with acid, insufficient number of replicates in study, incorrect calculation of k1 and k2 values, incorrect dosage form or pooled samples used in the study, and incorrect pH of study medium. The review and approval of these products may be accelerated if these common deficiencies are addressed in the original ANDA submissions.     

腹部钝伤CT诊断与临床分析

目的评价CT检查对腹部钝伤的诊断价值。方法对240例CT检出腹部脏器损伤病例进行回顾性分析。结果 240例腹部钝伤CT检出单一器官损伤125例,肝肾同时伤36例,复合伤25例,腹腔积血195例,腹膜后血肿40例。结论 CT对腹部脏器损伤的正确诊断和临床治疗提供重要信息。     

Calciphylaxis in end‐stage liver and renal disease patients before and after transplant

Calciphylaxis is a rare vascular disorder characterized by calcification of arterioles which causes tissue inflammation and necrosis. It is associated with the metabolic disturbances seen in end‐stage renal disease (ESRD) and has also been described in patients with cirrhosis with preserved kidney function. Characteristic calciphylaxis lesions are black eschars surrounded by retiform purpura, and the gold standard for diagnosis is skin biopsy. Reported 1‐year mortality rates range between 45% and 80%. No treatment modality has been evaluated in a prospective randomized trial, and reports of treatment efficacy vary. Kidney transplant has been reported as a successful therapy for calciphylaxis; however, cases exist of the initial onset of calciphylaxis following kidney transplant as well as simultaneous liver‐kidney (SLK) transplant. The decision to maintain a patient with end‐stage renal and liver disease on the waiting list for SLK transplant following the onset of calciphylaxis must consider the high 1‐year mortality associated with this condition. More research is necessary to understand how to allocate donor allografts to manage patients with calciphylaxis and ESRD and/or cirrhosis effectively.     

The Impact of Obesity and Metabolic Surgery on Chronic Inflammation

Background

Obesity and metabolic surgery is known to improve chronic inflammatory status. Whether improvement is related to anatomical changes or weight loss is still to debate.

Objective

The aim of this clinical trial is to compare the different bariatric procedures sleeve gastrectomy (SG), Roux-en-Y gastric bypass (RYGB), and One-anastomosis gastric bypass (OAGB), pertaining to their effects on inflammation markers.

Methods

Patients who underwent SG, RYGB, or OAGB as a primary treatment for severe obesity were included. The data collected preoperatively (T0) and 1, 3, and 6 (T6) months after surgery included gender, weight, comorbidities and toxic habits at baseline, body mass index (BMI), waist circumference, total body weight loss in % (TBWL), leukocyte count in ×?10³/μl, C-reactive protein (CRP) in mg/l, HbA1c in %, aspartate transaminase in U/l, alanine transaminase in U/l, gamma-glutamyltransferase in U/l, bilirubin in mg/dl, cholesterol in mg/dl, and triglycerides in mg/dl.

Results

Four hundred sixty-eight patients were included. Drop-out rate was 25.8% at T6. Preoperatively the mean value of leukocytes and CRP was 7.4?×?10³/μl?±?2 and 10.5 mg/l?±?8.1. At T6, mean value of leukocytes and CRP was 7.1?×?10³/μl?±?1.9 (p?=?0.075) and 7.2 mg/l?±?9.5 (p?<?0.001). TBWL % at T6 was 24.2?±?7.6 in the SG, 25.8?±?5.9 in the RYGB and 25.5?±?4.6 in the OAGB group. Comparing SG, RYGB, and OAGB in relation to leukocyte count and CRP no significant difference was seen between the groups.

Conclusion

CRP but not leukocyte count decreased after all three bariatric procedures but without any significance between the three groups. Surgically induced weight loss and not anatomical changes might play an important role for improvement in chronic inflammation.

Trial Registration

The National Clinical Trials number was NCT02697695 (https://clinicaltrials.gov/ct2/show/NCT02697695).

     

Cytopathological and immunocytochemical findings of pancreatic anaplastic carcinoma with ZEB1 expression by means of touch imprint cytology

Pancreatic anaplastic carcinoma (PAC) is rare and has an aggressive clinical course. We report an autopsy case of PAC focusing on the cytopathological characteristics of the tumor and immunocytochemical staining for vimentin, E‐cadherin, and zinc finger E‐box binding homeobox 1 (ZEB1), which markers are associated with epithelial markers of epithelial‐mesenchymal transition (EMT). A 50‐year‐old woman presented to our hospital with a chief complaint of jaundice. A pancreatic head tumor and multiple liver nodules were detected on abdominal computed tomography. Biliary cytology under endoscopic retrograde cholangiopancreatography suggested ductal adenocarcinoma. Three months after admission, she died of multiorgan failure. At autopsy, touch imprint cytology using squash preparation of the pancreatic tumor identified two different cell types; numerous isolated malignant cells with large and pleomorphic nuclei and a few clusters showing irregularly overlapped nuclei and irregular contours within the necrotic background. Immunocytochemically, isolated cells were positive for vimentin and ZEB1, and negative for E‐cadherin. Conversely, clusters were negative for vimentin and ZEB1, and positive for E‐cadherin. Histologically, the tumor was composed of sarcomatous cells with small foci of adenocarcinoma, which were consistent with a diagnosis of PAC. Immunohistochemical staining of the adenocarcinoma and sarcomatous cells corresponded to those of the clusters and isolated malignant cells, respectively. Immunostaining of these EMT markers is useful to distinguish sarcomatous cells from adenocarcinoma and can contribute to the accurate diagnosis of pancreatic tumors with EMT.     

Cytological findings of ROS1‐rearranged lung adenocarcinoma

ROS1‐rearranged lung adenocarcinoma has been recently identified. We report a case of ROS1‐rearranged lung adenocarcinoma with special emphasis on cytological findings. Here, we report a case of young woman with ROS1‐rearranged lung adenocarcinoma diagnosed by cytology and discuss the clinical, cytological, and molecular findings. Cytologically, the tumor consisted of small tight clusters of cells with high nuclear/cytoplasmic ratio. Nuclei were enlarged and small nucleoli were occasionally observed. Signet‐ring cells were focally identified. Neoplastic cells were positive for ROS1 immunocytochemistry. Subsequently, the translocation of ROS1 gene was confirmed in a histological specimen. In conclusion, the specific histology of adenocarcinoma on cytological materials should promote testing for ROS1 immunohistochemistry. Immunocytochemical detection of ROS1 protein helps identify patients suitable for molecular targeted therapy.