Kohta Iguchi

An eClinical trial system for cancer that integrates with clinical pathways and electronic medical records

Background Various information technologies currently are used to improve the efficiency of clinical trials. However, electronic medical records (EMRs) are not yet linked to the electronic data capture (EDC) system. Therefore, the data must be extracted from medical records and transcribed to the EDC system. Clinical pathways are planned process patterns that are used in routine clinical practice and are easily applicable to the medical care and evaluation defined in a trial protocol. However, few clinical pathways are intended to increase the efficiency of clinical trials. Purpose Our purpose is to describe the design and development of a new clinical trial process model that enables the primary use of EMRs in clinical trials by integrating clinical pathways and EMRs. Methods We designed a new clinical trial model that uses EMR data directly in clinical trials and developed a system to follow this model. We applied the system to an investigator-initiated clinical trial and examined whether all data were extracted correctly. At the protocol development stage, our model measures endpoints based on clinical pathways with the same diagnosis. Next, medical record descriptions and the format of the statistical data are defined. According to these observations, screens for entry of data, which are used both in clinical practice and for study, are prepared into EMRs with an EMR template, and screens are prepared for data checks on our EMR retrieval system (ERS). In an actual trial, patients are registered and randomly assigned to a protocol treatment. The protocol treatment is executed according to clinical pathways, and the data are recorded to EMRs using EMR templates. The data are checked by a local data manager using reports created by the ERS. After edit checks and corrections, the data are extracted by the ERS, archived in portable document format (PDF) with an electronic signature, and transferred in comma-separated values (CSV) format to a coordinating centre. At the coordinating centre, the data are checked, integrated, and made available for a statistical analysis. Results We verified that the data could be extracted correctly and found no unexpected problems. Limitation To execute clinical trials in our system, the EMR template and efficient ERSs are required. Additionally, to execute multi-institutional clinical trials, it is necessary to create templates appropriate for EMRs at all participating sites and for the coordinating centre to validate local templates and procedures. Conclusion We proposed and pilot tested a new eClinical trial model. Because our model is integrated with routine documentation of clinical practice and clinical trials, redundant data entries were avoided and the burden on the investigator was minimised. The reengineering of the clinical trial process would facilitate the establishment of evidence in the future.

Prediction of the Remnant Liver Hypertrophy Ratio after Preoperative Portal Vein Embolization

Background: Portal vein embolization (PVE) is considered to improve the safety of major hepatectomy. Various conditions might affect remnant liver hypertrophy after PVE. The aim of the present study was to clarify the factors that affect remnant liver hypertrophy and to establish a prediction formula for the hypertrophy ratio. Methods: Fifty-nine patients who underwent preoperative PVE for cholangiocarcinoma (39 patients), metastatic carcinoma (10 patients), hepatocellular carcinoma (8 patients), and other diseases (2 patients) were enrolled in this study. For the prediction of the hypertrophy ratio, a formula with stepwise multiple regression analysis was set up. The following parameters were used: age, gender, future liver remnant ratio to total liver (FLR%), plasma disappearance rate of indocyanine green (ICGK), platelet count, prothrombin activity, serum albumin, serum total bilirubin at the time of PVE and the maximum value before PVE (Max Bil), as well as a history of cholangitis, diabetes mellitus, and chemotherapy. Results: The mean hypertrophy ratio was 28.8%. The 5 parameters detected as predictive factors were age (p = 0.015), FLR% (p < 0.001), ICGK (p = 0.112), Max Bil (p < 0.001), and history of chemotherapy (p = 0.007). The following prediction formula was established: 101.6 - 0.78 × age - 0.88 × FLR% + 128 × ICGK - 1.48 × Max Bil (mg/dl) - 21.2 × chemotherapy. The value obtained using this formula significantly correlated with the actual value (r = 0.72, p < 0.001). A 10-fold cross validation also showed significant correlation (r = 0.62, p < 0.001), and a hypertrophy ratio <20% was predictable with a sensitivity of 100% and a specificity of 90.9%. Moreover, technetium-99m-diethylenetriaminepentaacetic acid-galactosyl human serum albumin scintigraphy showed a significantly smaller increase in the uptake ratio of the remnant liver in patients with prediction values <20% than in those with values ≥20% (6.8 vs. 20.8%, p = 0.030). Conclusions: The prediction formula can prognosticate the hypertrophy ratio after PVE, which may provide a new therapeutic strategy for major hepatectomy.

Validation of the Conventional Resection Criteria in Patients with Hepatocellular Carcinoma in Terms of the Incidence of Posthepatectomy Liver Failure and Long-Term Prognosis

Background/Aims: Resection criteria in hepatocellular carcinoma (HCC) should be established based on the risk of posthepatectomy liver failure (PHLF) and the survival benefit from hepatectomy. This study aimed at verifying the validity of the conventional criteria regarding the incidence of PHLF and the long-term prognosis of HCC patients. Methods: A retrospective study was performed on 265 patients who underwent major hepatectomy. Makuuchis criteria and the future liver remnant plasma clearance rate of indocyanine green (ICGK-rem) ≥0.05 criterion were evaluated. Results: A total of 107 and 158 patients were within and beyond Makuuchis criteria, respectively. Makuuchis criteria were associated with the incidence of PHLF (p = 0.03) but not with its severity (p = 0.12). No differences in disease-free survival (DFS) or overall survival (OS) were observed between the groups (p = 0.75 and p = 0.94, respectively). Using the ICGK-rem ≥0.05 criterion, 223 and 42 patients were within and beyond the criterion, respectively. ICGK-rem was correlated with both the incidence of PHLF (p = 0.002) and its severity (p = 0.03). No differences in DFS or OS were observed between the groups (p = 0.75 and p = 0.29, respectively). Conclusions: Strict criteria are likely to preclude some patients from obtaining the greater survival benefits of hepatectomy. New criteria that consider patient prognosis are needed.

Pancreatic Stellate Cells Have Distinct Characteristics From Hepatic Stellate Cells and Are Not the Unique Origin of Collagen-producing Cells in the Pancreas

Objectives The origin of collagen-producing myofibroblasts in pancreatic fibrosis is still controversial. Pancreatic stellate cells (PSCs), which have been recognized as the pancreatic counterparts of hepatic stellate cells (HSCs), are thought to play an important role in the development of pancreatic fibrosis. However, sources of myofibroblasts other than PSCs may exist because extensive studies of liver fibrosis have uncovered myofibroblasts that did not originate from HSCs. This study aimed to characterize myofibroblasts in an experimental pancreatic fibrosis model in mice. Methods We used transgenic mice expressing green fluorescent protein via the collagen type I &agr;1 promoter and induced pancreatic fibrosis with repetitive injections of cerulein. Results Collagen-producing cells that are negative for glial fibrillary acidic protein (ie, not derived from PSCs) exist in the pancreas. Pancreatic stellate cells had different characteristics from those of HSCs in a very small possession of vitamin A using mass spectrometry and a low expression of lecithin retinol acyltransferase. The microstructure of PSCs was entirely different from that of HSCs using flow cytometry and electron microscopy. Conclusions Our study showed that characteristics of PSCs are different from those of HSCs, and myofibroblasts in the pancreas might be derived not only from PSCs but also from other fibrogenic cells.

Cracking pattern of tissue slices induced by external extension provides useful diagnostic information

Although biopsy is one of the most important methods for diagnosis in diseases, there is ambiguity based on the information obtained from the visual inspection of tissue slices. Here, we studied the effect of external extension on tissue slices from mouse liver with different stages of disease: Healthy normal state, Simple steatosis, Non-alcoholic steatohepatitis and Hepatocellular carcinoma. We found that the cracking pattern of a tissue slice caused by extension can provide useful information for distinguishing among the disease states. Interestingly, slices with Hepatocellular carcinoma showed a fine roughening on the cracking pattern with a characteristic length of the size of cells, which is much different than the cracking pattern for slices with non-cancerous steatosis, for which the cracks were relatively straight. The significant difference in the cracking pattern depending on the disease state is attributable to a difference in the strength of cell-cell adhesion, which would be very weak under carcinosis. As it is well known that the manner of cell-cell adhesion neatly concerns with the symptoms in many diseases, it may be promising to apply the proposed methodology to the diagnosis of other diseases.

Chronological profiling of plasma native peptides after hepatectomy in pigs: Toward the discovery of human biomarkers for liver regeneration

Liver regeneration after partial hepatectomy (PHx) is a time-dependent process, which is tightly regulated by multiple signaling cascades. Failure of this complex process leads to posthepatectomy liver failure (PHLF), which is associated with a high rate of mortality. Thus, it is extremely important to establish a useful biomarker of liver regeneration to help prevent PHLF. Here, we hypothesized that alterations in the plasma peptide profile may predict liver regeneration following PHx and hence we set up a diagnostic platform for monitoring posthepatectomy outcome. We chronologically analyzed plasma peptidomic profiles of 5 partially hepatectomized microminipigs using the ClinProtTM system, which consists of magnetic beads and MALDI-TOF/TOF MS. We identified endogenous circulating peptides specific to each phase of the postoperative course after PHx in pigs. Notably, peptide fragments of histones were detected immediately after PHx; the presence of these fragments may trigger liver regeneration in the very acute phase after PHx. An N-terminal fragment of hemoglobin subunit α (3627 m/z) was detected as an acute-phase-specific peptide. In the recovery phase, the short N-terminal fragments of albumin (3028, 3042 m/z) were decreased, whereas the long N-terminal fragment of the protein (8926 m/z) was increased. To further validate and extract phase-specific biomarkers using plasma peptidome after PHx, plasma specimens of 4 patients who underwent PHx were analyzed using the same method as we applied to pigs. It revealed that there was also phase-specificity in peptide profiles, one of which was represented by a fragment of complement C4b (2378 m/z). The strategy described herein is highly efficient for the identification and characterization of peptide biomarkers of liver regeneration in a swine PHx model. This strategy is feasible for application to human biomarker studies and will yield clues for understanding liver regeneration in human clinical trials.