Long-term phenotypic study after allogeneic cultivated corneal limbal epithelial transplantation for severe ocular surface disea

Ophthalmology. 2010 Dec;117(12):2247-2254.e1. Epub 2010 Jul 29.Long-term phenotypic study after allogeneic cultivated corneal limbal epithelial transplantation for severe ocular surface diseases.Nakamura T, Sotozono C, Bentley AJ, Mano S, Inatomi T, Koizumi N, Fullwood NJ, Kinoshita S.Source

Department of Ophthalmology, Graduate School of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan. tnakamur@koto.kpu-m. ac.jpAbstractPURPOSE:

To determine the long-term epithelial lineage of origin of surgically removed grafts after allogeneic cultivated corneal limbal epithelial transplantation (CLET).DESIGN:

Interventional case reports.PARTICIPANTS:

We studied 2 eyes from 2 patients with total corneal stem cell destruction; 1 eye was from a patient with Stevens-Johnson syndrome and 1 eye had sustained chemical injury.METHODS:

Allogeneic cultivated corneal limbal epithelial sheets on human amniotic membrane (AM) were transplanted onto the ocular surface. Regrafting (1 eye, 42 months later) or penetrating keratoplasty (1 eye, 75 months later) were performed after the initial transplantation procedure for further visual rehabilitation.MAIN OUTCOME MEASURES:

The excised grafts were subjected to clinical evaluation and to light- and transmission electron microscopy (TEM) examination and to immunohistochemical analysis.RESULTS:

In clinically conjunctival grafts, TEM and immunohistochemical analysis disclosed only small areas where the original cultivated corneal epithelial cells persisted. Neighboring conjunctival epithelial cells had apparently invaded a large portion of the corneal surface (keratin 3/12(-), Muc5ac(+)). In clinically corneal grafts, transplanted allogeneic cultivated corneal epithelial cells clearly survived for a long period of time (keratin 3/12(+), Muc5ac(-)); there was no infiltration by inflammatory cells, nor was there dissolution of the AM substrate.CONCLUSIONS:

We theorize that the process of graft opacification after allogeneic CLET is responsible for the loss of transplanted cultivated corneal epithelial cells and that this is followed by conjunctival cell invasion onto the corneal surface. The results of this study confirmed that in the clinically evaluated corneal graft, transplanted cultivated corneal epithelial cells indeed survived for a long period of time on the corneal surface and maintained ocular surface integrity, even though the transplanted cells were allogeneic.

Copyright © 2010 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

treatments

Regenerative Medicine in Japan

Regenerative medicine is a new area of medicine based on molecular and cellular biology. We name only a few effective fields for a start, and will add to the list later.

Usage of CD-34 Positive hematopoietic stem cells from Apheresis

Infusion of Peripheral Stem Cell (CD-34 Positive hematopoietic stem cells) into ischemic muscle for angiogenesis (vascularization) or the growth of new blood vessels from existing vessels.

Cell Sheets Therapy on Eye Disease - Vision Loss Treatment

Cell Sheets Therapy on eye/ocular disease in Japan

Eye (Ocular) disease, specifically corneal opacification of eye, could be treated with allograft transplantation. Recent progress in regenerative medicine makes a new alternative treatment to the patients not requiring immunosuppression by allograft transplantation, or to the patients who could not get transplantations.

Regenerative Medicine on Dilated Cardiomyopathy, or Myocardial Infarction

Recent technological advances in cell sheets engineering extended to the pre-clinical trial of the treatment of heart disease patients often in need for the heart transplant.

Cardiac myoblast, or embryonic heart muscle cell has been proposed for the alternative treatment of the patients with dilated cardiomyopathy replacing the heart transplant treatment. However, its post-transplantation inflammatory responses made it difficult for the clinical applications.

International Hospital Ranking

Cancer Adoptive Cell Immunotherapy in Japan

Cell based Immunotherapy (Autologous immune enhancement therapy) has been more frequently practised in Japan.Techniques to harvest the cells are extremely intricate and delicate processes. For the treatments to be rountinely available to the cancer patients apart from the clinical trials, advanced engineering cell reprocessing center must be available with good corroboration with the hospitals.

Since Japan made the Immuno-Cell Therapy to be a part of health care systems, the cell processing centers (CPCs) rapidly increased in the past decades. For the therapy of high complexity such as dendritic cell / autologous enhancement immunotherapy to be regularly practiced in the hospital, those CPCs were essential, and this explains why much of innovations in cell based cancer immunotherapy took place in Japan. 

Endoscopic Submucosal Dissection (ESD) \ Endoscopic Mucosal Resection (EMR) in Japan

Both EMR and ESD was originally developed in Japan. EMR / ESD (endoscopic biopsy or polyp resection procedure on gastrointestinal tract) is the area that Japanese surgeons are leading the research at forefront. It is the minimally invasive endoscopic procedure that conserves organs / tissues, and patients can be discharged from the hospital in the same day or a week after the operations. It is usually applicable to early stage cancer / tumor, and improves the post-surgical health conditions such as loss of appetite, fever, chills, pains and life-long medication.

Proton Beam Therapy

Currently there are about 31 proton (or carbon ion) therapy facilities in the world, 8 of which is built in Japan. Proton Beam Therapy is much less invasive than other radiotherapy treatments, and can treat the cancer without incision of the body, and with much less side effects than X-ray treatments. Japan has invested in Proton beam therapy (PBT) / Carbon Ion Therapy infrastructure for a long time, and clinical level studies are numerous and thus well experienced with all kinds of localized tumors.

Radiofrequency Ablation (RFA) on Liver cancer (Hepatocellular carcinoma)

Japan has been leading the RFA intervention technology for a long time, and the yearly number of RFA interventions in Japan currently exceeds that of United States and China. (See the Table below.) Survival rates for the patients undergoing the RFA are not different from those of surgery. But the surgery is harder to be operated multiple times, whereas the RFA is not restricted by the number of interventions or by the presence of Hepatitis.  For this reason, RFA becomes a standard treatment in Japan.

Yearly volume of RFA on Liver Cancer
Japan 34,000
US 14,000
China 9,500

Table: Yearly number of Radiofrequency ablation of Liver or hepatic tumors by country.

Regenerative Medicine on Dilated Cardiomyopathy, or Myocardial Infarction

Recent technological advances in cell sheets engineering extended to the pre-clinical trial of the treatment of heart disease patients often in need for the heart transplant.

Micro-Catheter treatments on varicose veins (including the veins below the knee)

In japan, complex operations towards varicose veins below the knee are established with safey and high response rates. Various catheter and micro-catheter devices are extensively used, and some of them are only available in Japan.

Cancer and Heart Disease Treatment in Japan  

Medical technology in Japan for cancer screening and gastrointestinal diseases are known to be very strong, supported by good clinical statistics, i.e., high five year survival rate after the surgery (or radiology / chemotherapy) among the colon, rectal, stomach, and esophageal cancer patients as well as liver, lung, and larynx cancer (See Table below). 

Since Japanese health agency is notoriously slow and counter-productive when it comes to the approval of new drugs, Japan's hospitals and patients suffered for so long by the technology lag from the rest of the world. Ironically, these regulatory problems lead physicians to the innovations in the fields other than drug discoveries, i.e., in the surgical / laparoscopic, endoscopic, micro-catheter procedures, cell based immunotherapy / vaccinations, radiation (carbon ion and proton beam), and regenerative medicine (iPS cells, cell sheets).

Since the Japanese physicians had less options in chemotherapy, they had more opportunities in experiencing difficult surgeries, and tried the new treatments due to the low availability of new drugs. Thus, many exotic and unique medical technologies emerged out of the isolations casued by the incompetence of Japanese health agency.

Site (Survival Rate:  %)

7 Cancer Registrates in Japan

US SEER Program Eurocare-3
Esophagus 25 14 10
Stomach 58 22 23
Colon 66 62 51
Rectum 63 63 48
Liver 17 7 7
Gallbladder 18 16 12
Pancreas 6 4 4
Larynx 77 65 62
Lung, bronchus 20 15 11