Therapeutic goal of fetal precursor cell transplantation

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There are two types of clinical situations, where fetal precursor cell transplantation has been utilized for treatment in its 90+ years long history. First, there are diseases with no known treatment, and second, there are diseases where standard treatment has been available, and was used to keep the illness under control for some time, but when it progressed to the stage when it stopped being effective, i.e. disease became untreatable, then fetal precursor cell transplantation was discovered, usually by the desperate patient, as a therapeutic modality. The examples of the 1st group are neurodegenerative diseases, and nearly all genetic and chromosomal diseases, while a good example of the 2nd group is diabetes mellitus.


In patients of the 1st group the decision to select fetal precursor cell transplantation as treatment has been simple. There is no other therapy available, and since properly prepared fetal precursor cell transplants are ‘safer that aspirin’, fetal cell transplantation was, or should have been, carried out as soon after the diagnosis was made.


In 2nd group the situation is much more complicated, because the patient has usually continued one of the no longer effective therapies, without informing the fetal cell transplantologist about it, and when there was an improvement, the physicians and powerful business groups that oppose fetal precursor cell transplantation declared that the reason for the success is a new heretofore unknown benefit of the old therapy, and where there was a lack of success then fetal precursor cell transplantation was just ‘useless’, without considering the possibility that the old therapy was detrimental to fetal precursor cell transplants. The patient’s own opinion was ignored. As the patient’s state of mind was usually dominated by negative emotions due to confusing information coming from various corners, the evaluation of the benefit of fetal precursor cell transplantation became a complicated matter.


Specifically in diabetes, since all patients with IDDM have to continue insulin injections even after fetal precursor cell transplantation, albeit at a lower dosage, it is better to limit the use of fetal precursor cell transplantation to the patients with complications of diabetes mellitus: nephropathy, retinopathy, lower extremity vascular disease, and polyneuropathy, etc. that had reached the stage of being otherwise un-treatable, i.e. where the patient had clearly recognized that even the best insulin treatment by the best diabetologist cannot stop the progression of serious, disabling and life-threatening diabetic complication(s).


It is a matter of good clinical judgment to avoid treatment of those 93% of diabetics that suffer from NIDDM (non-insulin dependent diabetes mellitus) until they develop diabetic complications. NIDDM is not a disease, but a label for multiplicity of abnormal conditions of sugar and lipid metabolism. Until the etiology of the metabolic malfunction in such patients can be found it is hard to treat them successfully with fetal precursor cell transplantation. The exceptions are MODY, a mixed type 1-2 diabetes mellitus, or diabetes mellitus type 2 due to an identified genetic cause.


Unfortunately, as a matter of medical politics, children with recent onset of diabetes mellitus have not been permitted to be treated by some regulatory agencies by fetal precursor cell transplantation. In reality the only way to cure diabetes, or postpone its progression, is by treating children with recent onset of IDDM (insulin dependent diabetes mellitus) by fetal precursor cell transplantation, and thereby prolong the period of their normal growth and development. This has been proven by our team in USSR/Russia, confirming the report by Benikova et al. from Ukraine. [222] See the subchapter on ‘Diabetes mellitus’.


The following rules on the patient selection for the treatment by fetal precursor cell transplantation apply when your patient is a diabetic with complications. U.S. official statistics are utilized because similar data from other countries were not at the author’s disposal.


Among diabetics with nephropathy those patients with stage III of diabetic nephropathy as per NIDDK staging VI.BIBLIOGRAPHY [106] or ‘overt diabetic nephropathy’ with loss of albumin and other proteins exceeding 200 micrograms per minute, i.e. ‘dipstick-positive proteinuria’, and increased serum creatinine and BUN, and with early stage IV of diabetic nephropathy as per NIDDK staging VI.BIBLIOGRAPHY [106], or ‘advanced diabetic nephropathy’, with declining glomerular filtration rate, some hypertension, and noticeably increased serum creatinine and BUN, as a complication of insulin dependent diabetes mellitus (IDDM), that have not responded to intensive insulin therapy, together with angiotensin converting enzyme (ACE) inhibitors, are ‘ideal’ candidates for fetal precursor cell transplantations. They are ‘ideal’, because they reached the ‘point of no return’, and no one can claim that they got better as a result of any other treatment but fetal precursor cell transplantation.


In U.S. diabetes mellitus (DM) accounts for 35% of all new cases of end-stage renal disease (ESRD). VI.BIBLIOGRAPHY [105] In 1995, a total of 98,872 diabetics received a renal replacement therapy, and there were 27,851 new cases of diabetic ESRD.


NIDKK website states that 17 million of U.S. population has diabetes mellitus. VI.BIBLIOGRAPHY [106] 7% of this number, it means approximately 1, 1 million, suffers from IIDM. VI.BIBLIOGRAPHY [105] 30-50% of patients with IDDM would be expected to develop diabetic nephropathy after 40 years of DM. VI.BIBLIOGRAPHY [105] It has been observed that incidence of proteinuria rises during the first 10 years of IDDM, and then begins to decline after about 15 years, so that apparently only a subset of patients with IDDM is susceptible to the development of renal disease. VI.BIBLIOGRAPHY [105]. As stated above in DCCT intensive insulin therapy was associated with a 39% reduced risk of microalbuminuria and 54% reduced risk of macroalbuminuria. It is estimated that 20-30% of patients with DM has microalbuminuria (i.e. they are in stage II of diabetic nephropathy), and 20-30% of diabetics has macroalbuminuria (i.e. they are in stage III of diabetic nephropathy) In Wisconsin study, in group of IDDM patients, 21% had micro- and 21% had macro-albuminuria. VI.BIBLIOGRAPHY [105] In IDDM, the incidence of persistent proteinuria reaches 25% after 15 years of DM. VI.BIBLIOGRAPHY [105] Clinical proteinuria heralds a relentless decline of renal function leading to ESRD. Of IDDM patients at the Joslin Clinic in Boston, MA, 50% developed chronic renal failure after 10 years of persistent proteinuria. VI.BIBLIOGRAPHY [105] Taking all of the above statistical data into consideration it appears that approximately 12.5% of patients with IDDM should reach the stage V. of ESRD, i.e. about 137,000 patients. In absolute numbers 27,851 diabetic patients developed end-stage renal disease in 1995. In 1995, a total of 98,872 diabetics underwent dialysis or kidney transplantation. VI.BIBLIOGRAPHY [106]


There is at least 137,000 IDDM patients within the U.S. that should undergo fetal precursor cell transplantation as per the above statistics.


Among diabetics with retinopathy those patients with pre-proliferative stage of diabetic retinopathy as a complication of insulin dependent diabetes mellitus (IDDM), that have not responded to intensive insulin therapy for at least 6 months and photocoagulation of retina, are ‘ideal’ candidates for fetal precursor cell transplantation by the described in this book BCRO clinical method. They are ‘ideal’, because they reached the ‘point of no return’, and no one can claim that they got better as a result of any other treatment but fetal precursor cell transplantation.


Diabetic retinopathy is the leading cause of new cases of blindness of adults in the U.S.: 11% are due to diabetic retinopathy. In the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) 97% of IIDM patients had evidence of retinopathy by 15 years of diabetes mellitus (‘DM’). The most severe stage, proliferative diabetic retinopathy, was present in 30% of IDDM after 15 years of diabetes. VI.BIBLIOGRAPHY [105]


NIDKK website states that 15,7 million of U.S. population has diabetes mellitus. VI.BIBLIOGRAPHY [106] 7% of this number, it means approximately 1, 1 million, suffers from IIDM. VI.BIBLIOGRAPHY [105] According to WESDR, 97% of this number will have retinopathy after 15 years of diabetes, and 30% will have proliferative diabetic retinopathy. [105] As per DCCT, 60% of these patients will be helped by the intensive insulin treatment. VI.BIBLIOGRAPHY [105] In accordance with Diabetes Retinopathy Study (DRS), panretinal photocoagulation reduces the rate of severe loss of vision (visual acuity poorer than 5/200) by 50% or more. VI.BIBLIOGRAPHY [105] As per WESDR data, around 45% of new patients with proliferative diabetic retinopathy develops DRS high-risk characteristics for severe loss of vision. VI.BIBLIOGRAPHY [105] Based on the foregoing statistical data we estimate that there is in the U.S. a population of around 150,000 IDDM patients with pre-proliferative retinopathy with DRS high-risk characteristics for severe loss of vision who have not responded positively to DCCT-type intensive insulin treatment and any form of retinal photocoagulation treatment.


As an example, the population of 150,000 IDDM patients in U.S. with pre-proliferative retinopathy with DRS high-risk characteristics for severe loss of vision, that recognized the futility of DCCT-type intensive insulin treatment, together with that of retinal photocoagulation, in controlling the progression of their retinopathy, should be seeking fetal precursor cell transplantation treatment.


Among diabetics with lower extremity arterial disease those patients with a lower extremity arterial disease (LEAD) as a complication of insulin dependent diabetes mellitus (IDDM), that have not responded to intensive insulin therapy, and underwent already an unsuccesful revascularization surgery, or such surgery was contraindicated, or already had an amputation, are ‘ideal’ candidates for the described clinical method of BCRO cell precursor cell transplantation. They are ‘ideal’, because they reached the ‘point of no return’, and no one can claim that they got better as a result of any other treatment than BCRO cell transplantation.


In U.S. more than 50% of all amputations occur in patients with DM, which amounted to 67,000 amputations a year in each of the years 1993 - 5 VI.BIBLIOGRAPHY [106] The 4-year amputation incidence in WESDR cohort study was 2.2% for IDDM patients. VI.BIBLIOGRAPHY [105] 9 - 20% of patients with DM had a second amputation (ipsi- or contra- lateral) within 12 months after the first one. 28 - 51% of diabetic amputees had an amputation of the contralateral lower extremity within 5 years. VI.BIBLIOGRAPHY [105] The incidence of LEAD in patients with DM was ~10 times higher than that of non-diabetics. VI.BIBLIOGRAPHY [105] By the time LEAD becomes clinically manifest it may be too late to salvage an extremity. VI.BIBLIOGRAPHY [105]


NIDKK website states that 15,7 million of U.S. population has diabetes mellitus. VI.BIBLIOGRAPHY [106] 7% of this number, it means approximately 1, 1 million, suffers from IIDM. VI.BIBLIOGRAPHY [105] The full extent of diabetic foot problem in U.S. is unknown. VI.BIBLIOGRAPHY [105] The annual incidence of foot ulcers in patients with DM is 2 - 3% and prevalance 4 - 10%. VI.BIBLIOGRAPHY [105] In WESDR the incidence of foot ulcers in IDDM patients was 2.4%. VI.BIBLIOGRAPHY [105] Foot ulcers precede 85% of non-traumatic amputations in patients with DM. Intermittent claudication was found in 9% of patients with DM. VI.BIBLIOGRAPHY [105] Cumulative incidence of LEAD was 15% at 10 years after an initial diagnosis of DM and 45% after 20 years. VI.BIBLIOGRAPHY [105]. LEAD is in patients with DM compounded by the presence of diabetic neuropathy and susceptibility to infection. VI.BIBLIOGRAPHY [105] As per DCCT, none of these patients will be significantly helped by the intensive insulin treatment. VI.BIBLIOGRAPHY [105] In each of the years 1993 - 1995 as many as 67,000 amputations were due to diabetes mellitus. NIH statistics do not state the proportion of IDDM and NIDDM patients. Based on the foregoing statistical data, and on the 4-years’ amputation incidence in IDDM patients of 2.2% , we estimate that there is in U.S. a population of around 23,000 IDDM patients with diabetic major vasculopathy who have not responded positively to DCCT-type intensive insulin treatment, and revascularization surgery. Since one cannot wait until a gangrene develops, we estimate that our prospective patient population in U.S. is around 9% of 1.1 million of patients with IDDM, which amounts to approximately 100,000.


So as an example in the U.S. there is a patient population of 100,000 IDDM patients with LEAD, that recognized the futility of DCCT-type intensive insulin treatment, together with revascularization surgery, in controlling the progression of their lower extremity arterial disease, and should seek fetal precursor cell transplantation .


Among diabetics with polyneuropathy those patients with otherwise untreatable severe diabetic polyneuropathy as a complication of insulin dependent diabetes mellitus (IDDM), that have not responded to intensive insulin therapy, and their pain became intractable despite the ‘state-of-art’ pain treatment, are’ideal’ candidates for the described clinical method of BCRO fetal precursor cell transplantation. They are ‘ideal’, because they reached the ‘point of no return’, and no one can claim that they got better as a result of any other treatment but cell transplantation.


Official U.S. statistics show that the prevalence of any neuropathy with IDDM was 60%, of more severe forms 15%, and of very severe forms with intractable pain 6%. VI.BIBLIOGRAPHY [105] Prevalence of distal polyneuropathy increased from 17% at 0 - 4 years of duration of DM to 50% at >15 years of duration of DM. VI.BIBLIOGRAPHY [105]


NIDKK website states that 15, 7 million of U.S. population has diabetes mellitus. VI.BIBLIOGRAPHY [106] 7% of this number, it means approximately 1,1 million, suffers from IIDM. VI.BIBLIOGRAPHY [105] 6% of this number suffers from severe forms of neuropathy. In Rochester, MN, Diabetic Neuropathy Study, the prevalence was 60% for any neuropathy, 47% for distal polyneuropathy, 34% for carpal tunnel syndrome, and 5% for autonomic neuropathy. VI.BIBLIOGRAPHY [105]


Although DCCT trial showed that in patients with IDDM who had no neuropathy at baseline an intensive insulin treatment was associated with a 60% reduction in 5-year incidence of neuropathy VI.BIBLIOGRAPHY [105], there is still about one 40% of patients with severe diabetic neuropathy as a complication of IDDM remaining for who should seek fetal precursor cell transplantation. [36]


Based on the foregoing statistical data we estimate that there is in U.S. a population of around 55,000 IDDM patients with severe diabetic polyneuropathy who have not responded positively to DCCT-type intensive insulin treatment and intensive pain therapy, in controlling the progression of their neuropathy with intractable pain, who should seek fetal precursor cell transplantation.


As with any other untreatable disease, fetal precursor cell transplantation should be carried out immediately after any one of the above diabetic complications was diagnosed. This will be possible only after appropriate public education, and elimination of confusing media information.


There are abundant statistics to prove the effectiveness of fetal precursor cell transplantation as the treatment of choice for various complications of IDDM.


1/ In those patients with diabetic nephropathy in whom the progression of nephropathy cannot be therapeutically controlled by intensive insulin treatment together with ACE inhibitors treatment the success rate of fetal precursor cell transplantation is 60% in the experience of our JJBM team in Moscow. In the earlier stages of diabetic nephropathy the success rate would be higher.


Although DCCT trial showed that in patients with IDDM who had no nephropathy at baseline, intensive insulin treatment was associated with a 39% reduced risk of microalbuminuria, and 54% reduced risk of macroalbuminuria, [105] there is still about one half of patients with diabetic nephropathy as a complication of IDDM remaining for whom some other treatment is necessary: fetal precursor cell transplantation. [36] 20-30% of diabetics has stage II with microalbuminuria, i.e. ‘dipstick-negative’, and 20-30% stage III of diabetic nephropathy with macroalbuminuria, or proteinuria, i.e. ‘dipstick-positive’, which means loss of >500 mg of protein/day. [105] Many diabetologists doubt the optimistic conclusions of DCCT trial.


IDDM patients with late stage IV. and stage V. of diabetic nephropathy should not be accepted for treatment. Although the majority of patients will appreciate the improvement, as long as they will not get off the hemodialysis, the result will be classified the as ‘failure’.


Since in the WESDR the risk of developing heart attack, stroke, diabetic nephropathy, and amputation, was higher in those with proliferative diabetic retinopathy as compared with those with no or minimal nonproliferative retinopathy at baseline, [105], one has to expect that of the abovedescribed population of diabetic nephropathy patients, some will suffer from such diseases. Fetal cell transplantologists should beware of this. Patients suffering from more than one complication of IDDM should be considered individually and may not be accepted for treatment, since it has been established that the presence of microalbuminuria in IDDM is associated with a nearly threefold risk of death from cardiovascular and renal disease [105], and that the risk of lower extremity amputation in diabetics with proteinuria is two to four times that of those without proteinuria, and that the relationship between diabetic nephropathy and retinopathy is well established. [105] . The same applies to IDDM patients with diabetic nephropathy suffering also from other illnesses, not related to IDDM.


The criterion of effectiveness of the treatment by fetal precursor cell transplantation is the termination of any further progression of diabetic nephropathy proven by an objective evaluation of results of a battery of standard tests of kidney function. Whenever the tests show further deterioration of kidney function, that indicates a re-activation of the disease process, another fetal precursor cell transplantation must be carried out.



2/ In those patients with diabetic retinopathy in whom the progression of retinopathy cannot be therapeutically controlled by intensive insulin treatment and retinal laser treatment in the experience of our team the success rate of fetal precursor cell transplantation is 65%. In earlier stages of diabetic retinopathy the success rate would be higher.


Although Diabetes Control and Complications Trial (DCCT) showed that in patients with IDDM that had retinopathy at baseline, intensive insulin treatment was associated with a 54% reduction in progression of retinopathy, a 47% reduction in the incidence of pre-proliferative or proliferative retinopathy, and a 54% reduction in laser treatment, [105], and panretinal photocoagulation reduced the rate of severe loss of vision by 50% as well [105], there is still about one half of patients with diabetic retinopathy as a complication of IDDM with DRS (‘Diabetes Retinopathy Study’) characteristics for severe loss of vision remaining for whom some other treatment is necessary: fetal precursor cell transplantation. [36] Again the results of DCCT trial have been questioned.


IDDM patients with proliferative retinopathy should be accepted only in early stages. Destroyed retina of a blind eye cannot be expected to return back to function after fetal precursor cell transplantation.


Since in the WESDR the risk of developing heart attack, stroke, diabetic nephropathy, and amputation, was higher in those with proliferative diabetic retinopathy as compared with those with no or minimal nonproliferative retinopathy at baseline, [105], this should be considered in the treatment decision making process.


The criterion of effectiveness of the treatment by fetal precursor cell transplantation is the termination of any further progression of diabetic retinopathy proven by an evaluation of stereoscopic fundus photographs of seven standard photographic fields taken of each eye (as per WESDR). Whenever there is an objective evidence of re-activation of the disease process, another cell transplantation should be carried out without delay.


3/ In those patients with diabetic lower extremity arterial disease that have not responded positively to intensive insulin treatment as per DCCT, had an unsuccesful revascularization surgery, or such surgery was contraindicated, or had a previous amputation in the author’s experience the success rate of fetal precursor cell transplantation is 65%. Of course in earlier stages of diabetic lower extremity arterial disease the success rate would be higher.


Any diabetic with lower extremity arterial disease with progressively worsening intermittent claudication, or chronic leg ulcer, with positive clinical tests indicative of insufficient peripheral arterial circulation, that has been treated by DCCT-type intensive insulin treatment for more than 6 months, and underwent revascularization surgery, or such surgery was contraindicated, or had a previous amputation, without a success insofar the control of progression of LEAD is concerned, should be treated by fetal precursor cell transplantation.


Although DCCT trial showed a beneficial trend of glycaemic control on lower extremity arterial disease in IDDM, this trend was not statistically significant, [105] thus diabetics with LEAD represent a particularly difficult group to treat. It means that they should be given fetal precursor cell transplantation without delay because the progress of their disease toward gangrene may be very rapid.


Diabetics with lower extremity arterial disease in the stage of a gangrene, and smokers, should not be accepted for treatment by fetal precursor cell transplantation.


Since the mortality rates for diabetes mellitus patients with LEAD are 2 - 3 times higher than in general population [105], and 3-year survival after amputation is less than 50% [105], the fetal precursor cell transplantologist should beware that many diabetics with LEAD will suffer from advanced cardiovascular and other disease(s).


The criterion of effectiveness of the treatment by fetal precursor cell transplantation is the termination of any further progression of diabetic lower extremity arterial disease proven by an evaluation of objective standard clinical tests of peripheral arterial circulation. In case of worsening, i.e. Doppler study of peripheral pulses, or pre-gangrenous condition, an immediate repetition of cell transplantation is required.


4/ In those diabetics with severe diabetic polyneuropathy with intractable pain, that have been treated by DCCT-type intensive insulin treatment for at least 6 months, together with an intensive pain treatment, without a success insofar the control of progression of neuropathy and alleviation of severe pain is concerned in our experience the success rate of fetal precursor cell transplantation is 98%.


Any such patient should get fetal precursor cell transplantation treatment.


A special group are diabetics with autonomic neuropathy suffering from impotence. Of 5% of patients with autonomic neuropathy impotence was the most common problem, occurring in 13% of IDDM patients. [105]


Fetal precursor cell transplantologist should beware that severe neuropathy can be a cause of other serious problems, e.g. it is a major contributing cause of lower extremity amputations. [106]


The criterion of effectiveness of the treatment by fetal precursor cell transplantation is the termination of any further progression of severe diabetic polyneuropathy proven by a complete or significant disappearance of pain for a period of 6 months, as well as by standard objective clinical tests, and the subjective pain analog scale. Upon the recurrence of pain, cell transplantation should be repeated.


Fetal precursor cell transplantation is a unique therapeutic procedure due to the fact that fetal precursor cell transplants are individually prepared for a specific patient, and for a pre-determined date of implantation, so that fetal precursor cell transplants cannot be used by another patient, unless he is a ‘medical double’ of the scheduled patient, i.e. his illness(es) is very similar to the scheduled patient, and is prepared ‘to step in’ when the first patient does not show up for treatment.


For that reason the patient expressing the interest in the treatment must be made aware that the batch of fetal precursor cell transplants necessary for the treatment is individually, i.e. ‘custom’, prepared for each specific patient, and is ‘timed’, i.e. prepared for a specific date of an implantation. Once the date of implantation was set and the production of the batch of fetal precursor cell transplants begun, the batch has to be either implanted on the scheduled date to that specific patient or discarded: the full clinical effectivenessis guaranteed for 48 hours only since the release of the batch by the manufacturing laboratory. A rigid policy of pre-payment of all the production costs by patients prior to the start of the preparation of fetal precursor cell transplants is mandatory. [111] Patient's financial involvement has been one proven way to minimize non-compliance and wasting of a very precious material.


Based on the years of clinical experience in treating patients in many countries of the author, no serious risk and adverse reactions from FPCXT is to be anticipated providing that the preparation of fetal precursor cell xeno-transplants was ‘lege artis’.