Update April 2007

Mal's Musings

Malcolm A Traill

IN  THE  PUBLIC  INTEREST
Updated 10/4/2007

 

HYPERTHERMIA (HT)

 

CLARIFICATION OF TERMS AND APPLICATIONS

 

 

1.                  Gross tissue heating

 

Whole Body Hyperthermia (WBHT) – the body core temperature is raised – usually to augment chemotherapy or Deep X-ray Therapy (DXRT).

Augmentation role need not seek the levels that must be attained for HT monotherapy. Lower temperatures are referred to as Fever-range Hyperthermia (FRHT)

 

Local Hyperthermia (LHT) [eg side of chest], unless qualified, usually refers to the treatment of tumour masses or nodules, where there is an appreciable thickness, and has the problem of treating the cancer at depth without burning the overlying skin. It is often done with UHF, which induces currents in the tumour. Since tumours have lower resistance to electrical currents than normal tissues, they heat preferentially.

            Superficial (Local) Hyperthermia sets out to apply temperatures above about 42oC to skin which has cancer in it (or might have cancer in it), where there is no appreciable mass or nodule. The temperature of the skin approximates the temperature in the lower involved lymphatics.

 

2.                  “Athermal Heat” – Ultra High Frequency (UHF 434 MHz) From time to time it has been referred-to as Regional Hyperthermia (RHT)

Here heat (=molecular agitation) is induced at microscopic points in the cells such that there is little gross temperature rise, because the heat is widely dispersed in the cells’ relatively large volume of cytoplasm. The skin becomes warm, because standard gross tissue heating occurs as a side effect and is a limiting factor. (“Athermal Heat” has been a term used in studying the effects of mobile phones.)

 

 

 

Treatments given

Patient

UHF 434 MHz

Superficial HT

WBHT

Ms SO

+

 

—*

Ms ST

+

+

 

Mr TU

+

 

 

·         Whilst there was a session of warming at the patient’s request, there was never treatment of the cancer 


 

LITHIUM & UHF 434MHz

 

HISTORICAL NOTES

 

Preamble: In 1949, Dr John Cade, of Melbourne, published his finding that Lithium stabilized the moods of manic-depressive patients (bipolar affective disorder). He became famous and received accolades.

In 1973-4, Dr John Holt observed and reported on a resonance phenomenon he found associated with cancers in living human patients. He became discredited and ridiculed.

Why the difference, and what went wrong for Dr Holt ?

(These historical notes represent the Applicant’s understanding of what happened; they have not been meticulously researched, and are provided for background, general interest.)

 

A. Lithium. Dr Cade was working with experimental animals and seeing if nitrogen-containing metabolic breakdown substances affected the animals. Some of these (eg uric acid) are more soluble in lithium solutions. He observed that the animals became lethargic after the injections and, assuming the agent responsible was Lithium, by some giant leap of logic, tried Lithium salts on human manic patients. He observed a “sedating” effect far greater than could be explained by the early toxicity effects of Lithium on normal individuals.

One would doubt that such a discovery could pass an ethics committee today, but then, in ~1948, there were few options for sedating patients and, in the backwater area of state-run mental asylums, no-one was likely to care much what one did to the patients to try to sedate them, provided they were not killed in the process ! (Even then, the State had ways and means to reduce adverse publicity !)

Having discovered the Psychiatric place for Lithium, he lost interest in researching it further, leaving that to others. He became a Psychiatric Superintendent of Royal Park Psychiatric Hospital, where the Applicant worked between 1969 to1975. The Applicant wrote one paper on the therapeutic dosing with Lithium from Royal Park during that interval.

Lithium therapy was slow to be accepted in the USA – there had been earlier disasters, in which Lithium was used as a salt (Sodium) substitute for patients in cardiac failure. Its dosing was poorly or not controlled and there were fatalities, giving it a bad reputation. In addition, the pharmaceutical industry was hostile, and it was not made more easily available until a law was passed requiring the pharmaceutical industry to make preparations available. Even in more recent time, US customs tends to seize the tablets off travellers, and doctors seem unable to prescribe more than small amounts at a time.

Most research into Lithium has been done by those in Psychiatry looking for a higher qualification. Any other research would have to be funded by the state or benefactors – Lithium is dug out of the ground and cannot be patented, so the pharmaceutical industry is hostile to any research other than that which may unlock the secrets of how it works. Research then is for designer drugs that may be developed to do Lithium’s important function(s) better. The industry cannot be expected to fund the examination of its wider use, and is hardly likely going to send friendly drug reps around to doctors to remind them to use it ! Those who know about it and use it for non-psychiatric conditions are few and far between, and will have had to do their own reading of the literature and clinical assessments.

The Applicant is probably the only expert in the non-psychiatric uses of Lithium in Australia. The non-psychiatric uses would seem to be influenced by the methods of administration. Since the mode(s) of action of lithium are not yet known, the variables must be established by empirical means and close observation. The figure below sets out possible rationales.

 

 

                                                                          Figure 1

 

                      

Text Box: 6 h

Text Box: Serum Lithium level
     

Text Box: Time h=hour                    24 h

 

            Figure 1. This graph is a diagram to illustrate how serum Lithium levels change over time. After a single bolus (solid line), the Li+ has largely dispersed throughout the fluid pools of the body by 6 hour (=h). After 2 boluses 6 hour apart, this dispersed state is at about 12 hour. After each day’s dosages, the serum level falls below a threshold which may be unique for each cytokine (or other factor). As presented here, the total duration of the Lithium level above the threshold is greater for the double bolus in one day.

Cancer. A short, stout female born 4/3/1928 was found to have a peripheral lung cancer and mediastinal node involvement in October 2005 after X-ray/Computerized Tomography for an orthopaedic problem in October 2005. Following a failed bronchoscopy, she refused all further investigations other than blood tests. These revealed an elevated serum Carcinoembryonic antigen (CEA) of 20.3 μg/L (RR≤3.5), an elevated serum Neuron-specific enolase of 19 μg/L (RR≤12) and a normal serum CA125. She would seem to have a slow growing adenocarcinoma. She refused all recommended treatments by Oncologists, but was persuaded to try Lithium in bolus form as a marrow and immune stimulant at least. She followed instructions for a short time, then reduced her dose and finally ceased taking it, despite her family reporting that, with the Lithium, she seemed happier and improved. She was then not prepared to see any doctors, because she believed that the Orthopaedic surgeons and Imagists were responsible for all her problems, including her cancer. Some early results are set out in the Table 1 (below) and in Figures 2 (below).

 

                                                                              Table 1

                                                          Pre-Rx  Day 0   Day 6  Day 18  Day 26  Day 38  Day 45  Day 61

CEA μg/L                         27.8     28         26         28.2      29.2      32.8       33.3

Calcium (corr.)                  2.73      2.81       2.86     2.89      2.82      2.81        2.75    2.83

CD4:CD8                         1.64      1.87       1.66                               2.05

NK cells x10^9/L              ND       0.21      0.25                                0.23

 

Calcium (Corrected; corr.; mmol/L; RR=2.10-2.60) ~ Measured serum Calcium (mmol/L) x 43/Serum albumin (g/L)

Rx denotes Treatment. ND = not done

 

In assessing these results there are points of interest :

 

a)      The serum CEA seemed to fall after about a week of treatment, consistent with slowed tumour growth/activity and,

b)      The serum LDH showed a similar pattern, consistent with less LDH release from tumour cytoplasm and,                              

c)   The serum Urate showed a rise, consistent with increased purine catabolism, as may occur with degenerating cell nuclei (tumour &/or inflammatory cells) and,

d)   The Neutrophil count fell initially, consistent with consumption, later to rise after Lithium dose reduction/cessation, consistent with a  rebound from less consumption and stimulated bone marrow and,

e)   The urine Urate:creatinine ratio showed a rise, consistent with the serum Urate changes and,

   f)   The serum corrected Calcium showed a fall after about a week or two and,

  g)   The urine Calcium:creatinine ratio showed a rise consistent with  increased elimination of Calcium through the kidneys (cause unclear) and,

  h)   The urine Calcium excretion rise was well maintained even after the Lithium treatment ceased and,

                           i)    There were changes in the Lymphocyte T4:T8 ratio, with an early fall, then a rise and,

                          j)    The Natural Killer cells increased in numbers.

 

These changes are consistent with Lithium in bolus dosing having a beneficial effect on the patient’s immune defence against the tumour, not merely an increased defence against infections.

                                                                           Figure 2      

         

After over a year, her ability to cope declined and she was persuaded by her family to have an X-ray and then pathology. Her corrected Calcium was 2.96 mmol/L so her family was able then to persuade her for referral to hospital. Her results are set out in Figure 3. For the calculation of the tumour volumes, the length (l) and width (w) from the antero-posterior chest X-ray were measured and processed : Volume (cm3) ~ 4/3*π*(l/2)*(w/2)*[(l+w)/4], the estimated Tumour Volumes (pre Rx to recent) being 12.9, 8.1 and 68cm3 respectively. (The width of the chest, measured from outer cortex of the ribs at the level of the concavity of the arch of the aorta, showed no appreciable change with the examinations.)

                                                                           Figure 3             

         

Points of interest:

  1. The similarity (visual) in the slopes of the CEA and Tumour Volume post Lithium treatment is noteworthy, indicating that both should be valid parameters for assessment of the intrinsic (stem) cell multiplication rate in that interval ;
  2. There is a disparity in the two "survival benefit" assessments - that from the CEA extrapolation is ~80 day, that from the tumour volume ~320 day: the factors affecting the CEA production would appear of lesser importance, with relatively little reflection upon a decrease in cell size or cell loss;
  3. Using the concept of the tumour stem cells[1], the smaller "survival benefit" (blue) read from the CEA line of ~80 day would seem consistent with measuring mildly diminished CEA production per cell with a mild reduction in the number of cells. The changes in cell and tumour size (green), as a result of decreased stem cell paracrine stimulation, result in smaller progeny cells, as a result of the tumour stem cells having been reduced in number. Later, there may be a very mildly reduced intrinsic growth rate when growth recommences;
  4. (A similar conclusion could be made from the histopathology changes shown by the photomicrographs from the breast cancer patient[2] [elsewhere on the website] where the nuclei were ~48% of the pre-treatment volume, with nuclear crowding and apoptotic figures, consistent with less paracrine stimulation from the tumour stem cells.)
  5. The larger survival benefit from the tumour volume assessment (green) would be consistent with an appreciably decreased stem cell number, and with a reduction in the paracrine stimulation, the stem cells are then unable to support the same number of progeny as occurred previously, the number of progeny decreasing in number and size, but less markedly;
  6. The survival benefit, as estimated from the CEA results, reflects the changes in a non-lethal parameter - the CEA which, by itself, is not significantly toxic. The feared parameter, reflecting the approach to a lethal threshold, is the tumour volume. If the CEA graph largely reflects changes in the paracrine stimulation of the cells and a reduced supply of progeny, there will be expected a decrease in the progeny-to-stem cell ratio -  the number of progeny that the stem cells can support;
  7. There is no clear evidence of a catch-up recovery in tumour volume (~ cell numbers x cell volume), which could restore the original pre-treatment survival line during the relevant interval. Such a catch-up would (if it had occurred) indicate that the stem cells had not been affected appreciably.

    This simple, but unique and careful longitudinal study of an individual patient (who chose to decline medical contact and cooperation for much of the relevant time) would seem to indicate that Lithium, when administered as a monotherapy with a specific protocol, may not only have an anti-cancer role for those patients with incurable cancers, but it may reveal interesting aspects of the behaviour of stem cell and their progeny not easily studied by other means, and which may be applied safely to other patients.


     

    [1] Kim CF Jackson EL et al. Cell 2005; 121(6):823-35

    [2] Al Hajj M Wicka MS et al., Proc. Nat. Acad. Sci. (USA) 2003; 100(7):3983-3988  

     

B. UHF 434 MHz. David Spall gives a brief historical note on how the Tronado machine was identified in Germany, and how it was subsequently brought out to Australia (Exhibit B, Tab 1; MAT.002.001-2). David Spall suggested that Dr Holt go over to Germany to assess the equipment in late 1973. Holt claims that it was while he was in Germany at that time that he noticed that the power output from the machine rose when cancers were in the filed, and this did not happen when he went into the field. He brought a machine back to Australia in 1974 and made enthusiastic predictions about its role early that year.

However, the funding of the machine involved Holt personally receiving a grant of some one million dollars from the State Government. This made the machine a political football. One can imagine the scream that went up politically and from medical groups, because the Government had given this grant of the public’s money to a doctor in order to bring into Australia a heap of hocus-pocus quackery. An Inquiry was soon established under the NH&MRC which started to examine the Tronado machine in late 1974. Sadly, the Committee of the Inquiry was loaded by medical specialists who would not be expected to have the scientific knowledge in biophysics to understand the issues involved. In addition, the scientific adviser was a senior lecturer only.

Holt, his partner Alan Nelson and the German Salesman Herr Guettner (possibly slightly shifty) all spoke to the Inquiry about a resonance effect. There was some talk about magnetic spin resonance, which was dismissed. The opinion was stated that the dielectric within the soluble cell components was that of salt water (very low) and that the space-occupying components (organelles and membranes) were “black holes.” This dielectric issue was the key point and basis of the Fröhlich theoretical work of 1968. (Here, the dielectric of membranes was claimed to be astonishingly high. From this, Fröhlich developed an hypothesis which predicted resonance involving longitudinal waves in membranes, requiring intrinsic power, and a threshold for the external power. He published again in 1969 and 1970, the latter in Nature.)

Thus, the theoretical basis was there in 1974-5, but was missed. In addition, the Inquiry was too early for Holt, Nelson and at least one other doctor, to study the phenomenon adequately in order to bring some organized evidence before the Committee. The Inquiry directed its attention to the original claim by the Tronado machine salesman, that it could heat tumours enough to provide cancericidal hyperthermia. The findings were that its heat delivery was quite inefficient, with only about 350 Watts reaching the patient, and that this was inadequate to attain the required heat to be cancericidal. Accordingly, the Tronado machine was branded a hoax and its use condemned.

This meant that no-one in any institution would ever obtain funding to acquire or test the machine in any real way. Drs Holt and Nelson, who had done some work into the power absorption effects, including discovering that the tumours emitted a most unusual resonance spectrum when an oscilloscope with a spectrum analyzer was able to pick-up the emitted signals. David Spall claimed that this caused great interest amongst those working around the machine, and claims that he witnessed it also. With this personal knowledge, Holt and Nelson pursued the further work, with Nelson contributing to the funding.

Holt’s initial experimental work was into the power absorption, as demonstrated by the heating of patients with cancer (when the cancer was in the UHF field), normal subjects and water phantoms. Later, with the oscilloscope patters, he could try to modify the responses by injecting a range of chemicals intravenously. Chemicals of interest were the sulphydral compounds such as glutathione, especially in the oxidized state, and L-Glyceraldehye, because he had discovered the writings of Joseph Needham, published in 1938. This group, working on 3-4 day old chick embryos, described a glucolysis which turned glucose to L-Lactate by a relatively simple reaction, apparently without phosphate and any cofactors apart from glutathione. This reaction was blocked by the L-Glyceraldehyde. Under Holt, intravenous L-Glyceraldehyde also blocked the resonance phenomenon, meaning that this metabolic pathway may be the operative one to supply the endogenous power for the Fröhlich hypothesis. Sadly for Needham, his pathway did not seem to fit into the emerging and newly recognized pathways, and his research seemed to reach a dead end. Holt (potentially) rescued it from obscurity.

Having performed a vast amount of largely empirical work, Holt then went on to develop an hypothesis to try to explain the resonance phenomenon and how the UHF and the GBA may impede the growth of cancer. Later, he extended his hypotheses to include other diseases, and obtained Patents relating to the GBA chemicals. Given that he had no sound scientific theory on which to base a resonance effect, his basic hypothesis, was that there is a “glutathione cycle” located in entities which he chose to refer-to as ERex within cancer cell cytoplasm. He believed that these were activated by the UHF, obtaining electrons from glucose metabolism, and subsequently releasing two electrons for each one entering.

The concept that there are structures with glutathione reduction-oxidation cycles (on a large scale) within cellular cytoplasm, is not very dissimilar to that proposed by the Applicant – that there are centrioles, which have a membrane around a circumference, around which a resonance effect may run. (Holt believed that the ERex probably had something to do with mitochondria, which seems very unlikely – he did not have adequate knowledge of the microanatomy of cells.) He also believed that the X-ray augmentation effect of the UHF was due to breakdown of the “container” of the ERex, allowing electrons out. The Applicant believes that the UHF may damage the centriole membrane such that the X-rays produce an augmented damage.

Holt’s idea that there can be one electrons into his ERex and two out, creating an exponential expansion, appealed to his more fundamental belief that everything in the Universe was dominated and controlled by exponential forces – growth and decay: this was like a religion ! The electron issue is clearly unacceptable, and one can readily understand why there has been a reluctance for the editors of any “peer reviewed” journal to accept such a proposal.

The acceptance of Holt’s paper of 2004 by the Editor of the Journal of Molecular Liquids (BoE, Tab 106a) – a journal said to be “peer reviewed,” that was regarded by the reviewers at the Peter MacCallum Cancer Institute with shock and horror, can be explained, because the editorial Board almost certainly had knowledge of Professor Fröhlich’s work and also of the work by others (chiefly Russian) into the resonance effects in biological systems – they were knowledgeable biophysicists. They would have recognized the possibility and potential for such a phenomenon, but were unconcerned or did not understand where Holt took the phenomenon by application and hypothesis into the medical field – that was for medical workers (who could not understand the resonance !).

Holt’s resonance phenomenon crosses across most scientific specialty field, as well as Oncology (and possibly others) :

            Microanatomy

            Biochemistry

            Biophysics

            Physiology

Pharmacology

Physics

Pathology (academic)

Clinical Pathology (Specialist medical)

Clinical Chemistry

Immunology

Morbid anatomy (diagnostic)

Histopathology (diagnostic)

            Oncology

            Electrical engineering (UHF)

There are few Specialists around with sufficient background knowledge, training and experience who can cover all these specialty areas to the depth necessary to comprehend the issues involve. The Applicant submits that he is one of the few.

Problems were compounded by the failure of the first NH&MRC Inquiry of 1974 to :

a)      Allow sufficient time for Drs Holt and Nelson to study the phenomenon better

b)      Document and describe the resonance phenomenon reported by Holt, Nelson and Herr Guettner in scientific terms

c)      Adequately research the literature and find any of the 3 publications by Fröhlich readily available then

d)      Obtain scientific advice of sufficiently knowledgeable stature, breadth and standing.

This Inquiry concentrated its attention upon the generation of heat in tissues – hyperthermia. The conclusion was that the system was quite inefficient, with only about 350 Watts being effective on the subject. This was too low to allow real tissue heating. The Tronado could not perform gross hyperthermia. To the establishment, the equipment brought into Western Australia with Public money granted to a couple of eccentric doctors, was without a scientific basis or known effectiveness: pure quackery. Little wonder then, that no public institution could ever take up the work and study the phenomenon and ever do double blind controlled cancer trials.

Other important practical issues seem to be forgotten by the armchair critics: Holt discovered the resonance phenomenon in humans (large animals) who had large tumour masses, such as 5 cm diameter deposits. The likely factors involved, as outlined in my hypothesis, would seem to make cell culture and small animal experiments, such as on mice and rats, unlikely to be successful without very specialized equipment which may not be readily available (if at all).  So,  for any enterprising researcher to emulate the phenomenon in the laboratory setting, there would be required, not only the capital equipment, space and staff, but an animal house capable of dealing with medium-large animals, such as dogs and cats and upwards. The cost and time factors would make experimentation on in-bred lines prohibitive, meaning that the researchers would need to wait for spontaneous tumours to develop or introduce known and standardized laboratory tumour strains into the out-bred animals. The relationship that such experiments have with humans is always a problem and the critics will not be slow to point that out. Given that the safety of the UHF has already been established, one would have to ask just what would the laboratory experimenter be trying to achieve, and why cannot that experimentation be performed on cooperative human patients for whom the adjunctive role of the UHF may be applicable or where other treatment options are absent or have run out ?

Holt and Nelson had seen the phenomenon and had taken photographs of it. They knew there was something to study, so they kept their heads low and continued on, spending large sums of money on sulphydral and other compounds, in order to test the effects that these had on the phenomenon. (The experimentation with L-Glyceraldehyde is noteworthy because, not only is the compound very expensive, but it is unstable, making the trials using it particularly difficult in private practice.) Dr Nelson seems to have assisted Dr Holt financially in these endeavours.

Dr Holt should receive an award for his discovery, observational and empirical work, regardless of his hypotheses.

 

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