A New Generation of “Smart” Drugs
Chemotherapy has its uses. It has been the main approach to fighting cancer for many decades. But the non-specific nature of attack and resulting toxicity of chemotherapy drugs leaves much to be desired. It is a little bit like carpet bombing. You may get most of the bad guys (unless they are hiding in deep and heavily fortified bunkers), but the collateral damage to innocent people all around can be horrendous. There is increasing interest in immunotherapy, “smart” drugs that target specific cancer pathways. You have heard of Campath, Rituxan, Revlimid etc. Now read about perifosine, a new drug making its debut in an interesting clinical trial.
“Future Medicine”
This is a journal I read once in a while, to keep an eye on new therapy concepts that may be coming down the road for our patients. Here is a recent article that I found interesting, you can read it for free by clicking on the link. Very often the concepts are just that – concepts, a gleam in the eye of some research group, who knows when or if it will ever pan out in the real world. But this time around I lucked out. The concept is not only an intriguing one, it is already in clinical trials. And wait for the punch line please – it is already in clinical trials for relapsed, refractory CLL patients. I am willing to bet most of you have not heard of it – yet. But you will in time, if I am reading the tea leaves right.
“War on Cancer” – Why We Have Not Won It
Despite the immense sums of money spent on the effort, with the exception of a few specific cancers (testicular cancer, Hodgkin’s lymphoma and a few leukemias –not CLL ), we are not close to winning the “War on Cancer”. One of the problems can be mistaken understanding of what is driving the cancer. Until recently, it was thought that all cancers were caused by very rapid growth rates of malignant cells – in other words, cancerous cells having too many babies too quickly. Since proliferation is thought to be at the heart of the accumulation of cancer cells, drugs were developed to target the proliferation mechanisms. As it turns out, there are two parts to the equation: excessive rate of birth of new cancer cells, as well as a reluctance of old cancer cells from dying a graceful death when it is their turn to kick the bucket. Drugs that just targeted the proliferation pathways are inadequate for the job. We need to tackle both ends of the spectrum: birth of new cancer cells and death of old cancer cells. In the case of CLL, it is particularly important to get a good handle on the second part, the ability of old CLL cells to dodge death and keep on living long past their time.
Built-in Suicide Mechanisms
All normal and healthy cells have built in mechanisms for committing suicide when it is their turn to die. When the cell receives the signal to die (the signal can be initiated by its neighbors or even within itself), the cell initiates self-destruct in an orderly fashion. This orderly process of cell suicide is called “apoptosis”. CLL cells are particularly poor at apoptosis. Even though they proliferate only slowly, their avoidance of apoptosis means their numbers will increase – slowly but surely. Think of it as a country where new babies are born at just a tad over the normal rate, but none of the old folks ever die. The result is a population explosion – just as in the case of CLL. If we can re-educate cancer cells on the need to die in a peaceful fashion, no fuss and no mess and very little toxicity, we would have made major strides in winning the war on cancer.
Skin of the Cancer Cell
Just as you and I have skin to keep our innards nicely contained and separated from the outside, cells too have ‘skin’. It is called the plasma membrane. Floating around on the surface of the plasma membrane are little islands of fat – called lipid rafts. Cells need a wide range of receivers and broadcasters capable of receiving and sending messages, a way of interacting with the rest of the cells in the neighborhood. Much of this signaling machinery rides around on the lipid rafts. So, here is the concept: is there someway we can increase the concentration of the death signal receivers on the lipid rafts so that the “DIE!!” signal comes through loud and clear, the cell can no longer ignore the orders to commit suicide? As things stand, CLL cells are very capable of turning a deaf ear to death signals and that is the major part of the problem with this particular leukemia.
A New Class of Drugs
Researchers have been working with a new class of antitumor drugs called alkyl-phospholipids. Edelfosine and perifosine are but two examples of this class of drugs. These and their analogs are able to cluster a death receptor called Fas/CD95 in lipid rafts. Some of you who are interested in dietary methods of controlling cancer may have heard of resveratrol, obtained from the skin of red grapes. Recent research has shown that resveratrol too is capable of clustering death signal receivers in lipid rafts of cells. Who knew.
Laboratory and clinical work in several cancers has shown that perifosine is also able to mess with another important signaling pathway. AKT signaling is an important mechanism for cancer cell survival. It seems to be particularly important in CLL cell survival too, and that makes perifosine an interesting drug candidate for our guys. AKT pathway is receiving increasing scrutiny as a potential target for the next generation of immunotherapy drugs. In the next little while I will publish my long delayed review of CAL-101, another important drug in CLL clinical trials that also interferes with AKT signaling.
Hearing Aids For Deaf Cancer Cells
Recruitment of large numbers of apoptosis inducing molecules into lipid rafts has been shown to increase the rate at which the cell commits orderly suicide. Researchers love acronyms. A new one has been coined. CASMER stands for “cluster of apoptotic signaling molecule enriched rafts”. Phew. What a mouth full. But I think the concept itself is pretty nifty and not all that hard to understand. If you want a down-to-earth analogy, think of it as giving cancer cells a high tech hearing aid so that they can no longer turn a deaf ear to suicide orders from the rest of the body. CASMER causes death receptors and downstream signaling molecules inside the cell to come together effectively, so the job of suicide can proceed to its natural conclusion. Here is a link to the company (Keryx Biopharmaceuticals) website that lists the number and type of clinical trials that have been conducted with perifosine (KRX-04-01) in this country and Europe.
Cholesterol
Cholesterol is a critical constituent of lipid rafts and removing cholesterol from cell membrane disrupts CASMERs. Cancer cells are thought to be enriched in cholesterol, they have more cholesterol in their lipid rafts than normal healthy cells. Because of this, CASMERS may be the Achilles’ heel for cancer cells. Since CASMER mediated direct activation of apoptosis is likely to be independent of tumor suppressor genes such as p53, there is hope that this approach to treating cancer will not be hampered in patients that are p53 deleted. Now, pause a moment and think about that last sentence. I have written dozens of articles on this website as well as CLL Topics about the poor prognosis of patients with this particular FISH abnormality. Many of the standard issue drugs such as fludarabine will not work in p53 deleted patients. New drugs based on CASMER technology may be able to change that paradigm, since they can hopefully cause CLL cells to kill themselves, independent of whether or not they have working p53. Below is an abstract that describes some of this science.
Br J Pharmacol. 2010 May;160(2):355-66.
Disruption of cellular cholesterol transport and homeostasis as a novel mechanism of action of membrane-targeted alkylphospholipid analogues.
Carrasco MP, Jiménez-López JM, Ríos-Marco P, Segovia JL, Marco C.
Department of Biochemistry and Molecular Biology I, University of Granada, Spain. mpazcj@ugr.es <mpazcj@ugr.es>
Abstract
BACKGROUND AND PURPOSE: Alkylphospholipid (APL) analogues constitute a new class of synthetic anti-tumour agents that act directly on cell membranes. We have previously demonstrated that hexadecylphosphocholine (HePC) alters intracellular cholesterol traffic and metabolism in HepG2 cells. We now extended our studies to analyse the effects of other clinically relevant APLs, such as edelfosine, erucylphosphocholine and perifosine on intracellular cholesterol homeostasis. EXPERIMENTAL APPROACH: Using radiolabelled substrates we determined the effect of APLs on cholesterol metabolism and cholesterol traffic from the plasma membrane to the endoplasmic reticulum (ER). Protein levels and gene expression of the main proteins involved in cholesterol homeostasis were analysed by Western blot and RT-PCR respectively. Membrane raft and non-raft fractions were isolated from HepG2 cells by a detergent-free method. KEY RESULTS: All APLs inhibited the transport of cholesterol from the plasma membrane to the ER, which induced a significant cholesterogenic response in HepG2 cells. This response involved an increased gene expression and higher levels of several proteins related to the biosynthesis and the receptor-mediated uptake of cholesterol. Cell exposure to the APL-representative HePC enhanced the content of cholesterol mainly in the membrane raft fractions, compared with the untreated cells. CONCLUSIONS AND IMPLICATIONS: Membrane-targeted APLs exhibited a novel and common mechanism of action, through disruption of cholesterol homeostasis, which in turn affected specific lipid microdomains of cellular membranes.
PMID: 20423345
Perifosine Clinical Trial for CLL
Here is the link to clinicaltrials.gov that gives the full details of this trial being conducted at Duke University. If you are a relapsed and refractory CLL patient, volunteering to participate in this trial may be worth considering. Contact information, inclusion criteria etc are given in the link above, please read it carefully. Perifosine is an oral drug with reasonably well understood risk profile, based on its use in earlier clinical trials for multiple myeloma. There is very little hematological toxicity– such as destruction of platelets, neutrophils etc. Prior clinical trials in myeloma and Waldenstrom’s macroglobulinemia indicated patients may have significant GI tract issues such as nausea, vomiting and diarrhea. But the CLL clinical trial shows little of that in the patients recruited thus far (13 of them). This may be due to the fact that the dosing is different (twice daily, lower doses). Hey, whatever the reason, I will take the good news any time I can get it. Who wants to spend major portion of the day in the loo.
This is a Phase-II trial, looking to recruit 33 patients (13 spots have been filed already). As I said above, this is an oral drug, given twice daily for six months. Response rate will be measured within 3 months post treatment, but patients will be followed for 2 years to see what we can learn about overall survival and remission duration. My contact at Duke tells me there is also the option of continuing on the drug for more than 6 months if the physician and the patient feel this would be of help.
While this drug has been tested in other cancers including blood cancers, this is the first of its kind clinical trial in CLL patients. In the laboratory, CLL cells from patients have been shown to die very nicely when exposed to perifosine. Will it work as well in real live patients? The point of doing the clinical trial is to find the answer to that important question. Everything I have read thus far suggests toxicity side of the equation is likely to be low, therefore any rewards our guys get from this new drug class is all the more to be treasured. I have no doubt that down the road there will be combination therapies, combining perifosine and its analog drugs with more conventional drugs so as to get the cancer cells in the cross fire from multiple angles.
Recently I have been in contact with Dr. Daphne Friedman, a physician at Duke University who has a special interest in CLL. She is also the principle investigator for the perifosine clinical trial for CLL patients. She pointed me to their website dedicated to CLL and it has a lot more information on their perifosine clinical trial.
My Two Cents
There are a large number of ‘me-too’ clinical trials out there, tweaking the dosage a little, adding yet another drug to the alphabet soup of drug combos, substituting ofatumumab for Rituxan, digging out 40 year old drugs such as bendamustine and giving it a sexy new name like Treanda, anything to increase the ‘buzz’. An entirely new class of drugs, whose members are likely to have low toxicity and may work independent of p53 deletion, now that is worth sitting up and taking notice.
The US Food and Drug Administration (FDA) has just approved Fast Track designation for perifosine in the treatment of refractory advanced colorectal cancer. Perifosine previously was granted fast Track and orphan drug status by the FDA for the treatment of relapsed/refractory multiple myeloma and is currently in phase-3 trials under special protocol assessment. I like it when a drug has potential use in a number of different diseases. That way there is more chance that it will be developed, there will be money for continued research and its manufacture down the road if things pan out. I think all of us know money makes the world go round. If drug companies had just CLL patients to depend on for their future revenues they would not be all that enthusiastic about developing it. But solid cancers such as colorectal cancer are big mamas, with many more times the number of patients suffering and dying from them. If our guys can ride on the coat-tails of drug research done looking at more lucrative cancers, who am I to complain? I will take the crumbs falling off of the table where the big boys are feasting, if that is the way to get research done in our small niche of the cancer world.
Clinical trials are the life blood of medical research. And there is no way of conducting clinical trials without patient recruitment. How sad would it be if perifosine and its sister drugs go on to make headlines as novel therapy options for other cancers (multiple myeloma comes to mind) but their use in CLL lags behind because of poor patient recruitment. I wish I had a dollar for each time CLL patients wrote wistful emails to me asking when we are likely to get our version of “magic” drugs similar to Gleevec. Here is your chance to making that happen someday.
Each and every patient who participates in clinical trials is a true hero, a pioneer that shows the way to generations of patients to come after him/her. But I think you know by now, I am a big fan of truly informed consent. So, please make the effort to inform yourself and if this clinical trial fits your needs I hope you will volunteer to participate in it. I am particularly intrigued by the possibility that this new drug may work in high risk patients with poor FISH profiles. I have not met her, but Dr. Friedman sounds very nice and she has agreed to answer any questions you may have about their clinical trial. So, post your questions in the discussion section below and I will make sure she gets to see them. It may take a day or two for me to post her responses here.
21 comments on "Perifosine: A New Drug on the Horizon"
Cholesterol is a critical constituent of lipid rafts and removing cholesterol from cell membrane disrupts CASMERs. Cancer cells are thought to be enriched in cholesterol, they have more cholesterol in their lipid rafts than normal healthy cells. Because of this, CASMERS may be the Achilles’ heel for cancer cells.
THIS IS THE PART THAT CONFUSES ME.. I don’t understand if lowering of cholesterol is beneficial for the body as a whole IN cll if cholesterol is the critical constituent of lipid rafts. I have used red rice yeast for my cholesterol lowering for years. And buried in the literature is a low cholesterol rate is a risk factor for cancer.
With the red rice yeast I take, mine never is that low. It just keeps it around 220. But I am still confused on how this drug works. And it seems to me that it could correlate to a natural way to do this also.
Chaya,
the good news just keeps a-coming. I really hope the ‘fast track’ is fast enough for me, because I found chemo the first time round quite awful even though It got me a CR and people seem to think second time round chemo is not nearly so effective. These new smart drugs sound a lot more benign.
MarilynHL:
You have raised a question that has been bothering me for quite some time. I have raised it with Dr. Friedman, let us see what she has to say.
Is low cholesterol a marker brought about by cancer, or does low cholesterol actually increase the incidence of cancer? This is an important distinction. In one case low cholesterol levels in the blood are a symptom, not a causative factor. Below is an the link to an interesting article on the subject, as well as a longish quote from it. Notice the authors believe taking statins does not increase the risk of cancer incidence.
http://cebp.aacrjournals.org/content/18/11/2805.full
“Many epidemiologic studies published in the 1980s documented an association between low circulating cholesterol and higher overall cancer incidence and mortality (1). This association has been attributed to reverse causation, that is, undiagnosed cancer causing a reduction in cholesterol levels. Reverse causation is strongly supported by observations that cholesterol levels decline before cancer diagnosis (2, 3) and that associations between low cholesterol and cancer incidence and mortality weaken when the first few years of study follow-up are excluded (4). In addition, a meta-analysis of randomized trials of cholesterol-lowering statins found no effect on risk of cancer, although only short-term effects could be addressed due to the short duration of most trials (5). Despite strong evidence for reverse causation, it has been difficult to entirely rule out the possibility that low cholesterol levels might be associated with a modest long-term increase in risk of cancer. One very large study (6) found an association between low cholesterol and modestly increased cancer mortality even after excluding the first 5 years of follow-up, and a second study found an association between low cholesterol and elevated cancer incidence among men even after excluding the first 6 years of follow-up (7)”
Wow Chaya:
Thank you for this inspiring, informative article. Its exciting when new possibilities blink on the horizon without a smoke machine to “glam” them up! I have no idea how we would all learn of this research were it not for your focus. Great way to start a Tuesday…with a bounce in my step. We’re crossing our fingers on this one.
Barb & Blair
Chaya: If I read the following quote correctly, it appears to me that the participants can only come from the DUMC patient population.
from the perifosine clinical trial link above:
Subject recruitment and consent
Subjects will be identified from the patient populations of the Duke University Medical Center
Hematologic Malignancies program.
Have I got it right?
Thanks – Chris
trimmn:
No, that is not correct. Anyone can participate, provided they fit the inclusion criteria listed in the clinicaltrials.gov citation link I provided above.
Perhaps what is meant is that volunteers will be seen at the Duke University hematological center and will therefore automatically be part of their patient population.
Chaya:
This sounds very encouraging. My question for Dr. F. would be this: my husband has CLL. Quite a few years ago, he was treated with a very, very low dosage of Cladribine by a Margaret Yu who was doing research on low dosages of the drug. After a few shots, his white count went down considerably, so much so that he was dropped from the trial. (I think there were only 7 or so being treated.)
Would this preclude his being in this clinical trial, or might he be eligible? He may be starting FCR the end of June.
Thanks for being so helpful to so many! Judy
Judy:
This clinical trial specifically asks for volunteers who have had prior exposure to chemotherapy, and in need of therapy again at this point in time. Your husband qualifies on both counts.
I strongly urge you to read all the details of the trial (here is the link again for your conveniecne http://clinicaltrials.gov/show/NCT00873457 ) and if the rest of the details work and you are interested, please contact the Duke recruitment folks directly. Their contact information is also given in the link above.
Chaya,
This is the first time I’ve written (and contributed to your Web site). Thanks so much for finding and reporting on the Perifosine study. It sounds like it has a lot of possibilities for relapsed patients like me. I’ve been treated three times, in 1997, 2006, and most recently this year, with variants of FCR, and can no longer tolerate it. I had been considering entering a clinical trial involving revlimid when I received your email. I’m very grateful that you are out there looking out for developments and translating them for your readers. I will definitely check this out.
Linda B Myers, Ithaca NY
Chaya,
Thank you for this very informative article.
Monique
You speak of coat tails. Perifosine is further along in trials for other cancers? If approved for use separate from CLL, would it be legal to use it off label for CLL before being specifically approved for CLL?
The lower indicated toxicity to other cells is quite intriguing.
Chaya,
Would you know if this trial is likely to become available in the UK ?
My partner has been around the block, several times, with the who range of treatments and trials, and time is running out ?
Many thanks
United:
I am sorry to say this is still an experimental drug and not available outside of clinical trials. It may be in similar clinical trials in the UK, but I do not have that information. You might try contacting the comapny (Keryx Biopharmaceuticals) to see if they can point you in the right direction.
Sometimes companies have “compassionate use access” programs whereby they grant access to their drugs outside of clinical trials. The process involves a lot of red tape and negotiating skills, but it can be done. My husband got access to ofatumumab several years before it was commercially available on that basis. It gave him a couple more years of good health, for which I will be forever grateful.
Chaya,
I have to thank you for your informative articles and you are such a good writer! You make your articles easy to understand and interesting. You also pick topics that are so important. You are a life raft for us all.
Chris R
Very interesting concept.
In the pursuit of the goal for better subtyping of patients leading to better treatment options I wonder if the researchers have a comment on the following:
Background to my question – CLL was once thought to be solely a condition of Defective Apoptosis resulting in the accumulation of cancer cells. Because of the work of Dr. Nick Chiorrazzi at L.I.J. we are told that CLL can also be a disease of Dynamic Proliferation as well as cells that do not care to die.
Because CLL is so heterogeneous there is probably a significant difference in the patient population of those who have, at one end of the spectrum, a primary disease characteristic of Apoptosis Defect to those with a primary disease characteristic of Dynamic Proliferation. If the poorer prognosis markers, i.e. FISH 17p, 11q, and unmutated IgVH also infers the Dynamic Proliferation component,(I don’t know this to be necessarily true) Perifosine might not be as effective where it could conceivably be a stand alone, low side affect, therapy for the Defective Apoptosis cell accumulation weighted patient group. Will this trial be large enough to see a true efficacy result given the heterogeneous nature of CLL?
Too often I have seen a promising drug (e.g. TRU-16) give a better than hoped result for one or two heavily pretreated patients in a small trial with little or no effect to the majority of the patient cohort. This does not mean that the drug is no good, only that its mecanism of action is not fully understood.
Perifosine seems to me like the kind of drug that might be most effective in early stage CLL or in patients with less aggressive disease. I only hope it is given a fair shot at our diverse community.
Nice to have drug hope in the pipeline!!
Thanks for this important article.
WWW
Here is Dr. Friedman’s response to some of the questions raised above:
We are doing some laboratory based studies using CLL cells obtained from patients on this study. Unfortunately, looking at the proliferating group of cells is not one of those studies. Also, because of the size of this study, we won’t be able to definately say that one patient subgroup does better than another – the number in each group will be too small. The patients enrolled up to know have been heavily pre-treated. We feel that even if we get stabilization of disease in a patient who previously progressed on therapy, that this would be meaningful. Of course, we would love to see partial or complete responses too. If we do find that perifosine has activity in CLL in our study, we hope to be able to work with the pharmaceutical company to expand the study or perhaps do a combination study with another agent. In future studies, we might be able to answer Waynewells’s question.
And if people have questions about their specific situation and whether they would be eligible for the perifosine study, I would be happy to communicate with them directly by email. They can email CenterForCLL@duke.edu.
Dra Chaya
Thank you for your interesting and informative articles.Your work is fantastic.We are also crossing fingers with this news.
Many thanks.
Jorge& Ana
Dear Chaya
I always find the updates and the main web site informative and have tried to educate physicians in having a look in the UK. I have gained a lot and it has advanced my knowledge.
I became a victim of Cll in 2006. It progressed and I had ITU treated Pneumonia (PCP) then FCR for three cycles to neutropaenia which led to steriods etc. In late 2008 I had facial ulceration which progressed and treated with a whole cocktail of different antibiotic and antifungals. These did not work and I was in a terminal state and had RCVP treatment. I held on to the belief of science, as infection markers where rising in spite of treatment and eventually got Infection and Tropical Medicine involved. The diagnosis was Leishmaniasis which had progress to its visceral form. I had not been to any endemic area apart from the mediterian area.I had treatment with Pentostam and Miltefosine(parent drug to Perifosine). After five days of Miltefosine I felt a tremendous feeling of well being. I completed the full 28 days of 150mg per day. My blood picture is normal and is being maintained. Leishmania has been dealt with to date and we are on a wait and watch.
The point I wish to make is the Miltefosine ( Perifosine) appears to have promise from my experience and should be watched with interest. It is a relatively cheap drug.A first line treatment trial is needed in CLL. The other issue which you may know is leishmaniasis can mimic Cll and quite how important this is in my case is up for debate.
I am happy to correspond with Dr. Friedman but wanted to get this to you first.
T.C.
Terence:
What a wonderful case history! Thank you for sharing it with us. Yes, please do correspond with Dr. Friedman. daphne.friedman@duke.edu I am sure she will be interested.
I have to be honest and admit I did not know that an analog of perifosine is used to treat leishmaniasis! I will check this out a bit more to satisfy my own curiosity. All the best.
More on leishmaniasis.
It sounds like once infected this parasite stays dormant for a long while in the body. Similar to viral reactivation of herpes virusus during periods of immune suppression, leishmaniasis can raise its ugly head when there is a window of opportunity. Below is a short abstract that points to this feature of the parasite.
Cutaneous Manifestation of Leishmaniasis 40 Years After Exposure in a Patient with Chronic Lymphocytic Leukaemia
Leukemia and Lymphoma, Volume 21, Issue 3 & 4 January 1992
Abstract
Most individuals infected with the protozoan parasite Leishmania do not demonstrate overt disease, because of effective immune protection produced by T-cell mediated immunity. Acquired defects in T-cell responses may lead to emergence of leishmaniasis many years after exposure in endemic areas. We describe a case of a 75 year old man, who presented with a cutaneous manifestation of leishmaniasis 40 years after exposure, co-incident with the diagnosis of chronic lymphocytic leukaemia.
Dear Chaya
Thank you for the reply and I apologize for a couple of spelling mistakes in the first communication. I have seen the paper of Jewel and Frank Giles which was my starting point. I have uncovered a large number of related papers. The importance is that apparently no routine test for Leishmaniasis is carried out in the UK and the USA. A large number of papers focus on the association of between Leishmaniasis and Leukaemia.
If you have Cll and a dormant parasite it can be activated when the immune system is low as you have said but it is also possible that the parasite my be activated to mimic CLL. A good review paper on the Aspect of the association between leishmaniasis and malignant disorders by Petros Kopterides et al Royal Society of Tropical Medicine and Hygiene 2007 101, 1181-1189 is a good start in this area.
A letter to the editor in Bone marrow transplantation (2007)40,391-393 shows a case leishmaniasis which was diagnosed accidentially after bone marrow transplantation after only exposure to the mediterranean area of Cevennes region of France. The importance of a simple serological blood screen for this parasite should be routine in my opinion. In the USA cases of Leishmaniasis have been recorded in people who have not left there home town.
It is an unreported issue which in my opinion and experience needs to be highlighted.
In terms of Miltefosine as a treatment I was the third person in the UK to receive it. The team in Birmingham UK at the Tropical Medicine and Infections are going to treat a further 20 patients to get it on license for use in leishmaniasis in the UK.
It’s use for CLL as “united” has asked may be possible in the UK if her husband can convince the clinical haematologist to try it as an individual patient case using me as reason it is relatively not a high cost drug. It is clear if options are running out then it is worth a try. This is in not to short circuit the Perifosine trial and science in any way.
I thank you for Dr. Friedman email address and will be in contact with her. I am pleased to help but I repeat that a first line treatment trial is needed as “Waynewells” also indicates.
My case will get written up and presented and I will keep you informed.
Many thanks again
Terence
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