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Leadership
Medica and Leader for Chemist have always been in the front line in
following the developments of scientific research in the oncological
field, starting from the first studies on the various forms of leukaemia,
on the advances in bone marrow transplantation up to the use of stem
cells. The articles, covering every single stage of the research, were
written by the very people who conducted these studies, and among the
authors we mention Prof. Freireich, Prof. Gale and Prof. Lambertenghi
Deliliers. And now, in line with out past contributions, we are offering
as an advance news to the international scientific world the results
achieved by Prof. Pier Mario Biava in a research which represents a
crucial turning point in the treatment of oncological pathologies. In
order to document our work over the last decade, we are quoting here
the salient passages from the various articles published. Upon the release
of this issue, there will be a round-table conference with the participation
of Prof. Lambertenghi Deliliers and his team and of Prof. Biava, in
order to publicise, also through widely circulated papers, the latest
developments in oncological research, as well as its possible applications.
Emil
J. Freireich
History
of a Life and of a Discovery
Leadership
Medica 1990
Through
his long professional experience, the author retraces the most significant
steps in his research work on leukaemia, particularly for those forms
whose discovery he has contributed to, also testing new therapeutic
solutions.
Observations on the Natural History of Acute Leukemia
“The
first major observation made by us relates to the description of what
we called the “Ball” disease. Indeed, we found that some patients suffered
sudden and dramatic death from cerebral haemorrhage. In these patients,
there was a strict correlation between the survival of a blastic crisis
and the haemorrhagic event. We were also able to prove that the survival
of these “balls” was due to the sludging of leukaemic cells within the
smaller intracerebral vessels. This syndrome offers the foundation for
the concept that a blastic crisis represents an actual medical emergency.
Up to now, this concept of medical emergency has been resorted to worldwide.
In addition to the intracranic haemorrhage syndrome, we have acknowledged,
defined and treated childhood meningeal leukaemia.” Studies on Chemotherapy
of Adult Acute Leukemia “In 1965 the therapeutic schemes employed for
the treatment of acute leukaemia in the paediatric age had a 50% therapeutic
effectiveness. The therapeutic schemes led to a complete remission for
adult acute leukaemia only in 9% of cases. The first major step forward
in our understanding of the therapy for adult acute leukaemia was the
description of the therapeutic effectiveness of the substance named
arabinosyl-cytosine in conjunction with other drugs.” Research Work
on Clinical Trial Techniques “Although I was the chief organiser of
the first clinical trial employing placebo-controlled randomisation
for the therapeutic evaluation of tumours, in the late 60s it became
clear that this research method displayed serious limitations. We acknowledged
that the analysis of the prognostic factors allowed the distinction
of the patients responding to chemotherapy from those who were not expected
to respond. For the first time we employed the multiple-variable statistical
method, and in particular the one devised by Prof. Cox, to evaluate
the probability of each patient’s response before the therapy. These
techniques have allowed the development of logistic regression equations.
In addition, we designed statistical models aimed at predicting the
remission length. It was therefore possible to prospectively evaluate
these models with a view to assessing the possibility that they may
offer a guideline for therapy prescription based on response expectancy.
Research Work Carried out on other Neoplasias and on the Biology of
Tumours “During the research work conducted to identify new therapies
for leukaemia, we have identified new mechanisms which have contributed
to our understanding of the biology of this disease. It is not possible
to grow in vitro myelopoietic colonies from patients affected by acute
leukaemia in its active phase. We were the first to demonstrate that,
once the remission of the disease had been achieved, it was possible
to grow the above cells. This discovery has confirmed the hypothesis
that complete remission represents a return to normal haematopoiesis.
We also demonstrated that the non-specific immune function represents
an important prediction factor as regards the response to chemotherapy
in leukaemia and in other neoplasias. Furthermore, we were the first
to apply Adriamycin, Fluoroacil and Citoxan (FAC) in the therapy of
metastasis of breast neoplasia. We were also the first to employ Adriamycin
in conjunction with other agents for the therapy of lymphoma.”
Robert
Peter Gale
Bone
Marrow Transplantation
Leadership
Medica 1990
“Major
progress has been made in bone marrow transplantation therapy in cases
of leukaemia, lymphomas and other neoplasias. With this article, we
would like to take stock of the situation as regards current therapies,
recent progress and future prospects.”
Leukemia
“Bone marrow transplantation is often resorted to in the treatment of
leukaemia, also including patients affected by acute lymphoblastic leukaemia
(ALL), acute myeloid leukaemia (AML) and chronic myeloid leukaemia (CML)”.
Lymphomas “There is a significant interest in the resort to bone marrow
transplantation, chiefly in the form of autotransplantation, in the
intermediary and in the most serious stages of lymphomas and of Hodgkin’s
lymphoma. The studies carried out on the subject show that remission
can be achieved with high doses of chemotherapy, with or without radiotherapy
in patients affected by advanced stages of lymphoma. Autotransplantation
has been recently resorted to in the treatment of initial stages of
lymphoma. Results are encouraging and indicate a 20% survival rate in
the absence of the disease after 3 or 5 years. Results obtained with
chemotherapy display a 5% survival rate. The query to be solved is whether
autotransplantation should be used as the initial part of the therapy
in patients affected by Hodgkin’s lymphoma and displaying unfavourable
prognostic factors. A response on this subject can only be provided
through a randomised clinical study.” Problems and Prospects “Although
significant progress has been made in the use of bone marrow transplantation
as a therapy, certain problems continue to exist. Rejection rarely takes
place when the donor is a relative with an identical HLA structure.
However it is possible for the rejection rate to increase in the event
of alternative donating forms. The disease arising in the donated tissue
as a reaction towards the receiver (Tr. Vs. Os.) is another major problem
that may take place after bone marrow transplantation. This pathology
may be viewed as the opposite of rejection. Indeed, the T lymphocytes
of the donated tissue react against the receiver. Tr. Vs. Os. takes
place in 50% of receivers from HLS-identical subjects, in a higher rate
in transplantations with alterative donors. Recent studies show that
it is possible to obtain an incidence of Tr. Vs. Os. through immunosupression
with Cyclosporine and Metotrexate. The removal of T lymphocytes form
the marrow to be transplanted prevents the occurrence of this pathology.
However, this method has resulted in an increased incidence of leukaemia
recurrence and of rejection. The survival rate before recurrence has
not improved. Autotransplantation does not display the above complications.
The major problem we face with this method is that of establish whether
increased doses of antitumour substances and radiations bring about
recovery and whether the reinfused tissue contains tumorous cells. There
is an ongoing animated debate regarding the possibility that reinfused
malign cells may represent a major cause for neoplasia recurrence. Significant
efforts are being made to identify techniques which may enable the removal
of any existing neoplastic cells from the tissue to be transplanted”.
Future Prospects “Bone marrow transplantation is particularly important,
not only because it restores to health certain patients affected by
neoplasias which would otherwise be incurable, but also because it represents
a therapy model involving high doses of chemotherapy and/or radiations
against tumours. Based on our current knowledge of the subject, it is
not clear whether transplantation will continue to be associated with
high doses of chemotherapy or radiations, or whether it will prove preferable
to use the hematopoietic growth factor or the granulocite-stimulating
factor or macrophage granulocites without bone marrow transplantation.
In future, it will be possible to correct these pathologies by transplanting
bone marrow autologous cells that have been modified through of genetic
engineering. A further possibility of employing transplantation is its
use in conjunction with the transplantation of other organs. Indeed
bone marrow transplantation allows the replacement of the receiver’s
bone marrow with that of the donor. It could therefore become possible
to transplant organs such as heart, liver and lungs without the risk
of rejection. This strategy has been successfully employed with animals.
These future prospects may open a door to a wider resort to organ transplantation
in man.
Meeting
with Prof. Giorgio Lambertenghi Deliliers
New
Technologies in the Fight against Leukemia
Leadership
Medica 1994
“Professor
Lambertenghi, what is the future of bone marrow transplantation?” “The
future lies in the separation of stem cells from the umbilical cord
or from peripheral blood, and no longer from bone marrow only. These
cells are grown in vitro, expanded and then employed for transplantation.
We can therefore expect that in the near future we shall be freed from
the need to work on bone marrow: it will be sufficient to have a limited
number of totipotent stem cells, grown in vitro, expanded through haematopoietic
growth factors and transplanted.” “What is today’s objective?” Today’s
objective is the search of alternative sources of stem cells for patients
who do not have a family donor. These people represent 70% of the patient
sample requiring transplantation. In order to approach the bone marrow
transplantation issue, they have three options available: 1) consulting
the bone marrow donor registry and checking on the existence of an HLA-compatible
donor; however the probabilities of finding a donor increase in proportion
to the length of the registry itself: this is why we require international
cooperation; 2) the umbilical cord may be the next resource: the blood
taken form the placenta, which would otherwise be eliminated, is used
to set up a blood bank as an alternative source in addition to bone
marrow; 3) the third option is that of autologous transplantation; in
this field, the use of stem cells from peripheral blood appears to offer
numerous advantages compared to the use of medullar cells. Besides,
stem cells can be grown and expanded in vitro. “As regards the preparatory
phase for transplantation, have there been changes in the potential
donor selection criteria, over the last few years?” “The probabilities
of finding, within the patient’s family, a donor with the requested
features are in any case limited to approximately 30% of cases. We are
therefore left with 70% of “outstanding” cases. For these, it is necessary
to make an alternative choice, since we are dealing with patients who
can be treated with traditional therapies. We therefore require hematopoietic
stem cells coming from other sources.”
(traduzione
Interpres sas-Giussano)
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