The Patients' Stories

Successful Case Stories, Published in Scientific Journals

The Patients’ Stories

The first successful cure of a patient with a fulminant relapse following myeloablative stem cell transplantation using donor lymphocyte infusion

Allogeneic stem cell transplantation is considered the most effective treatment of otherwise resistant blood cancer. Patients with recurrent disease following successful myeloablative allogeneic stem cell transplantation were nearly always considered incurable. A simple cell-mediated treatment of relapse following allogeneic stem cell transplantation developed by Prof. Slavin changed the dogma and ...
Allogeneic stem cell transplantation is considered the most effective treatment of otherwise resistant blood cancer. Patients with recurrent disease following successful myeloablative allogeneic stem cell transplantation were nearly always considered incurable. A simple cell-mediated treatment of relapse following allogeneic stem cell transplantation developed by Prof. Slavin changed the dogma and confirmed that many patients relapsing following successful allogeneic stem cells transplantation may be cured by a simple procedure called donor lymphocyte infusion (DLI). On the left, we show the first patient successfully treated and cured following failure of a very aggressive myeloablative combination of chemotherapy and total body radiation. His donor is on the right. The story began when the mother of this patient, who was 30-months-old at that time, approached Prof. Slavin in 1986 to treat her son. He had been deemed incurable at another major medical center in Israel. He had been diagnosed with poor risk pre-B ALL, had relapsed on therapy twice, then presented with a fully-resistant 3rd relapse with no hope to respond to any known treatment. Although it was clear his aggressive leukemia could not be controlled even through a conventional myeloablative transplant procedure, the mother asked and insisted to provide the last hope by using allogeneic stem cell transplantation. Considering the need to eradicate fully resistant leukemia with wall-to-wall infiltration of leukemic blasts in the blood and in the bone marrow, the protocol chosen by Slavin consisted of the most aggressive conditioning ever offered to any patient, consisting of 4 times the lethal dose of whole-body radiation delivered from a high dose-rate linear accelerator, in addition to 3 different chemotherapy combinations prior to rescue with his sister’s bone marrow cells. Luckily, the patient survived the transplant procedure and was fully reconstituted with his sister’s cells. Leukemia cells were no longer visible, and it seemed for a while that the leukemia was completely eradicated. Unfortunately, a few weeks later, the patient was brought to the emergency room gasping for breath due to an obstructive mass in the upper airway tract, with visible lesions on his forehead like a unicorn and 3 additional extra-medullary lesions with blood and bone marrow massive infiltration with leukemic blasts. An emergency tracheotomy was done. At that stage, it was clear that there was no chance for any additional effective treatment, so the mother preferred to take the patient home for as long as he would last. Three days later, based on experiments done by Slavin in an animal model of lymphocytic leukemia, he called the mother and suggested a simple experimental treatment as a last resort, suggesting that due to engraftment of donor stem cells, the rejection of alloreactive donor lymphocytes could be prevented and result in the induction of graft-versus-leukemia (GVL) effects. Accordingly, an infusion of 20ml of freshly obtained blood from his sister was injected intravenously and the patient was sent home. A week later, after confirming he was still alive, the procedure of 20ml fresh blood infusion was repeated a second time. Later on, new injections were performed of 20ml of fresh blood each every week or two, for a total of 6 times. Although such patients are never expected to respond to any available treatment, the patient responded dramatically, with gradual disappearance of all visible tumor masses including the lesion that obstructed his airway in the trachea. In parallel, all leukemia blasts disappeared and all patient’s leukemic blasts were replaced with normal donor’s (female) cells. To date, 34 years later, this patient is alive, well and has never required any additional medical treatment since then. This is the first patient ever successfully treated and cured despite 100% resistant disease following the failure of maximally-tolerated myeloablative conditioning and allogeneic stem cell transplantation. The procedure used for treatment since then is known as donor lymphocyte infusion (DLI). DLI was confirmed effective in eradicating malignant cells that are fully resistant to lethal doses of chemo-radiotherapy following allogeneic stem cell transplantation. This happened at many transplant centres worldwide. DLI is also considered for prophylactic treatment against relapse in patients with high-risk disease. Furthermore, the anti-cancer effects of alloreactive donor lymphocytes, DLI, could be further amplified by activation of donor lymphocytes with interleukin 2 (IL-2). The patient’s successful cure, and that of those who followed, provided a clear indication that smart immunotherapy could be much more effective than any available anti-cancer treatment. Accordingly, the use of activated donor lymphocytes resulted in development of new therapeutic strategies for treatment of cancer focusing on smarter cellular therapy rather than relying exclusively on more aggressive and consequently more hazardous non-specific chemo-radiotherapy.
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1st successfully treated patient with acute myeloid leukemia successfully treated using reduced intensity non-myeloablative stem cell transplantation

In early 1990, non-myeloablative stem cell transplantation (NST) or reduced intensity conditioning (RIC) in preparation for allogeneic stem cell transplantation, was introduced for the first time. The first successfully-treated patient was a young woman with acute myeloid leukemia. Treatment was uneventful and, following successful stem cell transplantation, the patient got ...
In early 1990, non-myeloablative stem cell transplantation (NST) or reduced intensity conditioning (RIC) in preparation for allogeneic stem cell transplantation, was introduced for the first time. The first successfully-treated patient was a young woman with acute myeloid leukemia. Treatment was uneventful and, following successful stem cell transplantation, the patient got married a month and a half following NST. She then gave birth to a healthy baby a year and a half later. This was the first patient successfully treated by Slavin's new “mini-transplant” procedure, professionally known as NST or RIC or non-myeloablative stem cell transplantation (NST). Normally, conventional transplantation destroys the ovaries, and young women usually develop early menopause and lose their fertility. This spectacularly successful outcome confirmed for the first time that the new transplant procedure developed by Prof. Slavin is indeed a user-friendly procedure, much safer than the conventional myeloablative transplant procedure used until that time for treatment of malignant hematologic malignancies. The picture shows the baby of that young woman, born a year and a half after stem cell transplantation. NST was pioneered by Prof. Slavin and his team at the Hadassah Medical Center in Jerusalem. It has made it possible to cure patients with blood cancers and related hematological malignancies, as well as a long list of genetic and enzyme-deficiency disorders, including bone marrow deficiency disorders, minimizing treatment-related toxicity and mortality. This new approach for stem cell transplantation provided an option to cure patients that were not eligible for conventional myeloablative stem cell transplantation due to advanced disease, poor general condition or upper age limit. The procedure is now applied successfully all over the world.
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The first patient that underwent successful allogeneic stem cell transplantation for advanced chronic myeloid leukemia using NST

The principle of NST was based on the idea that elimination of chemotherapy- and radiotherapy-resistant cancer cells could be accomplished using alloreactive donor lymphocytes post-grafting. This could also apply to a large number of hematopoietic stem cells producing Philadelphia-positive chronic myeloid leukemia (CML) cells. Such procedure should take into consideration ...
The principle of NST was based on the idea that elimination of chemotherapy- and radiotherapy-resistant cancer cells could be accomplished using alloreactive donor lymphocytes post-grafting. This could also apply to a large number of hematopoietic stem cells producing Philadelphia-positive chronic myeloid leukemia (CML) cells. Such procedure should take into consideration that the role of the transplant procedure was to induce tolerance, or unresponsiveness, against a donor’s immune system cells following the engraftment of donor’s hematopoietic stem cells. This was against the pre-existing dogma, which was based on an attempt to eliminate all CML stem using maximum-tolerable doses of chemotherapy and/or radiation therapy prior to the transplant procedure. This is then followed by the administration of donor’s hematopoietic stem cells to rescue the patient from the irreversibly lethal conditioning used to maximize elimination of CML in the bone marrow and the blood. Indeed, this patient with CML presented with a large number of malignant cells. He was the first one to show that even patients who are not completely in remission could benefit from a successful and safe transplant procedure. This patient is still alive and well more than 25 years after successful NST. In other words, instead of trying to eliminate all cancer cells or genetically abnormal stem cells prior to the transplant procedure, a safer approach to eliminate a patient’s undesirable cells could be accomplished. This should follow the transplant procedure, using the patient’s graft-versus-malignancy or graft-vs-any-undesirable-hematopoietic-stem-cells. It would provide a safer treatment for any malignant or genetically abnormal stem cells, or even stem cells producing autoimmune-reactive lymphocytes in life-threatening autoimmune diseases.
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The first elderly patient who underwent successful allogeneic stem cell transplantation for advanced chronic lymphocytic leukemia on an outpatient basis

Clinical application of NST or RIC instead of the conventional myeloablative transplant procedure made it possible to offer a cure for elderly patients with no upper age limit or to patients with poor performance status, using safer allogeneic stem cell transplantation procedure. Such patients would have been otherwise excluded from ...
Clinical application of NST or RIC instead of the conventional myeloablative transplant procedure made it possible to offer a cure for elderly patients with no upper age limit or to patients with poor performance status, using safer allogeneic stem cell transplantation procedure. Such patients would have been otherwise excluded from a conventional transplant procedure because of the risks involved in the conventional myeloablative transplant procedure. The patient, a lawyer from San Francisco shown here underwent a successful and uncomplicated transplant procedure from his fully matched brother following NST procedure in 2008 on an outpatient basis, never staying in the hospital even for one day. Here too, the principle of NST was based on the idea that eliminating of chemo-radio resistant cancer cells can be mediated by alloreactive donor lymphocytes post-grafting and that the role of the transplant procedure was to induce tolerance and durable engraftment of the donor’s immune system cells following engraftment of donor’s hematopoietic stem cells. This went against the existing dogma, of attempting to eliminate all malignant cells by maximum-tolerable doses of chemotherapy and/or radiation therapy, followed by a transplant procedure to rescue the patient from irreversibly lethal conditioning that destroyed all other essential cells in the bone marrow compartment. In other words, instead of trying to eliminate all cancer cells prior to the transplant procedure, cure could be accomplished following the transplant procedure thanks to the graft-versus-leukemia effects capable of eliminating all residual malignant cells.
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Confirmation that mismatched donor lymphocytes are even more effective than fully matched donor lymphocytes for treatment of multi-drug resistant cancer

This patient from Ankara, Turkey, was referred to Prof. Slavin for treatment for a very aggressive blood cancer that was fully- resistant to myeloablative conditioning supported by autologous stem cell transplantation. A second myeloablative transplant procedure was accomplished, this time using her fully-HLA-compatible sibling as a donor. Unfortunately, leukemia recurred ...
This patient from Ankara, Turkey, was referred to Prof. Slavin for treatment for a very aggressive blood cancer that was fully- resistant to myeloablative conditioning supported by autologous stem cell transplantation. A second myeloablative transplant procedure was accomplished, this time using her fully-HLA-compatible sibling as a donor. Unfortunately, leukemia recurred again. A third transplant procedure was proposed as a last resort, this time using her haploidentically mismatched mother stem cells. Following successful engraftment of mother’s hematopoietic cells, additional treatment was followed by administration of the mother’s blood lymphocytes activated with interleukin 2 (IL-2) to maximize the capacity of mismatched donor lymphocytes to kill all resistant malignant cells. Graft-versus-leukemia (GVL) effects were induced by eliminating T cells and focusing on the donor’s natural killer (NK) cells. This prevented the hazardous graft-vs-host disease (GVHD). All malignant cells were eliminated with no clinical signs of GVHD and now, 18 years out, the patient enjoys an excellent quality of life, as shown in the pictures attached, heading a bank office in Ankara. This case convinced Slavin that the most effective cell-mediated anti-cancer immunotherapy can be accomplished by intentionally mismatched killer cells that can be further activated by interleukin 2 (IL-2).
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Using intentionally mismatched donor lymphocytes, including both T and NK cells, to induce stronger anti-cancer effects against minimal residual disease with no need for prior engraftment of donor’s stem cells

This patient, a 12-year-old girl from the Philippines, was referred to Prof. Slavin from UCLA for the potential treatment of acute myeloid leukemia, after conventional chemotherapy failed. No compatible donor was available and therefore, high dose myeloablative chemotherapy was accomplished, while the patient’s hematopoietic stem cells were cryopreserved ahead ...
This patient, a 12-year-old girl from the Philippines, was referred to Prof. Slavin from UCLA for the potential treatment of acute myeloid leukemia, after conventional chemotherapy failed. No compatible donor was available and therefore, high dose myeloablative chemotherapy was accomplished, while the patient’s hematopoietic stem cells were cryopreserved ahead of time. However, complete remission was not accomplished. Therefore, based on prior successful experience using donor lymphocytes, Slavin treated her following autologous hematopoietic stem cell transplantation at the stage of minimal residual disease. He used haploidentical (mismatched) mother blood lymphocytes activated with interleukin 2 (IL-2), both before and after cell infusion. This was done to maximize the capacity of mismatched donor lymphocytes to kill otherwise resistant malignant cells. The mother’s IL-2 activated blood lymphocytes, which contained both T cells and natural killer (NK) cells, were used for treatment under the assumption that no graft-vs-host disease (GVHD) will result because of anticipated rejection of donor’s T cells prior to development of GVHD. Indeed, as predicted, the treatment was uneventful. After a successful course of cell therapy, she was for the first time free of any residual malignant cells. At present, 28 years later, she continues to present no signs of the disease, and has had no need for treatment since then. Our former patient is now a physician working in the US. She is the happily-married mother of 3 children. The pictures shown below represents another example of anti-cancer effect of intentionally mismatched killer cells, including both T and NK cells, activated by IL-2 ex vivo prior to cell infusion and in vivo for 5 days following cell infusion in a patient with residual breast cancer liver metastases following high dose chemotherapy and autologous hematopoietic stem cell transplantation. We have now documented that mismatched donor lymphocytes, activated with interleukin 2 (IL-2), can be most effective against chemotherapy-resistant cancer cells. Following this, more patients were treated in Slavin’s outpatient clinic after completing conventional chemotherapy procedures. For these patients, we used anti-cancer immunotherapy focusing on administration of IL-2-activated intentionally-mismatched donor lymphocytes. These were harvested family members or unrelated volunteers and some could even be cured. Successful treatment with cell-mediated immunotherapy depends on treatment applied at the stage of minimal residual disease. Since mismatched donor lymphocytes are consistently rejected by the patient within a week, it is unlikely that treatment with intentionally mismatched killer cells could be effective in patients with late-stage bulky metastatic disease. Fortunately, a stage of minimal residual disease is normally accomplished in most patients with cancer, both in patients with hematologic malignancies and solid tumors. This is why it is important for patients and treating physicians to be aware of the potential benefits of anti-cancer immunotherapy at an early stage of the disease in patients at risk of recurrent disease
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1st successfully treated multi-transfused patient with severe aplastic anemia using reduced intensity non-myeloablative stem cell transplantation using total lymphoid irradiation (TLI) for prevention of graft rejection

This young woman presented with multiply-transfused severe aplastic anemia. Aplastic anemia is an acquired disease characterized by deficiency of hematopoietic stem cells. This results in severe anemia and a constant need of blood transfusions. Furthermore, the lack of production of white blood cells increases the risk of life-threatening infections. Poor ...
This young woman presented with multiply-transfused severe aplastic anemia. Aplastic anemia is an acquired disease characterized by deficiency of hematopoietic stem cells. This results in severe anemia and a constant need of blood transfusions. Furthermore, the lack of production of white blood cells increases the risk of life-threatening infections. Poor platelet production causes a serious risk of spontaneous bleeding. Allogeneic stem cell transplantation is the only possible approach for cure of severe aplastic anemia, depending on durable engraftment of normal donor’s hematopoietic stem cells. Due to multiple transfusions received prior to admission for transplant, there is an increased risk of graft rejection following a standard transplant procedure. Low dose total lymphoid irradiation (TLI) was applied for the first time in order to prevent rejection of donor’s stem cells, in addition to a well-tolerated and safe conditioning. Fast engraftment was accomplished, and the patient recovered without any major complications. This young woman got married several months later and gave birth to 3 children. Before Slavin’s time, conventional transplant procedures resulted in engraftment failure due to allograft rejection and using more aggressive conditioning for prevention of graft rejection resulted in an increased risk of loss of ovarian function in women and loss of sperm production in men. This former patient is currently over 38 years out with no need for any additional treatment since the transplant procedure. Avoiding the use of aggressive myeloablative conditioning also minimizes the risk of graft-vs-host disease (GVHD) following allogeneic stem cell transplantation, the most serious unavoidable complication following conventional allogeneic stem cell transplantation.
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A baby with severe beta thalassemia major cured by allogeneic stem cell transplantation using reduced intensity conditioning

The patient shown above underwent allogeneic stem cell transplantation to treat severe beta thalassemia major. This is an otherwise incurable genetic blood disorder caused by an abnormal production of red blood cells, resulting from genetically-abnormal hematopoietic stem cells. Patients born with this disease depend on frequent blood transfusions. Eventually, many suffer ...
The patient shown above underwent allogeneic stem cell transplantation to treat severe beta thalassemia major. This is an otherwise incurable genetic blood disorder caused by an abnormal production of red blood cells, resulting from genetically-abnormal hematopoietic stem cells. Patients born with this disease depend on frequent blood transfusions. Eventually, many suffer from deformities due to the unsuccessful attempt of hematopoietic cells located in the bone marrow to generate more red blood cells. These cells survive for a very short time, and cause many secondary cardio-vascular or other complications. Complete cure can only be accomplished through an early stem cell transplant from a normal donor, before secondary complications occur. This infant was lucky to show up for treatment at the age of 2. The transplant procedure was accomplished thanks to her fully-compatible brother. The principle of reduced intensity conditioning in preparation for stem cell transplantation was based on the same concept suggesting that sufficient immunosuppression for prevention of rejection of donor stem cells will result in durable engraftment of normal donor’s hematopoietic stem cells and then alloreactive donor lymphocytes could complete elimination of all residuals genetically abnormal stem cells post-grafting. The principle of graft-vs-genetically abnormal stem cells with replacement of abnormal host’s with normal donor’s stem cells using NST was also successfully accomplished for treatment of a long list of other genetic diseases that could only be cured by a successful allogeneic stem cell transplantation.
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Intrauterine stem cell transplantation in preparation for treatment of genetic diseases

Many genetic diseases can be treated by stem cell transplantation from a normal donor. Many genetic disorders can be diagnosed during early pregnancy using a diagnostic amniocentesis or chorionic villus biopsy. Because of this, it was important to investigate if stem cell transplantation could be safely accomplished in utero. To investigate ...
Many genetic diseases can be treated by stem cell transplantation from a normal donor. Many genetic disorders can be diagnosed during early pregnancy using a diagnostic amniocentesis or chorionic villus biopsy. Because of this, it was important to investigate if stem cell transplantation could be safely accomplished in utero. To investigate if pre-natal allogeneic stem cell transplantation was feasible, it was important to investigate whether such treatment can be safely accomplished. The first successful attempt investigating the feasibility of intra-uterine allogeneic stem cell transplantation to treat genetic disease was accomplished during pregnancy. This was done on a mother with a suspected beta thalassemic embryo. This case documents the first technically successful attempt to treat genetic disease by infusing the donor’s normal hematopoietic stem cells into the baby’s cord, while still connected to the placenta. For this, we used an ultrasound-guided needle. It can also be accomplished through a direct intra-peritoneal injection of normal donor’s stem cells. The picture shows Professor Slavin after the delivery of the baby. He is pointing to the spot where the needle (carrying the donor’s stem cells) was inserted. The procedure was uneventful for both the mother and the newborn baby.
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The first successful gene therapy of a baby with severe combined immune deficiency (SCID)

Severe Combined Immunodeficiency (SCID) caused by the deficiency of an enzyme known as Adenosine deaminase (ADA) is a lethal disease caused by unavoidable fatal infections. The disease is also known as “bubble baby“ because such newborns had to be protected from infections and locked inside closed bubbles. The only potential ...
Severe Combined Immunodeficiency (SCID) caused by the deficiency of an enzyme known as Adenosine deaminase (ADA) is a lethal disease caused by unavoidable fatal infections. The disease is also known as “bubble baby“ because such newborns had to be protected from infections and locked inside closed bubbles. The only potential cure could be provided by successful gene therapy by insertion of the gene responsible for synthesis of ADA inside multi-potent stem cells that are responsible for development of immune system cells. Unfortunately, all prior attempts for gene therapy of such SCID patients failed. In 2002, a new ADA-deficient SCID newborn was presented to Prof. Slavin. One child of the same family died of recurrent infections before being diagnosed. A sister with ADA-deficient SCID that was born later was cured by Slavin following successful allogeneic stem cell transplantation using normal cord-blood stem cells cryopreserved following delivery of a normal brother (picture shown on the left). No donor was available for the new case of SCID so Slavin decided to try and cure the baby using gene therapy using ADA-vector provided by Italian colleagues. Considering prior failures to cure similar SCID patients by several international teams using a similar ADA vector, Slavin decided to apply a different strategy for transplantation of patient’s own ADA-transduced cord blood and bone marrow stem cells. The new SCID baby girl shown in the picture, Tasnin, was cured in 2002 using successful gene therapy. This used the vector carrying the missing ADA gene that was introduced into her ADA-deficient hematopoietic stem cells. First, the SCID baby was conditioned using harmless non-myeloablative conditioning to create a “niche” for more effective homeostatic proliferation of genetically transduced autologous stem cells. Then, the patient’s genetically transduced stem cells were infused. Indeed, rapid engraftment and differentiation of genetically engineered stem cells resulted in rapid immune reconstitution of Tasnin following an uneventful recovery and no need for any additional treatment since then. Tasnin is the first successful patient treated with gene therapy for ADA-deficient SCID. This was based on Slavin’s method to ensure consistent engraftment and normal multi-lineage differentiation of genetically engineered stem cells. The photos show Tasnin on the right side with her sister and with her mother on the right, fully recovered 4 years after successful gene therapy. On the left side is Salsabil (Tasnin’s sister) who was also born with the same disease and was cured by allogeneic cord blood stem cell transplantation. The patient is alive and well and remains free of any medical problems since 2002.
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The use of oncolytic viruses for treatment of glioblastoma, an otherwise incurable brain cancer

Safe viruses that can cause lethal diseases in chicken, such as Newcastle disease virus (NDV), are sometimes used as oncolytic viruses (cancer killing viruses) to treat cancer safely. These pictures shown two patients with fully resistant recurrent glioblastoma, an otherwise incurable disease. One of the patients is currently 24 ...
Safe viruses that can cause lethal diseases in chicken, such as Newcastle disease virus (NDV), are sometimes used as oncolytic viruses (cancer killing viruses) to treat cancer safely. These pictures shown two patients with fully resistant recurrent glioblastoma, an otherwise incurable disease. One of the patients is currently 24 years out and the other one is 23 years old. The successful treatment was accomplished by prolonged administration of NDV, an oncolytic virus that can infect chickens but is harmless in men. Unfortunately, until recently, the success rate for the use of oncolytic viruses to treat cancer was extremely small. Therefore, this was considered an unreliable treatment. Ever since, it has been documented that treatment with oncolytic viruses can cure otherwise-incurable types of cancer, such as glioblastoma. Newer oncolytic viruses with a much higher cancer-killing capacity were recently developed in our center. Preliminary clinical experience suggests that our newly-available harmless oncolytic poultry viruses may induce much more consistent anti-cancer effects Furthermore, using newly-available oncolytic viruses, Slavin decided to amplify the anti-cancer effects induced by these viruses by combining this treatment with anti-cancer immunotherapy. This can generate a stronger immune response against residual cancer cells “decorated” with viral antigens. Shown below is the first patient with recurrent brain glioma that refused a second surgical removal of recurrent disease. She responded successfully to treatment with oncolytic viruses, combined with anti-cancer immunotherapy. Accordingly, our current strategy is to follow any treatments based on oncolytic viruses with intensive anti-cancer immunotherapy. Based on our successful preliminary experience, we predict that our oncolytic viruses may become one of the most effective future strategies for treating cancer. This can be combined with innovative anti-cancer immunotherapy, even against cancer cells that are fully resistant to all available anti-cancer modalities.
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