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EXPERIENCE IN COMBATING LYMPHOPAENIA IN ADVANCED CANCER WITH HUMAN FETAL THYMUS TRANSPLANT

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EXPERIENCE IN COMBATING LYMPHOPAENIA IN ADVANCED CANCER WITH HUMAN FETAL THYMUS TRANSPLANT
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  104 EXPERIENCE IN COMBATING LYMPHOPAENIA IN ADVANCEDCANCER WITH HUMAN FETAL THYMUS TRANSPLANT Niranjan Bhattacharya, Sanjukta Bhattacharya,Mahua Bhattacharya, Ranajit Nandy, Anuradha DasAnanya Bhadra, Tarashanker Banerjee #  Bijoygarh State Hospital, Calcutta-700032, India.#Dept. of Science and Technology, Govt. of West Bengal, Calcutta. KEY WORDS : HUMAN PRE-IMMUNE (12 WEEKS) AND HYPO-IMMUNE (16 WEEKS) FETALTHYMUS TRANSPLANT CAN GROW AND PROLIFERATE IN ADVANCED CANCER PATIENTS . Abstract The successful development of fetal cell/tissue transplantation in adults has resulted in the possibilityof eventual therapeutic solution with a variety of intractable diseases. Umbilical cord whole blood trans- plantation appears to be safe in the adult system. In severe forms of DiGeorge Syndrome, cultured thymustransplant can help in the reconstitution of the immune condition of the host. Successful fetal tissuetransplant in adults, raised the hope of future effective gene transplant and its manipulation prospects tocombat many diseases including hemopathies, inborn errors of metabolism, immunodeficiencies and evenin cancer and AIDS. Two cases of advanced cancer were treated with fetal (pre-immune 12 weeks and hypo-immune 16 weeks) thymus transplant in subcutaneous vascular axillary fold, which were removed after onemonth. Thymuses were collected from consenting mothers undergoing hysterotomy and ligation. Pre-im-mune and hypo-immune human fetal thymic transplant is not rejected in patients suffering from advancedcancer within one month (observation period). Thymic lymphocytes' shedding in the correction of leucope-nia in the background of non-Hodgkin's lymphoma may have many therapeutic implications. Background : During intra-uterine growth, the human fetus passes through the pre-immune (before 15 weeks) andsubsequently, through the hypo-immune phases of growth and maturation The expression of hypo-antige-nicity of the growing fetus in utero, provides an excellent opportunity for fetal tissue/organ transplantation.Recent reports suggest that umbilical cord whole blood transplantation appear to be safe in cases of adultsin need of whole blood transfusion.(1). In severe forms of DiGeorge syndrome, thymus or cultured thymiccells can help in the re-constitution of the immune condition of the host. (2,3,4,5,6,7,8,9,10). Methods : Two patients suffering from advanced cancer were taken as subjects for the present study on fetal thy-mus transplantation programme, after taking informed consent from the patients' guardian and the ethicalTrends Biomater. Artif. Organs. Vol. 17(2) pp 104-111 (2004)http//www.sbaoi.org  105 committee. Following standard antiseptic, aseptic and pre-medication protocol, the patients were injectedwith one percent lignocaine infiltration anaesthesia at the proposed site of transplantation in the axillaryfold of the skin of the recipients. A one centimeter long and one centimeter deep tissue space with goodvascularity was dissected and prepared in each case to receive the thymic graft. In an adjacent table, a fetuswas collected from a consenting mother undergoing ysterotomy and ligation (before 20 weeks) under general anaesthesia, for each case. Within a minute of hysterotomy, the thymus was dissected out from thefetus and transplanted at the prepared site in the subcutaneous space of the axilla and the skin closed by ( 00vicryl) atraumatic interrupted suture. Haematological parameters (Hb/Tc/Dc/ESR/Platelet, etc) were stud-ied (11) in the pre-operative phase and continued sequent- ially in the post-operative phase up to six weeksof the date of transplantation. After one month of the primary operation, the transplanted thymic tissue wastaken out with an elliptical incision under local anaesthesia for serial histological evaluation. Skin suturingwas completed with (00 atraumatic) vicryl. Case Reports : The first patient, Miss A.M. (14 years), was suffering for five years with non-Hodgkins lymphoma (AnnArbor Stage IV) and was receiving chemotherapy periodically with cyclophosphomide, vincristine, doxoru- bicin, and prednisolone after completion of her radiotherapy. However, the disease was showing features of  progressive dissemination and there was an overall deterioration of the patient's condition. After taking proper informed consent from the patient's guardian and the ethical committee, a 16 weeks hypo-immune(more than 15 weeks on the basis of the last menstrual period [LMP] calculation and ultrasound confirma-tion) human fetal thymus was transplanted in the patient. Pre-operative haematological assessment showed-haemoglobin : 13 gm percent, ESR : 45 mm /hr, peripheral blood total count (Tc) before the thymus trans- plant was 2400 /cmm with neutrophil 28 percent, lymphocyte 68 percent, eosinophil and monocyte two percent each, basophil was not present and the platelet count was 75,000 /cmm. On the seventh post-opera-tive day of placement of the thymic graft, the Tc was 3600/cmm with 36 percent neutrophil and 60 percentlymphocyte. On the eleventh post-operative day, the WBC count rose to 9400 /cmm with 80 percent lym- phocyte which became 86 percent with the total WBC count going up to 15,800 /cmm on the seventeenthday of the transplant. This ascending trend of the WBC continued unabated and reached 33,000 /cmm (86 percent lymphocyte) on the twenty-third day and 42,000 /cmm (88 percent lymphocyte without any blastcell) on the thirtieth day of thymic graft placement. The thymic graft was removed with the axillary adjacenttissue on the same day and on the seventh day of the removal of the human fetal thymic graft, the haematologicalassessment showed -haemoglobin : 11.6 gm percent, ESR : 68 mm /hr, Tc : 9900 /cmm with neutrophil 10 percent, lymphocyte 86 percent, along with eosinophil and monocyte two percent each without any baso- phil. The platelet count was 110,000 /cmm. The histology of the thymus after proper processing andstaining with haematoxylin and eosin, when compared with the pre-transplant same thymic tissue, showedgrowth and proliferation of the thymic tissue with Hassall's corpuscles, scattered and aggregated lympho-cytes showed comet like structures. There was no endarterites, thrombosis or any other specific graft vs.host reaction features. The second patient, Mrs. P.M., 35 years old, was suffering from cancer breast rightExperience In Combating Lymphopaenia In Advanced Cancer   106 side (T4, N2, M0 duct carcinoma) with negative oestrogen, progesterone and epidermal growth factor sta-tus, and was treated primarily with modified radical mastectomy and axillary clearance, with a follow-upchemotherapy consisting of cyclophosphomide, methotrexate and 5-fluorourocil. This patient received a pre-immune (less than 15 weeks) tiny human fetal thymus (12 weeks) which was collected from a consent-ing mother undergoing hysterotomy and ligation. The graft was placed in the left axillary fold subcutane-ous space under local anaesthesia. In this case, the pre-operative haematological assessment showedhaemogloin : 12.6 gm percent with total WBC count at 8500 /cmm, with neutrophil 70 percent, lymphocyte24 percent, eosinophil four percent, monocyte two percent, without any basophil, ESR 45 mm /hr and plate-let count 184,000 /cmm. On the seventh post-perative day the total count became 8600 /cmm, with neutro- phil 72 percent and lymphocyte 24 percent. The total count became 5000 /cmm on the twenty-first day with64 percent neutrophil and 34 percent lymphocyte. The WBC count rose to 9800 /cmm with 74 percentneutrophil and 22 percent lymphocyte on the twenty-third day. After removal of the thymic graft on thethirtieth day, the WBC count came down to 8000 /cmm on the seventh day with 68 percent neutrophil and 28 percent lymphocyte. The total count came down further to 6250 /cmm with neutrophil 68 percent and lym- phocyte 30 percent on the fifteenth day. The haemoglobin count was 11.8 gm percent, ESR 47 mm /hr, andthe platelet count was 162,000 /cmm on that day. Thymic histology revealed appearance of Hassal's cor- puscles, comet like structures on the aggregated lymphocytes, justifying proliferation and immuno-compe-tence of the transplanted thymus in the background of sweat, sebaceous glands and squamous epithelium of the recipient's skin. Discussion And Conclusion : The first point concerns the technique of thymus grafting-it has been shown by experiment that thymicfragments in which the structure is preserved are more effective than dissociated thymic cells in the resto-ration of functions. (12). Fragments of one thymus if placed in the muscle and compared with injection of thymic cell suspension in another muscle, the surgically placed pieces would show better survival.(13). The present technique utilized the quasi-total human fetal thymus, 16 weeks old, from which a little tissue wastaken out for histological comparison in the first place and the total thymus, 12 weeks old, was taken for thesecond case to avoid trauma and injury effect on this tiny thymic tissue (12 weeks). This simple method of human fetal thymus transplantation under local anaesthesia in advanced cancer patients without matching theHLA (human leucocytic antigen), showed that the graft is not rejected at one month (period of observation).There is no graft vs. host (GVH) reaction noted clinically or histologically, in either the case of non-Hodgkin'slymphoma (Case 1) or duct carcinoma breast (Case 2). However, the pre-transplant leucopenia was grosslyover-corrected (leucomoid reaction) on the impact of 16 weeks fetal thymus transplant and the leucocytecount returned to normal levels after the removal of the transplant in the case of non-Hodgkin's lymphoma,whereas the impact on the peripheral leucocyte count was less pronounced in the case of the patient withduct carcinoma breast, though the histological evidences of Case 1 and Case 2 both showed growth, prolif-eration and differentiation of the fetal thymus in the new host site. Niranjan Bhattacharya et. al.  107 Fetal growth is dependent upon an unique symbiotic environment where the mother provides all thenecessary factors for the growth and differentiation of the growing fetal organs, The fetal micro-environ-ment is distinctly different from the adult micro-environment.(14). It appears, therefore, that the develop-ing fetal organ prepares/(?) changes its own micro-environment in an altered metabolic situation taking (?)advantage of its hypo-immune and /or pre-immune status to survive, grow and differentiate. Harrison MR (15) has written an interesting review on the problem of surgery on the unborn which has discussed theadvantages and disadvantages of pre-immune /hypo-immune fetal tissue surgery. References : 1.Bhattacharya N, Mukherjee KL, Chettri MK, Banerjee T, Mani U, Bhattacharya S, " A Study Reportof 174 Units of Placental Umbilical Cord Whole Blood Safe Transfusion in 62 Patients As A RichSource of Fetal Haemoglobin Supply in Different Indications of Blood Transfusion", Clinical and  Experimental Obstretics and Gynecology , Vol. XXXIV, Feb /March 2001 (in press).2.Markert ML, Boeck A, Hale LP et al, "Transplantation of Thymus Tissue in Complete DiGeorgeSyndrome",  N Eng J Med  , 1999 Oct. 14; 341(16):1180-9.3.Markert ML, Hummel DS, Rosenblatt HM et al, "Complete Digeorge Syndrome; Persistence of Profound Immunodeficiency",  J Pediatr. ,1998 Jan.;132(1):15-21.4.Hanahan D, "Peripheral Antigen Expressing Cells in Thymic Medulla: Factors in Self-Tolerance andAutoimmunity", Curr Opin Immunol. ,1998 Dec.;10(6):656-62.5.Hong R, Moore AL, "Organ Culture for Thymus Transplantation", Transplantation , 1996 Feb15;61(3) : 444-8.6.Atkinson K, Storb R, Ochs HD et al, "Thymi Transplantation After Allogenic Bone Marrow Graft toPrevent Chronic Graft vs. Host Disease in Humans", Transplantation , 1982 Feb; 33(2);168-73.7.Hong R, "Present and Future Status of Thymus Transplantation",  Ann Clin Res. ,1981 ;13(4-5):350-7.8.Pahwa S, Pahwa R, Incefy G et al, "Future of Immunologic Reconstitution in A Patient with DiGeorgeSyndrome After Fetal Thymus Transplantation", Clin Immunol Immunopathol. ,1979 Sep; 14(1); 96-106.9.Touraine JL, Roncarolo MG, Royo C, Touraine F, "Fetal Tissue Transplantation, Bone Marrow Trans- plantation and Prospective Gene Therapy in Severe Immunodeficiencies and Enzyme Deficiencies", Thymus , 1987;10(1-2) :75-87.10.Hong R, "Thymus Transplantation",  Birth Defects Orig Artic Ser. , 1983;19(3);259-65.11.Dacie JV, Lewis SM,  Practical Hematology , 8th edn., Churchill Livingstone,1994.12.Kay HEM,"Fetal Thymus Transplants in Man", in Ontogeny of Acquired Immunity , A Ciba Founda-tion Symposium, Elsevier, Excerpta Medica, North Holland, 1972, p.249.13.Hong R's communication, Ibid.14.Miller RK," Fetal Drug Therapy : Principles and Issues", in Pitkin MR and Scott JR, eds., Clinics inObstetrics and Gynecology , June 1991,34(2):241-50.15.Harrison MR, "Fetal Surgery",  American Journal of Obstetrics and Gynecology ,1996;174(4);1255.Experience In Combating Lymphopaenia In Advanced Cancer   108 Photomicrograph of a 16 weeks pre-transplant fetal thymus stained with haematoxylin and eosin. Pho-tograph No. 1-Scan Power (up) ; Photograph No. 2-High Power (up).  Photograph No. -1 Photograph No. - 2 Photomicrograph of the transplanted fetal thymus (16 weeks) after four weeks of growth in a patientsuffering from non-Hodgkin's lymphoma. Photograph No. 3- Scan power (up); Photograph No. 4- LowPower (middle); Photograph No. 5 - High Power (low)  Photograph No. -3  Niranjan Bhattacharya et. al.
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