Associations of Exercise Habits in Adolescence and Old Age with Risk of Osteoporosis in Older Adults: The Bunkyo Health Study

We investigated effects of exercise habits (EHs) in adolescence and old age on osteoporosis prevalence and hip joint and lumbar spine bone mineral density (BMD). Body composition and BMD in 1596 people aged 65–84 years living in Bunkyo-ku, Tokyo, were measured using dual-energy X-ray absorptiometry. We divided participants into four groups by a combination of EHs in adolescence and old age: none in either period (None-None), only in adolescence (Active-None), only in old age (None-Active), and in both periods (Active-Active). Logistic regression models were employed to estimate multivariable-adjusted odds ratios (ORs) for osteoporosis determined by T-score (less than −2.5 SD) using the None-None reference group. In men, the combination of EHs in adolescence and old age was not associated with osteoporosis prevalence. However, the lumbar spine’s BMD was significantly higher in the Active-Active than the None-Active group (p = 0.043). In women, the Active-Active group had lower lumbar spine osteoporosis prevalence than the None-None group (OR 0.65; 95% CI, 0.42–1.00, p = 0.049). Furthermore, hip BMD was significantly higher in the Active-Active group than in the other three groups (p = 0.001). Older women with EHs in adolescence and old age had higher lumbar BMD and lower risk of osteoporosis.

THE INDIA MUTATIONS AND B.1.617 DELTA VARIANTS: IS THERE A GLOBAL "STRATEGY" FOR MUTATIONS AND EVOLUTION OF VARIANTS OF THE SARS-COV2 GENOME?

In this paper, we run for all INDIA mutations and variants a biomathematical numerical method for analysing mRNA nucleotides sequences based on UA/CG Fibonacci numbers proportions (Perez, 2021). In this study, we limit ourselves to the analysis of whole genomes, all coming from the mutations and variants of SARS-CoV2 sequenced in India in 2020 and 2021. We then demonstrate - both on actual genomes of patients and on variants combining the most frequent mutations to the SARS-CoV2 Wuhan genomes and then to the B.1.617 variant - that the numerical Fibonacci AU / CG metastructures increase considerably in all cases analyzed in ratios of up to 8 times. We can affirm that this property contributes to a greater stability and lifespan of messenger RNAs, therefore, possibly also to a greater INFECTUOSITY of these variant genomes. Out of a total of 108 genomes analyzed: None ("NONE") of them contained a number of metastructures LOWER than those of the reference SARS-CoV2 Wuhan genome. Eleven (11) among them contained the same number of metastructures as the reference genome. 97 of them contained a GREATER number of metastructures than the reference genome, ie 89.81% of cases. The average increase in the number of metastructures for the 97 cases studied is 4.35 times the number of SARS-CoV2 UA/CG 17711 Fibonacci metastructures. Finally, we put a focus on B.1.617.2 crucial exponential growth Indian variant. Then, we demonstrate, by analyzing the main worldwide 19 variants, both at the level of spikes and of whole genomes, how and why these UA / CG metastuctures increase overall in the variants compared to the 2 reference strains SARS-CoV2 Wuhan and D614G. Then, we discuss the possible risk of ADE for vaccinated people. To complete this article, an ADDENDUM by Nobelprizewinner Luc Montagnier vas added at the end of this paper.

The INDIA Mutations and B.1.617 Variant: Is There a Global "Strategy" for Mutations and Evolution of Variants of The SARS-CoV2 Genome?

ABSTRACT. In this paper, we run for all INDIA mutations and variants a biomathematical numerical method for analysing mRNA nucleotides sequences based on UA/CG Fibonacci numbers proportions (Perez, 2021). In this study, we limit ourselves to the analysis of whole genomes, all coming from the mutations and variants of SARS-CoV2 sequenced in India in 2020 and 2021. We then demonstrate - both on actual genomes of patients and on variants combining the most frequent mutations to the SARS-CoV2 Wuhan genomes and then to the B.1.617 variant - that the numerical Fibonacci AU / CG metastructures increase considerably in all cases analyzed in ratios of up to 8 times. We can affirm that this property contributes to a greater stability and lifespan of messenger RNAs, therefore, possibly also to a greater INFECTUOSITY of these variant genomes. Out of a total of 108 genomes analyzed: - None ("NONE") of them contained a number of metastructures LOWER than those of the reference SARS-CoV2 Wuhan genome. - Eleven (11) among them contained the same number of metastructures as the reference genome. - 97 of them contained a GREATER number of metastructures than the reference genome, ie 89.81% of cases. The average increase in the number of metastructures for the 97 cases studied is 4.35 times the number of SARS-CoV2 UA/CG 17711 Fibonacci metastructures.

The Sceptical Inquirer

This article treats of whether scepticism, in particular Pyrrhonian scepticism, can be said to deploy a method of any kind. I begin by distinguishing various different notions of method, and their relations to the concept of expertise (section 1). I then (section 2) consider Sextus’s account, in the prologue to Outlines of Pyrrhonism, of the Pyrrhonist approach, and how it supposedly differs from those of other groups, sceptical and otherwise. In particular, I consider the central claim that the Pyrrhonist is a continuing investigator (section 3), who in spite of refusing to be satisfied with any answer (or none), none the less still achieves tranquillity, and whether this can avoid being presented as a method for so doing, and hence as compromising the purity of sceptical suspension of commitment (section 4). In doing so, I relate—and contrast—the Pyrrhonists’ account of their practice to the ‘Socratic Method’ (section 5), as well as to the argumentative practice of various Academics (section 6), and assess their claim in so doing to be offering a way of instruction (section 7). I conclude (section 8) that there is a consistent and interesting sense in which Pyrrhonian scepticism can be absolved of the charge that it incoherently, and crypto-dogmatically, presents itself as offering a method for achieving an intrinsically desirable goal.

Non-Warfarin Oral Anticoagulants in Anti-Phospholipid Syndrome

Introduction: Anti-Phospholipid Syndrome (APS) is a serious and deadly disorder leading to a significant risk of thrombi, requiring lifelong therapeutic anticoagulation. Traditionally, the vitamin K antagonist (VKA) warfarin has been considered standard of care in this patient population. However, the VKAs require frequent laboratory monitoring, have a narrow therapeutic window, numerous drug interactions and dietary restrictions. Due to these factors, many patients suffer recurrent thrombi and/or major bleeding, warranting therapy modification or switching to parenteral anticoagulants. The non-warfarin oral anticoagulants (NOACs), specifically the direct Xa inhibitors apixaban and rivaroxaban, have been approved for the treatment of venous thromboembolism and represent attractive options for these patients. Methods: We designed a retrospective analysis of all patients at the University of Virginia with APS that were treated with either apixaban or rivaroxaban since September 2011. All patients were required to have a definitive diagnosis of APS [defined by the Sydney criteria as an arterial or venous thrombosis and IgM and/or IgG anti-cardiolipin antibody >40GLP, IgG and/or IgM beta-2 glycoprotein >99th percentile, and/or positive lupus anticoagulant (e.g. prolonged silica clot time or dilute Russell viper venom time)]. Patients were reviewed for recurrent thrombi, severe bleeding or other complications that led to changes in their management. Results: Sixty-six patients were identified with suspected APS, with 18 being treated with a NOAC. Of these, 10 had definitive APS per the Sydney criteria and were analyzed. 6/10 (60%) were treated with apixaban and 4/10 (40%) were treated with rivaroxaban. No patients developed severe bleeding or thrombotic complications and none required changes of their therapy. 30% started a NOAC as the first line outpatient regimen with the remaining 70% being previously treated with other anticoagulants. 7/10 (70%) were treated with warfarin and 3 patients were treated with fondaparinux before changing to a NOAC. Reasons for stopping warfarin were difficulty managing INRs (33%) or thrombi while on warfarin (66%). Of those previously on fondaparinux, reasons for changing therapy were transient ischemic attack (33%), difficulty with injections (33%) and cost (33%). Of these 10 patients, safe and effective anticoagulation with a NOAC was noted for up to 36 months without adverse effects. Conclusion: Apixaban and rivaroxaban showed to be a safe and effective first line outpatient regimen for patients with APS or patients with APS who develop recurrent thrombi on warfarin or parenteral anticoagulation. Further prospective studies are needed before their use should be considered standard of care. Table 1. Patients with Anti-Phospholipid Syndrome Treated with Non-Warfarin Oral Anticoagulant Patient First Positive Test Second Positive Test Serum Testing Performed off Warfarin Anticoagulant Length of Treatment (in months) Bleeding Complications Thrombotic Complications Prior Anticoagulant Use Reason Therapy was Changed 1 Cardiolipin IgG 52, β2 IgG >112 Cardiolipin IgG 76, β2 IgG >112; RVVT prolonged No Apixaban 8 None None Yes (warfarin) Difficult to control INR 2 Cardiolipin IgG >15;RVVT prolonged Cardiolipin IgG >15;RVVT prolonged Yes Apixaban 6 None None Yes (warfarin) Difficult to control INR 3 Cardiolipin & β2 >112 Cardiolipin & β2 >112 Yes Apixaban 2 None None Yes (warfarin) Stroke while on warfarin 4 Cardiolipin IgM 66, β2 IgM 68 Cardiolipin IgM 98, β2 IgM 87 Yes Apixaban 8 None None No N/A 5 β2 IgG 122;+ LA Cardiolipin & β2 >112 No Apixaban 7 None None Yes (warfarin) Multiple strokes while on warfarin 6 β2 IgM 29;+ LA Cardiolipin IgM 50, β2 IgM 74RVVT prolonged Yes Apixaban 4 None None Yes (Fondaparinux) Difficulty with injections 7 Cardiolipin IgG 73 Cardiolipin IgG & β2 IgG>112;RVVT prolonged Yes Rivaroxaban 36 None None Yes (warfarin & fondaparinux) Thrombi on warfarin & fondaparinux 8 Cardiolipin IgG>112;RVVT prolonged Cardiolipin IgG>112 Yes* Rivaroxaban 2 None None Yes (warfarin) Difficult to control INR 9 Cardiolipin IgM & β2 IgM>112 Cardiolipin IgM & β2 IgM>112 Yes* Rivaroxaban 15 None None No N/A 10 β2 IgG>100RVVT prolonged β2 IgG>100;RVVT prolonged No Rivaroxaban 31 None None Yes (warfarin & fondaparinux) Thrombi on warfarin & fondaparinux *Second serum testing drawn while on rivaroxaban Disclosures Off Label Use: Apixaban and rivaroxaban use in patients with Anti-phospholipid Syndrome.

Stimulation of Adrenergic Activity By Desipramine Enhances Hematopoietic Stem and Progenitor Cell Mobilization Along with G-CSF in Multiple Myeloma - a Pilot Study of Safety and Efficacy

Background: Hematopoietic stem cell release is regulated by the sympathetic nervous system through the β (3) adrenergic receptor [Mendez-Ferrer et al. Nature 2008]. Peripheral sympathetic nerve neurons express the G-CSF receptor and stimulation of peripheral sympathetic nerve neurons with G-CSF reduced norepinephrine (NE) reuptake significantly, suggesting that G-CSF potentiates the sympathetic tone by increasing NE availability [Lucas et al Blood 2012]. Based on preclinical data, we investigated the NE reuptake inhibitor desipramine in HSC mobilization. Despite augmentation with Plerixafor (CXCR4 inhibitor), 20% of all patients fail to mobilize 6*10^6 CD34 cells/kg in myeloma and the collection rate with G-CSF alone is 51.1% [Diperiso et al Blood 2012]. The cost of upfront plerixafor is $9,081 per patient while desipramine costs $40. We undertook a feasibility study of adult patients with MM undergoing autologous transplantation (ASCT) to study safety and efficacy of mobilization with desipramine and G-CSF. Patients & Methods: From 2013- 2014, 10 patients between the ages of 18-70, eligible for ASCT were enrolled. Desipramine 100mg daily was administered for 7 days, starting 4 days prior to starting G-CSF (D-3) and continue along with G-CSF for a total of 7 days. CBC and CD34 counts were determined on Day+5. If CD34 counts were > 10/ul, stem cell collection was commenced and if < 10/ul, plerixafor was added as salvage therapy. The endpoints were safety and efficacy in mobilizing CD34 cells for ASCT in patients with multiple myeloma. This trial was registered at clinicaltrials.gov as NCT01899326. Results Six of ten patients enrolled completed the protocol and underwent stem cell transplantation. Reasons for not completing were 1. Lack of insurance coverage 2. Non-compliance with study treatment 3. Disease relapse prior to ASCT. Five patients did not have any grade 3 or 4 adverse events and 1 had disease-related Grade 4 hypercalcemia and Grade 2 AKI at the time of stem cell mobilization. No patients had significant treatment related adverse effects. All 6 patients who completed the protocol achieved the target collection of 5*10^6 CD34 cells/kg. Four patients achieved 6*10^6 CD34 cells/kg or more and the remaining 2 patients achieved 5.52 and 5.92 *10^6 CD34 cells/kg respectively. Among the 6 patients, 2 patients received salvage plerixafor. The median time to achieve WBC >1000/ul, ANC >500/ul and platelets>20k was 11.5, 11, 13.5 days Table 1. Age Ind. Regimne Disease status P PB CD34/ul CD34 collected *10^6 / kg Total CD34/kg collected Engraftment (Days to) Adverse effects from desipramine D1 D2 D3 D4 D2 D3 D4 ANC >0.5 Platelets> 20k G1,G2 G3,G4 1 62 Free λ VRD VGPR N 45.8 66.0 7.01 7.01 12 13 none none 2 50 Free λ VRD VGPR N 88.0 143.5 12.22 12.22 12 12 none none 3 58 IgA VCD VGPR N 38.0 67.7 31.6 4.22 2.75 6.97 13 17 none none 4 70 IgAκ VRD VGPR Y 2.40 40.2 16.6 4.31 1.61 5.92 12 14 none none 5 56 IgGκ VCD VGPR Y 8.70 11.9 37.1 19.4 1.33 4.57 1.61 7.51 11 12 none none 6 70 IgGλ VD RD Relapse N 76.2 97.1 5.54 5.54 11 20 AKI hypercalcemia P-Plerixafor; V-Velcade; R-Lenalidomide; D-Dexamethasone; C-Cyclophosphamide Conclusions Overall G-CSF + Desipramine combination appears to be safe, well tolerated and shows signs of efficacy. G-CSF and desipramine was successful in 4/6 (66%) and all achieved the stem cell collection in 2 days or less. Desipramine, GCSF and Plerixafor was successful in all (6/6) patients to achieve a target of 5*10^6 CD34 cells/kg. The mean number of CD34 cells collected in the desipramine+ G-CSF mobilisers was 7.24*10^6 CD34 cells/kg which, based on historical data, is higher than what would be expected with G-CSF alone even though 3/4 of these patients had lenalidomide as induction therapy. Based on these results, a phase II clinical study evaluating the efficacy of G-CSF with desipramine with or without salvage plerixafor in multiple myeloma and lymphoma will be initiated. Disclosures Barta: Seattle Genetics: Research Funding.

Invasive Fusariosis in Patients with Hematologic Malignancies at a University Hospital

Introduction: Fusarium species cause severe infections in patients with hematologic malignancies. The types of infection caused by Fusarium spp. in humans range from infections of nail, skin, and eye in immunocompetent host to invasive and disseminated infections in mainly immunocompromised patients. Methods: We retrospectively indentified patients with hematologic malignancy and positive cultures for Fusarium species at the University Hospital (1995-2014). Results: Thirteen cases were identified over study period. Patient demographic and underlying risk factors for fusariosis are presented in Table I. Most patients had uncontrolled hematological malignancy. All patients were neutropenic at diagnosis. Pulmonary involvement was evident in 3/13 patients (23%). Skin lesions were present in 2/13 (15%) patients. Fusariosis presented as a breakthrough infection in 8/13 (62%) of patients (Table II). Positive blood cultures were in the 6/13 (46%). Conclusions: Our study has several limitations due to its retrospective nature and its relatively small size. Fusariosis, althought uncommon, continues to have poor prognosis in neutropenic leukemic patients who present with fungemia. The optimal therapy for fusariosis remains undefined, because of its rarity and the complex clinical scenarious in patients with severe immunosupression. Table 1. Characteristics of 13 patients with fusariosis No Sex/age Underlying disease Duration of neutropenia before/after (days) Fusarium spp. Diagnosis Breakthrough infections Concomitant infections Treatment of fusarium infection Outcome of Fusarium infection 1 F/41 AML/Ri 15 /6 F. verticillioides Blood None None Amp- B Eradicated, in 23 days 2 M/19 Aplastic anemia 67/54 F. proliferatum Bronchilavage None C. kefyr, C. glabrata, P. aeruginosa Amp- B, voriconazole Eradicated, in 51 days 3 M/38 AML/RÝ 31/1 F. proliferatum Bronchi lavage Fluconazole C. albicans Amp- B, voriconazole Eradicated, in 199 days 4 M/50 ALL/RÝ 25/0 F. proliferatum Blood Fluconazole K. pneumoniae Amp- B Died 5 M/43 AML/consolidation 37/9 F. solani SC haplotype 6 Skin biopsy Fluconazole C. bovis, S. arolis Voriconazole Died 6 M/45 Relapse AML/ RÝ 37/5 F. petroliphilum Blood + tissuebiopsy Itraconazole, voriconazole VRE, S. capitis, S. maltophilia Amp- B, voriconazole Died 7 M/65 AML/ RÝ 41/0 F. andiyazi Blood Posaconazol A. baumanii Amp - B Died 8 M/63 MDS tr. AML/ RÝ None F. petroliphilum Nasalbiopsy Fluconazole HSV, C. albicans, alternans spp. Amp- B, voriconazole Died 9 M/49 Refractary MDS tr. AML/ RÝ 67/94 F. solaniss. Nasalbiopsy None S. hominis, S. saprophyticus Voriconazole Eradicatedin 68 days 10 F/53 Relapse MDS tr. AML/ RÝ 25/27 F. proliferatum Nasalbiopsy Posaconazole VRE, Klebsiella, Enterobactericea Amp- B, voriconazole Eradicated, in 84 days 11 F/49 ALL/ RÝ 23/13 F. petroliphilum Nasalbiopsy None Enterococcus, S. epidermidis, E. faecalis, MRS, BLPS Amp- B, voriconazole Died 12 M/50 HCL 65/4 F. petroliphilum Blood None None Amp- B Died 13 M/52 Relapse AML/ consolidation 34/3 F. petroliphilum Blood , skin biopsy Posaconazole C. parapsilosis, C. meningosepticum, S. capitis Echinocandine, voriconazole Eradicated , in 90 days Table 2. Patient characteristics Demographic and disease characteristics Number of patients, n=13 (%) Median age 49(19-63) Male 49,5(19-63) Female 49(41-53) Female patient 3 (23) Male patient 10(77) AML/ MDS tr. AML 9 (69) Relapse 3 Remission induction 7 Consolidation 2 Reinduction 1 ALL (remission induction) 2 (15) Hairy cell leukemia 1 (8) Aplastic anemia 1 (8) Median duration of neutropenia before diagnosis (day) 34 (15-67) Median duration of neutropenia after diagnosis (day) 6 (0-94) History of DM 0 Albümin <3.5 mg/dL All Hýgh dose corticosteroid treatment within 30 days of diagnosis 1 Breakthrough infections 8 (62) While receiving posaconazole 3 (23) While receiving voriconazole 1 (8) While receiving fluconazole 4 (31) Concominant infection Bacterial, viral, fungal=11 (85) Exitus 7 (54) Disclosures No relevant conflicts of interest to declare.

Early Intravenous Immunoglobulin (IVIG) Therapy and Non Invasive Fetal Monitoring in Rh Alloimmunization (AI) and Pregnancy

High titer (HT), ≥1:32, anti-E, anti-c and anti-D Rh antibodies can cause hemolytic disease of the newborn (HDN). Maternal IVIG therapy may reduce need for intrauterine and exchange transfusions in HDN. Minimal data exists regarding optimal timing of therapy initiation, dose and frequency and fetal outcomes. Late administration of IVIG therapy beyond gestational age of 16 weeks have not been shown to improve fetal outcome. We describe the clinical course of 3 pregnant women with Rh AI. Two women with high titer Rh AI were treated with early IVIG dose of 1 gm/kg/week. A third woman with low titer Rh AI did not receive IVIG. Fetal status was monitored non-invasively with weekly Fetal Doppler ultrasound measurement of peak systolic velocity (PSV) of the middle cerebral artery (MCA). Patient 1 was a 38 year old Caucasian female with high anti- D (&gt; 1:500) and history of HDN; second baby required 3 exchange transfusions and third baby required 3 intrauterine transfusions during pregnancy and 2 exchange transfusions post delivery. IVIG weekly infusion was started on week 11. Amniocentesis done at week 21 showed that baby was Rh(D) positive and the Kleihauer-Bethke test was negative. Serial fetal MCA PSV done weekly till labor induction did not show evidence of significant fetal anemia. The IVIG infusions were completed on 33rd week and the patient delivered healthy baby by cesarean section on the 35th week. The baby did not receive any intra uterine or exchange transfusions. Patient 2 was a 37 year old caucasian woman with anti-c AI. The patient’s husband is c antigen positive and she had seroconversion during her third pregnancy which manifested as positive antibody screen in a routine type and screen with her third delivery which was uneventful. She subsequently had a miscarriage of her fourth pregnancy at 9 weeks. Her peak anti –c titer was 1: 128. She received IVIG infusion from week 11 to week 33 with stable anti-c titer of 1: 64. Serial MCA PSV assesments did not reveal significant fetal anemia. She had a normal vaginal delivery on week 34 with a healthy baby not requiring any exchange transfusions. Patient 3 was a 41 year old caucasian woman with low titer anti-E AI (1:8). No IVIG was administered as her titers remained low during her pregnancy course. Her titers were monitored every 2 weeks; peak antibody titer was 1:8. Fetal anemia was ruled out with Serial MCA PSV assesments. She delivered a healthy baby by Ceserean section at 38 weeks, 4 days. Patient 1 Patient 2 Patient3 Gravid status G4 P2103 G5 P3013 G8, P4034 Blood group A- A+ O+ Antibody identification Anti D Anti c Anti E H/o documented HDN Yes No No Number of doses of IVIG 23 23 NA Age of Gestation IVIG started 10 weeks 11 weeks NA Cumulative dose of IVIG 1580 gms 1750 gms NA Peak antibody titer 1048 128 8 Serial Fetal Peak MCA velocity Normal Normal Normal Intra uterine/Exchange transfusions none None None Pregnancy outcome normal fetus normal fetus normal fetus IVIG adverse effects Headache, fatigue None N/A Patient 1 Weeks of gestation Anti D Titer IVIG –Cumulative No. of doses MCA PSV (cm/s) MoM= Multiples of Median 9 1:512 12 1:1048 1 17 1:512 7 20 1:512 10 21 (0.83 MoM) 21 1:512 11 28 (1.04 MoM) 22 1:512 12 21.3 (0.76 MoM) 23 1:512 13 28.1 (0.96 MoM) 24 1:512 14 22 (0.71 MoM) 25 1:512 15 25 (0.77 MoM) 26 1:512 16 32 (0.95 MoM) 27 1:512 17 28 (0.79 MoM) 28 1:512 18 35 (0.94 MoM) 30 1:512 20 45 (1.11 MoM) 32 1:512 22 61 (1.37 MoM) 33 1:512 23 51.9 (1.1 MoM) Patient 2 Weeks of gestation Anti c Titer IVIG – Cumulative number of doses MCA PSV (cm/s) MoM= Multiples of Median 11 1:128 1 14 1:64 4 20 1:64 10 22 1:64 11 22.3 (0.79 MoM) 24 1:64 13 23.7 (0.77 MoM) 25 1:64 14 22.7 (0.70 MoM) 26 1:64 15 30.1 (0.89 MoM) 27 1:64 16 34.3 (0.97 MoM) 29 1:64 18 37.9 (0.98 MoM) 30 1:64 19 33.3 (0.82 MoM) 31 1:64 20 27.9 (0.65 MoM) 32 1:64 21 28 (0.62 MoM) 33 1:64 22 59 (1.26 MoM) 34 1:64 23 35 (0.71 MoM) Patient 3 Weeks of gestation Anti E Titer IVIG - Cumulative No. of doses MCA PSV (cm/s) MoM= Multiples of Median Median – 1.29 MoM = No fetal anemia 1.29 – 1.5 MoM = Mild anemia &gt;1.5 MoM = Severe anemia 12 1:8 0 19 1:8 0 26 1:8 0 28 1:8 0 40.6 (1.07 MoM) 29 1:4 0 39.7 (1.02 MoM) 32 1:4 0 42 (0.94 MoM 34 1:4 0 55 (1.12 MoM) Conclusion- Early initiation of weekly IVIg therapy at dose of 1 gm/kg at gestational age of 10 to 11 weeks in high titer (≥ 1:32) maternal Rh AI is well tolerated and can eliminate the need for invasive fetal monitoring, intrauterine transfusion and exchange transfusion.

Reduced Intensity Conditioning Is Safe and Effective for Transplantation of Patients with Shwachman Diamond Syndrome.

Allogeneic hematopoietic stem cell transplantation is the only potentially curative treatment for the bone marrow dysfunction seen in patients with Shwachman-Diamond Syndrome (SDS). Historically, these patients have fared poorly with intensive conditioning regimens with increased regimen-related toxicity especially involving the heart and lungs. We report our institutional experience with a reduced intensity conditioning protocol in 7 patients with SDS and bone marrow aplasia or MDS/AML. Patient demographics are summarized in Table 1 below. The preparative regimen consisted of Campath-1H for 4 successive days (day -22 to day -19), Fludarabine 30 mg/m2/day for 5 days (Day - 8 to day -4) followed by Melphalan 140 mg/m2 for 1 day (day -3). Four patients received matched related marrow, 2 received matched unrelated peripheral blood stem cells (PBSC) and 1 received matched unrelated marrow. All but one were 8/8 allele HLA matched. Graft-versus-host disease (GVHD) prophylaxis consisted of Cyclosporine(CSA) and Methotrexate in all except one patient who received tacrolimus and mycophenolate mofetil as she was CSA intolerant. All patients established 100% donor-derived hematopoiesis. No major regimen related toxicity was seen except hyperglycemia requiring insulin in one patient and Grade II renal insufficiency in 1 patient which resolved with conservative management. Transplant outcomes are described in Table 2. These data indicate that HSCT with reduced intensity conditioning is feasible in patients with SDS and associated with excellent hematopoietic recovery and modest morbidity. Table 1. Patient Demographics Patients #1 #2 #3 #4 #5 #6 #7 Age(yrs) 8 10 12 6 3 29 1 Gender Male Male Male Male Male Female Female SBDS mutation 183_184 TA to CT 183_184 TA to CT K62X 183_184 TA to CT 183_184 TA to CT IVS2+2 T to C 183_184 TA to CT Clinical status Transfusion dependence, recurrent infections Cytopenias Cytopenias Dysplasia Cytopenias Acute myeloid leukemia Dysplasia, Cytopenias Marrow cytogenetics del20q12 and del7q31 i(7)(q10) del20q12 del20q12 del20q12 Complex karyotype including monosomy 7,del5q Normal Table 2. Transplant outcomes Patients Patients #1 #2 #3 #4 #5 #6 #7 Days to myeloid engraftment 15 12 15 11 14 14 13 Platelet Recovery(days) 27 39 33 18 68 14 not engrafted Donor Chimerism 100% 100% 100% 100% 100% 99.8% 100% Hospital stay(days) 29 32 35 28 29 22 46 Length of follow-up(days) 758 723 679 385 218 65 33 Acute GVHD Gd II skin None None None None Gd I skin None Lansky scale 100% 100% 100% 100% 100% 90% 60%