Short term outcome of patients attending a renal-immunology clinic in central India.

Background: : Glomerular diseases (GDs) and other renal immunologic diseases are an important cause of morbidity and mortality. Providing a single point of service in collaboration with various specialists at a renal immunology clinic for such patients is not novel, but outcomes have not been reported. Here, we report the short-term outcome of Indian patients attending our clinic. Methods: : This single-center prospective cohort study enrolled biopsy-proven immunologically-mediated adults with renal diseases between April 2018 and December 2019, and followed them for six months. The primary end point for the analysis was an incidence of end-stage renal disease (ESRD) or loss of >50% estimated glomerular filtration rate (eGFR) and patient survival at six months. Secondary endpoints were the rate of complete or partial remission, and impact of demographic factors. Results: : Ninety two patients underwent renal biopsy for suspected immunological renal diseases. Fourteen (15.2%) cases were excluded for nonimmune etiologies, whereas 78 (84.7%) confirmed cases of immune etiology were included. Most common primary GD (n = 51) (93.5%) was membranous nephropathy (n = 20) (25.6%), whereas lupus nephritis was the most common (n = 8) (29.6%) secondary GD. Overall, 10 (12.8%) patients reached renal endpoint of ESRD or >50% fall in eGFR. Focal segmental glomerulosclerosis (FSGS) (27%) patients had worst renal outcome. Patient survival was 94.8%. Thirty patients (38.4%) achieved complete, whereas 24 each (30.7%) achieved partial remission and remained resistant to disease specific therapies, respectively. Univariate analysis identified hypertension, severity of hypertension, and resistance to achieve proteinuria remission as significantly associated (P < 0.001) factors with poor renal outcome. Conclusions: : The present study shows that short term renal outcome of Indian patients with renal immune diseases remains poor. FSGS remains the GD with the worst renal outcome. Hypertension, its severity, failure to achieve proteinuria remission were significantly associated with poor renal outcomes.

Do proximal hip geometry, trabecular microarchitecture, and prevalent vertebral fractures differ in postmenopausal women with type 2 diabetes mellitus? A cross-sectional study from a teaching hospital in southern India.

This study from southern India showed that the trabecular microarchitecture and proximal hip geometry were significantly impaired in postmenopausal women with diabetes as compared to age and BMI matched non-diabetic controls. This is despite there being no significant difference in bone mineral density at the femoral neck and hip not between both groups. One-third of the study subjects with type 2 diabetes had prevalent vertebral fractures. Bone mineral density assessment as a standalone tool may not adequately reflect bone health in subjects with diabetes. INTRODUCTION: There is limited information with regard to bone health in Indian postmenopausal women with type 2 diabetes. We studied the bone mineral density (BMD), trabecular bone score (TBS), prevalent vertebral fractures (VF), proximal hip geometry, and bone mineral biochemistry in ambulatory postmenopausal women with and without type 2 diabetes mellitus (T2DM). METHODS: This was a cross-sectional study conducted at a tertiary care center. BMD, TBS, prevalent vertebral fractures, and hip structural analysis (HSA) were assessed using a dual-energy X-ray absorptiometry (DXA) scanner. Bone mineral biochemical profiles were also studied. RESULTS: A total of 202 ambulatory postmenopausal women known to have type 2 diabetes mellitus with mean (SD) age of 65.6 (5.2) years and 200 age and BMI matched non-diabetic controls with mean (SD) age of 64.9 (4.7) years were recruited from the local community. Although the prevalence of lumbar spine osteoporosis was significantly lower among cases (30.7%) as compared to controls (42.9%), the prevalence of degraded bone microarchitecture (TBS < 1.200) was significantly higher among cases (51%) than in controls (23.5%); P < 0.001. Prevalent vertebral fractures were not significantly different in cases and controls. The various geometric indices of the proximal hip were significantly impaired in subjects with diabetes as compared to controls. CONCLUSION: This study may highlight the utility of the trabecular bone score and hip structural analysis in subjects with diabetes, where the bone mineral density tends to be paradoxically high, and may not adequately predict fracture risk.

Adipose tissue density on CT as a prognostic factor in patients with cancer: a systematic review.

BACKGROUND: Predicting oncologic outcomes is essential for optimizing the treatment for patients with cancer. This review examines the feasibility of using Computed Tomography (CT) images of fat density as a prognostic factor in patients with cancer. METHODS: A systematic literature search was performed in PubMed, Embase and Cochrane up to March 2020. All studies that mentioned using subcutaneous or visceral adipose tissue (SAT and VAT, respectively) CT characteristics as a prognostic factor for patients with cancer were included. The primary endpoints were any disease-related outcomes in patients with cancer. RESULTS: After screening 1043 studies, ten studies reporting a total of 23 - ten for SAT and thirteen for VAT - comparisons on survival, tumor recurrence and postsurgical infection were included. All ten studies included different types of malignancy: six localized, two metastatic disease, and two both. Five different anatomic landmarks were used to uniformly measure fat density on CT: lumbar (L)4 (n = 4), L3 (n = 2), L4-L5 intervertebral space (n = 2), L5-S1 intervertebral space (n = 1), and the abdomen (n = 1). Overall, six of ten SAT comparisons (60%) and six of thirteen VAT comparisons (46%) reported a significant (p < .05) association of increased SAT or VAT density with an adverse outcome. All remaining nonsignificant comparisons, except one, deviated in the same direction of being predictive for adverse outcomes but failed to reach significance. The median hazard ratio (HR) for the nine SAT and thirteen VAT associations where HRs were given were 1.45 (95% confidence interval [CI] 1.01-1.97) and 1.90 (95% CI 1.12-2.74), respectively. The binomial sign test and Fisher's method both reported a significant association between both SAT and VAT and adverse outcomes. CONCLUSION: This review may support the feasibility of using SAT or VAT on CT as a prognostic tool for patients with cancer in predicting adverse outcomes such as survival and tumor recurrence. Future research should standardize radiologic protocol in prospective homogeneous series of patients on each cancer diagnosis group in order to establish accurate parameters to help physicians use CT scan defined characteristics in clinical practice.

Vitamin D assessment and precision of clinical referrals: Insights gained from a teaching hospital in southern India.

OBJECTIVE: Vitamin D deficiency is widely prevalent worldwide. This has led to a significant surge in referrals for vitamin D assessment in recent years. The cost-effectiveness and rationalization of this practice is uncertain. This study aimed to evaluate the referral pattern for vitamin D testing from a tertiary center in southern India. MATERIALS AND METHODS: This was a cross-sectional study done over a period of one year (2017). A total of 95,750 individuals, referred for vitamin D screening were included in this study. Details regarding referring departments and indications for referral were obtained from the computerized hospital information processing system (CHIPS). RESULTS: The study population exhibited a female preponderance (54.1%) with mean (SD) age of 40.3 (18.5) years. Overall, 44% were found to have vitamin D deficiency. Most of the referrals were from nephrology (15.4%), neurology (10.1%), and orthopedics (9.1%). Nevertheless, dermatology, the staff-clinic, and hematology which contributed to 3.3%, 1.7%, and 1.7% of referrals, had a higher proportion of vitamin D deficiency of 59.1%, 57.7%, and 64.6%, respectively. Although the most common indications for referral were generalized body aches (20.5%) and degenerative bone disorders (20.1%), the proportion of subjects with vitamin D deficiency referred for these indications were 46.1% and 41.6%, respectively. In contrast, chronic steroid use that accounted for 3.3% of the referrals had 59.1% of subjects who were deficient in vitamin D. CONCLUSION: To ensure a rational approach to vitamin D testing, clinicians ought to use their discretion to screen those truly at risk for vitamin D deficiency on a case to case basis and avoid indiscriminate testing of the same.

Improvement over time in outcomes for patients undergoing endoscopic therapy for Barrett's oesophagus-related neoplasia: 6-year experience from the first 500 patients treated in the UK patient registry.

BACKGROUND: Barrett's oesophagus (BE) is a pre-malignant condition leading to oesophageal adenocarcinoma (OAC). Treatment of neoplasia at an early stage is desirable. Combined endoscopic mucosal resection (EMR) followed by radiofrequency ablation (RFA) is an alternative to surgery for patients with BE-related neoplasia. METHODS: We examined prospective data from the UK registry of patients undergoing RFA/EMR for BE-related neoplasia from 2008 to 2013. Before RFA, visible lesions were removed by EMR. Thereafter, patients had RFA 3-monthly until all BE was ablated or cancer developed (endpoints). End of treatment biopsies were recommended at around 12 months from first RFA treatment or when endpoints were reached. Outcomes for clearance of dysplasia (CR-D) and BE (CR-IM) at end of treatment were assessed over two time periods (2008-2010 and 2011-2013). Durability of successful treatment and progression to OAC were also evaluated. RESULTS: 508 patients have completed treatment. CR-D and CR-IM improved significantly between the former and later time periods, from 77% and 56% to 92% and 83%, respectively (p<0.0001). EMR for visible lesions prior to RFA increased from 48% to 60% (p=0.013). Rescue EMR after RFA decreased from 13% to 2% (p<0.0001). Progression to OAC at 12 months is not significantly different (3.6% vs 2.1%, p=0.51). CONCLUSIONS: Clinical outcomes for BE neoplasia have improved significantly over the past 6 years with improved lesion recognition and aggressive resection of visible lesions before RFA. Despite advances in technique, the rate of cancer progression remains 2-4% at 1 year in these high-risk patients. TRIAL REGISTRATION NUMBER: ISRCTN93069556.

Status of DDT and pyrethroid resistance in Indian Aedes albopictus and absence of knockdown resistance (kdr) mutation.

BACKGROUND & OBJECTIVES: Aedes albopictus is one of the vectors for dengue and chikungunya and emergence of pyrethroid resistance in this species could be of a major concern in controlling the vector. This study reports insecticide susceptibility status of Ae. albopictus to DDT and pyrethroids in some Indian populations and status of presence of knockdown resistance (kdr) mutations. METHODS: Three to four day old adult female Ae. albopictus collected from Delhi, Gurgaon (Haryana), Hardwar (Uttarakhand), Guwahati (Assam) and Kottayam (Kerala) were bio-assayed with DDT (4%), permethrin (0.75%) and deltamethrin (0.05%) impregnated papers using WHO standard susceptibility test kit. Mosquitoes were PCRgenotyped for F1534C kdr-mutation in the voltage-gated sodium channel (VGSC) gene. DDT and pyrethroid resistant individuals were sequenced for partial domain II, III and IV of VGSC targeting residues S989, I1011, V1016, F1534 and D1794 where kdr mutations are reported in Ae. aegypti. RESULTS: Adult bioassays revealed varying degree of resistance against DDT among five populations of Ae. albopictus with corrected mortalities ranging between 61 and 92%. Kerala and Delhi populations showed incipient resistance against permethrin and deltamethrin respectively. All other populations were susceptible for both the synthetic pyrethroids. None of the kdr mutations was detected in any of DDT, deltamethrin and permethrin resistant individuals. INTERPRETATION & CONCLUSION: Ae. albopictus has developed resistance against DDT and there is emergence of incipient resistance against pyrethroids in some populations. So far, there is no evidence of presence of knockdown resistance (kdr) mutation in Ae. albopictus.

Endoscopic ablation of Barrett's neoplasia with a new focal radiofrequency device: initial experience with the Halo60.

Radiofrequency ablation (RFA) is an accepted treatment for the eradication of dysplastic Barrett's esophagus (DBE) and residual Barrett's esophagus after endoscopic resection of intramucosal adenocarcinoma. Circumferential balloon-based and focal catheter-based RFA devices are currently used (the Halo360 and Halo90). However, a new smaller focal ablation device (the Halo60) has been developed, which may be of benefit in patients with short tongues of Barrett's neoplasia, small residual islands, difficult anatomy, or strictures. We report the first use of this device in 17 patients with either DBE or residual Barrett's esophagus after endoscopic resection of intramucosal adenocarcinoma.

T lymphocytes with a normal ADA gene accumulate after transplantation of transduced autologous umbilical cord blood CD34+ cells in ADA-deficient SCID neonates.

Adenosine deaminase-deficient severe combined immunodeficiency was the first disease investigated for gene therapy because of a postulated production or survival advantage for gene-corrected T lymphocytes, which may overcome inefficient gene transfer. Four years after three newborns with this disease were given infusions of transduced autologous umbilical cord blood CD34+ cells, the frequency of gene-containing T lymphocytes has risen to 1-10%, whereas the frequencies of other hematopoietic and lymphoid cells containing the gene remain at 0.01-0.1%. Cessation of polyethylene glycol-conjugated adenosine deaminase enzyme replacement in one subject led to a decline in immune function, despite the persistence of gene-containing T lymphocytes. Thus, despite the long-term engraftment of transduced stem cells and selective accumulation of gene-containing T lymphocytes, improved gene transfer and expression will be needed to attain a therapeutic effect.

Prevalence of cirrhotic cardiomyopathy and its relationship with serum pro-brain natriuretic peptide, hepatorenal syndrome, spontaneous bacterial peritonitis, and mortality.

OBJECTIVES: This study aims at estimating the prevalence of cirrhotic cardiomyopathy in a cohort of cirrhosis patients in northern India using the World Congress of Gastroenterology 2005 criteria and its relationship with grades of cirrhosis, its complications, and all-cause mortality. METHODS: This was a prospective study in which 53 cirrhosis patients underwent the 2D color Doppler, and tissue Doppler echocardiography. Echocardiography findings were compared with thirty age- and sex-matched healthy controls. Additionally, serum pro-brain natriuretic peptide (pro-BNP) and troponin-T levels were measured. Patients were followed up for 6 months to look for complications and mortality. RESULT: 2D echocardiography findings revealed that diastolic cardiomyopathy with no gross systolic dysfunction was significantly prevalent in cirrhosis patients. Using the Montreal criteria, we found the incidence of diastolic cardiomyopathy to be 56.6%. Tissue Doppler echocardiography findings were also correlated. Diastolic dysfunction correlated with the severity of cirrhosis, and patients with higher Child score had more diastolic dysfunction. Serum pro-BNP levels and QTc interval were also higher in patients with diastolic dysfunction. On survival analysis, patients with cirrhotic cardiomyopathy had shorter survival and greater frequency of encephalopathy and hepatorenal syndrome (HRS) episodes as compared with cirrhotic patients without cardiomyopathy, though the differences were not statistically significant. CONCLUSION: The study showed that diastolic dysfunction was highly prevalent (56.6% of the study population) in cirrhosis patients. QTc interval and pro-BNP were also significantly raised. Also, complications of cirrhosis like HRS, spontaneous bacterial peritonitis, and hepatic encephalopathy were more common in the cirrhotic cardiomyopathy group.

Unrelated donor hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis.

We report outcomes after unrelated donor hematopoietic cell transplantation (HCT) for 91 patients with hemophagocytic lymphohistiocytosis (HLH) transplanted in the US in 1989-2005. Fifty-one percent were <1 year at HCT and 29% had Lansky performance scores<90%. Most (80%) were conditioned with BU, CY, and etoposide (VP16) with or without anti-thymocyte globulin. Bone marrow was the predominant graft source. Neutrophil recovery was 91% at day-42. The probabilities of grades 2-4 acute GVHD at day-100 and chronic GVHD at 5 years were 41 and 23%, respectively. The overall mortality rate was higher in patients who did not receive BU/CY/VP16-conditioning regimen (RR 1.95, P=0.035). The 5-year probability of overall survival was 53% in patients who received BU/CY/VP16 compared to 24% in those who received other regimens. In the subset of patients with known disease-specific characteristics, only one of five patients with active disease at HCT is alive. For those in clinical remission at HCT (n=46), the 5-year probability of overall survival was 49%. Early mortality rates after HCT were high, 35% at day-100. These data demonstrate that a BU/CY/VP16-conditioning regimen provides cure in approximately 50% of patients and future studies should explore strategies to lower early mortality.

Rapidly deteriorating renal function with membranoproliferative glomerulonephritis Type 1 associated with hepatitis C treated successfully with steroids and antiviral therapy: a case report and review of literature.

INTRODUCTION: The hepatitis C virus (HCV) infection is associated with several renal diseases including mixed essential cryoglobulinemia, membranoproliferative glomerulonephritis (MPGN) and less frequently membranous nephropathy and crescentic glomerulonephritis. We present a case of HCV-associated cryoglobulin-negative, MPGN Type 1 with features of early crescents and rapidly deteriorating renal function requiring urgent treatment. CASE: A 35-year-old male was admitted with history of arthralgia and erythematous rash. His past medical history included being an intravenous drug abuser. Biochemistry test showed raised serum creatinine of 150 micromol/l. He had nephrotic range proteinuria of 6 g/day and a serum albumin of 23 g/l. Viral serology for hepatitis B and HIV was negative but confirmed evidence of HCV infection with genotype 3A and viral load of 151,014 copies. He had a renal biopsy and histology demonstrated features of crescentic MPGN Type 1. His renal function deteriorated rapidly with his serum creatinine rising to 300 micromol/l over 2 days. We commenced treatment with intravenous methylprednisolone, 500 mg once daily (o.d.) for 3 days, followed by oral prednisolone 40 mg o.d. Concurrently, pegylated Interferon- (IFN) I+/- was commenced. After a 2-week treatment, his renal function showed remarkable recovery with creatinine reduced to 140 micromol/l. After 3 months, ribavirin was added when his renal function remained stable. He had tolerated his treatment without any major side effects. At 6 months follow-up clinic, his renal function was normal with serum creatinine of 69 micromol/l, 24-h urinary protein had dropped to 0.35 g/day, serum albumin increased to 38 g/l and HCV PCR was negative. DISCUSSION: The current treatment strategy of HCV-associated renal diseases includes targeting viral trigger HCV with interferon and ribavirin. Both IFN-I+/- and ribavirin have their limitation and adverse effects. In a clinical scenario where there is evidence of rapidly deteriorating renal function with crescentic glomerulonephritis, cautious use of immunosuppressive therapy may well be essential in the acute stage to halt the progression of kidney damage. Literature review of the treatment strategy for MPGN Type 1, cryoglobulin-negative with early features of crescents associated with HCV showed that there was no report or guideline available. CONCLUSIONS: To our knowledge, this is the first case in the literature of rapidly progressing MPGN Type 1 associated with HCV and nephrotic syndrome treated successfully with antiviral drugs and steroids concurrently. Our case highlights an important treatment strategy and may be beneficial to nephrologists facing this clinical scenario in the future. However, a randomized controlled trial is required to evaluate the efficacy of this treatment combination before it can be a standard treatment.

Defective expression of T cell-associated glycoprotein in severe combined immunodeficiency.

A T cell surface membrane-associated glycoprotein, Tp40 (40,000 mol wt), also designated as CD-7, was not expressed by the T cells of a patient with severe combined immunodeficiency. In addition to this abnormality, T cell proliferative responses to mitogens were defective and the IL-2 receptor expression was deficient on the patient's T lymphocytes. However, his T cells were found to provide help for the differentiation of normal B cells to Ig-secreting cells. Abundant circulating B cells were detected. These B cells proliferated normally in the presence of anti-mu antibodies and B cell growth factors, but did not differentiate into antibody-secreting cells when provided with the help of normal T cells. In addition, his activated B cells did not proliferate to IL-2 even though IL-2 receptors were expressed. A successful allogeneic histocompatible bone marrow transplantation resulting in T cell engraftment corrected both the T and B cell immunodeficiencies. These findings support the hypothesis that the Tp40 deficiency present in this patient is related to a defect of the T cell precursors, and that Tp40 plays important roles not only essential to T cell interactions but also to certain aspects of T-B cell interaction during the early lymphoid development.

Remote ischemic preconditioning attenuates EGR-1 expression following myocardial ischemia reperfusion injury through activation of the JAK-STAT pathway.

BACKGROUND/OBJECTIVES: Remote ischemic preconditioning (RIPC) protects the myocardium from ischemia/reperfusion (I/R) injury however the molecular pathways involved in cardioprotection are yet to be fully delineated. Transcription factor Early growth response-1 (Egr-1) is a key upstream activator in a variety of cardiovascular diseases. In this study, we elucidated the role of RIPC in modulating the regulation of Egr-1. METHODS: This study subjected rats to transient blockade of the left anterior descending (LAD) coronary artery with or without prior RIPC of the hind-limb muscle and thereafter excised the heart 24h following surgical intervention. In vitro, rat cardiac myoblast H9c2 cells were exposed to ischemic preconditioning by subjecting them to 3cycles of alternating nitrogen-flushed hypoxia and normoxia. These preconditioned media were added to recipient H9c2 cells which were then subjected to 30min of hypoxia followed by 30min of normoxia to simulate myocardial I/R injury. Thereafter, the effects of RIPC on cell viability, apoptosis and inflammatory markers were assessed. RESULTS: We showed reduced infarct size and suppressed Egr-1 in the heart of rats when RIPC was administered to the hind leg. In vitro, we showed that RIPC improved cell viability, reduced apoptosis and attenuated Egr-1 in recipient cells. CONCLUSIONS: Selective inhibition of intracellular signaling pathways confirmed that RIPC increased production of intracellular nitric oxide (NO) and reactive oxygen species (ROS) via activation of the JAK-STAT pathway which then inactivated I/R-induced ERK 1/2 signaling pathways, ultimately leading to the suppression of Egr-1.

Radiation-free preparation for allogeneic bone marrow transplantation in adults with acute lymphoblastic leukemia.

PURPOSE: The study was undertaken to investigate the effectiveness of allogeneic bone marrow transplantation from HLA-identical siblings after preparation with busulfan and cyclophosphamide in adults with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Thirty-nine patients aged 15 to 42 years underwent transplantation at three different centers from November 1984 through November 1990. All patients received 16 mg/kg busulfan and 120 mg/kg cyclophosphamide as preparative therapy. Cyclosporine plus methotrexate or cyclosporine plus corticosteroids with or without methotrexate were given for prevention of graft-versus-host disease (GVHD). RESULTS: Twelve patients died of treatment-related complications, 12 patients relapsed, and 15 patients are leukemia-free survivors. For 27 patients in group 1 (first remission, second remission, first relapse), the estimated leukemia-free survival (LFS) rate is 42.3% (95% confidence interval [CI], 22.9% to 71.7%) at 3 years. For 12 patients with more advanced disease (group 2), the 1-year LFS rate is 13.5% (95% CI, 0% to 37.1%). Chronic GVHD occurred at an estimated incidence of 63.3% and developed significantly more frequently among patients who received corticosteroids for prevention of acute GVHD. Chronic GVHD was associated with a significantly lower incidence of relapse and with improved LFS rates. CONCLUSION: LFS rate in this study is comparable to that obtained with radiation-containing regimens; however, the effectiveness of this preparative regimen in ALL requires further study.

Specific inhibitory activity against granulocyte-progenitor cells produced by non-T lymphocytes from patients with neutropenia.

Bone marrow and peripheral blood cells of patients with non-leukemic neutropenia contain and elaborate a granulocyte-progenitor cell inhibitory activity. The inhibitory activity is common to the neutropenias of the various etiologies studied, which included congenital, idiopathic, autoimmune, cyclical, common variable immuno-deficiency with hypogammaglobulinemia and drug induced states. It derives from non-adherent, low density, slowly sedimenting and non-E-rosetting cells and appears to require RNA and protein synthesis, but not cell division, for its production. The material is not species specific, inhibits autologous and allogeneic normal CFUgm and leukemic CFUgm, is not cell-cycle specific in action and is most effective against granulocyte colony forming cells (CFUg), less effective against mixed granulocyte-macrophage colony forming cells (CFUgm) and least or non-effective against macrophage colony forming cells (CFUm). This inhibitory activity has no influence on cells which generate CFUc in suspension culture or on the erythroid colony forming (CFUe) and burst forming (BFUe) units. It is different from other known inhibitory activities such as lactoferrin, leukemia inhibitory activity, E type prostaglandins, interferon and immunoglobulins. This inhibitory activity, while at present an in vitro phenomenon, may be produced as a secondary response within a compromised host.

Hematopoietic stem cell transplantation for primary lymphoid immunodeficiencies.

Hematopoietic stem cell (HSC) transplantation is curative therapy for many primary immunodeficiencies. All forms of severe combined immune deficiency (SCID) can be cured, but the extent of the immunologic correction is dependent on the pathophysiology of the primary defect. Defects involving lymphocyte differentiation are more easily corrected than defects in lymphocyte function because a selective advantage exists for the progeny of the normal donor HSC when the primary defect affects lymphocyte differentiation. T-cell-depleted (TCD), haploidentical-HSC transplantation can cure many forms of SCID, but not other primary immunodeficiencies like the Wiskott-Aldrich syndrome (WAS). Unrelated bone marrow and umbilical cord blood are alternative sources of HSC for patients who do not have histocompatible donors.

Conformational transitions in serum high density apoproteins of hypercholesterolemic monkeys.

Conformational transitions in serum high density apolipoproteins of normal and hypercholesterolemic monkeys have been studied by circular dichroism. This study has revealed that under hypercholesterolemic conditions the secondary structure of apolipoproteins suffers permanent changes which could be observed even after a lengthy procedure of isolation, purification and delipidation of high density lipoprotein.

Allogeneic bone marrow transplantation for acute myelogenous leukemia, acute lymphocytic leukemia, and multiple myeloma following preparation with busulfan and cyclophosphamide (BuCy2).

The combination of busulfan (Bu) and cyclophosphamide (Cy) has been found to be effective preparative therapy for patients treated with allogeneic bone marrow transplantation (BMT). We developed the BuCy2 regimen, which contains a lower dose of cyclophosphamide than the original BuCy regimen, in the hope of reducing regimen-related toxicities. We have studied the use of BuCy2 as preparation for allogeneic BMT in patients with acute myelogenous leukemia, acute lymphocytic leukemia, and multiple myeloma. In patients with acute myelogenous leukemia, the leukemia-free survival and regimen-related toxicity rates obtained in our study appear similar to those achieved with other preparative regimens, including those containing Cy and total body irradiation (TBI). BuCy2 is also an effective BMT preparative regimen in patients with acute lymphocytic leukemia and multiple myeloma. Treatment with BuCy2 results in a lower incidence of severe stomatitis and probably of interstitial pneumonia than does treatment with Cy/TBI, but hepatic veno-occlusive disease occurs more frequently in BuCy-treated patients. The incidence of veno-occlusive disease appears to be affected by agents used as prophylaxis for graft-versus-host disease. Compared with Cy/TBI regimens, BuCy treatment is likely to result in fewer delayed effects of treatment, such as impairment of fertility and second malignancies. Current clinical efforts are focusing on ways to improve the antileukemic activity of the BuCy preparative regimen and to reduce regimen-related toxicities.

Marrow transplantation for juvenile osteopetrosis.

Two children with the juvenile form of osteopetrosis were treated with marrow transplants from their HLA identical siblings. Following transplantation each child exhibited extensive bone reabsorption with a marked augmentation of osteoclastic function attributable to donor osteoclasts, including remodeling of bone with expansion of intramedullary hematopoiesis and correction of associated abnormalities of thymic factor and natural killer cells. Osteopetrosis ultimately recurred in one patient in whom engraftment of donor hematopoietic elements was not achieved. Our studies indicate that marrow transplantation will correct osteopetrosis but that permanent reconstitution necessitates sustained engraftment of marrow precursors of cells with osteoclastic activity.

Hyperfractionated total body irradiation for bone marrow transplantation. Results in seventy leukemia patients with allogeneic transplants.

From May, 1979 to March, 1981, 76 leukemia patients were prepared for bone marrow transplantation (BMT) with a new hyperfractionated total body irradiation (TBI) regimen (1320 cGy in 11 fractions, 3x/day), followed by cyclophosphamide, 60 mg/kg, for two days. Partial lung shielding was done on each treatment, with supplemental electron beam treatments of the chest wall to compensate, and of the testes, a sanctuary site. This regimen was initiated to potentially reduce fatal interstitial pneumonitis as well as decrease leukemic relapse. These patients were analyzed in May, 1982, for a minimum follow-up of 14 months. Overall actuarial survival at 1 year for acute non-lymphocytic leukemia (ANLL) patients is 63%, while relapse-free survival at 1 year is 53%. For those ANLL patients who underwent BMT while in remission (first, second, and third combined), relapse-free survival is 61% at 1 year compared with 40% for those patients who had their BMT at the time of relapse (greater than or equal to 10% blasts in marrow). On the other hand, for acute lymphocytic leukemia (ALL) patients, there is no significant difference between relapse or remission patients with regard to overall survival or relapse-free survival, when relapse is defined as greater than 5% blasts in the marrow at the time of cytoreduction. Overall actuarial survival at 1 year for ALL is 61% and relapse-free survival is 45% at 1 year. Patients with ALL who had their BMT cytoreduction at the time of relapse have a survival equal to that of our remission patients, and greater than that of patients in relapse cytoreduced with a single dose as reported by others. However, patients with greater than or equal to 10% blasts have not fared as well, having only a 22% 1 year relapse-free survival compared with a 68% 1 year relapse-free survival for patients with less than 10% blasts. Fatal interstitial pneumonitis has dropped to 18% compared with 50% in our previous single-dose TBI regimen (1000 cGy), in which the same doses of cyclophosphamide were given prior to TBI. In conclusion, not only has fatal interstitial pneumonitis been reduced by hyperfractionation and partial lung blocking, but there may be a survival advantage in ALL patients in relapse, who have a survival equal to that of remission patients. This may indicate a greater cell kill with the higher dose (1320 cGy) attained with this regimen, in these patients with a higher leukemic cell burden.