Correction: Population pharmacokinetics of fludarabine in patients with aplastic anemia and Fanconi anemia undergoing allogeneic hematopoietic stem cell transplantation.

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Long-term outcome of mixed chimerism after stem cell transplantation for thalassemia major conditioned with busulfan and cyclophosphamide.

Mixed chimerism (MC) occurs frequently after allogeneic hematopoietic stem cell transplantation (HSCT) for thalassemia major (TM) and may be associated with rejection. We report the outcome of MC in 132 TM patients conditioned with Busulphan/Cyclophosphamide, who had successful engraftment and had ⩾1 year follow-up. Chimerism was first assessed at day +28, then every 3-9 months or more frequently if there was MC. If rejection was suspected, immunosuppression was stopped and donor-lymphocyte infusion (DLI) was given if there was no response. Among 132 patients, aged 7 years (range: 2-24), 46/132 (34.8%) had MC in the first year, 32/46 (69.6%) at day +28 and another 14 (30%) between day +28 and 1 year post HSCT. MC was quantified at level 1 (residual host chimerism (RHC) <10%) in 20 (43.5%), level II (RHC 10-25%) in 14 (30.4%) and level III (RHC >25%) in 12 (26.1%). On tapering immunosuppression, 15 (32.6%) developed acute GvHD and 8 (17.4%) had chronic GvHD with reversal to complete chimerism (CC). DLI was administered to 5/46 (10.9%), 1 evolved to CC but 4 rejected the graft. At median follow-up of 60 months (range: 16-172), 20/46 (43.5%) had CC, 18/46 (39.1%) had persistent MC with hemoglobin of 11.5 g/dL (range: 8.4-13.6), whereas 8 (17.4%) rejected the graft. Close monitoring and early intervention is needed with increasing recipient chimerism. Novel strategies are required for preventing graft rejection.

Population pharmacokinetics of fludarabine in patients with aplastic anemia and Fanconi anemia undergoing allogeneic hematopoietic stem cell transplantation.

Although hematopoietic stem cell transplantation (HSCT) with a conditioning regimen consisting of fludarabine (F-araA) and cyclophosphamide (Cy) is associated with improved outcome in young patients with aplastic anemia (AA) and Fanconi anemia (FA), several factors limit the success of the procedure. We evaluated the population pharmacokinetics (POPPK) of F-araA and its influence on HSCT outcome in patients (n=53) with AA and FA undergoing HSCT. Patients carrying a 5'-UTR polymorphism in NT5E gene (rs2295890 G>C) exhibited significantly lower plasma F-araA clearance compared to those with wild-type genotype (7.12 vs 5.03 L/h/m2 (29%) P<0.05). F-araA clearance was significantly higher in patients with AA compared to FA (2.46 ×, P<1e-6). Of all the outcome parameters evaluated (engraftment, rejection/graft failure, GvHD, TRM, OS), high F-araA AUC (>29.4 µm*h) was the only significant factor associated with the development of aGvHD by both univariate and multivariate analysis (P=0.02). The influence of plasma F-araA levels need to be evaluated in a larger cohort of patients to propose the need for therapeutic drug monitoring.

Rationale and efficacy of proteasome inhibitor combined with arsenic trioxide in the treatment of acute promyelocytic leukemia.

Arsenic trioxide (ATO) mediates PML-RARA (promyelocytic leukemia-retinoic acid receptor-α) oncoprotein degradation via the proteasome pathway and this degradation appears to be critical for achieving cure in acute promyeloytic leukemia (APL). We have previously demonstrated significant micro-environment-mediated drug resistance (EMDR) to ATO in APL. Here we demonstrate that this EMDR could be effectively overcome by combining a proteasome inhibitor (bortezomib) with ATO. A synergistic effect on combining these two agents in vitro was noted in both ATO-sensitive and ATO-resistant APL cell lines. The mechanism of this synergy involved downregulation of the nuclear factor-κB pathway, increase in unfolded protein response (UPR) and an increase in reactive oxygen species generation in the malignant cell. We also noted that PML-RARA oncoprotein is effectively cleared with this combination in spite of proteasome inhibition by bortezomib, and that this clearance is mediated through a p62-dependent autophagy pathway. We further demonstrated that proteasome inhibition along with ATO had an additive effect in inducing autophagy. The beneficial effect of this combination was further validated in an animal model and in an on-going clinical trial. This study raises the potential of a non-myelotoxic proteasome inhibitor replacing anthracyclines in the management of high-risk and relapsed APL.

Adefovir nephrotoxicity in a renal allograft recipient.

Adefovir dipivoxil, an oral prodrug of adefovir, is used in the treatment of lamivudine-resistant hepatitis B virus (HBV) infection. Nephrotoxicity manifesting as proximal renal tubular dysfunction and acute tubular necrosis (ATN) were commonly reported in the past, when higher doses were used for the treatment of human immunodeficiency virus infection. However, nephrotoxicity is rare at lower doses that are currently recommended for the treatment of HBV infection. A 31-year-old female was detected to be hepatitis B surface antigen positive months after a kidney transplant. The patient was initiated on lamivudine, but developed resistance after 1 year of treatment, at which time low-dose adefovir was added. The patient developed renal allograft dysfunction after 10 months of starting adefovir. Serum creatinine increased from 1.1 mg/dl to 1.9 mg/dl, along with progressively increasing sub-nephrotic proteinuria. Renal allograft biopsy revealed features of ATN. After discontinuation of adefovir, proteinuria resolved and renal dysfunction improved slowly over the next 2 years. Adefovir-induced nephrotoxicity, although uncommon at lower doses, needs to be considered in the differential diagnosis of renal dysfunction and sub-nephrotic proteinuria occurring in patients receiving adefovir for prolonged periods.

Collapsing glomerulopathy following anabolic steroid use in a 16-year-old boy with IgA nephropathy.

Collapsing glomerulopathy (CG) is a proliferative podocytopathy, increasingly recognized in a variety of disease conditions. We report a case of CG in a 16-year-old boy with IgA nephropathy (IgAN) who presented with acute kidney injury, marked proteinuria and hypertension following a short period of anabolic steroid use. Although CG has been associated with long-term anabolic steroid use among body builders, there is no data on the effect of anabolic steroid use in persons with underlying renal disease like IgAN. We postulate that development of CG in our patient could be temporally linked to intake of body-building steroids along with a predisposing background renal disease of IgAN.

Immunoglobulin G4-related tubulointerstitial nephritis associated with interstitial pulmonary disease: Report of a case with review of literature.

Immunoglobulin G4-related disease (IgG4-RD) is an emerging clinicopathological entity. Renal involvement is dominated by tubulointerstitial nephritis (TIN) with IgG4-positive plasma cells and fibrosis. IgG4-RD commonly affects middle-aged to elderly men with accompanying extra-renal lesions such as sialadenitis, lymphadenopathy, or type 1 autoimmune pancreatitis, all of which respond favorably to corticosteroid therapy. The disease burden of IgG4-related kidney disease (IgG4-RKD) in India remains largely underestimated. We report a case of IgG4-RKD manifesting as TIN associated with interstitial pulmonary disease, illustrating typical clinico-pathologic, serologic, immuno-histochemical, and ultrastructural features of this condition. In view of potential amelioration of renal dysfunction with appropriate therapy, the need for awareness of this condition and early diagnosis is highlighted.

Clinicopathologic features of non-small cell lung cancer in India and correlation with epidermal growth factor receptor mutational status.

INTRODUCTION: We performed retrospective analysis of 106 patients with lung cancer for which formalin-fixed paraffin-embedded tissues was available. Their epidermal growth factor receptor (EGFR) mutation status and treatment outcomes are described. MATERIALS AND METHODS: All patients with confirmed non-small cell lung cancer (NSCLC) during Jan 2008 to Dec 2010 were included. EGFR sequencing was performed with ABI PRISM 310 genetic analyzer. RESULTS: Forty-two (39.6%) patients had mutation in one of the four exons characterized. Patients whose EGFR mutational status was not available at presentation before the start of treatment were started on chemotherapy, n = 46 (43.39%). If EGFR mutational analysis was available and mutations were present, the patients were started on either upfront tyrosine kinase inhibitor (TKI), n = 15 (14.15%) or if on chemotherapy arm were allowed to finish six cycles and then start with maintenance TKIs, n = 26 (24.52%). The median progression free survival for patients with and without mutations was 11 months (95% CI,7-14) and 9 months (95% CI,7-10) respectively. A median PFS of 14 months (95%CI, 12-16) was seen in the mutation-positive group that received both chemotherapy followed by switch maintenance with TKIs versus 8 months (95%CI, 7-8 months) in the group that received only TKI. CONCLUSION: The prevalence of EGFR mutations in this population of NSCLC patients was 39.6% with exon 19 mutation being the most common. The observed benefit of addition of chemotherapy over TKI in EGFR mutation-positive group raises the question, can we offer the therapy of chemotherapy-TKI combination to EGFR mutation-positive lung cancer patients as shown in the present study.

Primary intrarenal teratoma in an adult: A case report and review of literature.

A 35-year-old male presented with left loin pain. On evaluation, he was diagnosed to have a left renal lower polar mass. He underwent partial nephrectomy. The histopathological examination was suggestive of teratoma of the kidney. We present this case, as intrarenal teratomas in adults are extremely rare and only a very few cases are reported in literature.

Primary mediastinal synovial sarcoma with transdiaphragmatic extension presenting as a pericardial effusion.

Synovial sarcoma is a distinctive soft tissue neoplasm, most commonly seen in the extremities of young adults. Mediastinal synovial sarcoma is a well-documented entity; however, in many cases, the differentiation between this and other spindle cell tumours may be difficult, especially in monophasic tumours. Unlike most pleuropulmonary synovial sarcomas which are well circumscribed, mediastinal tumours are often infiltrative and resection may not be adequate, leading to a high rate of recurrence. We present a 49-year-old man with a primary pericardial synovial sarcoma, with transdiaphragmatic intra-abdominal extension, which clinically, radiologically and grossly mimicked a tuberculous pericarditis.

Malignant phyllodes tumour with intraductal and invasive carcinoma and lymph node metastasis.

Phyllodes tumours constitute 2-3 percent of fibroepithelial breast tumours, with a 1-2 percent rate of malignancy. Metastasis is usually haematogeneous, and axillary lymph node dissection is not routinely performed. Carcinoma in a phyllodes tumour is distinctly uncommon, but has been known to occur in benign phyllodes tumours. We describe a 51-year-old woman with a malignant phyllodes tumour with foci of intraductal carcinoma within the tumour and adjacent breast tissue. Though the carcinoma was found to be invasive based on the presence of carcinomatous lymph node metastasis, extensive sampling did not yield an invasive component within the breast, probably because of the marked stromal overgrowth of the phyllodes. A malignant phyllodes tumour with foci of intraductal carcinoma and axillary lymph node metastases was diagnosed rather than carcinosarcoma. Chemotherapy and irradiation were included in the postoperative management. Coexistence of phyllodes tumour and carcinoma is rare, and extensive sampling may be necessary to find the foci of carcinoma within an extensive and obviously malignant stromal overgrowth. There is little consensus on the treatment and prognosis in these cases, and it is recommended that treatment be tailored to individual patients, based on the presence of invasion, lymph node metastasis and/or distant metastasis.

Outcomes of renal transplantation in patients with immunoglobulin A nephropathy in India.

BACKGROUND: There is a paucity of data on the course of renal transplant in patients with immunoglobulin A (IgA) nephropathy (IgAN) from India. While the natural history of IgAN in the Indian context is rapidly progressive, the post-transplant course remains speculative. AIM: To study the graft survival in renal transplant recipients whose native kidney disease was IgAN and the incidence and correlates of recurrent disease. SETTINGS AND DESIGNS: Retrospective case control study from a Nephrology unit of a large tertiary care center. MATERIALS AND METHODS: The outcomes of 56 transplant patients (58 grafts) with biopsy-proven IgAN and of 116 patients without IgAN or diabetic nephropathy, transplanted during the same period were analyzed. Correlates of biopsy-confirmed recurrent disease were determined. STATISTICAL ANALYSIS: Means were analyzed by Student's t test and Mann-Whitney test; proportions were determined by Chi-square analysis and graft survival curves were generated using the Kaplan-Meier. RESULTS: Five-year graft survival for IgA patients was not significantly different from that in the reference group (90% and 79%, P = 0.6). During a mean follow-up of 42 months (range, 1-144), 28 event graft biopsies were required in 20 grafts of IgAN. Histological recurrence was diagnosed in five of the 20 available biopsies (25%) after a mean duration of 28 months. Recurrence did not correlate with donor status, HLA B35 and A2, recipient age, gender or immunosuppression. CONCLUSIONS: Renal transplantation is an appropriate treatment modality for IgA nephropathy patients with end-stage renal disease in India, despite the potential for recurrent disease. The posttransplant course is an indolent one when compared to the malignant pretransplant phase.

Spectrum of severe chronic kidney disease in India: a clinicopathological study.

BACKGROUND: The healthcare burden due to chronic kidney disease has increased worldwide in the past decade. Elucidating the aetiology of chronic kidney disease may help in identifying strategies for prevention, both in the population and the Individual patient. Only a clinicopathological study can define the exact spectrum of chronic kidney disease since epidemiological studies have not shown a consistent aetiological profile. The histological evidence used to support the diagnosis varies with the degree to which renal biopsy is done. Renal biopsy is the gold standard in making an aetiological diagnosis in renal failure, but as a diagnostic tool in chronic kidney disease it is underutilized. METHODS: This prospective study done at Christian Medical College, Vellore in southern India from 1998 to 2003 aimed to determine the aetiological profile of severe chronic kidney disease by analysing renal biopsies. The value of pre-renal biopsy clinical Judgement in predicting the histological diagnosis was also assessed. Patients with diabetic nephropathy were excluded from the study. RESULTS: Four hundred and fifty-seven patients had evidence of chronic kidney disease as evidenced on biopsy as well as on clinical parameters. Three hundred and twenty-two of these patients (70.5%) had glomerulonephritis as the histological diagnosis. Fifty-five (12%) had Interstitial nephritis, 30 (6.6%) had hypertensive arteriosclerosis and 28 (6.1%) had metabolic nephropathies. The positive predictive value of a pre-biopsy clinical diagnosis in predicting interstitial nephritis was very low (33%). A large number of patients clinically diagnosed to have chronic interstitial nephritis had other aetiologies of chronic kidney disease. CONCLUSION: Glomerulonephritis was the most common cause of chronic kidney disease, not including diabetic nephropathy, followed by interstitial disease and benign arterionephrosclerosis. In patients with unidentified severe chronic kidney disease, renal biopsy provided an aetiological diagnosis.

Teratoma of the placenta.

Primary non-trophoblastic tumours of the placenta reported to date are chorioangioma and teratoma, both of which are extremely rare. A case of teratoma in a term placenta is reported.

Pulmonary hydatid disease mimicking sequestration: differentiation on magnetic resonance imaging.

A case of hydatid disease of the lung proven by thoracotomy and histopathological evaluation is described. It was clinically and radiologically suggestive of a complicated pulmonary sequestration or non-resolving consolidation.

Prognostic factors in diffuse proliferative lupus nephritis.

BACKGROUND: Patients with diffuse proliferative lupus nephritis (DPLN) can have variable clinical course. Identification of the predictors of outcome would help to improve the management. We have studied the prognostic significance of clinical, laboratory and histological parameters in patients with DPLN. METHODS: Twenty nine patients diagnosed to be having DPLN seen between 1987 and 1991 were followed up for over 57 months. Parameters assessed for prognostic significance included serum creatinine, urine protein at the time of biopsy, blood pressure, type of immunosuppression, composite scores and individual components of activity index (AI) and chronicity index (CI). Kaplan-Meier survival curves were plotted and the results were compared using log rank test. Fishers' exact test was used to study the risk factors. RESULTS: End stage renal failure developed in 7/29 (24.1%) patients; 7/19 (36.8%) who had hypertension and 7/16 (43.8%) who had nephrotic proteinuria developed renal failure, while none who had normal blood pressure or nonnephrotic proteinuria, developed renal failure (p < 0.01). Three patients had high activity index (> 12) and all three developed renal failure. Other parameters such as age, gender, serum creatinine, type of immunosuppression, CI and individual components of AI failed to predict the outcome (p > 0.05). CONCLUSION: Hypertension, nephrotic proteinuria and high AI were predictive of progression to end stage renal failure in patients with diffuse proliferative lupus nephritis.

Sacral hydatidosis: value of MRI in the diagnosis.

We present a case of primary hydatid disease of the sacrum. The diagnosis was made on MR imaging obtained to evaluate the spine for recurrent disc disease. The patient had previously undergone laminectomy elsewhere for L4-5 radiculopathy. Ultrasound-guided aspiration and visualisation of scolices confirmed the diagnosis. No other site of involvement was found.

Treatment of diffuse proliferative lupus nephritis: an Indian experience.

BACKGROUND: Immunosuppressive therapy has improved the prognosis in lupus nephritis. However, infectious complications may contribute to morbidity. There is also debate on the best form of therapy. We, therefore, compared the results of two different forms of therapy. METHOD: Twenty-nine patients diagnosed to have diffuse proliferative lupus nephritis were followed up over 54 months. The treatment consisted of azathioprine (1.5 mg/kg/day) or pulse intravenous cyclophosphamide (500 mg/m2 body surface area monthly) along with prednisolone (2 mg/kg on alternate days). RESULTS: Seventeen patients received azathioprine (group A) and 12 received cyclophosphamide (group B). The mean (SD) follow up in groups A and B were 54.35 (33.6) and 52 (35.8) months, respectively. Apart from the higher number of males in group B, both groups were comparable for age, presence of hypertension, renal function, 24-hour urinary protein excretion and composite scores for histological activity and chronicity indices (p > 0.05). The renal survival estimated by the Kaplan-Meier method was similar in both groups (p > 0.05). Four patients had renal failure requiring replacement therapy in group A and 3 in group B. Major infective episodes were more common in group B than in group A (p = 0.03). CONCLUSION: Azathioprine was as effective as pulse intravenous cyclophosphamide in preserving renal functions up to 54 months. Major infective episodes were more common with pulse intravenous cyclophosphamide.

Nondiabetic renal disease in noninsulin-dependent diabetics in a south Indian Hospital.

Eighty patients with non-insulin-dependent diabetes mellitus being treated in a south Indian hospital were biopsied to confirm suspected nondiabetic renal disease (NDRD). The positive predictive value of the standard clinical indicators for NDRD in the presence or absence of diabetic retinopathy was 54 and 87%, respectively. These values are higher than those given by comparable studies in Western populations. This is probably due to a higher prevalence of NDRD in the population of south India, and especially of proliferative glomerulonephritis, which was found in 21.5% of the patients studied. Standard clinical predictors of NDRD in diabetics have a high predictive value in the tropics where there is a high prevalence of proliferative glomerulonephritis.