Anup J. Devasia

Serum homocysteine as a risk factor for carotid intimal thickening in acute stroke: A cross sectional observational study.

Introduction: The present study aimed to analyse if there is a correlation between carotid intima medial thickening (CIMT) and Hcy in stroke patients. Methodology: We studied 100 consecutive cases of acute anterior circulation strokes at St. John′s Medical College, Bangalore, India. Fasting serum samples for homocysteine were sent within 24 hours of admission and all patients underwent a carotid Doppler scan and carotid intima-medial thickness (CIMT) was estimated on both sides. Results: There was significant correlation between serum homocysteine levels and carotid intima-medial thickness (r = 0.409, p = 0.000). Also after controlling for other possible risk factors it was found that elevations in serum homocysteine levels would cause a variation of 60% in the carotid intima-medial thickening. Conclusion: Serum Hcy levels correlate well with CIMT and hence may predict atherothrombotic events.

Asymptomatic gastrosplenic fistula in a patient with marginal zonal lymphoma transformed to diffuse large B cell lymphoma—a case report and review of literature

Dear Editor, Gastrosplenic fistula (GSF) is a rare and potentially fatal complication of lymphoma which can occur both spontaneously and after chemotherapy [1–4]. Here, we report a patient with diffuse large B cell lymphoma (DLBCL) who was incidentally diagnosed with a GSF on interim PET-CT after three cycles of chemotherapy. A 57-year-old gentleman, who had no significant past history, presented with intermittent low-grade fever and occasional cough of 2 weeks duration. Clinical examination was insignificant except for a single right axillary lymph node (1 cm×1 cm) and palpable spleen. Imaging studies revealed multiple intra-abdominal lymphadenopathy and splenomegaly of 15 cm with two well-defined hypoechoic lesions. He underwent a right axillary lymph node biopsy which was consistent with marginal zone lymphoma (low MIB-1 proliferation index—20 %). He was started on cyclophosphamide and prednisolone, in view of a low-grade lymphoma, as therapy, and was on regular follow up. Two years after the initial diagnosis, he presented with complaints of weight loss and easy fatigability. Clinical evaluation revealed bilateral inguinal lymphadenopathy and hepatosplenomegaly. Repeat imaging of the abdomen showed multiple intra-abdominal lymph nodes and increase in splenomegaly with welldefined heterogeneous lesion measuring 9×8 cm. A new heterogeneous lesion in the left lobe of the liver measuring 8.5×8 cm was noted. High grade transformation of the initial low-grade lymphoma was suspected and an ultrasoundguided biopsy of the para-aortic lymph node revealed DLBCL with aMIB-1 proliferation index of 60%. Hewas subsequently started on R-CHOP 21 chemotherapy which he tolerated well. Interim PET-CT done after three cycles to assess the disease status revealed persistent splenomegaly with two focal lesions, of which the larger lesion had eroded the stomach wall forming a GSF with surrounding stomach wall thickening. There was persistence of the hepatic lesion and intraabdominal lymphadenopathy. The PET confirmed the GSF to be metabolically active (Fig. 1). He had no abdominal pain or symptoms suggestive of gastrointestinal bleeding and stool was negative for occult blood. Endoscopy of the upper gastrointestinal (GI) tract revealed a big excavated ulcer with erythematous, elevated, and irregular margins in the gastric fundus with an opening noted at one edge of the ulcer with food particles in it. Biopsy from the margins of the ulcer showed features ofHelicobacter pylori associated gastritis with extensive ulceration. The patient was started on triple drug therapy for H. pylori . He remained completely asymptomatic for his incidentally detected GSF. However, in view of an impending bleed, surgery consultation was sought and planned to proceed with a surgical correction, involving a sleeve gastrectomy. However, the patient refused any surgical intervention andwas lost to follow up thereafter. GSF has been described in gastric adenocarcinoma [5], Crohn’s disease [6], splenic abscess [7], and trauma. GSF has also been described in connection to both Hodgkin and non-Hodgkin lymphomas [1], developing spontaneously or after chemotherapy. Splenic lymphomas have a high propensity for invasion of adjacent structures. In one series of ten patients with splenic DLBCL [8], nine showed breach of the splenic capsule and seven invading the structures, of which four involved the stomach. Colonosplenic fistulas have also been described in context to lymphoma [9]. Gastric MALTomas resulting in gastrosplenic, gastrocolic, and J. Senapati (*) :A. J. Devasia :A. Viswabandya Department of Clinical Haematology, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India e-mail: jsalwayswins@gmail.com

Early T cell precursor lymphoid blast crisis of chronic myeloid leukemia - a novel transformation.

Chronic myeloid leukemia (CML) is a myeloproliferative disorder with an overall incidence of 0.6 to 2 cases per 100,000 per year. The breakpoint cluster region– Abelson (BCR–ABL) fusion protein with constitutive tyrosine kinase activity drives uncontrolled cell proliferation leading to accumulation of myeloid precursors and mature cells in the peripheral blood, bone marrow and extramedullary sites. Tyrosine kinase inhibitors (TKI) have dramatically improved the prognosis of CML, with an estimated median survival of 25 to 30 years. Disease progression to accelerated phase or blast crisis remains the main cause of mortality. The incidence of myeloid blast crisis is around 50% compared to around 25% each for lymphoid blast crisis and undifferentiated phenotypes. Almost 95% of lymphoid blast crises are of B cell

Unmasking and successful management of light chain deposition disease of kidney in pregnancy: a complex case, mirroring the complex needs of pregnancy with kidney disease in India

Pregnancy offers a precious window of opportunity to diagnose previously undetected or new onset kidney diseases in emerging countries like India, where access to medical, educational and health care facilities are not equitably distributed across varied sections of society. We report a case of a 33 year-old primi gravida who had a successful pregnancy following what was initially considered to represent preeclampsia at 38 weeks of gestation, in whom a subsequent kidney biopsy for persistence of pregnancy-related acute kidney injury (Pr-AKI) revealed light chain deposition disease (LCDD). The etiological evaluation of LCDD led to the detection of an underlying plasma cell dyscrasia which was treated effectively with chemotherapy and autologous stem cell transplant. In this report, we explore the hitherto uncharted pathophysiological relationship between LCDD and pregnancy-related kidney injury by transmission electron microscopic (TEM) studies of endothelial injury in this setting, and underscore the benefits of medical care in a multidisciplinary environment which yielded gratifying results in preservation of maternal kidney health and fetal outcome.

Clinical Outcomes in Multiple Myeloma Post-Autologous Transplantation—A Single Centre Experience

There is paucity of data from developing countries on the clinical outcomes in myeloma post-autologous transplantation. In this retrospective study, we used hospital records to retrieve data of patients with multiple myeloma undergoing autologous stem cell transplantation (ASCT) from January 1995 to December 2014 at our centre. During the study period, 245 patients underwent ASCT for myeloma. Of these, 19%, 37% and 37% were in complete response, very good partial response and partial response respectively at the time of ASCT. Only in 14 (5.7%) patients, the stem cells were cryopreserved. The transplant related mortality was 2.86%. The median follow up was 40.7 months (range 0–237.4 months). The 5-year overall survival (OS) and progression-free survival (PFS) for the entire cohort was 61.6% ± 3.8% and 37.2% ± 3.9% respectively. Independent predictors of OS included mononuclear cell dose infused, pre- and post-transplant response; and the use of maintenance therapy. Independent predictors of PFS included age at diagnosis, pre- and post-transplant response; and the use of maintenance therapy. In a resource limited setting, ASCT for myeloma is associated with low transplant related mortality. Pre- and post-transplant response and maintenance therapy are predictors of survival.

Arsenic Trioxide Enhances the NK Cell Cytotoxicity Against Acute Promyelocytic Leukemia While Simultaneously Inhibiting Its Bio-Genesis

Natural killer cells (NK) contribute significantly to eradication of cancer cells, and there is increased interest in strategies to enhance it’s efficacy. Therapeutic agents used in the treatment of cancer can impact the immune system in a quantitative and qualitative manner. In this study, we evaluated the impact of arsenic trioxide (ATO) used in the management of acute promyelocytic leukemia (APL) on NK cell reconstitution and function. In patients with APL treated with single agent ATO, there was a significant delay in the reconstitution of circulating NK cells to reach median normal levels from the time of diagnosis (655 days for NK cells vs 145 and 265 days for T cells and B cells, respectively). In vitro experiments demonstrated that ATO significantly reduced the CD34 hematopoietic stem cell (HSC) differentiation to NK cells. Additional experimental data demonstrate that CD34+ sorted cells when exposed to ATO lead to a significant decrease in the expression of IKZF2, ETS1, and TOX transcription factors involved in NK cell differentiation and maturation. In contrast, exposure of NK cells and leukemic cells to low doses of ATO modulates NK cell receptors and malignant cell ligand profile in a direction that enhances NK cell mediated cytolytic activity. We have demonstrated that NK cytolytic activity toward NB4 cell line when exposed to ATO was significantly higher when compared with controls. We also validated this beneficial effect in a mouse model of APL were the median survival with ATO alone and ATO + NK was 44 days (range: 33–46) vs 54 days (range: 52–75). In conclusion, ATO has a differential quantitative and qualitative effect on NK cell activity. This information can potentially be exploited in the management of leukemia.

Management of Relapse in Acute Promyelocytic Leukemia Treated with Upfront Arsenic Trioxide Based Regimens

S210 dnAML, while TP53 (OR 0.39, p 1⁄4 0.001) mutations were more enriched in stAML. NPM1 (OR2.18, p 1⁄4 0.036) and NRAS (OR 2.58, p 1⁄4 0.049) mutations were more enriched in previouslyuntreated patients, whereas WT1 (OR 0.44, p 1⁄4 0.02) and U2AF1 (OR 0.23, p 1⁄4 0.012) mutations were more enriched in R/R AML. Class 1 mutations (NPM1, FLT3, PTPN11, NRAS) were associated with proliferative disease (high WBC, blast, LDH), whereas patients with mutations in TP53, STAG2, BCOR, and ASXL1 had non-proliferative disease. We detected rare mutations in MYC (8 hotspot SNVs in exon 2 and 1 ITD) and MYCN (1 SNV) in 9 (2%) patients. Patients with MYC mutations showed significantly higher MYC expression than those without by IHC staining (median H score 22 vs. 15, p < 0.001). Conclusion: We identified significant association between mutations and certain clinical phenotype. MYC mutations were associated with MYC protein overexpression in AML.

Antenatal chemotherapy in a case of diffuse large B-cell lymphoma

A 28-year-old pregnant woman in the sixth month of gestation presented with complaints of altered bowel habit for a month, on examination found to have generalised lymphadenopathy, pedal oedema and locally infiltrating ano-rectal growth. Rectal growth biopsy was reported as high-grade B-cell lymphoma. After a discussion in a multidisciplinary panel consisting of haemato-oncologists, obstetricians and physicians, she was planned to receive antenatal chemotherapy. She delivered a live baby of 1.86 kg at 36 weeks of gestational age by normal vaginal delivery. After 6 cycles of chemotherapy she had complete regression of the disease.

Second Hematopoietic Stem Cell Transplant for Thalassemia Major: Improved Clinical Outcomes with a Treosulfan-Based Conditioning Regimen

Graft rejection (GR) after allogeneic stem cell transplantation (allo-SCT) occurs in 10% to 20% of patients with β-thalassemia major (TM). There are limited data on the clinical profile and long-term outcome of patients who have had a GR. We undertook a retrospective analysis of patients who had a graft failure after allo-SCT for TM at our center. From October 1991 to June 2016, 55 of 506 patients (11%) transplanted for TM had a graft failure. An additional 7 patients with graft failure after allo-SCT done at other centers were referred to us for a second transplant. The median age was 8 years (range, 1 to 19), and there were 38 males (61.2%). Thirty-two patients (52.4%) were primary graft failures (15 with aplasia and 17 with autologous recovery) and 30 (47.6%) were secondary graft failures (5 with aplasia and 25 with autologous recovery). On conventional risk stratification 40 patients (64.5%) were class III. Seventeen patients (53.12%) with primary graft failure and 16 (53.3%) with secondary graft failure did not receive a second transplant. Twenty-nine patients (46%) with GR underwent a second allo-SCT. With the exception of 1 patient (first allo-SCT with an unrelated cord blood product), the donor for the second transplant was the same as the first transplant. Conditioning regimen for the second SCT was busulfan-based myeloablative (MAC) in 7 patients (24%), treosulfan-based MAC in 12 patients (41.3%), and the remaining received non-MAC regimens in view of pancytopenia and perceived inability to tolerate MAC. None of the patients conditioned with a treosulfan-based regimen had a GR, although 1 patient died with complications secondary to chronic graft-versus-host disease. Of the remaining 17 patients, 10 died after the second GR and 3 of regimen-related toxicity. Four are alive, of which 1 has recurrent TM and the rest are well and transfusion independent at 55, 80, and 204 months, respectively, from second transplant (all busulfan-based MAC). On a univariate analysis a nontreosulfan-based conditioning regimen and time from GR to second transplant of <1 year was significantly associated with an adverse impact. However, on a multivariate analysis only a nontreosulfan-based regimen was associated with a significant adverse impact on event-free survival (HR, 11.5; 95% CI, 1.13 to 116.4; P = .039). In conclusion, there has been a significant improvement in clinical outcomes in our experience with the use of a treosulfan-based reduced-toxicity MAC regimen for second allo-SCT for TM. It would be reasonable, where feasible, to defer the second transplant by a year after the first GR.

Post-Transplant Cyclophosphamide as Sole Graft-versus-Host Disease Prophylaxis Is Feasible in Patients Undergoing Peripheral Blood Stem Cell Transplantation for Severe Aplastic Anemia Using Matched Sibling Donors

High-dose cyclophosphamide (PTCY) after allogeneic hematopoietic cell transplantation (HSCT) has been shown to be effective in preventing graft-versus-host disease (GVHD) after HLA-matched bone marrow transplantation. We performed a phase II study of PTCY given at 50 mg/kg i.v. on days 3 and 4 as the sole GVHD prophylaxis after HSCT for severe aplastic anemia (SAA) in patients receiving granulocyte colony-stimulating factor-mobilized peripheral blood stem cell (PBSC) grafts from HLA-matched related donors after conditioning with fludarabine, CY, and single-dose total body irradiation. Thirty patients with a median age of 29 years (range, 16 to 49) were enrolled in this study. Engraftment was seen in 27 patients (90%) at a median of 16 days (range, 12 to 21) post-HSCT. None of the patients developed veno-occlusive disease of the liver or hemorrhagic cystitis. Grades II to IV acute GVHD was seen in 22% of patients with grades III to IV GVHD in 11.1%. The 2-year cumulative incidence of chronic GVHD was 22.7%. Fourteen patients (46.6%) did not require any further immunosuppression after receiving PTCY. Comparing with 2 historical cohorts of 30 patients each who received cyclosporine and methotrexate (MTX; at 15 mg/m2 [MTX15] and 10 mg/m2 [MTX10]), the incidence of grades II to IV acute GVHD was lower, albeit not significantly, with the use of PTCY (PTCY, 22.2%, vs MTX15, 37.1%, vs MTX10, 53.8%; P = .056), whereas rates of chronic GVHD were significantly reduced (PTCY, 22.7%, vs MTX15, 63.6%, vs MTX10, 76.2%; P = .013). Viral infections including cytomegalovirus were significantly higher with the use of PTCY (60%) compared with cyclosporine and MTX (MTX15, 23.3%, vs MTX10, 33.3%; P = .008). Overall survival was similar between the 3 groups. We conclude that PTCY as the sole GVHD prophylaxis is associated with low rates of acute and chronic GVHD in patients undergoing PBSC transplant for SAA using HLA-matched donors. This trial is registered at CTRI/2010/091/001480.