Positive direct antiglobulin tests in cancer patients on immune checkpoint inhibitors: A case series from India.

Tumour cells activate immune checkpoints such as programmed death receptor-1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) signalling pathways to inhibit T lymphocyte activation and thus escape from immune surveillance. Immune checkpoint inhibitors (ICPis) reactivate T lymphocytes to recognize cancer cells by blocking CTLA-4 or PD-1. Autoimmune haemolytic anaemia is a rare, but often severe, complication of ICPis. Therefore, we performed a retrospective clinical case review, including serologic, haematology, and biochemistry laboratory results, of three patients who developed autoantibodies to erythrocytes following treatment with pembrolizumab, an anti-PD-1 inhibitor. Serologic testing of blood samples from these patients showed their red cells were positive for direct antiglobulin test (DAT + for IgG in two cases and IgG with C3d in one case). Antibody detection test was negative. No patient had clinical and laboratory features of haemolysis. There were no additional immune-related adverse events. IgG antibodies coating red cells were neither IgG1 nor IgG3 in class and elution was found negative in all. In conclusion, immunohaematology laboratories should be aware of the possibility of erythroid autoantibodies and their nature in cancer patients receiving ICPis. The result of a positive DAT should be interpreted carefully in these patients to exclude other possible causes of anaemia.

Evaluation of Vascular Health of E-Beta Thalassemia Patients: Effect of Iron Overload.

Hb E-ß thalassemia is the most common form of hemoglobinopathy in Southeast Asia and eastern India. Iron overload resulting from blood transfusion and increased intestinal iron absorption promotes the formation of reactive oxygen species (ROS), leading to oxidative stress, organ dysfunction, and tissue damage. Of these, cardiovascular complications are the leading cause of mortality. Impaired endothelial function is a biomarker of vascular health in patients with cardiovascular risks. Therefore, assessment of endothelial function is a useful prognostic tool. In the present study, 60 E- ß thalassemia patients and 60 healthy, age, sex matched control subjects were taken. The mean hemoglobin and ferritin of thalassemic patients were 7.43gm/dl and 1032 mcg/dl respectively. The vascular health was compared by measuring flow-mediated vasodialation (FMD), arterial elastic parameters, and carotid intima-medial thickness (CIMT). There was lower FMD (7.49%) and higher CIMT (0.46mm) in thalassemic group than control (10.52 % and 0.36mm respectively) (p value< 0.05). Also arterial stiffness is elevated and arterial distensibility is lower in thalassemic patients than control. Among the thalassemic patients FMD or CIMT did not correlate with serum ferritin value. So, the E- ß thalassemia patients had poor vascular health and are at a higher risk of developing atherosclerosis and cardio-vascular complication than normal population. The vascular dysfunction does not correlate with serum ferritin value, so regular monitoring with Doppler study is required for early diagnosis of subclinical atherosclerosis in this group of patients. However the effects of chelation therapy, Hydroxyurea, or other targeted therapies needs to be validated by further study.

The Impact of Thromboelastography on Blood Transfusion Policy in Adult Cardiac Surgery-A Retrospective Observational Study from Eastern India.

This study was conducted to determine the impact of thromboelastography (TEG) on blood transfusion policy regarding utilization and preparation of cryoprecipitate in adult cardiac surgery. The differences in total transfusion requirement, length of postoperative ICU stay and 24 h mortality were also studied after introduction of TEG in transfusion protocol. It was a retrospective, single-center, observational study conducted in adult patients underwent cardiac surgery from April 2008 to March 2016. Two thousand patients underwent surgery when TEG was used compared with 1000 control patients before availability of TEG. Significantly more patients in the TEG group versus the control group received cryoprecipitate (41 vs. 7%; p < 0.05), while fewer received a transfusion (60 vs. 87.5%; p < 0.05). Significant increase in cryoprecipitate preparation was observed after introduction of TEG. Patients underwent surgery in TEG group showed substantial reduction in administration of PRBC (2.1 vs. 3.5 U; p < 0.05); FFP (2.4 vs. 3.8 U; p < 0.05) and platelets (1.1 vs. 2.7 U; p < 0.05) compared to control group without compromising the length of ICU stay or postoperative mortality. A TEG-guided approach in adult patients undergoing cardiac surgery may increase the use of cryoprecipitate, while decreasing the overall requirement of blood transfusion.

Pancreatitis in Acute Promyelocytic Leukemia: Drug-induced or Differentiation Syndrome?

Acute promyelocytic leukemia (APL) constitutes about 15% of all acute myeloid leukemia patients and can now be treated even without any chemotherapy, with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). Acute pancreatitis (AP) is a rare adverse event in APL, which is primarily reported to be secondary to hypertriglyceridemia. Here, we have reported AP developed in a patient of APL, during induction with ATRA and ATO, but it was not associated with hypertriglyceridemia. Rather, it was associated with respiratory distress and weight gain, coincidental leukocytosis, bilateral pleural effusion, and edematous pancreatitis without any necrosis. Hence, AP in this case is diagnosed to be a manifestation of differentiation syndrome, and it responded to steroid.

POEMS Syndrome with Biclonal Gammopathy: A Rare Association.

Polyneuropathy, Organomegaly, Endocrinopathy, M protein and Skin changes (POEMS) syndrome is rare plasma cell dyscrasia with multisystem involvement. The name comes from the five characteristic features: Polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes. The presence of biclonal M band is a rare manifestation. Here, we are describing the cases of a 60-year-old lady, presented with bilateral pedal oedema and pericardial effusion and peripheral neuropathy. She also had hepatosplenomegaly, hyperpigmented rash and hypothyroidism and hyperparathyroidism. The serum protein electrophoresis and the immunofixation electrophoresis revealed two distinct monoclonal bands, immunoglobulin IgG kappa and IgA lambda. There was a mild increase in plasma cells and sclerotic bone lesion in pelvis. The POEMS syndrome is generally associated with lambda light chain restriction. The presence of biclonal gammopathy involving kappa and lambda is a rare manifestation. The pathogenic or prognostic role of different paraprotein is not known. Further studies are required to delineate such effect.

Role of thromboelastography in the management of snake bite: A case report from India.

In the absence of a specific laboratory test of envenomation, there is a need for an alternative mechanism for the early recognition of envenomation following hematotoxic snake-bite in tropical countries. Abnormalities of clotting are commonly associated with hematotoxic snake bite either due to systemic envenomation or due to the release of an inappropriate tourniquet applied as 'first-aid' often by the rural people before presentation to the hospital. Thromboelastography (TEG) has been used to monitor the coagulation abnormalities in various clinical scenarios. Here we narrate our experience where regular monitoring of hemostasis by TEG had helped us to successfully manage a case of hematotoxic snake-bite in a 45 year old male patient from rural India.

Disseminated Histoplasmosis in Immunocompetent Individuals- not a so Rare Entity, in India.

INTRODUCTION: Histoplasmosis is a rare fungal disease caused by dimorphic fungi Histoplasma capsulatum. The causative fungus persists in soil, infects through inhalation and manifests in three main types-acute primary, chronic cavitary and progressive disseminated histoplasmosis. Disseminated Histoplasmosis (DH) is defined as a clinical condition where the fungus is present in more than one location. Among the forms of histoplasmosis, DH is the rarest and mostly found in an immuno-compromised individual. Here we are presenting our experiences of the series of cases of DH in immuno-competent individuals who have been diagnosed in our institute in last 5 years. MATERIALS AND METHODS: This is a single centre retrospective observational study, conducted in Institute of Haematology and Transfusion Medicine, which is a referral centre for Eastern India, from May 2009 to April 2014. Only cases with DH in otherwise healthy immuno-competent individuals were included in the study. The histoplasmosis was confirmed either by presence of Histoplasma in biopsy specimen from an extrapulmonary organ or by positive growth in fungal culture. RESULT: Total seven patients met the inclusion criteria. Five out of 7 patients were male. The mean age was 35 years. Five of the 7 patients presented with fever for a long duration. Six patients complained of significant weight loss before diagnosis. On examination, one patient had skin nodules, five patients had hepato-splenomegaly, and two patients had lymphadenopathy. The laboratory investigations revealed anaemia in six out of 7 patients, and pancytopenia in 3 patients. Two patients had features of the hemophagocytic syndrome in the bone marrow. All patients were treated with conventional amphotericin B deoxycholate and azole antifungal. One patient with adrenal involvement died in hospital. The patient with skin nodule had recurrent relapses. The other patients had resolution of symptoms and were clinically cured. CONCLUSION: DH is not an uncommon aetiology of fever of prolonged duration even in immuno-competent individual and should be kept as a differential diagnosis. Targeted investigation through early bone marrow biopsy and fungal culture may help in the diagnosis of DH. Imaging study to exclude adrenal involvement prevents case fatality. Cytopenia may be due to a secondary hemophagocytic syndrome, which improves with anti-fungal therapy. Treatment with either amphotericin B or itraconazole gives excellent outcome though therapy may have to be given for a prolonged period in case of relapses.

Haemolytic anaemia as first manifestation of Wilson's disease: a report of two cases.

Wilson's disease can have different manifestations like jaundice, cirrhosis of liver, extrapyramidal symptoms and dementia. Haemolytic anaemia may occur but it is commonly associated with florid manifestation of liver disease. Sometimes, liver cell necrosis can release huge free copper ions in blood, giving rise to oxidant damage to erythrocytes. Oxidative damage to cell membrane, haemoglobin and erythrocyte metabolism causes haemolytic crisis. In some cases, liver involvement is subclinical, but nonetheless, free copper is released from necrosed hepatocytes and causes oxidative damage to erythrocytes.We had two cases of Wilson's disease with initial presentation as severe haemolytic anaemia and no other clinical feature suggestive of Wilson's disease was present. In unclear cause of haemolytic anaemia, especially in adolescents or young adults, Wilson's disease should be considered. As Wilson disease is rare and its initial presentation with haemolytic anaemia is rarer, high level of suspicion is required to diagnose it.

Haemorrhagic pericardial effusion in type I Gaucher's disease.

Gaucher's disease is a rare lysosomal storage disorder. Excess accumulation of glucosylceramide predominantly occurs in abdominal viscera. Cardiac involvement is rare, though they generally represent as restrictive cardiomyopathy and pericarditis. Our case, a 19-year old boy initially presented with hepatosplenomegaly but later diagnosed with haemorrhagic pericardial effusion. Enzyme supplementation gives successful outcome but our case was managed symptomatically with pericardiocentesis.

Hashimoto's encephalopathy.

Hashimoto's encephalopathy (HE) is a completely treatable but relapsing neuroendocrine disorder associated with Hashimoto's thyroiditis (HT). Though numerous neurological manifestations are often associated with thyroid disorder, this entity is less documented. We are reporting a case of HE in a 65 year old female presenting with sudden onset deep coma following an attack of mild fever and vomiting for two days. Patient was a known diabetic. Hypoglycemic coma, diabetic ketacidosis and hyperosmolar coma were excluded by laboratory investigations. High blood sugar was corrected with insulin. She had hyponatremia and hypokalemia which were corrected with electrolyte replacement. Liver function tests were normal, but serum ammonia was mildly raised. CSF study was normal. Despite correction of her metabolic derangements patient failed to regain her consciousness. CT scan of brain was normal. MRI of brain revealed diffuse brain atrophy. Patient's thyroid function tests were normal but anti-thyroid peroxidase (anti-TPO) antibody was highly raised. EEG showed diffuse slow wave pattern. Intravenous dexamethasone (24 mg/d) was started. Patient regained consciousness slowly over a period of one month. To reduce the toxicity of steroid, oral azathiprine 50 mg/day was added later with tapering of steroid dose. HE must be kept in mind in comatose patients when other metabolic, infective and structural neurological causes have been excluded. Proper and timely treatment can salvage the patient.

Remitting seronegative symmetrical synovitis with pitting edema (RS3PE); a rare association with phyllodes tumour of breast.

Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is a rare entity mainly found in elderly males. It is characterized by pitting edema mainly of dorsum of both hands giving a "boxing glove hand" appearance; rarely involving feet also, acute in onset, negative rheumatoid factor and a good response to low dose corticosteroid therapy. Clinically it almost resembles a case of polymyalgia rheumatica, late onset rheumatoid arthritis or other seronegative spondyloarthropathy.Though there are multiple underlying factors causing this rare entity but it has very close associations with many malignancies.So far its association with solid tumours and hematological malignancies has been reported. Phyllodes tumour of breast shows wide spectrum of activity from a benign condition to a locally aggressive and sometimes metastatic tumour.One fourth of the cases recur after definitive treatment.Our case represent an unusual association with recurrent phyllodes tumour of breast with RS3PE.

Right ventricular endomyocardial fibrosis.

Endomyocardial fibrosis is a variety of restrictive cardiomyopathy, in which endocardium of one or both ventricles is thickened markedly with involvement of underlying myocardium. Partial obliteration of ventricular cavities by fibrous tissue and thrombus causes diastolic dysfunction with increased resistance to ventricular filling. Systolic function is well preserved till late stages. Biventricular or isolated left ventricular involvement is common. Isolated right ventricular involvement is relatively uncommon. Case reports on endomyocardial fibrosis have declined in literature. In India, endomyocardial fibrosis is mainly reported from Kerala. A case of right ventricular endomyocardial fibrosis from West Bengal is reported here. Isolated right sided endomyocardial fibrosis, massive right atrial enlargement, complete disorganization of tricuspid valve, massive pericardial effusion, normal absolute eosinophil count and its sporadic occurrence outside 15 degrees of the equatorial belt were interesting features in this case of endomyocardial fibrosis. X-ray features were typical of pericardial effusion masking underlying endomyocardial fibrosis. Endomyocardial fibrosis is a neglected research field. It needs more attention from biomedical researchers.

Assessment of efficacy of pamidronate in undifferentiated spondyloarthropathy (uSpA): a placebo control trial in a tertiary level center.

Undifferentiated spondyloarthropathy (uSpA) is a nonspecific form of spondyloarthropathy where nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatic drugs are still mainstay of treatment. We evaluated the efficacy and adverse effect profile of pamidronate, in uSpA patients refractory to NSAIDs therapy. A case series of 87 patients fulfilling the modified Amor criteria for the diagnosis of uSpA, having active disease even after 3-month continuous therapy with two NSAIDs, were selected. Active disease was defined as a VAS score >50 in a scale of 0-100 in 3 out of four following parameters: patients' global assessment, pain, BASFI and BASDAI morning stiffness. Sixty-six patients among those were administered monthly pamidronate infusion (60 mg over 4 h in 500 ml of normal saline) for 6 months. Other 21 patients (placebo group) transfused with normal saline. Treatment outcome was assessed by comparing baseline and 6 months value of BASDAI, BASFI, BASMI, BAS-G, CRP and ESR in both groups and improvement by ASAS-20 and BASDAI-50. Among the 66 patients, 48 patients (72.73%) achieved ASAS-20 and 42 patients (63.64%) achieved BASDAI-50 response. Among the treatment group, mean ESR, CRP, BASDAI, BASFI, BAS-G and BASAMI reduced by 54.81 mm/h (64.95%), 3.94 mg/l (43.3%), 3.74 (48.38%), 3.73 (49.40%), 4.47 (58.97%) and 4.28 (58.15%), respectively, after treatment, whereas in placebo group, increased by 5.48 mm/h (6.34%), 0.34 mg/l (3.77%), 0.24 (3.02%), 0.45 (6.03%), 0.05 (0.67%) and 0.52 (7.13%), respectively, after 6 months. Intravenous pamidronate has very good efficacy for the treatment of uSpA.

Carotid intima-media thickness in type 2 diabetes mellitus patients with cardiac autonomic neuropathy.

INTRODUCTION: Cardiac autonomic neuropathy (CAN) is an important complication of type 2 diabetes mellitus (T2DM). Accelerated atherosclerosis is also common in T2DM. Carotid intima media thickness (CIMT) is a surrogate marker of atherosclerosis. We conducted a study to assess the CIMT in T2DM patients with CAN. METHODS: In 84 T2DM patients cardiac autonomic function was assessed by five clinical tests including: 1) heart rate variation during deep breathing, 2) hear rate response to standing, 3) Valsalva ratio, 4) postural fall in systolic blood pressure (BP) three minutes after standing, and 5) resting heart rate. CAN was defined as two or more positive tests out of five for cardiac autonomic function. CIMT was measured by two dimensional (2D) ultrasound. We also examined for presence of any atherosclerotic plaque over intima of carotid artery as well as within the carotid bulb. RESULTS: Thirty six (42.85 percent) out of 84 patients were detected to have CAN. CAN was significantly associated with duration of disease after its detection (P = 0.0253), high LDL cholesterol (P = 0.0418), low HDL cholesterol (P = 0.0001), fasting blood sugar (FBS) level (P = 0.0012) and CIMT (P = 0.0001) equal to or more than 69 mm. CONCLUSION: Increased CIMT equal to or more than 69 mm is associated with high occurrence of CAN in diabetic population. Duration of diabetes, abnormal lipid tests and FBS level significantly influence the development of CAN.

4-aminoquinolines active against chloroquine-resistant Plasmodium falciparum: basis of antiparasite activity and quantitative structure-activity relationship analyses.

Chloroquine (CQ) is a safe and economical 4-aminoquinoline (AQ) antimalarial. However, its value has been severely compromised by the increasing prevalence of CQ resistance. This study examined 108 AQs, including 68 newly synthesized compounds. Of these 108 AQs, 32 (30%) were active only against CQ-susceptible Plasmodium falciparum strains and 59 (55%) were active against both CQ-susceptible and CQ-resistant P. falciparum strains (50% inhibitory concentrations [IC50s], ≤25 nM). All AQs active against both CQ-susceptible and CQ-resistant P. falciparum strains shared four structural features: (i) an AQ ring without alkyl substitution, (ii) a halogen at position 7 (Cl, Br, or I but not F), (iii) a protonatable nitrogen at position 1, and (iv) a second protonatable nitrogen at the end of the side chain distal from the point of attachment to the AQ ring via the nitrogen at position 4. For activity against CQ-resistant parasites, side chain lengths of ≤3 or ≥10 carbons were necessary but not sufficient; they were identified as essential factors by visual comparison of 2-dimensional (2-D) structures in relation to the antiparasite activities of the AQs and were confirmed by computer-based 3-D comparisons and differential contour plots of activity against P. falciparum. The advantage of the method reported here (refinement of quantitative structure-activity relationship [QSAR] descriptors by random assignment of compounds to multiple training and test sets) is that it retains QSAR descriptors according to their abilities to predict the activities of unknown test compounds rather than according to how well they fit the activities of the compounds in the training sets.

Nephropathy in association with annular psoriasis.

Occurrence of glomerular diseases in psoriasis is rare, although the number of reports is increasing in recent years. Different types of glomerular involvement have been reported but mesangioproliferative glomerulonephritis with IgA deposits, AA amyloidosis and membranous nephropathy are relatively common in association with psoriasis. The term 'psoriatic nephropathy' has been introduced recently. We contribute a case to the ongoing discussin regarding psoriatic nephropathy. Our patient had mesangio-proliferative glomerulonephritis (with IgG and C3 deposition) in association with annular psoriasis (rare variety of chronic plaque psoriasis). Presence of messangio-proliferative glomerulonephritis with IgG deposition is rare in association with psoriasis. The patient responded well to weekly methotrexate (15 mg) injection. Methotrexate has not been tried previously in psoriatic nephropathy or reported to be effective in it.

Hypokalemic periodic paralysis due to proximal renal tubular acidosis in a case with membranoproliferative glomerulonephritis.

Proximal renal tubular acidosis (pRTA) is a rare disorder. Hypokalemia may be associated with it; occasionally leading to features like hypokalemic periodic paralysis. Though pRTA is a tubulointerstitial kidney disease, glomerulonephritis may occasionally lead to pRTA by tubular damage through leaking proteins, cytokines or by inflammatory infiltrates. In our reported case a 27 year old male had recurrent episodes of hypokalemic quadriparesis. Investigations revealed features of pRTA including hypokalemia and non-anion-gap hyperchloremic metabolic acidosis. His urine pH dropped to 5 with NH4Cl loading test. Kidney biopsy showed membranoproliferative glomerulonephritis with tubulointerstitial damage. Hypokalemic periodic paralysis and pRTA are uncommon associations of membranoproliferative glomerulonephritis.