Impact of Conditioning Regimen and Graft-versus-Host Disease Prophylaxis on The Outcome of Haploidentical Peripheral Blood Stem Cell Transplantation for High-Risk Severe Aplastic Anemia in Children and Young Adults: A Report from the Pediatric Severe Aplastic Anemia Consortium of India.

Allogenic hematopoietic cell transplantation (HCT) is the best curative approach for patients with severe aplastic anemia (SAA). The outcomes of HCT from haploidentical family donors (HFDs) have improved, making it a feasible option for patients lacking an HLA-identical donor. However, data on HFD-HCT for younger patients with SAA is sparse. In this multicenter retrospective study, we evaluated the outcomes of 79 patients undergoing HFD-HCT for SAA. All the patients were heavily pretransfused, the median time to HCT was >12 months, and 67% had failed previous therapies. Conditioning was based on fludarabine (Flu)-cyclophosphamide (Cy)-antithymocyte globulin (ATG)/total body irradiation (TBI) with or without thiotepa/melphalan (TT/Mel). Post-transplantation Cy (PTCy) and calcineurin inhibitors (CNIs)/sirolimus were used as graft-versus-host disease (GVHD) prophylaxis with or without abatacept. The rate of primary graft failure (PGF) was 16.43% overall, lower in patients conditioned with TT/Mel. The incidences of acute and chronic GVHD were 26.4% and 18.9%, respectively. At a median follow-up of 48 months, the overall survival (OS) and event-free survival (EFS) were 61.6% and 58.1%, respectively. Both OS and EFS were better in the TT/Mel recipients and with abatacept as GVHD prophylaxis. On multivariate analysis, the use of abatacept was found to favorably impact the outcome variables, including GVHD and EFS. Our study suggests that PTCy-based HFD-HCT is a reasonable option for young patients with high-risk SAA, in whom optimization of conditioning and GVHD prophylaxis might further improve outcomes.

Association of the Val66Met polymorphism of the BDNF gene and the deletional mutation of CYP2D6 gene with the prevalence and severity of depressive disorder in an Eastern Indian population.

Background: The Val66Met single nucleotide polymorphism (SNP) of the brain-derived growth factor (BDNF) and deletional mutation of the cytochrome P4502D6 (CYP2D6) have been reported to be linked to the etiology and severity of depressive disorders (DD) in a variable manner among different ethnicities and populations. Aims: The present study was aimed to find the relationship of mutational variations of these two neurotrophins with the severity of DD and their serum cortisol levels as a marker of the stress factor. Methods: In 104 drug-naïve newly diagnosed cases of DD and 106 control subjects, the severity of depression was assessed using the HAM-D score. Val66Met SNP of the BDNF was analyzed in them using restriction digestion of its polymerase chain reaction (PCR) product. CYP2D6 deletional variants were detected by the absence of their PCR products. Serum cortisol levels were measured by the enzyme-linked immunosorbent assay (ELISA) technique. Results: The Chi-square test (Χ2 = 1.42, P = 0.49) did not show any higher prevalence of Val66Met SNP of the BDNF gene in the case group. A correlation coefficient (R) of -0.14 for HAM-D score with a P value of 0.29 signified no direct link of the severity of DD with this SNP. However, a Χ2 of 12.68 with P < 0.001 indicated a significantly higher prevalence of the CYP2D6 deletional mutants in DD cases, whereas an R-value of 0.39 for HAM-D score with P < 0.001 suggested a significantly higher severity of DD having with them. Serum cortisol level showed a significant positive correlation with the deletional variants of CYP2D6 (R = 0.198, P = 0.04) and the HAM-D score (R = 0.22, P = 0.025). Conclusion: We conclude that CYP2D6 deletion significantly contributes to the severity and stress factor in the DD patients in our study population. Early identification of these mutations may provide important molecular and cellular predisposition for the disease and may lay the ground for possible more effective measures of intervention.

A Difficult Case of Pyrexia of Unknown Origin.

This is the case of a 15-y-old boy who presented with fever and back pain with MRI features of spondylitis. A CT-guided vertebral biopsy showed acute and chronic inflammatory cells and grew Pseudomonas aeruginosa on aerobic culture. The child was treated for 2 wk with antibiotics with no response. Meanwhile, he developed new lung, liver, and splenic lesions on CT imaging. Empiric antitubercular therapy was then started and continued for 8 wk during which time there was progressive clinical deterioration. At this time the patient underwent bronchoscopy with lavage and endoscopic ultrasound-guided subcarinal lymph node and lung biopsy. The Xpert MTB/Rif ULTRA was "trace positive" in the bronchoscopic lavage with indeterminate rifampicin resistance, while it was negative in lymph node and lung biopsy. The lymph node and lung biopsy histopathology showed nonspecific inflammatory changes with no granulomas or malignant cells. In view of the positive Xpert ULTRA with indeterminate rifampicin resistance and no response to first-line drugs, treatment with second-line antitubercular drugs was initiated. The clinical condition continued to deteriorate; here the imaging findings were reviewed again and repeat aspiration cytology and biopsy from intra-abdominal nodes was carried out. This yielded the diagnosis of Hodgkin lymphoma. The patient had stage IVB disease. He responded well to standard chemotherapy and is currently in remission. The case illustrates the need to avoid empiric therapy, repeat invasive procedures if so needed, choose the site/method of biopsy appropriately and interpret results of investigations carefully when evaluating a patient with pyrexia of unknown origin.

The Spectrum of Clinical, Immunological, and Molecular Findings in Familial Hemophagocytic Lymphohistiocytosis: Experience From India.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune dysregulation characterized by hyperactivation of the immune system, excessive cytokine secretion and severe systemic inflammation. HLH is classified as familial (FHL) when associated with mutations in PRF1, UNC13D, STX11, and STXBP2 genes. There is limited information available about the clinical and mutational spectrum of FHL patients in Indian population. This study is a retrospective analysis of 101 molecularly characterized FHL patients over the last 10 years from 20 different referral centers in India. FHL2 and FHL3 together accounted for 84% of cases of FHL in our cohort. Patients belonging to different FHL subtypes were indistinguishable based on clinical and biochemical parameters. However, flow cytometry-based assays viz. perforin expression and degranulation assay were found to be specific and sensitive in diagnosis and classification of FHL patients. Molecular characterization of respective genes revealed 76 different disease-causing mutations including 39 (51%) novel mutations in PRF1, UNC13D, STX11, and STXBP2 genes. Overall, survival was poor (28%) irrespective of the age of onset or the type of mutation in our cohort. Altogether, this article sheds light on the current scenario of FHL in India. Our data reveal a wide genetic heterogeneity of FHL in the Indian population and confirms the poor prognosis of FHL. This study also emphasizes that though mutational analysis is important for diagnostic confirmation of FHL, flow cytometry based assays help significantly in rapid diagnosis and functional validation of novel variants identified.

Optimizing pediatric peripheral blood stem cell collection.

INTRODUCTION: Pediatric PBSC harvests pose specific challenges during apheresis and a knowledge of the same and variables affecting PBSC collection are very important in planning these procedures. In the present study safety profile of pediatric PBSC procedures and variables influencing the successful collection were analyzed. METHOD: Pediatric PBSC harvest data for 3 years was reviewed for donor, procedural and product parameters and any specific challenges faced during the procedures. Successful PBSC collection was defined when CD34 dose obtained was ≥2 × 106 cells/Kg of recipients' body weight. RESULTS: 85 PBSC collections performed on 46 children (age range 1.5-15 years) were included. Sixty-two procedures were on autologous donors and 23 on allogenic donors. The median CD34+ cell dose in the PBSC product per procedure was 2.12 × 106 cells/Kg for autologous procedures and 4.6 × 106 cells/Kg for allogenic procedures. Systemic adverse reaction was observed during only one procedure (0.01 %) and was managed conservatively. Successful dose was collected in 52 procedures (61.17 %) and was significantly associated with CD34+ count of more than 19.7/µL, monocyte count of more than 1.65 × 106/µL, allogenic collection and female gender (p = 0.00001, p = 0.011, p = 0.00052, and p = 0.0001, respectively). CONCLUSION: PBSC collection is safe in pediatric age groups and pre-procedure CD34 count of ≥20/µL on the day of collection may result in successful collection of stem cell dose. It is important to identify factors associated with failed collection for appropriate counselling and justifying pre-emptive use of stem cell mobilizing agents.

Indian Academy of Pediatrics Guidelines on School Reopening, Remote Learning and Curriculum in and After the COVID-19 Pandemic.

JUSTIFICATION: With the unprecedented COVID-19 pandemic and the resultant school closure, children all over the country are undergoing a lot of educational, psychosocial, and physical problems. There is an urgent and deep felt need to offer scientific and concrete guidance for these concerns and support children in their educational development during these testing times. OBJECTIVE: To review the guidelines and recommendations given by various international agencies and formulate guidelines in the Indian context on (a) how and when to reopen the schools; (b) ways and means of remote learning; and (c) to identify the contents of curriculum that need restructuring in context of the current situation. PROCESS: Indian Academy of Pediatrics (IAP) formed a task force of pediatricians, educationists and technological experts who connected through various video and social platforms. They gathered and exchanged information and thoughts. The writing committee drafted the guidelines and got approval of all the members of the task force. RECOMMENDATIONS: Schools can be reopened only when the local epidemiological parameters are favorable, the administration is equipped with adequate infrastructure and health care facilities, and the stakeholders (teachers, students, parents, and support staff) are prepared for the new normal. In the meanwhile, remote learning (media-based and /or otherwise) should reach to the last student to maintain uninterrupted education. The curriculum needs to be revised, with focus on revision and core contents. Informal learning of psychosocial empowerment and daily living skills should be encouraged rather than stressful formal learning.

Risk factors of breast cancer among women in eastern India: a tertiary hospital based case control study.

AIM: Breast cancer is one of the most common cancers of women in India with high fatality rate. Over a 1 year study period 105 consecutive biopsy or fine needle aspiration cytology confirmed breast cancer patients were interviewed by direct questionnaire method regarding risk factors attending Surgery and Radiotherapy OPD of Medical College Kolkata, West Bengal while taking other 105 patients attending Surgery Department for some other disease as controls. The data were compiled in MS Excel 2007 and analyzed by Epi info 3.5.1 software. Among the cases, rural residence, illiteracy and low socio-economic status was significantly higher than controls. Late onset of menarche, late onset of menopause, ever OCP usage, breast feeding for 1-2 years and age of 1st childbirth between 20-30 years were found to be significant protective factors. People should be made aware regarding the modifiable risk factors to prevent breast cancer.

Management of large amoebic liver abscess--a comparative study of needle aspiration and catheter drainage.

Amoebiasis in endemic in the tropical countries with amoebic liver abscesses being a common complication. Different modalities of treatment of amoebic liver abscess are conservative (medical management), percutaneous needle aspiration, percutaneous catheter drainage, surgical drainage and endoscopic drainage. This study was carried out to compare the efficacy, safety and outcome of needle aspiration comparing with percutaneous catheter drainage of large (> or = 5cm diameter) amoebic liver abscesses. This was a prospective study carried over a period of two years (2006-2008) at the general surgery department of Calcutta National Medical College and Hospital, Kolkata. A total of 45 patients were included in this study. All of them had amoebic liver abscess with diameter of abscess cavity > or = 5cm. They were divided into two groups. Group A included 22 patients and they were treated with needle aspiration. Group B included 23 patients and they were treated by catheter drainage. Improvement in clinical features, liver function tests, ultrasonic evidence of decrease in the size of abscess cavity was considered as criteria for successful treatment. The sex ratio and the age incidence in the two groups were similar. In about 80% patients the right lobe was affected, in about 18% the left lobe was affected and in rest the abscess involved both lobes. Needle aspiration was successful in 15 (68.2%) and catheter drainage was successful in 23 patients (100%). The mean hospital stay of patients treated with needle aspiration was more than those treated with catheter drainage. The mean time in days taken for 50% decrease in the size of abscess cavity was significantly greater in group treated with needle aspiration than in those treated with catheter drainage (9 days versus 4 days). It is concluded that percutaneous catheter drainage is more effective in management of large amoebic liver abscess than needle aspiration.

A clinical and pathological study of triple negative breast carcinoma: experience of a tertiary care centre in eastern India.

Breast cancers which do not express oestrogen, progesterone, or HER-2 neu receptors are known as triple negative breast carcinomas. In western literature they have been found to be extremely aggressive with a poor prognosis. However there is scarcity of data regarding this variety of breast cancer in India.To examine the clinical and pathological character of triple negative breast carcinomas and to compare their characteristics with other variants of breast carcinomas which presented to Medical College, Kolkata, a randomised sample of 72 patients were included with breast cancer attending the department of surgery from January 2008 to June 2008.The clinical and histopathological data along with ER/PR status and HER-2 neu expression examined by immunohistochemical methods were recorded.Twenty patients (27.78%) were found to be triple negative.The mean age at presentation was 35.4 +/- 1.95 years with 17 (85%) out of 20 being premenopausal. At presentation, mean tumour size was 4.7 +/- 0.21 cm. Though 15 patients (75%) presented with stage III disease and 16 patients (80%) had grade III histology, 14 (70%) were node negative and 20 (80%) did not have involvement of nipple areola complex and 19(95%) did not have multicentric disease. Triple negative breast cancer is prevalent in eastern India.They are locally aggressive, common in premenopausal women, but strangely do not tend to present with lymph node involvement or involvement of nipple areola complex. Therefore a more conservative approach might have a role in these seemingly aggressive tumours.

Panayiotopoulos syndrome presenting with status epilepticus and cardiorespiratory arrest: a case report.

Panayiotopoulos syndrome is early-onset benign childhood epilepsy, now classified as an electroclinical syndrome. The original description in 1989 focused on the triad of nocturnal seizures, tonic eye deviation, and vomiting. With available data from the long-term studies, a wide variety of manifestations have been described, with recognition of autonomic features as being the most prominent aspect of this epilepsy. The presenting symptoms are usually focal seizures comprising autonomic symptoms and/or behavioral changes. Majority of these seizures are in sleep, with half of the seizures progressing to become secondarily generalized. Occasionally, these seizures can present with prominent autonomic features such as ictal vomiting, pallor, flushing/cyanosis, and tachycardia with prolonged thermoregulatory changes lasting for hours, constituting autonomic status epilepticus. Recovery from this autonomic status epilepticus is within hours and is always complete. Autonomic status epilepticus has been previously reported in this epilepsy syndrome, but ictal cardiorespiratory arrest is extremely rare, with only 4 cases being reported in literature. All 4 cases reported in literature recovered spontaneously and did not require resuscitation. Here we present a 3½-year-old male child with Panayiotopoulos syndrome who presented with status epilepticus and ictal cardiorespiratory arrest requiring cardiopulmonary resuscitation for revival.

Unnecessary appendicectomy in suspected cases of acute appendicitis.

Acute appendicitis is a common emergency encountered by general surgeons and is managed effectively by timely appendicectomy. Open appendicectomy is usually the first abdominal operation which a surgical resident learns during his training. In this study, 912 appendicectomies were performed on clinical suspicion of acute appendicitis during the period of 6 years (2003-2008) at Medical College, Kolkata and all the appendix specimens were sent for histopathological confirmation. The negative appendicectomy rate in this study was 36.40% which was significantly higher (p < 0.01) than other contemporary studies. Similarly, females had a higher number of negative appendicectomy at 40.34% as against 26.80% for males ( p < 0.001). Of the 409 specimens (44.85%) thought of "normal" appendix intra-operatively, 77 came out to be having acute appendicitis in histopathology report (intra-operative assessment sensitivity of 86.72% and negative predictive value of 81.17%). So even though there is increased morbidity and mortality if acute appendicitis is not diagnosed early, there is always a tendency among surgeons for over diagnosis and adding to the cost of already burdened government healthcare centres in developing countries. A thorough work-up with pre-operative imaging and diagnostic laparoscopy where applicable is advised for appendicectomy before subjecting a patient presenting with right iliac fossa pain.

Metastasis--an unusual cause of retroperitoneal fibrosis.

Retroperitoneal fibrosis is one of the rare fibrotic processes mainly involving caudal aspect of the retroperitoneum. In up to 70% of patients no causative factor for retroperitoneal fibrosis can be identified, where it resembles auto-immune reaction. A 30-year-old lady presented with progressive oedema of the lower extremities, jaundice and abdominal swelling. Clinical examination revealed doughy abdominal feel and diffuse tenderness. Ultrasonography showed dilated intrahepatic bilary radicles and mild ascites. Contrast CT-scan showed enhancing sheath of soft tissue extending from porta down to aortic bifurcation encasing common bile duct, aorta, inferior vena cava and the ureters. CT-guided fine needle aspiration cytology revealed metastatic adenocarcinoma. Ascitic fluid did not show any malignant cell. No abdominal mass could be detected. The patient died during the course of palliative chemotherapy.