Unexpected Noncovalent Off-Target Activity of Clinical BTK Inhibitors Leads to Discovery of a Dual NUDT5/14 Antagonist.

Cofactor mimicry represents an attractive strategy for the development of enzyme inhibitors but can lead to off-target effects due to the evolutionary conservation of binding sites across the proteome. Here, we uncover the ADP-ribose (ADPr) hydrolase NUDT5 as an unexpected, noncovalent, off-target of clinical BTK inhibitors. Using a combination of biochemical, biophysical, and intact cell NanoBRET assays as well as X-ray crystallography, we confirm catalytic inhibition and cellular target engagement of NUDT5 and reveal an unusual binding mode that is independent of the reactive acrylamide warhead. Further investigation of the prototypical BTK inhibitor ibrutinib also revealed potent inhibition of the largely unstudied NUDIX hydrolase family member NUDT14. By exploring structure-activity relationships (SARs) around the core scaffold, we identify a potent, noncovalent, and cell-active dual NUDT5/14 inhibitor. Cocrystallization experiments yielded new insights into the NUDT14 hydrolase active site architecture and inhibitor binding, thus providing a basis for future chemical probe design.

Role of HLA alleles polymorphism in systemic lupus erythematosus: A prospective study from North India.

Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder and has complex etiopathogenesis. The most appropriate hypothesis states that genetic susceptibility in the presence of environmental risk factors predisposes to SLE. HLA class II alleles are critical to immune response and are highly polymorphic. Various alleles in HLA-DR and -DQ regions were analyzed in SLE patients and healthy controls to see their role in susceptibility or protection to SLE. Materials and Methods: This was a prospective observational study, in which a total of 100 SLE patients and 100 controls were analyzed. HLA typing was done by polymerase chain reaction (PCR)-sequence-specific oligonucleotide (SSO) method (SSO probe). Results: DRß1*0301 was significantly increased in SLE patients when compared to controls and had the highest odds ratio. Other risk factor alleles found to be increased were DRß1*0701, DQß1*0202, and DQß1*0301, which had a significant positive association with SLE, suggesting their role in susceptibility to SLE. In contrast, DRß1*0401, DRß1*1401, DRß1*1404, DRß1*1501, DQß1*0501, and DQα1*0201 showed statistically significant reduction in SLE patients, while these were much more common in controls, suggesting their protective role. Conclusion: This study is only the second study in patients from North India and it determines the role of DRß1*0301, DRß1*0701, DQß1*0202, and DQß1*0301 alleles as risk factors in SLE patients.

Clinicoradiological Profile of COVID-19-Associated Rhino-Orbital Cerebral Mucormycosis with a Focus on Computed Tomography: A Clinical Case Series and Review.

COVID-19-associated rhino-orbital cerebral mucormycosis (ROCM) has a rapidly evolving course with high morbidity and mortality. We describe imaging features of COVID-19-associated ROCM based on noncontrast computed tomography (NCCT). This retrospective single-center observational study included 50 patients with COVID-19 from January 1, 2021 to June 30, 2021 who subsequently developed ROCM confirmed by fungal culture studies. All patients underwent NCCT of the paranasal sinuses as the diagnostic workup. The involvement of the nasal cavity, paranasal sinuses, orbits, and intracranial cavity was identified and graded. The ethmoid sinuses were most commonly involved [right (n = 46 of 50) > left (n = 45 of 50)], followed by the maxillary, sphenoid, and frontal sinuses. Thinning and erosions of the hard palate were noted in 18% of patients (n = 9), whereas 34% (n = 17) showed dehiscence of the lamina papyracea. Retromaxillary fat stranding was noted in 68% of patients (n = 34). Severe ethmoid sinusitis was associated significantly with ipsilateral pterygopalatine fossa involvement. The extraocular muscles were involved in 64% of patients (n = 32), with 84% (n = 42) showing orbital fat stranding. Proptosis of the affected eye was seen in 66% of patients, optic nerve involvement in 52%, and irregularity of globe contour in 12% (n = 6). The cavernous sinuses were affected in 10% of patients (n = 5), with three of them having temporal infarcts. COVID-19-associated ROCM is an acute, invasive fungal disease characterized by multisinus involvement, often with orbital and intracranial extension. Bilateral involvement with rapid progression should alert one to underlying COVID-19 disease.

A single-blinded, randomized controlled trial of standard versus higher dose carboplatin-based intravenous chemotherapy for group D and E retinoblastoma.

BACKGROUND: Access to intra-arterial chemotherapy for retinoblastoma in low- and middle-income countries (LMICs) is limited. There is a need to optimize the efficacy of systemic chemotherapy for advanced intraocular retinoblastoma, particularly in LMICs. The aim was to compare the efficacy of standard versus higher dose carboplatin-based intravenous chemotherapy for group D and E retinoblastoma. METHODS: The single-center, single-blinded, randomized study was conducted during 2019-2021. Patients with newly diagnosed group D or E retinoblastoma were randomized to receive vincristine, etoposide, and standard versus higher dose (<36 months: 18.6 vs. 28 mg/kg; ≥36 months: 560 vs. 840 mg/m2 ) carboplatin. Examination under anesthesia and ultrasonography was performed at diagnosis and following three cycles of chemotherapy. Group E eyes with poor likelihood of globe/vision salvage at diagnosis were excluded. RESULTS: Thirty-two eyes of 30 patients were analyzed: 17 group D and 15 group E eyes. The tumor response to chemotherapy with regards to regression pattern (p = .72), tumor shrinkage (diameter: p = .11, height: p = .96), subretinal seeds (p = .91), and vitreous seeds (p = .9) were comparable between the two treatment arms. The globe salvage (group D [82% vs. 67%; p = .58]; group E [12.5% vs. 29%; p = .57]) and salvage of meaningful vision (group D [100% vs. 75%; p = .13]; group E [100% vs. 50%; p = .48]) were comparable between standard and higher dose arms. No excess treatment-related toxicity was observed in the higher dose arm. CONCLUSIONS: Higher dose carboplatin-based intravenous chemotherapy did not result in superior globe or vision salvage in group D or E retinoblastoma.

Overexpressed Nup88 stabilized through interaction with Nup62 promotes NF-κB dependent pathways in cancer.

Bidirectional nucleo-cytoplasmic transport, regulating several vital cellular processes, is mediated by the Nuclear Pore Complex (NPC) comprising the nucleoporin (Nup) proteins. Nup88, a constituent nucleoporin, is overexpressed in many cancers, and a positive correlation exists between progressive stages of cancer and Nup88 levels. While a significant link of Nup88 overexpression in head and neck cancer exists but mechanistic details of Nup88 roles in tumorigenesis are sparse. Here, we report that Nup88 and Nup62 levels are significantly elevated in head and neck cancer patient samples and cell lines. We demonstrate that the elevated levels of Nup88 or Nup62 impart proliferation and migration advantages to cells. Interestingly, Nup88-Nup62 engage in a strong interaction independent of Nup-glycosylation status and cell-cycle stages. We report that the interaction with Nup62 stabilizes Nup88 by inhibiting the proteasome-mediated degradation of overexpressed Nup88. Overexpressed Nup88 stabilized by interaction with Nup62 can interact with NF-κB (p65) and sequesters p65 partly into nucleus of unstimulated cells. NF-κB targets like Akt, c-myc, IL-6 and BIRC3 promoting proliferation and growth are induced under Nup88 overexpression conditions. In conclusion, our data indicates that simultaneous overexpression of Nup62 and Nup88 in head and neck cancer stabilizes Nup88. Stabilized Nup88 interacts and activates p65 pathway, which perhaps is the underlying mechanism in Nup88 overexpressing tumors.

Understanding the killer-cell immunoglobulin like receptor polymorphism in retinoblastoma.

BACKGROUND: The KIR receptors present on the natural killer (NK) cells play a crucial role by exercising cytotoxicity to eliminate tumor cells. Both KIR and class-I HLA molecules exhibit extensive polymorphism. Although RB1 inactivation triggers the initiation of retinoblastoma; however additional immune alterations trigger tumor development. The aim was to explore the KIR/HLA polymorphism and its role in the pathogenesis of retinoblastoma. METHODS: Patients with unilateral, non-familial retinoblastoma were enrolled as cases. Healthy individuals matched for ethnicity were enrolled as controls. KIR genotyping was performed by sequence-specific primer assay. The investigated KIR genes included: inhibitory (2DL1, 2DL2, 2DL3, 2DL4, 2DL5A, 2DL5B), activating (2DS1, 2DS2, 2DS3, 2DS4*FUL, 2DS4*DEL, 2DS5, 3DL1, 3DL2, 3DL3, 3DS1) and pseudogenes (2DP1, 3DP1*FUL, 3DP1*DEL). In addition, HLA ligands were investigated by sequence-specific oligonucleotide assay for HLA-A, B, and C locus. RESULTS: KIR genotyping was performed in 48 cases and 107 controls. The mean age of cases was 2.9 ± 2.2 years (range: 0.25-10). Among the 19 KIR genes, the frequency of KIR2DS4*FUL (p = 0.0019) and 2DS5 (p = 0.0095) was increased among cases. HLA ligands were investigated in 25 cases and 50 controls. The frequency of HLA ligands (C1/C2, Bw4, A3/A11) was similar among cases and controls. However, the KIR/HLA combination frequency for KIR3DS1/HLA-Bw4 was decreased in cases (p = 0.006). CONCLUSION: It is the pioneer study to report the association of killer cell immunoglobulin-like receptors in retinoblastoma. KIR2DS4*FUL and KIR2DS5 had a susceptible, and KIR3DS1/HLA-BW4 had a protective role in retinoblastoma. The results will aid in exploring the therapeutic potential of NK cell-based therapy for retinoblastoma.

A fungal epidemic amidst a viral pandemic: Risk factors for development of COVID-19 associated rhino-orbital-cerebral mucormycosis in India.

PURPOSE: To study the risk factors for development of COVID-19 associated rhino-orbital-cerebral mucormycosis (ROCM) during the COVID-19 pandemic in India. METHODS: Multi-centric retrospective case-control study conducted from October 2020 to May 2021. Cases comprised of consecutive patients of COVID-19-associated ROCM (CA-ROCM) presenting at the participating ophthalmic institutes. Controls comprised of COVID-19-positive or COVID-19-recovered patients who did not develop ROCM. Comparative analysis of demographic, COVID-19 infection, treatment parameters and vaccination status between cases and controls performed. Clinical and imaging features of CA-ROCM analyzed. RESULTS: There were 179 cases and 361 controls. Mean age of presentation in cases was 52.06 years (p = .001) with male predominance (69.83%, p = .000011). Active COVID-19 infection at the time of presentation of ROCM (57.54%, p < .0001), moderate to severe COVID-19 (p < .0001), steroid administration (OR 3.63, p < .00001), uncontrolled diabetes (OR 32.83, p < .00001), random blood sugar >178 mg/dl were associated with development of CA-ROCM. Vaccination showed a protective effect (p = .0049). In cases with intracranial or cavernous sinus extension there was history of steroid administration (OR 2.89, p = .024) and orbital apex involvement on imaging (OR 6.202, p = .000037) compared to those with only rhino-orbital disease. CONCLUSION: Male gender, active COVID-19 infection, moderate or severe COVID-19, uncontrolled diabetes, steroid administration during COVID-19 treatment are risk factors for developing rhino-orbital-cerebral mucormycosis. Vaccination is protective. Random blood sugar of >178 mg/dl in COVID-19 positive or recovered patients should warrant close observation and early detection of ROCM. Presence of ophthalmoplegia, blepharoptosis at first clinical presentation and orbital apex involvement on imaging are associated with intracranial extension in ROCM.

CTLA4 Gene Polymorphism and its Association with Disease Occurrence, Clinical Manifestations, Serum Markers and Cytokine Levels in SLE Patients from North India.

Background: Cytotoxic T lymphocyte-associated protein-4 (CTLA-4) or CD152 is an inhibitory receptor expressed constitutively on CD4+CD25+ T regulatory lymphocytes (Treg) and transiently on activated CD4+ and CD8+ T lymphocytes. Association of CTLA4 gene polymorphisms with Systemic Lupus Erythematosus (SLE) has been reported in south Indians, but not in north Indians. This study aims to investigate CTLA4 gene polymorphism and its association with the occurrence of SLE, its clinical manifestation and serological markers in north Indians. Methods: This cross sectional study was done in a tertiary health care centre in north India. Patients reporting to the hospital and diagnosed with systemic lupus erythematosus were included in study. +49 A/G (snp- rs231775) CTLA4 gene polymorphism was analysed in 41 SLE patients and 21 matched healthy controls by real time PCR method. ANA (Antinuclear Antibody), anti dsDNA, Interferon-γ (IFN- γ), TGF-ß, IL-10 were measured by ELISA kits. Complement (C3 and C4) and immunoglobulins (IgA, IgG, IgM) estimation were done with the turbidometry method. Chi-square test was used for comparison between groups and odds ratio with 95% confidence interval was calculated to estimate the associated risk. Results: A/A genotype was most common (51.2%) followed by the A/G genotype (46.3%) and G/G genotype (2.4%, detected in only 1 patient). The frequency of A allele was 74.4%, while of G allele was only 25.6%. A/G genotype SLE patients showed a higher risk (odds ratio 37.5, 95% CI- 6.048-232.51) of developing edema compared to A/A genotype patients. There was no statistically significant association of various CTLA4 genotypes with the occurrence of SLE and serum markers. Conclusions: A/A was the most common CTLA4 genotype in both SLE patients and healthy controls of north India. Contrary to the previous report in south Indians, there was no statistically significant association between CTLA4 genotype and occurrence of SLE in north Indians. Only the presence of generalised edema was found significantly associated with the A/G genotype.

Histological Spectrum of Clinical Kidney Disease in Type 2 Diabetes Mellitus Patients with special Reference to nonalbuminuric Diabetic Nephropathy: A Kidney Biopsy-based Study.

BACKGROUND: Diabetic nephropathy (DN) is an important and catastrophic complication of diabetes mellitus (DM). Kidney disease has heterogeneity in histology in diabetes patients and includes both diabetic kidney disease (DKD) (albuminuric or nonalbuminuric) and nondiabetic kidney disease (NDKD) either in isolation or in coexistence with DN. Diabetic nephropathy is hard to overturn. While NDKD is treatable and reversible. MATERIALS AND METHODS: We enrolled a total of 50 type 2 diabetes mellitus (T2DM) patients with clinical kidney disease, of both genders and age >18 years, who underwent kidney biopsy from October 2016 to October 2018. Patients with proteinuria <30 mg per day were excluded from the study. The indications of the renal biopsy were nephrotic syndrome (NS), active urinary sediment, rapid decline in renal function, asymptomatic proteinuria, and hematuria. RESULT: A total of 50 (males: 42 and females: eight) patients with T2DM who underwent kidney biopsy were enrolled. The clinical presentation was: NS 26 (52%), chronic kidney disease (CKD) 11 (22%), asymptomatic proteinuria and hematuria six (12%), acute kidney injury (AKI) four (8%), and acute nephritic syndrome (ANS) three (6%). Diabetic retinopathy (DR) was noted in 19 (38%) cases. Kidney biopsy revealed isolated DN, isolated NDKD, and NDKD superimposed on DN in 26 (52%), 14 (28%), and 10 (20%) cases, respectively. Idiopathic membranous nephropathy (MN) (4) and amyloidosis (2) were the most common forms of NDKD, whereas diffuse proliferative glomerulonephritis (DPGN) was the main form of NDKD superimposed on DN. Diabetic nephropathy was observed in 15 (79%) cases in presence of DR and also in 11 (35.5%) cases even in absence of DR. Of eight patients with microalbuminuria four (50%) cases have biopsy-proven DN. CONCLUSION: About 48% of patients had NDKD either in isolation or in coexistence with DN. Diabetic nephropathy was found in absence of DR and in patients with a low level of proteinuria. The level of proteinuria and presence of DR does not help to distinguish DN vs NDKD. Hence, renal biopsy may be useful in selected T2DM patients with clinical kidney disease to diagnose NDKD.

A Study of Head and Neck Cancer Patients with Reference to Tobacco Use, Gender, and Subsite Distribution.

Richa ChauhanContext Head and neck cancer (HNC) is very common in India, constituting 30% of all the cancers because of the widespread use of tobacco across India. The prevalence and pattern of tobacco use vary in different regions and states of the country. Although predominantly seen in males, studies have reported that the male-to-female ratio varies worldwide and also by anatomical subsite. Aims This study was done with an aim to determine the difference in pattern and prevalence of tobacco use in male and female patients with HNCs and compare them with different subsites' involvement in our region. Methods and Materials This is a retrospective analysis of 500 consecutive biopsy-proven HNC patients from a large comprehensive cancer hospital from Bihar during the period of January 2019 to June 2019. Data collected for the study included age, gender, site of the disease, and use of tobacco. The categorical data were analyzed by a chi-square test using SPSS (version 16). Results Our study showed a male-to-female ratio of 8.43:1 with tobacco addiction in 84.40% patients. Smokeless tobacco was used by 52.20%, combustible form by 12.80%, and both by 19.40% of the patients. Tobacco use was seen in 87.25% of male patients as compared with only 60.38% of female patients ( p -value = 0.0001). Oral cavity cancer was seen in 60.85% of male patients and 37.74% of female patients ( p -value = 0.0012), whereas oropharyngeal cancer was seen in only 11.63% of male patients as compared with 25.83% of female patients ( p -value = 0.0008). The subsite analysis showed that in patients with oral cavity cancers, no addiction was found in only 10.29% of male patients as compared with 30% of the female patients ( p -value = 0.008). Conclusions Our study confirms a high prevalence of tobacco use among HNC patients. So, we need to continue our efforts to create awareness against tobacco use. Besides, there is also a need for more studies to look into other etiological factors among nontobacco users.

A comparative analysis of the clinicopathological profile of early-onset versus late-onset rectal cancer patients.

Introduction: Colorectal cancer has been primarily considered a disease of the elderly, but recent data have shown an alarming rise among young people. It has been also suggested that young age is associated with aggressive histopathological characteristics and advanced stages of the disease at diagnosis. As there are few studies and none from our part of the country evaluating the clinicopathological profile of early-onset versus late-onset rectal cancer patients, this analysis was conducted to assess and compare the clinical and pathological characteristics of patients with rectal cancer diagnosed with ages over and below 50 years. Materials and method: The relevant details of all biopsy proven rectal cancer patients undergoing radiotherapy at a tertiary cancer hospital, from January 2017 to December 2019, were collected. All the data were categorised into two groups, an early-onset group (age <50 years) and a late-onset group (age ≥50 years), and comparison of the clinicopathological characteristics between the two groups was made. Results: A total of 224 patients with rectal cancer, 150 male and 74 female, were included in the study. About two-thirds of the patients were less than 50 years of age, with an average age of 42 years. The comparative analysis showed a significantly higher number of young patients presenting with bleeding and pain. Patients below 50 years also had a significantly higher number of adenocarcinoma grade III and clinical stage III than those in the late-onset group. Conclusion: Our study revealed a significant number of early-onset rectal cancer patients. There should be a high index of suspicion in any young patient presenting with symptoms suggestive of rectal malignancy and they should be evaluated promptly.

Serum complements and immunoglobulin profiles in systemic lupus erythematosus patients: An observational study at a teaching hospital.

Context: Serum complement proteins and autoantibodies play an important role in the pathogenesis and diagnosis of systemic lupus erythematosus (SLE). Abnormalities in various immunoglobulin levels are described in patients of SLE. Aims: To study the spectrum of clinical manifestations and measure the serum levels of complement C3, complement C4, autoantibodies and immunoglobulin G (IgG) in patients of SLE and compare with healthy controls. Settings and Design: The present study is a prospective hospital-based observational study conducted between May 2014 and December 2018. Statistical Analysis Used: Unpaired t-test was used to compare the mean values between the SLE patients and healthy controls. Material and Methods: A total of 100 cases of SLE and 100 healthy controls were included in the study. The clinical data were retrieved. Serum antinuclear antibody, anti-ds DNA antibody, and anti-Smith antibody levels, and complements C3, C4 and IgG were measured. Results: Arthritis (89%) and anaemia (65%) were two common clinical presentations. The low complement C3 levels and C4 were detected in 64 and 62% of the SLE patients. Serum IgG was increased in 41% of the patients. A reduced level of IgG was detected in 6% of the patients. Conclusion: Primary care physicians should be aware of the clinical and serological manifestations of SLE as early detection will reduce end-organ damage. Autoantibody testing and complement testing should be done in all suspected cases. This study showed a significantly reduced C3 and C4 and elevated IgG in many cases of SLE as compared to control. Hypogammaglobulinemia was also present in a minority of the cases.

Thyroid eye disease with concurrent orbital lymphoma: a radiological surprise.

Summary: Thyroid eye disease (TED) is the most common extra-thyroidal manifestation in Graves' disease (GD). Additional/concurrent/synchronous pathologies may be present, especially in elderly patients who present with atypical features such as non-axial (or eccentric) proptosis, absence of lid lag and restricted superior extra-ocular movements. A 70-year-old female presented with progressive proptosis of her left eye and diplopia. She was diagnosed with GD a year prior and initiated on carbimazole. On examination, she had eccentric proptosis, restricted superior extra-ocular movements and a palpable mass in the supero-temporal quadrant of the left eye. Her T3 (1.33 ng/mL) and T4 (8.85 µg/dL) were normal with carbimazole. Thyroid-stimulating hormone (TSH)-receptor antibody was positive (3.15 IU/L, reference range <1.75). MRI revealed an enhancing lesion infiltrating the left superior rectus, with concurrent characteristic muscle belly involvement bilaterally. Orbital biopsy showed atypical lymphoid cells (CD20+), suggesting marginal zone lymphoma. CT thorax and abdomen, fluorodeoxyglucose-positron emission tomography and bone marrow examination were normal. The patient was administered orbital radiotherapy for her localised lymphoma and carbimazole was continued. TED is the most common cause of orbital involvement overall and in GD. However, additional or alternative pathology may be present which requires evaluation. MRI can be a useful adjunct in these patients. Orbital lymphoma needs to be staged with workup for disseminated disease. Radiotherapy is the treatment of choice for localized disease. The index case provides evidence for synchronous presentation of dual pathology and highlights the importance of astute clinical examination as well as keeps a low threshold for MRI in selected cases. Learning points: Thyroid eye disease can co-exist with other ocular pathology, especially in elderly individuals. Eccentric proptosis, absent lid lag and restriction of eye movements (suggesting tendon involvement) should alert towards the presence of alternative pathology. Orbital imaging using MRI not only has greater sensitivity in diagnosing radiologically bilateral disease in patients who have unilateral involvement clinically but is also useful to identify concurrent neoplasms.

Pre-treatment hematological parameters as a cost effective predictive marker for response to concurrent chemo radiation in locally advanced cervical cancer.

INTRODUCTION: Locally advanced cervical cancer is still a major cause of mortality in developing countries. Recently, personalized medicine has changed the treatment paradigm for many solid cancers but no robust biomarkers has yet been validated for predicting response to chemo radiation in cervical cancer patients. AIM: To assess the role of hematological parameters as a cost-effective predictive marker of response to concurrent chemo radiation in cervical cancer patients. MATERIALS AND METHOD: This is a retrospective analysis of 90 cervical cancer patients treated with concurrent chemo radiation in a tertiary cancer center. Clinical details of the patients were extracted from the case records. For end point evaluation, the pre-treatment levels of hemoglobin, neutrophil, lymphocyte, platelet, platelet lymphocyte ratio (PLR) and neutrophil lymphocyte ratio (NLR) were compared and statistically analyzed between responders and non-responders. The optimal cutoff values of hematological parameters were estimated by the receiver operating characteristics (ROC) curve. RESULT: Out of 90 patients, 60 (66.66%) were complete responders and remaining 30 (33.33%) were non-responders. The mean value of platelet, NLR, and PLR was significantly higher in the non-responder group. ROC curve analysis showed the optimal cut-off value of pre-treatment Hb, PLT, NLR and PLR to be 11 gm/dl, 3, 177 × 109/L, and 70 respectively. CONCLUSION: Our study suggests that simple hematological markers like NLR, PLT count and PLR could be used as a cost effective pretreatment predictive marker for response to chemo radiation in cervical cancer patients.

Waldenström Macroglobulinemia of the orbit: A diagnostic challenge.

PURPOSE: Ocular adnexal lymphomas (OAL) constitute 55% of all orbital tumors. Waldenström Macroglobulinemia (WM) presenting as an orbital mass with diffuse extraocular muscle (EOM) involvement is rare. We report an elderly patient who presented to the ophthalmologist for an orbital mass which on evaluation, turned out to an ocular adnexal WM. OBSERVATIONS: A 75 years old man presented with a palpable mass in the left anterior superior orbit and bilateral restricted ocular motility in all gazes. Computed tomography scan revealed a hyperdense mass with diffuse thickening of extraocular muscles and enlarged lacrimal gland on the left side. Incisional biopsy of the mass revealed a lymphoproliferative neoplasm with plasmacytic morphology. Immunohistochemistry (IHC) of the orbital mass as well as the bone marrow was sought, lymphoplasmacytic lymphoma (CD20+, CD38+, MUM1+, BCL 2+, CD3-, CD5-, CD10-, CD23-, cyclin D1). Bone marrow flow cytometry showed CD5-, CD10- kappa restricted B cell neoplasm. Serum analysis significantly elevated IgM levels. This indicated a diagnosis of ocular adnexal Waldenström Macroglobulinemia. CONCLUSION AND IMPORTANCE: This case highlights the importance of clinical evaluation, histopathology, and immunohistochemistry for phenotyping of ocular adnexal lymphomas.

Development of a Clinical Prediction Model for In-hospital Mortality from the South African Cohort of the African Surgical Outcomes Study.

BACKGROUND: Data on the factors that influence mortality after surgery in South Africa are scarce, and neither these data nor data on risk-adjusted in-hospital mortality after surgery are routinely collected. Predictors related to the context or setting of surgical care delivery may also provide insight into variation in practice. Variation must be addressed when planning for improvement of risk-adjusted outcomes. Our objective was to identify the factors predicting in-hospital mortality after surgery in South Africa from available data. METHODS: A multivariable logistic regression model was developed to identify predictors of 30-day in-hospital mortality in surgical patients in South Africa. Data from the South African contribution to the African Surgical Outcomes Study were used and included 3800 cases from 51 hospitals. A forward stepwise regression technique was then employed to select for possible predictors prior to model specification. Model performance was evaluated by assessing calibration and discrimination. The South African Surgical Outcomes Study cohort was used to validate the model. RESULTS: Variables found to predict 30-day in-hospital mortality were age, American Society of Anesthesiologists Physical Status category, urgent or emergent surgery, major surgery, and gastrointestinal-, head and neck-, thoracic- and neurosurgery. The area under the receiver operating curve or c-statistic was 0.859 (95% confidence interval: 0.827-0.892) for the full model. Calibration, as assessed using a calibration plot, was acceptable. Performance was similar in the validation cohort as compared to the derivation cohort. CONCLUSION: The prediction model did not include factors that can explain how the context of care influences post-operative mortality in South Africa. It does, however, provide a basis for reporting risk-adjusted perioperative mortality rate in the future, and identifies the types of surgery to be prioritised in quality improvement projects at a local or national level.

Immunogenetic Study of Diabetes Mellitus in Relation to HLA DQ and DR.

INTRODUCTION: Type-1 diabetes mellitus (T1DM) which is also known as insulin-dependent diabetes is diagnosed mainly during childhood and accounts for approximately 5%-10% of all cases of DM. In India, early onset diabetes (<15 years age) constitutes about 1%-4% of the total diabetic population. The insulitis as well as to a humoral (B cell) response with production of antibodies to IAA, GAD, and the protein tyrosine phosphatase IA2 (IA-2AA) is the main pathogenesis of T1DM. Human leukocyte antigen (HLA)-DR and DQ contributes approximately 40%-50% of the inherited susceptibility for T1DM and most frequently involved haplotypes are DRB1*0301-DQB1*0201, DRB1*0301-DQA1*0501-DQB1*0201, and DRB1*0401-DQB1*0302. METHOD AND MATERIAL: Total 70 cases of DM in age group of 10 years to 65 years and 25 healthy controls of same age group 30 cases of complicated diabetic mellitus were included in the study. 2 mL blood was taken in an EDTA vial for HLA typing and 5 mL blood was taken in a plain vial for anti-GAD antibody. HLA DQB1 and DRB1 were done by sequence specific priming polymerase chain reaction method. Indirect immunofluorescent test was used for anti-GAD antibody. Statistical analysis was performed using SPSS version-16. RESULTS: Total 40.9% cases of type-I DM were found seropositive for anti-GAD antibody. None of the cases of type-II DM was anti-GAD antibody positive. HLA DRB1*03010 were significantly more in diabetic patient (P < 0.011) as compared to control. DRB1*O403/6 shows that a relative risk of 1.08 was slightly more frequent in DM cases as compared to the control. DQB1*0201 was significantly high (P < 0.004) in DM patient as compared to control with a relative risk of 1.68. Correlation of DR, DQ antigen with types of DM showed that in type-I DM, DRB1*03010 was significantly high (P = 0.009) with a relative risk of 2.78 as compared type-II DM. In DQ typing, DQB1*0201 was significantly high in type-I DM in comparison to type-II DM (65% vs. 30%, P = 0.026, RR = 2.05). Comparison of DQB1 in type-I DM with healthy control showed that DQB1*0201 was significantly high in type-I DM as compared to healthy control (P = 0.0003, RR = 3.09). In type-I DM patient's homozygosity at DRB1*03010, DRB1*03010 was significantly high as compared to the control (P < 0.047, RR = 2.33). Correlation of anti-GAD antibody with DRB1 and DQB1 showed that 77.7% anti-GAD antibody positive cases were DRB1*03010 positive. Similarly, in DQB1 typing, 66.6% anti-GAD positive cases have DQB1*0201. CONCLUSION: Prevalence of anti-GAD antibody in Indian population was found up to 45%. HLA DRB1*3010 and HLA DQB1*0201 were the most susceptible haplotypes for type-I DM. HLA DRB1*14 and HLA DRB1*15 were the protective haplotypes for type-I DM. Susceptibility to type-I DM increases when the homozygosity for DRB1*03010 was present. Diagnosis of type-I DM by anti-GAD antibody was possible in only 40.9% cases but if DRB1 and DQB1 typing is added in the diagnosis then diagnostic efficacy increases up to 83%.

Ocular oncology practice guidelines during COVID-19 pandemic-An expert consensus.

The outbreak of rapidly spreading COVID-19 pandemic in December 2019 has witnessed a major transformation in the health care system worldwide. This has led to the re-organization of the specialty services for the effective utilization of available resources and ensuring the safety of patients and healthcare workers. Suspension of oncology services will have major implications on cancer care due to delayed diagnosis and treatment leading to irreversible adverse consequences. Therefore various oncology organizations have called for a continuation of cancer care during this crisis with diligence. The COVID-19 pandemic has forced the clinicians to transform the components of care from screening to outpatient care and primary management. The purpose of this article is to establish guidelines and recommendations for ocular oncology in the management of ocular tumors set by a multidisciplinary team of experts including ocular, medical and radiation oncologists, and pathologists. As the pandemic is evolving fast, it will require constant updates and reformation of health strategies and guidelines for safe and quality health care.

Interleukin 6 and disease transformation in chronic myeloid leukemia: A Northeast Indian population study.

BACKGROUND: Interleukin 6 (IL6) has been suggested to be a valuable prognostic marker in chronic myeloid leukemia (CML). IL6 is a pleiotropic cytokine and plays an important role in immune response, hematopoiesis, and acute phase response. IL6 is regarded as a prominent target for clinical interventions. OBJECTIVE: The aim of the present study was to investigate the serum levels of IL6 in CML to provide greater insight to their role in disease transformation in Indian patients. MATERIALS AND METHODS: A total of 50 CML cases and 10 acute lymphocytic leukemia (ALL) cases along with 20 healthy controls were included in the study between 2015 and 2016. About 4 mL blood samples were collected from all cases in plain vial and serum was separated. Levels of IL6 were determined in all cases by enzyme-linked immunosorbent assay. RESULTS: The study suggests that both ALL and CML are associated with significantly elevated serum IL6 level than the healthy control group. Mean levels of serum IL6 are 223.4 ± 53.403 pg/mL in CML, 71.020 ± 29.549 pg/mL in ALL, and 5.360 ± 0.467 pg/mL in healthy control group. Serum IL6 correlated with different phases of CML. Mean IL6 levels are 50.93 ± 29.37 pg/mL in chronic phase (CP), 69.02 ± 22.60 pg/mL in accelerated phase (AP), and 652.77 ± 124.62 pg/mL in blast crisis (BC) phase of CML. In compared to CP and AP, in BC, IL-6 is significantly elevated ( P = 0.00 and 0.00, respectively); however, we did not find a significant difference in IL-6 serum levels between CP and AP ( P = 0.703). CONCLUSION: Study suggests that the detection of IL6 level in newly diagnosed patient can predict the severity of the disease. There might be association of level of IL6 with the disease transformation.