Structural and biophysical analysis of cytochrome P450 2C9*14 and *27 variants in complex with losartan.

The human cytochrome P450 (CYP) 1, 2 and 3 families of enzymes are responsible for the biotransformation of a majority of the currently available pharmaceutical drugs. The highly polymorphic CYP2C9 predominantly metabolizes many drugs including anticoagulant S-warfarin, anti-hypertensive losartan, anti-diabetic tolbutamide, analgesic ibuprofen, etc. There are >80 single nucleotide changes identified in CYP2C9, many of which significantly alter the clearance of important drugs. Here we report the structural and biophysical analysis of two polymorphic variants, CYP2C9*14 (Arg125His) and CYP2C9*27 (Arg150Leu) complexed with losartan. The X-ray crystal structures of the CYP2C9*14 and *27 illustrate the binding of two losartan molecules, one in the active site near heme and another on the periphery. Both losartan molecules are bound in an identical conformation to that observed in the previously solved CYP2C9 wild-type complex, however, the number of losartan differs from the wild-type structure, which showed binding of three molecules. Additionally, isothermal titration calorimetry experiments reveal a lower binding affinity of losartan with *14 and *27 variants when compared to the wild-type. Overall, the results provide new insights into the effects of these genetic polymorphisms and suggests a possible mechanism contributing to reduced metabolic activity in patients carrying these alleles.

The Impact of Homemade Laparoscopic Box Trainers on Medical Student Surgical Skills: A Randomized Control Pilot Study.

Objective: While instructional videos are commonly used in surgical education, there is a paucity of data on home laparoscopic box trainers. This pilot study evaluated impacts of augmenting instructional videos with these devices. Design: This was a randomized controlled pilot study evaluating laparoscopic surgical performance on the LapSim virtual surgical simulator before and after a 2 week curriculum of instructional videos alone (n = 8, 47.1%) vs videos plus a home laparoscopic box trainer (n = 9, 52.9%). The LapSim recorded mistake number, time, and instrument path length to complete each task. Participants completed surveys about their perceptions of surgery before and after the course. Participants: Preclinical medical students were recruited. Those with extensive surgical experience or did not complete the course were excluded. Results: For the box trainer group vs the videos alone group: mean change in mistakes was -10.0 (standard deviation [SD]:17.1) vs +.5 (SD:21.59) (P = .28); mean change in time was -433.24 (SD:304.67) seconds vs -366.16 (SD:240.10) seconds (P = .62); mean change in instrument path length was -4.27 (SD:4.38) meters vs -3.19 (SD:4.86) meters (P = .64). The box trainer group ranked "I feel as though surgery comes naturally" 1.58 points higher (95% confidence interval [CI]: .85, 2.32; P < .01) and "I am worried about being skilled at surgery" 1.26 points lower (95% CI: 2.29, -.24; P = .02) upon completing the study. The videos alone group reported no significant changes in survey responses. Conclusion: Home laparoscopic box trainers can generate confidence and reduce anxiety regarding surgical fields. This study provides a framework for future larger scale works.

Experience of Nivolumab Prior to Autologous Stem Cell Transplant for Relapsed Refractory Hodgkin Lymphoma.

Purpose Nivolumab is an anti-programmed cell death protein 1 (PD1) monoclonal antibody that is indicated in relapsed/refractory Hodgkin lymphoma (R/R HL) after autologous stem cell transplant (autoSCT). Purpose of our retrospective study was to assess safety and efficacy of Nivolumab in R/R HL as a bridge to autoSCT in patients who are refractory to ≥ 2 lines of chemotherapy. Methods Demographic data, number of chemotherapy regimens given previously, number of Nivolumab doses taken, and disease status on PET/CT were noted. Nivolumab was administered as a 3 mg/kg IV infusion every 2 weeks. The immunotherapy related adverse events (irAEs) were noted if any and documented. Results A total of 16 patients were included in the study. Ten patients were male and 6 were female. Median age was 22 years (range 3-32 years). The median number of treatment lines prior to Nivolumab was 3 (range 2-7). Nine patients had Complete Response (CR), 3 had Partial response (PR), 2 had Stable Disease (SD), 1 patient had pseudo-progression; classified as IR (3) and 1 expired before end of treatment evaluation. The drug was well tolerated, with mild irAEs noted. Twelve patients (75%) successfully underwent autoSCT. At a median follow up of 17.5 months (range 0.5-35 months), the progression- free survival (PFS) was 75% and overall survival (OS) was 87.5%. Conclusion Nivolumab is effective and safe in patients with R/R HL and is a good bridging therapy to autoSCT.

Insights into the Genetic Variations of Human Cytochrome P450 2C9: Structural Analysis, Characterization and Comparison.

Cytochromes P450 (CYP) are one of the major xenobiotic metabolizing enzymes with increasing importance in pharmacogenetics. The CYP2C9 enzyme is responsible for the metabolism of a wide range of clinical drugs. More than sixty genetic variations have been identified in CYP2C9 with many demonstrating reduced activity compared to the wild-type (WT) enzyme. The CYP2C9*8 allele is predominantly found in persons of African ancestry and results in altered clearance of several drug substrates of CYP2C9. The X-ray crystal structure of CYP2C9*8, which represents an amino acid variation from arginine to histidine at position 150 (R150H), was solved in complex with losartan. The overall conformation of the CYP2C9*8-losartan complex was similar to the previously solved complex with wild type (WT) protein, but it differs in the occupancy of losartan. One molecule of losartan was bound in the active site and another on the surface in an identical orientation to that observed in the WT complex. However, unlike the WT structure, the losartan in the access channel was not observed in the *8 complex. Furthermore, isothermal titration calorimetry studies illustrated weaker binding of losartan to *8 compared to WT. Interestingly, the CYP2C9*8 interaction with losartan was not as weak as the CYP2C9*3 variant, which showed up to three-fold weaker average dissociation constant compared to the WT. Taken together, the structural and solution characterization yields insights into the similarities and differences of losartan binding to CYP2C9 variants and provides a useful framework for probing the role of amino acid substitution and substrate dependent activity.

Unmanipulated Stem Cell Boost for Mixed Chimerism in Transfusion Dependent Thalassemia.

Early mixed chimerism (MC) can lead to secondary graft rejection post allogeneic hematopoietic stem cell transplantation in transfusion dependent thalassemia (TDT) patients. Reduction of immunosuppression and donor lymphocyte infusions is the mainstay for treating MC. We report our experience of administering unmanipulated stem cell boost (SCB) in reversing progressive early MC. There were 70 transplants done for 69 TDT patients at our center between September 2005 and January 2020. Mixed chimerism was defined by > 5% recipient cells and the severity was assigned according to the proportion of recipient cells as level 1 = < 10%, level 2 = 10-25%, level 3 = > 25%. For patients developing MC level 2 and 3, we administered unmanipulated SCB and analyzed its safety and efficacy. Out of 70 transplants 7 (10%) had MC level 2 (3/7) and 3 (4/7). These patients received unmanipulated SCB at a median CD34 cell dose of 4.5 × 106/kg (range-3.5 × 106/kg-5.5 × 106/kg). Overall Response (stable MC and/or transfusion independency) to unmanipulated SCB was seen in 5 patients (71.4%). Five patients (71.4%) developed acute graft versus host disease (GVHD) of which 1 patient expired due to severe GVHD. SCB infusion was well tolerated by majority of our patients. The 3 year overall survival and thalassemia free survival was 85.7% (6/7) and 57.1% (4/7) respectively. Timely monitoring of chimerism is important for detecting early MC. Development of acute GVHD is common after administration of unmanipulated SCB and requires vigilance and prompt management. Unmanipulated SCB is a feasible modality for treating progressive MC and salvaging the graft especially in resource-constrained settings.

Impact of nationwide lockdown on cancer care during COVID-19 pandemic: A retrospective analysis from western India.

BACKGROUND AND AIMS: COVID-19 has impacted healthcare system worldwide including cancer case. Aim of this study was to describe the experience of lockdown on cancer care concerning patient's visit and reception of treatment in western India. METHODS: This is a retrospective observational study conducted in patients with cancer attending a tertiary care center pre-lockdown and during lockdown (from January to May 2020). Data related to demographic parameters, type of tumor, type of treatment received and functional status of patients were retrieved from hospital medical records of patients. RESULTS: Of the 5258 patients included, 4363 visited hospital pre-lockdown (median age, 50 years) and 895 visited during the lockdown period (median age, 47 years). A total of 1168 and 106 patients visiting hospital before and during lockdown, respectively, had comorbidities. Breast cancer (25.6% and 29.7%), head and neck cancer (21.3% and 16.9%) were the most common type of solid tumors; leukemia (58.0% and 73.0%), lymphoma (18.8% and 13.5%) and multiple myeloma (18.6% and 12.2%) were the most common type of hematological malignancies observed in patients visiting pre-lockdown and during lockdown, respectively. Chemotherapy was most commonly received treatment (pre-lockdown, 71.8%; during lockdown, 45.9%). Other therapies reported includes supportive/palliative, targeted, hormonal, and immunotherapy. The majority of patients who visited the hospital pre-lockdown (68.4%) and during lockdown (62.8%) had 0 or 1 Eastern Cooperative Oncology Group (ECOG) score. CONCLUSION: Overall observations highlight a substantial impact of an imposed nationwide lockdown during COVID-19 pandemic on cancer care of patients in terms of reduced patient visits and number of treatments received.

Considerations for Pediatric Retirement from Athletics Following Repetitive Concussive Traumatic Brain Injury: Incorporating the Right to an Open Future.

Guidance regarding the decision to remove an adolescent from athletic competition immediately following an acute concussive injury and the safe return of play in the short term is widely accepted and supported by clinical evidence, local institutional policies, and state and federal laws. There is considerably less guidance regarding the decision to permanently retire an adolescent athlete for medical reasons due to concussive injuries. In this article, we discuss the clinical and non-clinical considerations that should guide clinicians in discussions regarding the adolescent athlete's permanent retirement by emphasizing the ethical obligation to protect the child's right to an open future as possibly determinative in otherwise ambiguous cases.

Post-transplant Hemophagocytic Lymphohistiocytosis in Benign Hematological Disorders: Experience of 4 Cases with Review of Literature.

Post transplant Hemophagocytic lymphohistiocytosis (HLH) is a form of secondary HLH, which can be either early onset or late onset and is associated with significant morbidity and mortality. With the increasing popularity of post transplant cyclophosphamide based haploidentical stem cell transplantation (SCT), post transplant HLH is becoming a significant complication especially in benign hematological disorders. Methods: We present 4 cases of post transplant HLH occurring in 2 cases of severe aplastic anemia (post haploidentical SCT) and 2 cases of thalassemia major (post matched sibling SCT). All 4 cases had early onset variety with dismal prognosis. Conclusion: Post-transplant HLH is an important entity in benign hematological disorders, which needs to be identified early and treated promptly with steroids, monoclonal agents or immunosuppressive therapy. Serum ferritin levels are an important biomarker and help in monitoring response.

Structure of Cytochrome P450 2C9*2 in Complex with Losartan: Insights into the Effect of Genetic Polymorphism.

The human CYP2C9 plays a crucial role in the metabolic clearance of a wide range of clinical therapeutics. The *2 allele is a prevalent genetic variation in CYP2C9 that is found in various populations. A marked reduction of catalytic activity toward many important drug substrates has been demonstrated by CYP2C9*2, which represents an amino acid variation at position 144 from arginine to cysteine. The crystal structure of CYP2C9*2 in complex with an antihypertensive drug losartan was solved using X-ray crystallography at 3.1-Å resolution. The Arg144Cys variation in the *2 complex disrupts the hydrogen-bonding interactions that were observed between the side chain of arginine and neighboring residues in the losartan complex of CYP2C9 and the wild-type (WT) ligand-free structure. The conformation of several secondary structural elements is affected, thereby altering the binding and orientation of drug and important amino acid side chains in the distal active site cavity. The new structure revealed distinct interactions of losartan in the compact active site of CYP2C9*2 and differed in occupancy at the other binding sites previously identified in the WT-losartan complex. Furthermore, the binding studies in solution using losartan illustrated lower activity of the CYP2C9*2 compared with the WT. Together, the findings yield valuable insights into the decreased hydroxylation activity of losartan in patients carrying CYP2C9*2 allele and provide a useful framework to investigate the effect of a single-nucleotide polymorphism that leads to altered metabolism of diverse drug substrates. SIGNIFICANCE STATEMENT: The *2 allele of the human drug-metabolizing enzyme CYP2C9 is found in different populations and results in significantly reduced activity toward various drug substrates. How the CYP2C9*2 variant induces altered drug metabolism is poorly understood given that the Arg144Cys variation is located far away from the active site. This work yield insight into the effect of distal variation using multitude of techniques that include X-ray crystallography, isothermal titration calorimetry, enzymatic characterization, and computational studies.

Pediatric chronic myeloid leukemia: A single-center experience.

BACKGROUND: The rationale of this study is to reveal the statistics of pediatric chronic myeloid leukemia (CML) patients. SUBJECTS AND METHODS: It is a retrospective analysis conducted to assess pediatric CML data from January 1998 to December 2014. There are 65 (3.2%) pediatric CML patients out of entire 2008 patients of CML. Data were analyzed regarding epidemiological characteristics, clinical presentations, response and side effects of imatinib, event-free survival, and overall survival of the pediatric CML patients. RESULTS: The median age of diagnosis was 11.84 years, and 76.9% patients were male and 23.07% patients were female. Sixty (92.3%) patients were in CML-chronic phase, 3 (4.6%) patients in CML-accelerated phase, and 2 (3.07%) patients in CML-blastic crisis. Most common initial symptoms and signs are weakness (60.0%), abdominal pain (55.38%), splenomegaly (100%), and hepatomegaly (86.5%). 67.3% of patients have white blood counts <100 × 109/L and 92.3% had platelets >150 × 109/L. In the initial months of 2002, imatinib was available and utilized in 54 patients. Of 54 patients, complete hematological response at 3 months, partial cytogenetic response at 6 months, complete cytogenetic response at 12 months, and major molecular response (MMR) at 18 months were 77.77%, 59.2%, 48.14%, and 40.74%, respectively. MMR at 36 months was 62.96% ( n = 34). Most common imatinib-related side effects are gastrointestinal upset and myelosuppression. CONCLUSION: Pediatric CML in India is comparable with Western countries regarding epidemiological characteristic, clinical presentations, and tolerance of imatinib. As there is a paucity of universal literature regarding pediatric CML (especially data from Southeast Asian region), this article may fill up that space.

Understanding basic concepts of developmental diagnosis in children.

Developmental diagnosis is based on an understanding of basic concepts of typical and atypical developmental progression. Child development is influenced by multiple factors, including the development of the nervous system and other organ systems, and the child's physical and social environment. Different factors interplay with each other in influencing the overall development of the child. Development and behavior of the child are intricately associated. Typical child development follows certain basic principles. Some of the more commonly reported developmental concerns include global developmental delay, intellectual disability, cerebral palsy, delayed speech and language, attention deficits, autism, and specific learning disabilities. The clinical presentation of atypical development varies, depending up on the age of the child; with motor delay in early infancy, and learning difficulties in school age child. Regular surveillance and periodic screening help identify specific areas of developmental and behavioral concerns and suggest a need for further appropriate psychological, medical and laboratory evaluation. The principles of management of a child with developmental concerns include early intervention and response to treatment approach, remediation, accommodation, and specific behavioral and pharmacological interventions when indicated.

Primary Central Nervous System Burkitt Lymphoma in HIV Positive Pediatric Patient: A Rare Case Report.

Burkitt lymphoma is a high-grade B-cell lymphoma with aggressive course of disease and primarily systemic nodal involvement. Primary Burkitt lymphoma with isolated central nervous system (CNS) involvement and that too in pediatric population has been rarely reported. Here, we present a case of a primary Burkitt lymphoma involving brain in an human immunodeficiency virus-positive pediatric patient who was on antiretroviral therapy. Currently, there are no established protocols or guidelines for management of primary CNS Burkitt lymphoma thus posing challenges in the management of such cases. Our patient was successfully treated by surgical resection followed by chemotherapy and radiotherapy.

Clinical and epidemiological profile of neuroendocrine tumors: An experience from a regional cancer center from Western India.

BACKGROUND: Most of the data on neuroendocrine tumors (NETs) are from the Western literature. Indian studies regarding clinicopathological characteristics and treatment outcomes are lacking. METHODS: This is a prospective observational study of all new patients with NETs (except small-cell lung cancer) registered at our tertiary care cancer institute from November 2014 to November 2016. A total of 97 new patients were registered, of which 20 were lost to follow-up before starting any planned treatment. Epidemiological and clinicopathological features of all these 97 patients were studied, and the remaining 77 patients were analyzed for treatment response and survival analysis. RESULTS: The median age at diagnosis was 49 years (20-74 years) with male preponderance (M: F = 1.85:1). The most common primary site of origin was pancreas (34/97 = 35%), followed by unknown primary origin (19%), small intestine (9%), and pulmonary (6%). Of 97 patients, 91 (93.8%) presented with nonfunctional symptoms, 3 (3.1%) had purely functional symptoms, and 3 (3.1%) presented with both functional and nonfunctional symptoms. The most common presenting symptom was abdominal pain (59.7%), followed by jaundice (9.3%), whereas watery diarrhea (83.3%) and flushing (66.7%) were the most common functional symptoms. Sixty-six percent (64/97) of cases were metastatic at presentation. A strong correlation was noted between the primary site of origin and metastatic presentation (P = 0.016). Chemotherapy was the most common primary therapy (40.2%), followed by surgery (28.6%), watchful waiting (15.6%), and somatostatin analogs (11.7%). The median event-free survival was highest for patients undergoing surgery (10 months). CONCLUSIONS: The clinicopathological profile of NETs in the Indian population differs from Western countries. Majority of patients present with metastatic disease, thus representing a need for creating awareness among patients and medical fraternity and formulating Indian guidelines for optimized treatment.

Immunosuppressive therapy for aplastic anemia: a single-center experience from western India.

Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine A (CsA) is the first-line therapy for acquired aplastic anemia (AA) in those not suitable for bone marrow transplant. Horse ATG (hATG) is preferred for this purpose, but its use is often impeded by shortages and costs. Being a rare disease, there is limited data on this therapy. This study aimed to evaluate this therapy in a large cohort of AA patients from western India. We retrospectively analyzed AA patients who received an indigenous preparation of hATG along with CsA as first-line treatment, between 2012 and 2015, at our center and evaluated the response, survival, and occurrence of adverse events. The response was further assessed separately for adults and children. During the period, 91 AA patients (4 non-severe, 57 severe and 30 very severe) were treated with IST. At 2 years, 23.5% adults and 39.1% children showed complete response and an overall of 68.1% cases became transfusion independent. More than half of the patients developed febrile neutropenia while roughly one sixth of the patients developed gum hypertrophy and/or hypertension. Two patients had clonal evolution. Mortality rate was calculated to be 31%; most common causes of death were infection and intracranial hemorrhage. The results of the study substantiate the effectiveness of IST in AA, using an inexpensive indigenous preparation of hATG along with CsA.

Clinical and microbiological profile of infections during induction phase of acute myeloid leukemia.

BACKGROUND: The primary objective of this study is to describe clinical and microbiological profile of infections during induction phase of acute myeloid leukemia (AML). PATIENTS AND METHODS: We reviewed the case records of 50 hospitalized patients with AML undergoing standard dose induction chemotherapy from January to December 2015. RESULTS: Out of 50 cases, 34 were males 16 females with median age of 30 years. Most common presenting symptoms were fever followed by bleeding diathesis. The clinical sites of infections were gastrointestinal tract including oral cavity (48%), respiratory tract (4%), skin/soft tissue (4%) and genitourinary tract (4%). Clinically (58%) or microbiologically (30%) documented infections were 88%, while 12% had fever without identifiable source. Overall, in 21 episodes microorganisms were isolated. Common sites of isolates were blood stream (11), stool (8), sputum (1) and urine (1). Gram negative infections accounted for 81% of total isolates; Escherichia coli (E. coli) being the commonest. Gram positive microorganisms were isolated in 19% of which methicillin resistant staphylococcus aureus (MRSA) was the most common. Gram negative bacterial infections were associated with higher mortality. CONCLUSION: Gastrointestinal tract is the most common clinical site of infection. Blood stream infection is the most common site for positive bacterial isolates. Gramnegative bacilli were the predominant cause of infections with E. coli being the most common pathogen isolated. Empiric antibiotic treatment for febrile neutropenia should be tailored to the locally prevalent pathogens and their susceptibility patterns.

Interdigitating dendritic cell tumor: A rare case report with review of literature.

Interdigitating dendritic cell tumor/sarcoma (IDCT) is a very rare and aggressive neoplasm arising from antigen-presenting cells. It usually involves lymph nodes, but extranodal sites can also be involved. Because of the rarity of the disease, consistent standard treatment guidelines have not been established till date. We report a case of a 35-year-old female who presented with right-sided neck swelling and anterior mediastinal mass. Histopathology revealed large mononucleated cells with background of mixed polymorphous inflammatory cells suspicious of Hodgkin's lymphoma. Hence, to confirm the diagnosis, immunohistochemistry was done. Immunohistochemistry revealed that the tumor was CD30 - negative, CD10 - negative, CD2 - negative, leukocyte common antigen - positive, vimentin - positive, and S-100 - positive, diagnostic of IDCT. Patient was treated with eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisolone regimen chemotherapy followed by involved field radiotherapy and showed dramatic response with complete resolution of mediastinal mass.

Role of Inflammation in Diabetic Retinopathy.

Diabetic retinopathy is a common complication of diabetes and remains the leading cause of blindness among the working-age population. For decades, diabetic retinopathy was considered only a microvascular complication, but the retinal microvasculature is intimately associated with and governed by neurons and glia, which are affected even prior to clinically detectable vascular lesions. While progress has been made to improve the vascular alterations, there is still no treatment to counteract the early neuro-glial perturbations in diabetic retinopathy. Diabetes is a complex metabolic disorder, characterized by chronic hyperglycemia along with dyslipidemia, hypoinsulinemia and hypertension. Increasing evidence points to inflammation as one key player in diabetes-associated retinal perturbations, however, the exact underlying molecular mechanisms are not yet fully understood. Interlinked molecular pathways, such as oxidative stress, formation of advanced glycation end-products and increased expression of vascular endothelial growth factor have received a lot of attention as they all contribute to the inflammatory response. In the current review, we focus on the involvement of inflammation in the pathophysiology of diabetic retinopathy with special emphasis on the functional relationships between glial cells and neurons. Finally, we summarize recent advances using novel targets to inhibit inflammation in diabetic retinopathy.

Primary mediastinal synovial sarcoma with subsequent development of primary adenoid cystic carcinoma of lung presenting as superior vena cava syndrome.

Primary mediastinal sarcomas are aggressive tumors with a very rare incidence. This report describes the case of a 35 year old male patient who presented with acute symptoms of dyspnoea, facial puffiness, engorged neck veins and hoarseness of voice. With the clinical picture consistent with the superior vena caval (SVC) syndrome, the patient was investigated with computed tomography of the chest. This revealed a large soft tissue density mass lesion compressing the SVC along with other critical superior mediastinal structures. Histopathological evaluation of the mass revealed features consistent with a soft tissue sarcoma and positive staining was observed for vimentin and S-100. Cytogenetic analysis by fluorescent in-situ hybridization (FISH) demonstrated the t(X: 18) translocation. Thus diagnosis was established as primary mediastinal synovial sarcoma. Patient was treated with three-cycles of neo-adjuvant (ifosfamide 2400mg/m2 on days 1-5 and doxorubicin 37.5 mg/m2 on days 1 & 2) chemotherapy, to which there was a partial response as per the RECIST criteria. Surgical excision of the mediastinal mass was performed, and further post-operative treatment with adjuvant chemo-radiotherapy was provided. Patient was under regular surveillance at our clinic and remains free of symptoms one-year after treatment completion. But after 14 months of treatment completion patient again had symptoms of progressive dyspnea, hoareness of voice and mild facial puffiness over a period of 2 months. On further investigating he was found to have right-sided centrally located mass with cystic and necrotic changes with extension and compression of trachea, SVC, right upper lobe bronchus and its branches. Histopathological examination of the biopsy from the lesion revealed adenoid cystic carcinoma of the lung. Rest of the metastatic work up was within normal. Immunohistochemistry of the specimen revealed c-Kit positivity. In view of the morbid second surgery he was put on Imatinib 400mg once a day and celecoxib 200mg twice a day. After 4 months patient had partial response and presently continuing with the same regimen. Extensive literature search didn't reveal much information on combined primary mediastinal sarcoma and adenoid cystic carcinoma of lung.

Central retinal artery occlusion, an early sign of crizotinib resistance in an alk positive adenocarcinoma of lung: A rare case report.

About 4% of non-small-cell lung carcinomas involve an EML4-ALK tyrosine kinase fusion gene and occur almost absolutely in carcinomas arising in non-smokers. Crizotinib, the first inhibitor of anaplastic lymphoma kinase (ALK), ROS1 and c-Met receptor kinase, has been used in the treatment of ALK-positive non-small cell lung cancer. Side effects of crizotinib mostly consist of grade 1-2 gastrointestinal events (nausea, vomiting, diarrhea and constipation), grade 1-2 edema and fatigue; grade 1 visual disorders, rare cases of elevated liver enzymes and pneumonitis. We are presenting a case of adenocarcinoma of lung, who progressed on first-line chemotherapy and received crizotinib as second line therapy for 9 months. Patient has very good partial response to crizotinib and had some side effects of crizotinib like nausea, vomiting, diarrhea, fatigue, asthenia and anorexia, asymptomatic transaminitis in the first 2 to 3 weeks of therapy and managed symptomatically. But after 9 months, he developed sudden onset left sided vision loss. On fundoscopic examination he was found to have "cherry red spot" and fundus flourescein angiography revealed central retinal artery occlusion (CRAO). After 15 days of vision loss patient developed pleural effusion, and pleural fluid cytology was positive for malignant cells. Visual symptoms are very well known in the literature as side effects of crizotinib, but CRAO is not yet been documented. As this patient is not having any prothrombotic state like diabetes, hypertension, atherosclerosis, hyperhomocysteinemia or any genetic disorders except malignancy. Hypercoagulability disorders are known to be commonly associated with a variety of cancer types including lung cancer. This appears to be a sign of early crizotinib resistance in this patient because there was no history of prior hypercoagulable state. To the best of our knowledge this is the first case report in the world literature, as CRAO presenting as a sign of crizotinib resistance in an adenocarcinoma of lung patient who was on crizotinib.