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Low-grade oncocytic tumour (LOT) of the kidney has recently emerged as a potential novel tumour type. Despite similarity to oncocytoma or eosinophilic chromophobe renal cell carcinoma, it shows diffuse keratin 7 immunohistochemistry (IHC) and negative KIT (CD117), which differs from both. We aimed to identify the molecular characteristics of these tumours. Seventeen tumours (one male, 16 female, nine previously published) fitting the original description of this entity (solid eosinophilic cell morphology, often with areas of tumour cells loosely stretched in oedematous stroma, and the above IHC features) were analysed with a next-generation sequencing panel of 324 cancer-associated genes from formalin-fixed, paraffin-embedded tissue. All tumours harboured at least one alteration in either TSC1 (n = 7, 41%), TSC2 (n = 2, 12%), MTOR (n = 5, 29%) or PIK3CA (n = 4, 24%). Four tumours harboured a second alteration, including two NF2, one each in conjunction with MTOR and TSC2 alterations, one PTEN with TSC1 alteration and one tumour with both MTOR and TSC1 alterations. No other renal cancer-related or recurring gene alterations were identified. In addition to the previously described IHC findings, 16 of 16 were positive for GATA3. Eleven patients with follow-up had no metastases or recurrent tumours. Recurrent tuberous sclerosis/MTOR pathway gene alterations in LOT support its consideration as a distinct morphological, immunohistochemical and genetic entity. PIK3CA is another pathway member that may be altered in these tumours. Further study will be necessary to determine whether tumour behaviour or syndromic associations differ from those of oncocytoma and chromophobe carcinoma, warranting different clinical consideration.
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Adenoma Oxifílico , Carcinoma de Células Renales , Neoplasias Renales , Humanos , Masculino , Femenino , Recurrencia Local de Neoplasia , Carcinoma de Células Renales/genética , Neoplasias Renales/genética , Mutación , Adenoma Oxifílico/genética , Riñón , Serina-Treonina Quinasas TOR/genética , Factor de Transcripción GATA3/genética , Fosfatidilinositol 3-Quinasa Clase I/genéticaRESUMEN
Low-grade oncocytic tumor (LOT) has been recently proposed as a unique renal tumor. However, we have encountered tumors with more oncocytoma-like morphology that show diffuse keratin 7 reactivity, which we sought to characterize molecularly. Eighteen tumors with a diffuse keratin 7 positive and KIT negative pattern were identified from 184 with predominantly oncocytoma-like histology. These tumors were subjected to detailed immunohistochemical evaluation and 14 were evaluated using the Illumina® HiSeq 4000 platform for 324 cancer-associated genes. Patients' ages ranged from 39 to 80 (median = 59.5 years) with a male to female ratio of 1.25:1. Morphology was predominantly oncocytoma-like with discrete nests, compared to the solid and edematous patterns described in LOT. Other than positive keratin 7 and negative KIT, the tumor cells were positive for PAX8, E-cadherin, AE1/AE3, Ber-EP4, AMACR, CD10, and MOC31, and were negative for other studied markers. FH and INI1 were normal. Eleven of 14 harbored genomic abnormalities, likely sporadic, primarily involving the MTOR pathway (73%). Overall, the alterations included MTOR activating mutation (n = 1), TSC1 inactivating mutation (n = 1), TSC2 mutation (p.X534 splice site, n = 1), STK11 (a negative regulator of the MTOR pathway) mutation (n = 1), both STK11 and TSC1 mutations (n = 1), biallelic loss of PTEN and TSC1 deletion (n = 1), and MET amplification and TSC1 inactivating mutation (n = 1). Amplification of FGFR3 was identified in one additional tumor. Other alterations included FOXP1 loss (n = 1), NF2 E427 homozygous loss (n = 1), and PI3KCA activating mutation (n = 1). At a median follow-up of 68 months (2-147 months) for 15 patients, all were alive without disease. Oncocytic renal tumors with diffuse keratin 7 labeling show frequent alterations in the TSC/MTOR pathway, despite more oncocytoma-like morphology than initially described in LOT, likely expanding the morphologic spectrum of the latter.
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Carcinoma de Células Renales , Neoplasias Renales , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/patología , Femenino , Factores de Transcripción Forkhead , Humanos , Inmunohistoquímica , Queratina-7 , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Proteínas Represoras , Sirolimus , Serina-Treonina Quinasas TOR/genéticaRESUMEN
ABSTRACT: Multiloculated peritoneal inclusion cysts, usually arise from peritoneal mesothelium lining the serous cavity of the abdomen, pelvis and retroperitoneum. These lesions can be incidentally found on imaging or during surgery, and confirmation of the diagnosis is done by radiological imaging, histomorphology and immunohistochemical findings. Although fewer than 200 cases of solitary peritoneal inclusion cysts have been reported, their occurrence in a disseminated fashion has hardly ever been described in literature. Herein, we report a case of multiloculated peritoneal inclusion cysts that involved the whole abdominal and pelvic cavity and were successfully treated with surgery.
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AIMS: Diagnosis of IgG4-related ophthalmic disease (IgG4-ROD) rests on the correlation of clinical features, serological testing and histopathology, using internationally accepted diagnostic criteria for objective interpretation; however, several mimickers of IgG4-RD overlap in clinical presentation and histopathology. We assess histopathological features in a series of presumptive IgG4-ROD cases, with emphasis on histopathological mimics and comparison of three IgG4-ROD diagnostic/classification criteria (organ-specific (OS), revised comprehensive diagnostic (RCD) and American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) criteria). METHODS: The histopathology database was screened for cases with clinical/histopathological suspicion of IgG4-ROD. Slides were reviewed, OS, RCD and ACR/EULAR criteria were applied, and the final clinicopathological diagnosis was recorded. RESULTS: 37 patients (24 females, 13 males; 19-73 years) were diagnosed as either IgG4-ROD (n=18) or non-IgG4-related disease (n=19). Non-IgG4-related disease group showed elevated serum IgG4 (55.5%), fibrosis (100%), dense lymphoplasmacytic inflammation (92.8%), with an increase in tissue IgG4+plasma cells (57.1%) and elevated IgG4:IgG+plasma cell ratio (14.3%). ACR/EULAR missed 50% (9/18, sensitivity-52.8%) of true IgG4-ROD cases, while OS and RCD criteria missed 11.1% (2/18, sensitivity-88.9%) of IgG-ROD cases. ACR/EULAR criteria mislabelled 7.14% (1/14, specificity-90.9%) while OS and RCD criteria wrongly categorised 71.4% (10/14, specificity-47.4%) and 50% (7/14, specificity-63.2%) specific non-IgG4-ROD cases as IgG4-ROD. Storiform fibrosis, obliterative phlebitis, increased IgG4:IgG+plasma cell ratio and elevated serum IgG were statistically significant in distinguishing IgG4-ROD from its mimics. CONCLUSION: ACR/EULAR criteria showed high specificity but were cumbersome and sensitivity was low, while RCD and OS criteria showed low specificity. Stringent clinicopathological correlation to exclude mimics is critical in avoiding diagnostic errors in IgG4-ROD.
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BACKGROUND: The understanding of molecular mechanisms involved in non-small cell lung carcinoma (NSCLC) has revolutionized significantly in the recent years. These have helped to develop personalized management strategies by identifying specific molecular alterations such as mutations in EGFR, ROS1, BRAF, ERBB2, MET, ALK, and KRAS genes. These mutations are targetable ensuring a better clinical outcome. Next-generation sequencing (NGS) methodology is the recommended technique for the identification of driver mutations in the five hot-spot genes (EGFR, ALK, ROS1, MET, and BRAF) involved in the NSCLC. NGS has numerous advantages including multiplexing, tissue conservation, identification of rare and novel variants, and reduced cost over the sequential single gene testing. Herein, we sought to demonstrate the mutational profile in NSCLC and their clinicopathologic correlation in a contemporary cohort of Indian NSCLC patients. Additionally, we studied the correlation of oncogenic driver mutations with PD-L1 status in these patients. MATERIALS AND METHODS: Five fifty-two stage IV NSCLC patients (adenocarcinoma=490; squamous cell carcinoma=51; adenosquamous carcinoma=5; large cell carcinoma=2; sarcomatoid carcinoma=3; spindle cell carcinoma=1) underwent broad molecular profiling by a custom-made, targeted DNA- and RNA-based five hot-spot genes lung cancer panel (EGFR, ALK, ROS1, BRAF, and MET), compatible with the NGS Ion S5 system. The mutations were correlated with the clinicopathologic characteristics. Additionally, PD-L1 expression status, available on 252 tumors, was correlated with the oncogenic drivers. RESULTS: Validation of the 5 gene panel yielded the following results: a) specificity of 99.74%; b) sensitivity of 100% for single nucleotide variants (SNVs) (>5% variant allele frequency, VAF), indels (>10% VAF) and fusions; c) 100% intra- and inter-run reproducibility; d) 88% inter-laboratory agreement. Validated panel was then used to analyze clinical samples. Sixty percentage tumors harbored either one (54.71%) or multiple (3.26%) mutations. EGFR and BRAF V600E mutations, ALK and ROS1 rearrangements, and MET exon 14 skipping mutation were observed in 38.41% (n = 212) and 2.72% (n = 15) patients, 12.14% (n = 67) and 3.62% (n = 20) patients, and 1.09% (n = 6) patients, respectively. EGFR exon 19 deletion accounted for 52.83% of all mutations, followed by L858R (35.85%), T790M (5.19%), exon 20 insertions (6.6%), and other rare mutations (G719X, L861Q, S768I) (9.91%). Concurrent EGFR with ALK, EGFR with ROS1, EGFR with MET, and EGFR with BRAF were observed in 10, 4, 1, and 3 patients, respectively. PD-L1 was expressed in 134 patients (53.2%). Exon 19 deletion was more prevalent in PD-L1 negative tumors whereas exon 21 substitution (L858R) was seen more in PD-L1 positive tumors. CONCLUSIONS: This is one of the largest cohorts of NSCLC for comprehensive targeted mutational profiling and correlation with the PD-L1 expression. The mutations are more prevalent in non-smoker females for all genes, except ALK (non-smoker males). MET and BRAF mutations are more common in elderly population whereas EGFR mutations, and ALK and ROS1 genes rearrangements are more prevalent in younger population. The most common histopathologic subtype/feature associated with various mutations was as follows: acinar with EGFR, solid with ALK, macronucleoli with ROS1, signet ring with MET, and micropapillary with BRAF.
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Carcinoma de Pulmón de Células no Pequeñas , Carcinoma , Neoplasias Pulmonares , Masculino , Femenino , Humanos , Anciano , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Proteínas Proto-Oncogénicas B-raf/genética , Antígeno B7-H1/genética , Reproducibilidad de los Resultados , Mutación , Proteínas Proto-Oncogénicas/genética , Inhibidores de Proteínas QuinasasRESUMEN
Mutations in the phosphatase and tensin homolog (PTEN) gene are associated with severe neurodevelopmental disorders. Loss of PTEN leads to hyperactivation of the mechanistic target of rapamycin (mTOR), which functions in two distinct protein complexes, mTORC1 and mTORC2. The downstream signaling mechanisms that contribute to PTEN mutant phenotypes are not well delineated. Here, we show that pluripotent stem cell-derived PTEN mutant human neurons, neural precursors, and cortical organoids recapitulate disease-relevant phenotypes, including hypertrophy, electrical hyperactivity, enhanced proliferation, and structural overgrowth. PTEN loss leads to simultaneous hyperactivation of mTORC1 and mTORC2. We dissect the contribution of mTORC1 and mTORC2 by generating double mutants of PTEN and RPTOR or RICTOR, respectively. Our results reveal that the synergistic hyperactivation of both mTORC1 and mTORC2 is essential for the PTEN mutant human neural phenotypes. Together, our findings provide insights into the molecular mechanisms that underlie PTEN-related neural disorders and highlight novel therapeutic targets.
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Diana Mecanicista del Complejo 1 de la Rapamicina , Diana Mecanicista del Complejo 2 de la Rapamicina , Neuronas , Organoides , Fosfohidrolasa PTEN , Humanos , Fosfohidrolasa PTEN/metabolismo , Fosfohidrolasa PTEN/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Organoides/metabolismo , Neuronas/metabolismo , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Mutación/genética , Proteína Asociada al mTOR Insensible a la Rapamicina/metabolismo , Proteína Asociada al mTOR Insensible a la Rapamicina/genética , Transducción de Señal , Proliferación Celular , Proteína Reguladora Asociada a mTOR/metabolismo , Proteína Reguladora Asociada a mTOR/genética , FenotipoRESUMEN
OBJECTIVE: Endometrial cancer (EC) outcome data from developing countries are sparse. We undertook this retrospective analysis to report outcome in our patient population. MATERIALS AND METHODS: Two hundred forty-nine patients with stage I and II and type I histology ECs referred/treated at our institution from 1998 to 2004 were analyzed. All the details including demographic profile, surgical and histopathological details, as well as International Federation of Gynecology and Obstetrics stage and adjuvant therapy were compiled. The 1988 International Federation of Gynecology and Obstetrics staging and risk stratification were performed on the basis of PORTEC risk groups. RESULTS: With a median age of 54 years (26-72 years), 136 patients (55%) underwent surgery elsewhere; 118 (47.3%) underwent a complete surgical staging. There were 60 (24.1%), 124 (49.8%), 65 (26.1%) patients in the low-risk (LR), intermediate-risk (IR), and high-risk (HR) groups, respectively. Adjuvant radiation was given in 160 patients (LR, 18; IR, 85; and HR, 57). With a median follow-up of 36 months (mean, 40 months), 10 patients had vault recurrences, (LR, 3; IR, 4; and HR, 3), 11 had nodal (5 also had local recurrence; LR, 2; IR, 4; and HR, 5), and 16 had distant recurrences (3 also had nodal; LR, 4; IR, 5; HR, 7). The 5-year disease-free survival (DFS) and overall survival (OAS) rates were 80% and 95%, respectively. The DFS and OAS rates at 5 years were 84% and 97%, 85% and 98%, and 60% and 85% for the LR, IR, and HR groups, respectively. On multivariate analysis, grade (P = 0.002) and type of radiation (P = 0.027) had significant impact on DFS and OAS. Late toxicities (grade 3/4) were vaginal stenosis in 4 (1%) and radiation proctitis in 3 (1%) patients. CONCLUSIONS: In our study, ECs are seen in relatively younger population. There is a trend toward incomplete staging surgery outside the oncological referral network. However, the clinical outcome for early-stage type I histology ECs within our population are similar to those reported in the literature.
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Carcinoma Endometrioide/mortalidad , Países en Desarrollo/estadística & datos numéricos , Neoplasias Endometriales/mortalidad , Adulto , Anciano , Carcinoma Endometrioide/radioterapia , Carcinoma Endometrioide/cirugía , Neoplasias Endometriales/radioterapia , Neoplasias Endometriales/cirugía , Femenino , Humanos , India/epidemiología , Persona de Mediana Edad , Radioterapia Adyuvante/efectos adversos , Estudios Retrospectivos , Centros de Atención Terciaria/estadística & datos numéricosRESUMEN
Because of simple synthetic strategies, randomly functionalized amphiphilic polymers have gained much attention. Recent studies have demonstrated that such polymers can be reorganized into different nanostructures, such as spheres, cylinders, vesicles, etc., similar to amphiphilic block copolymers. Our study investigated the self-assembly of randomly functionalized hyperbranched polymers (HBP) and their linear analogues (LP) in solution and at the liquid crystal-water (LC-water) interfaces. Regardless of their architecture, the designed amphiphiles self-assembled into spherical nanoaggregates in solution and mediated the ordering transitions of LC molecules at the LC-water interface. However, the amount of amphiphiles required for LP was 10 times lower than that required for HBP amphiphiles to mediate the same ordering transition of LC molecules. Further, of the two compositionally similar amphiphiles (linear and branched), only the linear architecture responds to biorecognition events. The architectural effect can be attributed to both of these differences mentioned above.
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OBJECTIVE: Poor glycemic management increases the risk of cardiac, microvascular, and other complications. Therefore, timely assessment and control of glycemic levels is paramount in diabetes. Recent advancements in automated management methods is the use of a continuous glucose monitoring system (CGMS). The objective was to study its clinical and economic impact in the glucose level monitoring and how it can be effectively used or reimbursed for wider population. METHODS: Comprehensive search was done using multiple databases to capture relevant and most recent evidence. All steps were conducted by two independent researchers and discrepancies resolved by a third reviewer. Quality appraisal was performed by relevant scale depending on study design. RESULTS: Twenty-six and 12 studies were included for clinical and economic outcomes, respectively. Clinical outcomes like HbA1c and glucose variation, time in range, accuracy, etc. were captured. Comparison of different CGMS types was also reported. Major economic outcomes were direct cost, healthcare resource utilization, and work absenteeism. CONCLUSIONS: CGMS in patients with diabetes is associated with a valuable clinical implications in reducing hypoglycemic events, glucose and HbA1c level. Additionally, it has an impact on direct and indirect costs of management. Further, quantitative analysis would be required to produce concrete evidence.
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Automonitorización de la Glucosa Sanguínea , Diabetes Mellitus Tipo 1 , Glucemia/análisis , Automonitorización de la Glucosa Sanguínea/métodos , Glucosa , Hemoglobina Glucada/análisis , HumanosRESUMEN
Stroke is the third leading cause of death and disability around the globe. The aim of the present investigation was to evaluate the protective effect of hesperidin and its nitric oxide mechanism against cerebral ischemia reperfusion injury. Bilateral common carotid artery occlusion for 30 min followed by 24 h reperfusion was given to induce ischemia in rats. Animals were pretreated with hesperidin (50 and 100 mg/kg, po) for 7 days. Various behavioural tests, oxidative stress parameters, endogenous antioxidant system, antioxidant enzyme activity and mitochondrial enzyme complex (I, II, III and IV) dysfunctions in cortex and striatum were assessed subsequently. Hesperidin (50 and 100 mg/kg) significantly improved neurobehavioral alterations (neurological score, locomotor activity, resistance to lateral push and hanging wire latency), attenuated oxidative damage, restored antioxidant and mitochondrial complex enzyme activities in cortex and in striatum regions of the brain as compared to their respective controls. L-arginine (100 mg/kg) or L-NAME (10 mg/kg) pretreatment with lower dose of hesperidin (50 mg/kg) significantly reversed or potentiated its protective effect, respectively which was significant as compared to hesperidin (50 mg/kg). The results highlight the involvement of nitric oxide mechanism in the protective effect of hesperidin against ischemia reperfusion injury induced alterations.
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Isquemia Encefálica/tratamiento farmacológico , Hesperidina/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Óxido Nítrico/metabolismo , Daño por Reperfusión/prevención & control , Animales , Arginina/farmacología , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Encéfalo/metabolismo , Isquemia Encefálica/complicaciones , Isquemia Encefálica/metabolismo , Hesperidina/administración & dosificación , Masculino , Actividad Motora/efectos de los fármacos , NG-Nitroarginina Metil Éster/farmacología , Fármacos Neuroprotectores/administración & dosificación , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Daño por Reperfusión/etiología , Daño por Reperfusión/metabolismoRESUMEN
Background Coagulation abnormalities are common in acute leukemia (AL) and disseminated intravascular coagulation (DIC) frequently complicates the onset of AL. Aim To determine the prevalence of overt DIC in AL using the International Society on Thrombosis and Haemostasis (ISTH) scoring system. Materials and Methods This prospective observational study was performed on 57 newly diagnosed or relapsed cases of AL. Detailed clinical history and coagulation profile of the patients were evaluated. Diagnosis of overt and nonovert DIC was established using the ISTH scoring system and results tabulated. Observations A total of 57 patients with AL participated in the study, including 31 (54.39%) patients with acute lymphoblastic leukemia (ALL) and 26 (45.61%) with acute myeloid leukemia (AML). In total, 18 of 57 patients (31.58%) with AL fulfilled the criteria of overt DIC according to the ISTH scoring system, including 10 (32.25%) patients with ALL and 8 (30.76%) patients with AML. The highest prevalence of DIC was seen in the M3 subtype among AML and the L1 subtype among ALL, respectively. The mean ISTH score in patients of overt DIC in ALL and AML patients was 5.1 and 5, respectively. Abnormalities in platelet count and D-dimer levels were the most useful parameters in diagnosing overt DIC and the difference between overt DIC and nonovert DIC groups was highly significant. Conclusions Overt DIC was observed in approximately one-third of patients with AL. Prevalence of overt DIC was found to be comparable in patients with ALL and AML. Mean platelet count and D-dimer levels were the most useful parameters in detecting overt DIC.
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Background There is sparse literature on trabectedin in advanced soft-tissue sarcomas from developing world. It would be interesting to know about use and outcomes of trabectedin in Indian patients. Method In a retrospective study, consecutive patients treated with trabectedin from 2016 to 2019 were analyzed. Patients with L-sarcomas were treated at a dose of 1.5 mg/m 2 , while those with translocation-related sarcomas were treated at a dose of 1.2 mg/m 2 as a 24-hour infusion through peripherally inserted central catheter line. From July 2019, infusions were administered through an ambulatory elastomeric pump, while before that patients were admitted for 24 hours. We used SPSS version 23.0 for statistical calculation. Result A total of 20 patients received trabectedin with a total of 116 infusions. The median age was 46 years (range: 22-73 years). The male ( n = 11, 55%) and female patients were almost equal ( n = 9, 45%). Thirteen patients (65%) had Eastern Cooperative Oncology Group Performance Status 1. Majority of the patients had leiomyosarcoma ( n = 8, 40%); remaining comprised of liposarcoma (3, 15%), translocation-related sarcomas excluding myxoid liposarcoma ( n = 8, 40%) and others ( n = 1,5%). Most common site was extremity ( n = 11, 55%) followed by retroperitoneal ( n = 3, 15%), visceral ( n = 3, 15%), and others ( n = 3,15%). Median number of previous lines received was 2 (range: 0-4). Median number of trabectedin cycles received was 4 (range: 1-17). Best response assessed was stable disease ( n = 10, 50%), progressive disease ( n = 6, 30%), partial response ( n = 1, 5%), and not assessed in 3 patients. After a median follow-up of 19 months, median progression-free survival was 4 months. Conclusion In this heavily treated population (composed of L-sarcomas and translocation-related sarcomas) with many patients with poor performance status, the outcome with trabectedin is in synchrony with literature. However, the need of 24-hour admission might deter quality of life. Elastomeric pump seems to be a reasonable alternative to admission and can be a breakthrough in administering trabectedin, especially in developing countries.
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BACKGROUND: Immunotherapy with checkpoint inhibitor programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) antibodies targeting the cellular immune checkpoints is the present area of interest showing promising results in patients with advanced non-small cell lung cancer (NSCLC). As there is paucity of PD-L1 expression data from the Indian perspective, we studied the correlation of clinicopathologic profile and oncogenic driver mutations in these patients. MATERIALS AND METHODS: Samples from 252 advanced NSCLCs patients were studied for PD-L1 expression through immunohistochemistry using rabbit anti-human PD-L1 monoclonal antibody (clone SP263) on Ventana BenchMark ULTRA autostainer. Simultaneously, genetic mutations were studied by next generation sequencing (for EGFR, ALK, ROS, MET, and BRAF). PD-L1 expression was analyzed for association with clinicopathologic features and various mutations. RESULTS: PD-L1 positivity was seen in 134 patients (53.2 %). It was twice more prevalent in males than females. No significant correlation was observed between PD-L1 expression with age, gender, site of testing (primary vs. metastatic tumors), smoking status, tumor laterality, stage, or histologic type; however, there was significant difference among solid and acinar types of adenocarcinoma combined together vs. other adenocarcinoma subtypes (p = 0.013), and well and moderately differentiated vs. poorly differentiated tumors (p = 0.022). When types/extent of PD-L1 positivity (≥25 %) were compared with demographics, clinical, and pathologic variables, significant differences were observed across the tumor grades (high-grade vs. low-grade) (p = 0.009) and stages (p = 0.039). The PD-L1 expression failed to demonstrate any statistical significance with oncogenic drivers. High PD-L1 expression (TPS ≥ 50) was observed in 27.6 % patients, and it was more prevalent in female patients (32.4 %), aged ≥60 years (33.8 %), smokers (27.3 %), poorly differentiated (36.8 %) and stage IV tumors (28.2 %). Exon 19 deletion was more prevalent in PD-L1 negative tumors whereas exon 21 substitution (L858R) was seen more in PD-L1 positive tumors. CONCLUSIONS: This is the largest Indian study demonstrating PD-L1 expression in NSCLC patients comparing with clinicopathologic and genomic parameters. PD-L1 expression was significantly associated with high-grade, solid, and acinar types of adenocarcinoma and advanced tumors. High PD-L1 expression was more prevalent in female patients, aged ≥60 years, smokers, and poorly differentiated and stage IV tumors (28.2 %). Exon 19 deletion was more in PD-L1 negative tumors whereas exon 21 substitution (L858R) was more in PD-L1 positive tumors. PD-L1 is a potential predictive marker stratifying patients who benefit from PD-1 pathway-targeted therapy.
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Antígeno B7-H1/biosíntesis , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Femenino , Humanos , India , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Persona de Mediana Edad , MutaciónRESUMEN
OBJECTIVES: Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene of non-small cell lung carcinomas (NSCLC) can be targeted by the tyrosine kinase inhibitors. A number of molecular diagnostic platforms are used to detect actionable targets in the exon(s) 18, 19, 20, and 21 of the EGFR gene. The Idylla™ system (Biocartis, Mechelen, Belgium) is a relatively novel technique and is unique in integrating both sample processing and real-time polymerase chain reaction (RT-PCR) in a single cartridge. We sought to conduct this study to compare the turnaround time (TAT) and concordance of Idylla™ system with the conventional RT-PCR and next-generation sequencing (NGS) for EGFR mutation detection. METHODS: In this retrospective analysis, 38 formalin-fixed, paraffin-embedded NSCLC tissue blocks with known NGS results by Ion Torrent™ S5 NGS platform were retested by the RT-PCR and Idylla™ platforms. RESULTS: A total of 15 of 38 (39.4 %) tumors that showed various EGFR mutations by NGS and conventional RT-PCR techniques were subjected to the Idylla™testing. These cases satisfied the specimen adequacy criteria of at least 10 % tumor cells for the testing. The mutations detected by the NGS were also detected by the Idylla™ testing. However, NGS identified additional 3 mutations in 3 cases, involving T709 V (exon 18, n = 1) and V774 M (exon 20, n = 2). The tumors with wild type EGFR on NGS did not have any actionable mutation detected by the Idylla™. Average EGFR testing TAT by Idylla™ was only 7.2 h (4-12 hours), as compared to conventional RT-PCR taking 54 h (31-79 hours) and NGS requiring 10.7 days (7.1-14 days). The actual procedure time by conventional RT-PCR was 24 h, NGS was 6.5 days, and Idylla™ was only 3 h. CONCLUSIONS: In summary, the Idylla™EGFR testing is an efficient, rapid, and fairly simple tool that can be used in the routine molecular laboratory with limited expertise and infrastructure and using the lowest amount of tissue material.
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Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Análisis Mutacional de ADN , Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias Pulmonares/genética , Mutación , Reacción en Cadena en Tiempo Real de la Polimerasa , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/patología , Receptores ErbB/genética , Exones , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Estudios Retrospectivos , Factores de Tiempo , Flujo de TrabajoRESUMEN
OBJECTIVES: To estimate COVID-19 infections and deaths in healthcare workers (HCWs) from a global perspective during the early phases of the pandemic. DESIGN: Systematic review. METHODS: Two parallel searches of academic bibliographic databases and grey literature were undertaken until 8 May 2020. Governments were also contacted for further information where possible. There were no restrictions on language, information sources used, publication status and types of sources of evidence. The AACODS checklist or the National Institutes of Health study quality assessment tools were used to appraise each source of evidence. OUTCOME MEASURES: Publication characteristics, country-specific data points, COVID-19-specific data, demographics of affected HCWs and public health measures employed. RESULTS: A total of 152 888 infections and 1413 deaths were reported. Infections were mainly in women (71.6%, n=14 058) and nurses (38.6%, n=10 706), but deaths were mainly in men (70.8%, n=550) and doctors (51.4%, n=525). Limited data suggested that general practitioners and mental health nurses were the highest risk specialities for deaths. There were 37.2 deaths reported per 100 infections for HCWs aged over 70 years. Europe had the highest absolute numbers of reported infections (119 628) and deaths (712), but the Eastern Mediterranean region had the highest number of reported deaths per 100 infections (5.7). CONCLUSIONS: COVID-19 infections and deaths among HCWs follow that of the general population around the world. The reasons for gender and specialty differences require further exploration, as do the low rates reported in Africa and India. Although physicians working in certain specialities may be considered high risk due to exposure to oronasal secretions, the risk to other specialities must not be underestimated. Elderly HCWs may require assigning to less risky settings such as telemedicine or administrative positions. Our pragmatic approach provides general trends, and highlights the need for universal guidelines for testing and reporting of infections in HCWs.
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COVID-19/mortalidad , Personal de Salud , Salud Global , Humanos , Pandemias , SARS-CoV-2RESUMEN
BACKGROUND: In this decade the treatment of advanced sarcoma has seen many highs and lows in terms of successful trials and failed trials. This is possible due to great collaborations, newer therapies and histology focused trials. METHODS: In ASCO 2019 many sarcoma trials were presented and we chose 3 challenging clinical trials that widen our perspective on soft tissue sarcoma. We have critically analyzed the data and have discussed the implications of these trials on current practice. First trial was ANNOUNCE trial which was done to confirm the efficacy of olaratumab after its dramatic success in advanced soft tissue sarcoma in a phase 2 trial. Another trial STRASS trial, which was unique because of being first successfully conducted randomized trial addressing preoperative radiotherapy in retroperitoneal soft tissue sarcoma. Third trial was phase 2 trial SARC 028 trial exploring the role of immunotherapy in pleomorphic undifferentiated sarcoma and liposarcoma subgroup. RESULT: ANNOUNCE trial failed to show OS benefit in olaratumab/doxorubicin arm as compared to doxorubicin/placebo arm. Based upon this FDA has revoked the approval of olaratumab leading to nihilism and disappointment amongst oncologists. In STRASS trial failed to meet the primary end point though there was a benefit in the liposarcoma subgroup in terms of abdominal recurrence free survival. There are several reasons that this trial might have failed. First, RPSs are not homogeneous population. RPSs might behave very differently as per the histopathology ranging from well differentiated LPS to leiomyosarcoma. Since the event rate in well-differentiated liposarcoma might happen late, the median follow-up of 43 months might not be sufficient. In SARC trial ORR in pleomorphic undifferentiated sarcoma (PUS) cohort was 9/40 (22.5%), while response rates in liposarcoma cohort were 4/39 (10.2%). There was poor correlation between the response and the tumor cells' PD-L1 positivity. Simultaneously, we must not take for granted the role of pembrolizumab in PUS as the previous study (PEMBROSARC) had also showed dismal outcomes with immunotherapy. CONCLUSION: In this paper we discuss the intricacies of these trials and how they affect the rapidly changing landscape in advanced soft tissue sarcoma.
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PURPOSE: There is no study till date determining the spectrum of adverse events of pazopanib in Indian patients with advanced sarcoma. MATERIALS AND METHODS: We conducted a retrospective study by analyzing the case records of metastatic sarcoma patients treated with pazopanib from January 2016 to July 2017 in sarcoma medical oncology clinic. Toxicity was assessed according to CTCAE v.4.03 criteria. SPSS version 23 was used for statistical evaluation. RESULTS: A total of 33 patients received pazopanib. The median age was 41 years (range, 19-75 years), with a male predominance (54.5%). Twenty-six patients (78.8%) had ECOG performance status 1 at the time of pazopanib initiation. The most common type of sarcoma was synovial sarcoma, and the mean duration of pazopanib intake in patients was 4.12 months. The median follow-up was 13 months. Median progression-free survival was 5 months, and median overall survival was 18 months. Overall response rate was 6.0%. Out of the 33 patients, 42.4% (n = 14) received it after first line of therapy. Six patients (18.2%) required dose reductions due to toxicity. Thirteen (39.4%) patients experienced CTCAE grade 3 or 4 toxicities. Most common grade 3 and 4 toxicities experienced among patients were hand-foot skin reaction (18.2%) and proteinuria (9.1%). No significant difference was seen when analyzed for variables such as age, sex, ECOG performance status, comorbidities, and number of previous lines received in patients experiencing grade 3 and 4 toxicities. CONCLUSIONS: The spectrum of adverse events in Indian patients at doses lower than the recommended dose is distinctly different from the western population. However, this unique toxicity profile needs to be validated in prospective studies.
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Inhibidores de la Angiogénesis/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Pirimidinas/efectos adversos , Sarcoma/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Sulfonamidas/efectos adversos , Adulto , Anciano , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Femenino , Estudios de Seguimiento , Humanos , Indazoles , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Sarcoma/secundario , Neoplasias de los Tejidos Blandos/patología , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: Head-and-neck soft-tissue sarcomas (HNSTS) are extremely rare and lack definite guidelines. METHODS: We retrospectively analyzed consecutive adult patients with HNSTS who presented to our sarcoma medical oncology clinic from January 2016 to October 2017. RESULTS: There were a total of 30 patients. Unresectable localized disease was seen in 13 (43%) patients, metastatic disease 10 (34%) patients, while resectable disease in 7 (23%) patients only. Among unresectable localized disease, 3 (25%) patients could be converted to resectable disease after neoadjuvant therapy. Median follow period was 11 months. Progression-free survival was 19 months in patients with resectable disease and 6 months in patients with the unresectable/metastatic disease. Median OS was not reached. CONCLUSION: Unresectable HNSTS has a poor outcome. Neoadjuvant therapy can be tried in selected cases for achieving respectability or for vital organ preservation until robust data are available. A multidisciplinary approach for local control is crucial in managing unresectable HNSTS.
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PURPOSE: Osteosarcoma (OS) is a relatively chemosensitive primary bone tumor, with the peak age of onset occurring in late childhood and early adolescence. The treatment paradigm of nonmetastatic OS has typically been multimodality therapy, including neoadjuvant and adjuvant chemotherapy with definitive surgery. Over the years, various permutations and combinations of chemotherapeutic agents have been used. However, the majority of recent trials have still used high-dose methotrexate as the backbone, with cisplatin and doxorubicin (MAP). In the last decade, various strategies targeted to improving outcomes in OS have included the addition of a fourth drug to the three-drug MAP regimen, changing therapy according to histopathologic response and the addition of immunotherapies. Through this review, we sought to underscore a few pertinent issues related to chemotherapy in nonmetastatic OS, with special reference to challenges confronted in Indian settings. METHODS: We reviewed the literature, focusing on studies comparing high-dose methotrexate and non-high-dose methotrexate-containing regimens. In addition, this review focuses on non-methotrexate-containing triple-drug therapy. RESULTS: Although a high-dose methotrexate regimen has become standard of care in developed countries, there are few data to suggest that it is superior to a non-high-dose methotrexate regimen. CONCLUSION: Developing countries with lack of infrastructure and logistics for high-dose methotrexate might resort to non-high-dose methotrexate-containing regimens with a simultaneous focus on early detection, decreasing abandonment, multidisciplinary clinics, improved surgery, and meticulous pathologic evaluations.