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BACKGROUND: Our case report provides the first clinical evaluation of autopsy practices for a patient death that occurs on the cloud. We question how autopsy practices may require adaptation for a death that presents via the 'Internet of Things', examining how existing guidelines capture data related to death which is no longer confined to the patient's body. CASE PRESENTATION: The patient was a British man in his 50s, who came to the attention of the medical team via an alert on the cloud-based platform that monitored his implanted cardioverter defibrillator (ICD). The patient had a background of congenital heart disease, with previous ventricular fibrillation cardiac arrest, for which the ICD had been implanted two years earlier. Retrospective analysis of the cloud data demonstrated a gradually decreasing nocturnal heart rate over the previous three months, falling to a final transmission of 24 beats per minute (bpm). In the patient post-mortem the ICD was treated as medical waste, structural tissue changes precluded the effective evaluation of device hardware, potential issues related to device software were not investigated and the cause of death was assigned to underlying heart failure. The documentation from the attending law enforcement officials did not consider possible digital causes of harm and relevant technology was not collected from the scene of death. CONCLUSION: Through this patient case we explore novel challenges associated with digital deaths including; (1) device hardware issues (difficult extraction processes, impact of pathological tissue changes), (2) software and data limitations (impact of negative body temperatures and mortuary radio-imaging on devices, lack of retrospective cloud data analysis), (3) guideline limitations (missing digital components in autopsy instruction and death certification), and (4) changes to clinical management (emotional impact of communicating deaths occurring over the internet to members of family). We consider the implications of our findings for public health services, the security and intelligence community, and patients and their families. In sharing this report we seek to raise awareness of digital medical cases, to draw attention to how the nature of dying is changing through technology, and to motivate the development of digitally appropriate clinical practice.
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Autopsia , Desfibriladores Implantables , Humanos , Masculino , Persona de Mediana Edad , Nube ComputacionalRESUMEN
INTRODUCTION: Evidence on the impact of nutrient-rich animal source foods such as eggs for improving child growth and cognition is inconsistent. This study aims to examine the impact of an egg intervention in children, along with behaviour change communication (BCC) to the mother, on linear growth and cognition, and nutritional status in children aged 9-18 months. METHODS AND ANALYSIS: A 9-month open-labelled randomised controlled trial will be conducted in three urban slums in Hyderabad, India, as a substudy of an observational cohort study (n=350) following pregnant women and their children until 18 months of age in a population at risk of stunting. The children born to women enrolled during the third trimester of pregnancy will be block randomised in a 1:4 ratio into the intervention (n=70) and control (n=280) groups. Children in the intervention group will be supplemented with one egg per day starting from 9 months until 18 months of age. BCC designed to enhance adherence to the intervention will be used. The control group will be a part of the observational cohort and will not receive any intervention from the study team. The primary outcome will be length-for-age z-scores, and the secondary outcomes will include cognition, blood biomarkers of nutritional status including fatty acid profile and epigenetic signatures linked with linear growth and cognition. Multivariate intention-to-treat analyses will be conducted to assess the effect of the intervention. ETHICS AND DISSEMINATION: The study is approved by the Institutional ethics committees of ICMR-National Institute of Nutrition, Hyderabad, India and London School of Hygiene and Tropical Medicine, UK. The results will be published in peer-reviewed journals and disseminated to policy-makers. Findings will also be shared with study participants and community leaders. TRIAL REGISTRATION NUMBER: CTRI/2021/11/038208.
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Madres , Estado Nutricional , Lactante , Niño , Humanos , Femenino , Embarazo , Preescolar , Trastornos del Crecimiento , Suplementos Dietéticos , Cognición , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Observacionales como AsuntoRESUMEN
The present study describes a 7-year-old male child who had attended the Pediatric Oncology Clinic of the Regional Cancer Centre, Thiruvananthapuram, Kerala, India, and was pathologically confirmed to have B-Acute Lymphoblastic Leukemia (B-ALL). Conventional cytogenetics analysis at diagnosis showed the presence of a double Philadelphia chromosome and the karyotype of the case was 47, XY, t(9;22)(q34;q11.2), + der(22)t(9;22). FISH, done as a molecular confirmation of the translocation, t(9;22)(q34;q11.2), and this case showed an additional fusion signal that confirms the presence of double Ph. As far as we are aware, this represents the initial and only occurrence of an abnormality report regarding the double Philadelphia chromosome in pediatric B-ALL within India. The double Philadelphia chromosome in B-ALL has a very poor prognosis despite aggressive treatment with chemotherapy. This study reveals the importance of conventional and molecular cytogenetic analysis in risk stratification and prognosis prediction of pediatric B-ALL. The risk stratification based on the conventional and molecular cytogenetic analysis may be taken into consideration for deciding the treatment strategy for each patient.
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Background: t(8;21)(q22;q22) is the most frequent recurrent translocation in acute myeloid leukemia (AML) resulting in an in-frame fusion of RUNX1/RUNX1T1 that regulates various genes involved in the signaling pathways. This leukemogenic alteration is usually associated with a favorable clinical outcome. Variants of t(8;21) can be formed involving a third or fourth chromosome in ~3-4% of t(8;21)-AML. Due to the rarity of variant t(8;21), its clinicopathological features and prognostic significance are still unclear. Here we present three AML cases with cryptic rearrangements of chromosomes 8 and 21 without standard RUNX1/RUNX1T1. Materials and Methods: Conventional karyotyping and fluorescence in situ hybridization and/or spectral karyotyping of the pretreatment bone marrow aspirate of de novo AML patients were performed to delineate chromosomal abnormalities. Results: We identified three cases with novel variants of t(8;21); der(13)t(8;21;13), isodicentric derivative 8 with chromosome 21[,+idicder(8)(q11.1)t(8;21)(q22;q11.1)] and der(21)t(8;12;21)(q22;q?;q22). Conclusion: AML with t(8;21)(q22;q22);RUNX1-RUNX1T1 forms a distinct WHO subcategory and hence the identification of variants or unusual translocations associated with t(8;21) deserves more attention. Contribution to the variant/ unusual t(8;21) database will further refine the risk stratification and may help to significantly advance the current treatment regimen.
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Subunidad alfa 2 del Factor de Unión al Sitio Principal , Leucemia Mieloide Aguda , Cromosomas , Cromosomas Humanos Par 21 , Cromosomas Humanos Par 8 , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Translocación GenéticaRESUMEN
Acute myeloid leukemia (AML) is the most common acute leukemia in adults that affects the myeloid lineage. The recent advances have upgraded our understanding of the cytogenetic abnormalities and molecular mutations associated with AML that further aids in prognostication and risk stratification of the disease. Based on the highly heterogeneous nature of the disease and cytogenetic profile, AML patients can be stratified into favourable, intermediate and adverse-risk groups. The recurrent genetic alterations provide novel insights into the pathogenesis, clinical characteristics and also into the overall survival of the patients. In this review we are discussing about the cytogenetics of AML and the recurrent gene alterations such us NPM1, FLT3, CEBPA, TET-2, c-KIT, DNMT3A, IDH, RUNX1, AXSL1, WT1, Ras gene mutations etc. These gene mutations serve as important prognostic markers as well as potential therapeutic targets. AML patients respond to induction chemotherapy initially and subsequently achieve complete remission (CR), eventually most of them get relapsed.
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Biomarcadores de Tumor/genética , Regulación Leucémica de la Expresión Génica , Leucemia Mieloide Aguda/patología , Terapia Molecular Dirigida/métodos , Mutación , Supervivencia sin Enfermedad , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genéticaRESUMEN
Urothelial carcinoma is the most common histologic subtype of bladder cancer, accounting for approximately 90%. We herein report a case of a 78-year-old man with an unusual association of bladder stones with an aggressive plasmacytoid variant of urothelial cancer. Initially he presented in 2009 with a very large bladder stone and was treated by an open cystolithotomy. Histology from a bladder biopsy at that time was benign. He failed to attend follow-up appointments but subsequently he attended in 2016 with a recurrent urinary tract infection and an acute kidney injury. A CT scan showed multiple bladder stones. The cause of our patients' multiple bladder stones is unclear and unusual. He then underwent a further open cystolithotomy according to our multidisciplinary team recommendation. Post-operatively he unfortunately developed a non-healing vesicocutaneous fistula for which he was performed cystoscopy and biopsy but ended with transurethral resection due to the extent of abnormal/necrotic tissue. Histology confirmed a plasmacytoid variant of urothelial cancer. To our knowledge, this is the first case of an association of bladder stones with a plasmacytoid variant of urothelial cancer.
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Identification of BCR-ABL1 fusion gene amplification status is critically important in the effective management of chronic myelogenous leukemia (CML) patients. Earlier reports suggested that overexpression of BCR-ABL1 either through amplification of BCR-ABL1 fusion gene or by the up regulation of BCR-ABL1 transcript level might be an early phenomenon in the establishment of IM resistance and disease evolution in CML. In the current study, we performed dual color dual fusion locus specific BCR/ABL1 FISH analysis along with karyotype analysis using GTG banding (G-banding using trypsin and Giemsa) technique in 489 patients with different clinical stages of CML at diagnosis or during the course of the disease to unravel the spectrum of BCR-ABL1 fusion gene amplification status. Among the study group analyzed, it was found that prevalence of occurrence of BCR-ABL1 fusion gene amplification was significantly higher in advanced stages of disease and in IM resistant CML-CP patients when compared to initial stage of disease, de novo CML-CP. Cytogenetic and metaphase FISH characterization on our study samples revealed that BCR-ABL1 fusion gene amplification was occurred through the formation of extra copies Ph chromosomes and isoderived Ph chromosomes. Current study suggests that unrestrained activity of BCR-ABL1 played a vital role in resistance to targeted therapy and disease evolution in CML. In our study population, patients in progressive stage CML and in IM resistant CP with multiple copies of BCR-ABL1 fusion gene displayed a poor response to targeted treatment with IM. Hence, the early identification of BCR-ABL1 fusion gene amplification using FISH technique will lead to improved interventions and outcome in future CML patients.
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Proteínas de Fusión bcr-abl , Amplificación de Genes , Leucemia Mielógena Crónica BCR-ABL Positiva , Cromosoma Filadelfia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Bandeo Cromosómico , Femenino , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Hibridación Fluorescente in Situ , Leucemia Mielógena Crónica BCR-ABL Positiva/enzimología , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Masculino , Persona de Mediana EdadRESUMEN
Elucidation of cryptic BCR/ABL1 gene rearrangement is exceptionally important in the clinical diagnosis and prognosis of chronic myelogenous leukemia (CML). Previous reports indicated an adverse prognostic effect of atypical BCR/ABL1 gene rearrangements with submicroscopic ABL1-BCR deletions on derivative chromosome 9 [der(9)] in CML patients. Dual color dual fusion locus-specific BCR/ABL1 fluorescent in situ hybridization (FISH) analysis together with G-banding using trypsin and Giemsa (GTG banding) was performed in 489 patients at different stages of CML to investigate the spectrum of BCR/ABL1 gene rearrangements. Among the study group analyzed, a significantly higher frequency of BCR/ABL1 gene rearrangements that is consistent with der(9) deletion were observed in the blast crisis (BC) phase at 41.67%, followed by the accelerated phase (AP) at 36.84%, the imatinib mesylate (IM)-resistant chronic phase (CP) at 23.08%, and the lowest incidence was found in de novo CP at 16.61%. 1R1G1F (1 red, 1 green, 1 fusion) with concurrent loss of ABL1-BCR fusion gene on der(9) chromosome was the major signal pattern identified in each group. The results from the current study show that this unusual BCR/ABL1 gene rearrangement is one of the steering forces toward disease progression in CML. Patients in AP/BC of CML with der(9) deletion showed poor response to IM therapy; however, patients with der(9) deletion in the early phases of CML responded well to IM treatment. Therefore, the establishment of an atypical FISH signal pattern in CML is of paramount important because it is associated with adverse clinical prognostic implications in advanced stages of the disease.
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Deleción Cromosómica , Cromosomas Humanos Par 9/genética , Reordenamiento Génico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Hibridación Fluorescente in Situ , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Masculino , Persona de Mediana Edad , Pronóstico , Adulto JovenRESUMEN
AIMS: Treatment strategies for breast cancer continue to evolve. No uniformity exists in the UK for the management of node-positive breast cancer patients. Most centres continue to use conventional histopathology of sampled sentinel lymph nodes (SLNs), which requires delayed axillary clearance in up to 25% of patients. Some use touch imprint cytology or frozen section for intraoperative testing, although both have inherent sensitivity issues. An intraoperative molecular diagnostic approach helps to overcome some of these limitations. The aim of this study was to assess the clinical effectiveness of Metasin, a molecular method for the intraoperative evaluation of SLNs. METHODS AND RESULTS: RNA from 3296 lymph nodes from 1836 patients undergoing SLN assessment was analysed with Metasin. Alternate slices of tissue were examined in parallel by histology. Cases deemed to be discordant were analysed by protein gel electrophoresis. There was concordance between Metasin and histology in 94.1% of cases, with a sensitivity of 92% [95% confidence interval (CI) 88-94%] and a specificity of 97% (95% CI 95-97%). Positive and negative predictive values were 88% and 98%, respectively. Over half of the discordant cases (4.4%) were ascribed to tissue allocation bias (TAB). CONCLUSIONS: Clinical validation of the Metasin assay suggests that it is sufficiently sensitive and specific to make it fit for purpose in the intraoperative setting.
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Biomarcadores de Tumor/análisis , Neoplasias de la Mama/patología , Metástasis Linfática/diagnóstico , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Ganglio Linfático Centinela/patología , Femenino , Humanos , Periodo Intraoperatorio , Biopsia del Ganglio Linfático Centinela/métodosRESUMEN
The BCR-ABL1 fusion gene derived from the Philadelphia chromosome, resulting from a classical translocation event t(9;22)(q34.13;q11.23), is responsible for the pathogenesis of chronic myeloid leukemia (CML) in more than 90% of the patients. The isoderivative chromosome 22, ider(22), and relative amplification or duplication of the BCR-ABL1 gene have been considered as one of the major reasons associated with the resistance to chemotherapy with imatinib mesylate, but the data remain unclear. GTG-banding together with FISH were performed to identify the presence of the ider(22) chromosome. Reverse transcription-polymerase chain reaction (RT-PCR) for the detection of BCR-ABL1 fusion transcripts and BCR-ABL1 kinase domain mutation analysis were carried out in this study. Conventional and molecular cytogenetic analysis on metaphase chromosomes confirmed the presence of ider(22) chromosomes in both patients. Molecular characterization revealed the presence of a 210-kDa BCR-ABL1 type b3a2 and lack of mutations at the kinase domain region on the fusion product in both patients. The occurrence of the ider(22) chromosome could be considered as an important marker correlated with the aggressive progression of CML as well as the emergence of drug-resistant cell clones.
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Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos/genética , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Cromosoma Filadelfia , Adulto , Humanos , Cariotipificación , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Masculino , Persona de Mediana EdadRESUMEN
Nodal status is one of the most important prognostic factors in breast cancer. Established tests such as touch imprint cytology and frozen sections currently used in the intra-operative setting show variations in sensitivity and specificity. This limitation has led to the development of molecular alternatives, such as GeneSearch, a commercial intra-operative real-time quantitative Polymerase Chain Reaction (RT-qPCR) assay that allows the surgeon to carry out axillary clearance as a one-step process. Since GeneSearch has been discontinued, we have developed the replacement Metasin assay, which targets the breast epithelial cell markers CK19 and mammaglobin mRNA and identifies metastatic disease in sentinel lymph nodes. The optimised assay can be completed within 32 min (6 min for RNA preparation and 26 min instrument run time), making its use feasible in the intraoperative setting. An analysis by Metasin of 154 archived lymph node homogenates previously analysed by both parallel histology and GeneSearch showed concordance for 148 cases. The sensitivity and specificity of Metasin compared with GeneSearch were 95% (CI 83%-99%) and 97% (CI 91%-99%) respectively; compared with histology they were 95% (CI 83%-99%) and 97% (CI 91%-99%), respectively. The sensitivity and specificity of GeneSearch compared with histology were 90% (CI 77%-96%) and 97% (CI 93%-99%) respectively. The positive predictive value of Metasin was 90% and negative predictive value was 98% for both histology and GeneSearch. The positive predictive value of GeneSearch was 92% and the negative predictive value was 97% compared to histology. The discordance rates of Metasin with both GeneSearch and histology were 3.89%. In comparison, the discordance rate of GeneSearch with histology was 4.5%. Metasin's robustness was independently evaluated on 193 samples previously analysed by GeneSearch from the Jules Bordet Institute, where Metasin yielded comparable results.
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Metástasis Linfática , Biopsia del Ganglio Linfático Centinela , Neoplasias de la Mama , Humanos , Ganglios Linfáticos , Mamoglobina A , Sensibilidad y EspecificidadRESUMEN
Somatic and germline mutations in the dual zinc-finger transcription factor GATA3 are associated with breast cancers expressing the estrogen receptor (ER) and the autosomal dominant hypoparathyroidism-deafness-renal dysplasia syndrome, respectively. To elucidate the role of GATA3 in breast tumorigenesis, we investigated 40 breast cancers that expressed ER, for GATA3 mutations. Six different heterozygous GATA3 somatic mutations were identified in eight tumors, and these consisted of: a frameshifting deletion/insertion (944_945delGGinsAGC), an in-frame deletion of a key arginine residue (991_993delAGG), a seven-nucleotide frameshifting insertion (991_992insTGGAGGA), a frameshifting deletion (1196_1197delGA), and two frameshifting single nucleotide insertions (1224_1225insG found in three tumors and 1224_1225insA). Five of the eight mutations occurred in tumors that retained GATA3 immunostaining, indicating that absence of GATA3 immunostaining is an unreliable predictor of the presence of GATA3 mutations. Luciferase reporter assays, electrophoretic mobility shift assays, immunofluorescence, invasion and proliferation assays demonstrated that the GATA3 mutations resulted in loss (or reduction) of DNA binding, decrease in transactivational activity, and alterations in invasiveness but not proliferation. The 991_992insTGGAGGA (Arg330 frameshift) mutation led to a loss of nuclear localization, yet the 991_993delAGG (Arg330deletion) retained nuclear localization. Investigation of the putative nuclear localization signal (NLS) sites showed that the NLS of GATA3 does not conform to either a classical mono- or bi-partite signal, but contains multiple cooperative NLS elements residing around the N-terminal zinc-finger which comprises residues 264-288. Thus, approximately 20 % ER-positive breast cancers have somatic GATA3 mutations that lead to a loss of GATA3 transactivation activity and altered cell invasiveness.
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Neoplasias de la Mama/genética , Transformación Celular Neoplásica/genética , Factor de Transcripción GATA3/genética , Invasividad Neoplásica/genética , Secuencia de Aminoácidos , Neoplasias de la Mama/patología , Núcleo Celular/metabolismo , Núcleo Celular/patología , Femenino , Factor de Transcripción GATA3/metabolismo , Humanos , Células MCF-7 , Mutación , Invasividad Neoplásica/patología , Receptores de Estrógenos/genética , Activación Transcripcional/genéticaRESUMEN
BACKGROUND: Parathyroidectomy for primary hyperparathyroidism (PHPT) is followed by a decrease in the severity of symptoms reported on the Pasieka's parathyroid symptoms score (PPSS) and SF-36 questionnaires. Some argue that such benefits are short-lived. This study investigates the severity of symptoms at more than 12 months after parathyroidectomy. METHODS: A prospective database collected clinical/operative data on consecutive patients with PHPT. PPSS was calculated as the sum of the 13 parameters self-assessed using a visual analog scale. SF-36(v2) was analyzed using commercially available software (QualityMetric Inc., Lincoln, USA). RESULTS: Over 3-year interval, 166 patients (119 F/47 M, age 15-89 years) were operated for with PHPT (Ca 2.90 ± 0.25 mmol/L, PTH 21.64 ± 23.05 pmol/L). Their preoperative PPSS ranged 0-1,260 (median 413) and did not correlate with the severity of hypercalcemia. One hundred and seven patients responded when contacted by post at 18 ± 6 months postoperatively. Their postoperative PPSS was significantly lower (398 ± 226 to 231 ± 203, p < 0.001) and in 55 of 107 patients the severity of symptoms reduced by at least 50%. Most significant improvements were for mood (36 ± 33 vs. 16 ± 23), weakness/tiredness (37 ± 32 vs. 17 ± 23), irritability (35 ± 31 vs. 17 ± 21), and thirst (37 ± 32 vs. 18 ± 25; p < 0.0001). Physical and mental component scores of SF-36 questionnaire improved in patients whose PPSS decreased postoperatively. CONCLUSION: Symptomatic benefits persist for at least 1 year after parathyroidectomy in the majority of patients with PHPT.
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Hiperparatiroidismo Primario/diagnóstico , Hiperparatiroidismo Primario/cirugía , Paratiroidectomía/métodos , Calidad de Vida , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Bases de Datos Factuales , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Hormona Paratiroidea/sangre , Satisfacción del Paciente , Cuidados Posoperatorios/métodos , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Perfil de Impacto de Enfermedad , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Breast pain and tenderness affects 70% of women at some time. These symptoms have been attributed to stretching of the nerves with increase in breast size, but tissue mechanisms are poorly understood. METHODS: Eighteen patients (n = 12 breast reduction and n = 6 breast reconstruction) were recruited and assessed for breast pain by clinical questionnaire. Breast skin biopsies from each patient were examined using immunohistological methods with specific antibodies to the capsaicin receptor TRPV1, related vanilloid thermoreceptors TRPV3 and TRPV4, and nerve growth factor (NGF). RESULTS: TRPV1-positive intra-epidermal nerve fibres were significantly increased in patients with breast pain and tenderness (TRPV1 fibres / mm epidermis, median [range] - no pain group, n = 8, 0.69 [0-1.27]; pain group, n = 10, 2.15 [0.77-4.38]; p = 0.0009). Nerve Growth Factor, which up-regulates TRPV1 and induces nerve sprouting, was present basal keratinocytes: some breast pain specimens also showed NGF staining in supra-basal keratinocytes. TRPV4-immunoreactive fibres were present in sub-epidermis but not significantly changed in painful breast tissue. Both TRPV3 and TRPV4 were significantly increased in keratinocytes in breast pain tissues; TRPV3, median [range] - no pain group, n = 6, 0.75 [0-2]; pain group, n = 11, 2 123, p = 0.008; TRPV4, median [range] - no pain group, n = 6, [0-1]; pain group, n = 11, 1 [0.5-2], p = 0.014). CONCLUSION: Increased TRPV1 intra-epidermal nerve fibres could represent collateral sprouts, or re-innervation following nerve stretch and damage by polymodal nociceptors. Selective TRPV1-blockers may provide new therapy in breast pain. The role of TRPV3 and TRPV4 changes in keratinocytes deserve further study.