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We present two cases of malignant ossifying fibromyxoid tumor (OFMT) which eluded diagnosis due to compelling clinicopathologic mimicry, compounded by similarly elusive underlying molecular drivers. The first is of a clavicle mass in a 69 year-old female, which histologically showed an infiltrative nested and trabeculated proliferation of monomorphic cells giving rise to scattered spicules of immature woven bone. Excepting SATB2 positivity, the lesion showed an inconclusive immunoprofile which along with negative PHF1 FISH led to an initial diagnosis of high-grade osteosarcoma. Next generation sequencing (NGS) revealed a particularly rare CREBBP::BCORL1 fusion. The second illustrates the peculiar presentation of a dural-based mass in a 52 year-old female who presented with neurologic dyscrasias. Sections showed a sheeted monotonous proliferation of ovoid to spindle cells, but in contrast to Case #1, the tumor contained an exuberance of reticular osteoid and woven bone deposition mimicking malignant osteogenic differentiation. NGS showed a novel CREBZF::PHF1 fusion. Both tumors recurred locally less than 1 year post-operatively. As such we reiterate that careful morphologic examination is axiomatic to any diagnosis in our discipline, but this paradigm must shift to recognize that molecular diagnostics can provide closure where traditional tools have notable limitations.
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Neoplasias Ósseas , Fibroma Ossificante , Fibroma , Osteossarcoma , Sarcoma , Neoplasias de Tecidos Moles , Feminino , Humanos , Idoso , Pessoa de Meia-Idade , Proteínas de Ligação a DNA , Fibroma Ossificante/diagnóstico , Fibroma Ossificante/genética , Fibroma Ossificante/patologia , Osteogênese , Proteínas do Grupo Polycomb , Recidiva Local de Neoplasia , Fibroma/patologia , Osteossarcoma/diagnóstico , Osteossarcoma/genética , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Neoplasias de Tecidos Moles/patologia , Fatores de Transcrição de Zíper de Leucina BásicaRESUMO
Pleomorphic rhabdomyosarcoma (PRMS) is a rare and highly aggressive sarcoma, occurring mostly in the deep soft tissues of middle-aged adults and showing a variable degree of skeletal muscle differentiation. The diagnosis is challenging as pathologic features overlap with embryonal rhabdomyosarcoma (ERMS), malignant Triton tumor, and other pleomorphic sarcomas. As recurrent genetic alterations underlying PRMS have not been described to date, ancillary molecular diagnostic testing is not useful in subclassification. Herein, we perform genomic profiling of a well-characterized cohort of 14 PRMS, compared to a control group of 23 ERMS and other pleomorphic sarcomas (undifferentiated pleomorphic sarcoma and pleomorphic liposarcoma) using clinically validated DNA-targeted Next generation sequencing (NGS) panels (MSK-IMPACT). The PRMS cohort included eight males and six females, with a median age of 53 years (range 31-76 years). Despite similar tumor mutation burdens, the genomic landscape of PRMS, with a high frequency of TP53 (79%) and RB1 (43%) alterations, stood in stark contrast to ERMS, with 4% and 0%, respectively. CDKN2A deletions were more common in PRMS (43%), compared to ERMS (13%). In contrast, ERMS harbored somatic driver mutations in the RAS pathway and loss of function mutations in BCOR, which were absent in PRMS. Copy number variations in PRMS showed multiple chromosomal arm-level changes, most commonly gains of chr17p and chr22q and loss of chr6q. Notably, gain of chr8, commonly seen in ERMS (61%) was conspicuously absent in PRMS. The genomic profiles of other pleomorphic sarcomas were overall analogous to PRMS, showing shared alterations in TP53, RB1, and CDKN2A. Overall survival and progression-free survival of PRMS were significantly worse (p < 0.0005) than that of ERMS. Our findings revealed that the molecular landscape of PRMS aligns with other adult pleomorphic sarcomas and is distinct from that of ERMS. Thus, NGS assays may be applied in select challenging cases toward a refined classification. Finally, our data corroborate the inclusion of PRMS in the therapeutic bracket of pleomorphic sarcomas, given that their clinical outcomes are comparable.
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Rabdomiossarcoma Embrionário , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Rabdomiossarcoma Embrionário/genética , Rabdomiossarcoma Embrionário/patologia , Rabdomiossarcoma/genética , Rabdomiossarcoma/patologia , Rabdomiossarcoma/classificação , Mutação , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Genômica/métodos , Biomarcadores Tumorais/genética , Proteínas de Ligação a Retinoblastoma/genética , Ubiquitina-Proteína LigasesRESUMO
GLI1(12q13.3) amplification is identified in a subset of mesenchymal neoplasms with a distinct nested round cell/epithelioid phenotype. MDM2 and CDK4 genes are situated along the oncogenic 12q13-15 segment, amplification of which defines well-differentiated liposarcoma (WDLPS)/dedifferentiated liposarcoma (DDLPS). The 12q amplicon can occasionally include GLI1, a gene in close proximity to CDK4. We hereby describe the first cohort of GLI1/MDM2/CDK4 coamplified WD/DDLPS. The departmental database was queried retrospectively for all cases of WD/DDLPS having undergone next-generation (MSK-IMPACT) sequencing with confirmed MDM2, CDK4, and GLI1 coamplification. Clinicopathologic data was obtained from a review of the medical chart and available histologic material. Four hundred eighty-six WD/DDLPS cases underwent DNA sequencing, 92 (19%) of which harbored amplification of the GLI1 locus in addition to that of MDM2 and CDK4. These included primary tumors (n = 60), local recurrences (n = 29), and metastases (n = 3). Primary tumors were most frequently retroperitoneal (47/60, 78%), mediastinal (4/60, 7%), and paratesticular (3/60, 5%). Average age was 63 years, with a male:female ratio of 3:2. The cohort was comprised of DDLPS (86/92 [93%], 6 of which were WDLPS with early dedifferentiation) and WDLPS without any longitudinal evidence of dedifferentiation (6/92, 7%). One-fifth (13/86, 17%) of DDLPS cases showed no evidence of a well-differentiated component in any of the primary, recurrent, or metastatic specimens. Dedifferentiated areas mostly showed high-grade undifferentiated pleomorphic sarcoma-like (26/86,30%) and high-grade myxofibrosarcoma-like (13/86,16%) morphologies. A disproportionately increased incidence of meningothelial whorls with/without osseous metaplasia was observed as the predominant pattern in 16/86 (19%) cases, and GLI1-altered morphology as described was identified in a total of 10/86 (12%) tumors. JUN (1p32.1), also implicated in the pathogenesis of WD/DDLPS, was coamplified with all 3 of MDM2, CDK4, and GLI1 in 7/91 (8%) cases. Additional loci along chromosomal arms 1p and 6q, including TNFAIP3, LATS1, and ESR1, were also amplified in a subset of cases. In this large-scale cohort of GLI1 coamplified WD/DDLPS, we elucidate uniquely recurrent features including meningothelial whorl-like and GLI-altered morphology in dedifferentiated areas. Assessment of tumor location (retroperitoneal or mediastinal), identification of a well-differentiated liposarcoma component, and coamplification of other spatially discrete genomic segments (1p and 6q) might aid in distinction from tumors with true driver GLI1 alterations.
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Quinase 4 Dependente de Ciclina , Amplificação de Genes , Lipossarcoma , Proteína GLI1 em Dedos de Zinco , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Biomarcadores Tumorais/genética , Quinase 4 Dependente de Ciclina/genética , Lipossarcoma/genética , Lipossarcoma/patologia , Proteínas Proto-Oncogênicas c-mdm2/genética , Estudos Retrospectivos , Proteína GLI1 em Dedos de Zinco/genéticaRESUMO
Portosinusoidal vascular disorder (PSVD) is a recently proposed histopathologic entity that encompasses a spectrum of often subtle hepatic microvascular lesions and related microarchitectural abnormalities. Clinical manifestations may arise years after histologic diagnosis and include extrahepatic portal vein thrombosis and portal hypertension. While the histopathologic features of PSVD have been associated with numerous clinical conditions, most notably prothrombotic/vasculopathic disorders, PSVD has not yet been described in sickle cell disease. This gap is striking given the central role of microvascular dysfunction in sickle cell disease and well-described patterns of hepatic injury and dysfunction in this population. This case series is the first to explore the prevalence and pathogenesis of PSVD in sickle cell disease. Forty-one diagnostically adequate liver biopsies from patients with sickle cell disease were identified across the archives of 5 tertiary medical centers. All biopsies exhibited at least 1 histopathologic feature associated with PSVD (mean 3.8 features/case). Overall, 90.2% of patients met the criteria for a diagnosis of PSVD based on the presence of specific histopathologic and/or clinical findings. Immunohistochemical stains for von Willebrand factor, CD34, and glutamine synthetase were performed on 36 cases (87.8%). Aberrant (centrilobular sinusoidal) CD34 and von Willebrand factor staining was present in 97.2% and 86.1% of cases, respectively. Glutamine synthetase reactivity was at least mildly decreased in zone 3 hepatocytes in 52.8% of cases. We posit that chronic erythrocyte sickling results in dysfunction and remodeling of the portal microvasculature, culminating in regression of zone 3 hepatocytes. The presence of PSVD may explain, at least in part, the hepatic dysfunction observed in this patient population. These patients may also benefit from extended clinical surveillance for portal hypertension and other complications. While subtle and prone to overdiagnosis, the features of PSVD should be carefully considered when interpreting liver biopsies from patients with sickle cell disease.
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Anemia Falciforme , Hipertensão Portal , Humanos , Glutamato-Amônia Ligase , Fator de von Willebrand , Anemia Falciforme/complicações , Hipertensão Portal/etiologiaRESUMO
RAD51B-rearranged sarcomas are rare neoplasms that exhibit a heterogeneous morphology. To date, 6 cases have been reported, all involving the uterus, including 4 perivascular epithelioid cell tumors (PEComas) and 2 leiomyosarcomas (LMS). In this study, we describe the morphologic, immunohistochemical, and molecular features of 8 additional sarcomas with RAD51B rearrangement, including the first extrauterine example. All patients were women with a median age of 57 years at presentation. Seven tumors originated in the uterus, and one in the lower extremity soft tissue, with a median tumor size of 12 cm. Histologically, 4 tumors showed predominantly spindle cell morphology with eosinophilic fibrillary cytoplasm, with or without nuclear pleomorphism, whereas 2 tumors exhibited pleomorphic epithelioid cells, featuring clear to eosinophilic, granular cytoplasm. Two neoplasms exhibited undifferentiated cytomorphology, including one with uniform small blue round cells. All tumors showed high-grade cytologic atypia and high mitotic activity (median: 30/10 high-power fields), whereas coagulative necrosis was noted in 6 cases and lymphovascular invasion in 2. By immunohistochemistry, 2 showed myoid and melanocytic markers in keeping with PEComa, whereas 4 cases were only positive for smooth muscle markers consistent with LMS (including 3 myxoid). The remaining 2 cases had a nonspecific immunoprofile. Five cases tested by targeted RNA sequencing (Archer FusionPlex, Illumina TruSight) showed different fusion partners (HMGA2, PDDC1, and CEP170). RAD51B rearrangements were identified by FISH in the remaining 3 cases. Targeted DNA sequencing in 2 cases was negative for TSC gene alterations. Clinical outcome, available in 5 patients (median follow-up, 19 months), revealed 3 local recurrences, 2 lung metastases, and 4 deaths due to disease. Our results expand the spectrum of sarcomas with RAD51B fusions, demonstrating variable clinical presentations, morphologic spectrum, and fusion partners. These tumors have a predilection for a uterine location, with either LMS, PEComa, or undifferentiated phenotypes, and are associated with an aggressive clinical course.
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Leiomiossarcoma , Neoplasias de Células Epitelioides Perivasculares , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Biomarcadores Tumorais/genética , Sarcoma/genética , Sarcoma/patologia , Leiomiossarcoma/genética , Neoplasias de Células Epitelioides Perivasculares/patologia , Neoplasias de Tecidos Moles/genética , Fenótipo , Proteínas de Ligação a DNA/genéticaRESUMO
INTRODUCTION AND HYPOTHESIS: Pregnancy is associated with an increase in pelvic floor dysfunction. Yoga, an ancient Indian practice involving asanas (physical postures), pranayam (breathing patterns) and meditation, can help women to control their pelvic floor muscles. However, the literature to support yoga as a remedy for pelvic floor dysfunction is lacking. We hypothesized that yoga could be an important method in improving pelvic floor dysfunction in pregnancy. METHODS: In a randomised control study, 200 pregnant women matched for age, weight, parity and physical activity were randomised at the 13- to 20-week period of gestation into two groups: group I (n = 100, undergoing yoga therapy) and group II (n = 100, given usual antenatal care). A trained instructor provided two physical sessions, each lasting for 60 min and further online sessions for 5 days a week for 3 months. The Pelvic Floor Distress Inventory (PFDI-20) questionnaire was used to assess the primary outcome at recruitment, 32 weeks (antenatal), 1 week and 6 weeks post-partum in both groups. RESULTS: In the 200 women randomised and matched for age and parity, there were no complications seen throughout the pregnancy and none of the patients was lost to follow-up in either group. The proportion of women exhibiting a decline in PFDI-20 scores was greater in group 1 (24%) than in group 2 (8%). The mean difference of scores between recruitment and 6 weeks post-partum was statistically significant (p value = 0.0026). CONCLUSIONS: Yoga in pregnancy significantly improves pelvic floor dysfunction in an easy manner with no proven adverse effects.
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BACKGROUND: Our study aimed to establish 'real-world' performance and cost-effectiveness of ovarian cancer (OC) surveillance in women with pathogenic germline BRCA1/2 variants who defer risk-reducing bilateral salpingo-oophorectomy (RRSO). METHODS: Our study recruited 875 female BRCA1/2-heterozygotes at 13 UK centres and via an online media campaign, with 767 undergoing at least one 4-monthly surveillance test with the Risk of Ovarian Cancer Algorithm (ROCA) test. Surveillance performance was calculated with modelling of occult cancers detected at RRSO. The incremental cost-effectiveness ratio (ICER) was calculated using Markov population cohort simulation. RESULTS: Our study identified 8 OCs during 1277 women screen years: 2 occult OCs at RRSO (both stage 1a), and 6 screen-detected; 3 of 6 (50%) were ≤stage 3a and 5 of 6 (83%) were completely surgically cytoreduced. Modelled sensitivity, specificity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV) for OC were 87.5% (95% CI, 47.3 to 99.7), 99.9% (99.9-100), 75% (34.9-96.8) and 99.9% (99.9-100), respectively. The predicted number of quality-adjusted life years (QALY) gained by surveillance was 0.179 with an ICER cost-saving of -£102,496/QALY. CONCLUSION: OC surveillance for women deferring RRSO in a 'real-world' setting is feasible and demonstrates similar performance to research trials; it down-stages OC, leading to a high complete cytoreduction rate and is cost-saving in the UK National Health Service (NHS) setting. While RRSO remains recommended management, ROCA-based surveillance may be considered for female BRCA-heterozygotes who are deferring such surgery.
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Proteína BRCA1 , Proteína BRCA2 , Neoplasias Ovarianas , Feminino , Humanos , Proteína BRCA1/genética , Proteína BRCA2/genética , Diagnóstico Tardio , Predisposição Genética para Doença/epidemiologia , Células Germinativas/patologia , Mutação , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/economia , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Ovariectomia , Medicina Estatal/economia , Salpingectomia , Reino Unido/epidemiologia , Vigilância da População , Análise de Custo-EfetividadeRESUMO
BACKGROUND: In UKCTOCS, there was a decrease in the diagnosis of advanced stage tubo-ovarian cancer but no reduction in deaths in the multimodal screening group compared with the no screening group. Therefore, we did exploratory analyses of patients with high-grade serous ovarian cancer to understand the reason for the discrepancy. METHODS: UKCTOCS was a 13-centre randomised controlled trial of screening postmenopausal women from the general population, aged 50-74 years, with intact ovaries. The trial management system randomly allocated (2:1:1) eligible participants (recruited from April 17, 2001, to Sept 29, 2005) in blocks of 32 using computer generated random numbers to no screening or annual screening (multimodal screening or ultrasound screening) until Dec 31, 2011. Follow-up was through national registries until June 30, 2020. An outcome review committee, masked to randomisation group, adjudicated on ovarian cancer diagnosis, histotype, stage, and cause of death. In this study, analyses were intention-to-screen comparisons of women with high-grade serous cancer at censorship (Dec 31, 2014) in multimodal screening versus no screening, using descriptive statistics for stage and treatment endpoints, and the Versatile test for survival from randomisation. This trial is registered with the ISRCTN Registry, 22488978, and ClinicalTrials.gov, NCT00058032. FINDINGS: 202â562 eligible women were recruited (50â625 multimodal screening; 50â623 ultrasound screening; 101â314 no screening). 259 (0·5%) of 50â625 participants in the multimodal screening group and 520 (0·5%) of 101â314 in the no screening group were diagnosed with high-grade serous cancer. In the multimodal screening group compared with the no screening group, fewer were diagnosed with advanced stage disease (195 [75%] of 259 vs 446 [86%] of 520; p=0·0003), more had primary surgery (158 [61%] vs 219 [42%]; p<0·0001), more had zero residual disease following debulking surgery (119 [46%] vs 157 [30%]; p<0·0001), and more received treatment including both surgery and chemotherapy (192 [74%] vs 331 [64%]; p=0·0032). There was no difference in the first-line combination chemotherapy rate (142 [55%] vs 293 [56%]; p=0·69). Median follow-up from randomisation of 779 women with high-grade serous cancer in the multimodal and no screening groups was 9·51 years (IQR 6·04-13·00). At censorship (June 30, 2020), survival from randomisation was longer in women with high-grade serous cancer in the multimodal screening group than in the no screening group with absolute difference in survival of 6·9% (95% CI 0·4-13·0; p=0·042) at 18 years (21% [95% CI 15·6-26·2] vs 14% [95% CI 10·5-17·4]). INTERPRETATION: To our knowledge, this is the first evidence that screening can detect high-grade serous cancer earlier and lead to improved short-term treatment outcomes compared with no screening. The potential survival benefit for women with high-grade serous cancer was small, most likely due to only modest gains in early detection and treatment improvement, and tumour biology. The cumulative results of the trial suggest that surrogate endpoints for disease-specific mortality should not currently be used in screening trials for ovarian cancer. FUNDING: National Institute for Health Research, Medical Research Council, Cancer Research UK, The Eve Appeal.
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Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Resultado do Tratamento , Programas de Rastreamento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND: The pattern-based (Silva) classification of invasive human papilloma virus (HPV)-associated endocervical adenocarcinomas (HPVA) is an established and reproducible method to predict outcomes for this otherwise stage-dependent group of tumours. Previous studies utilising targeted sequencing have shown a correlation between mutational profiles and an invasive pattern. However, such correlation has not been explored using comprehensive molecular testing. DESIGN: Clinicopathologic data including invasive pattern (Silva groups A, B, and C) was collected for a cohort of invasive HPVA, which previously underwent massive parallel sequencing using a panel covering 447 genes. Pathogenic alterations, molecular signatures, tumour mutational burden (TMB), and copy number alterations (CNA) were correlated with pattern of invasion. RESULTS: Forty five HPVA (11 pattern A, 17 pattern B, and 17 pattern C tumours) were included. Patients with pattern A presented at stage I with no involved lymph nodes or evidence of recurrence (in those with >2 months of follow-up). Patterns B and C patients also mostly presented at stage I with negative lymph nodes, but had a greater frequency of recurrence; 3/17 pattern B and 1/17 pattern C HPVAs harboured lymphovascular space invasion (LVI). An APOBEC mutational signature was detected only in Silva pattern C tumours (5/17), and pathogenic PIK3CA changes were detected only in destructively invasive HPVA (patterns B and C). When cases were grouped as low-risk (pattern A and pattern B without LVI) and high-risk (pattern B with LVI and pattern C), high-risk tumours were enriched in mutations in PIK3CA, ATRX, and ERBB2. There was a statistically significant difference in TMB between low-risk and high-risk pattern tumours (P = 0.006), as well as between Pattern C tumours with and without an APOBEC signature (P = 0.002). CNA burden increased from pattern A to C. CONCLUSION: Our findings further indicate that key molecular events in HPVA correlate with the morphologic invasive properties of the tumour and their aggressiveness. Pattern B tumours with LVI clustered with pattern C tumours, whereas pattern B tumours without LVI approached pattern A genotypically. Our study provides a biologic foundation for consolidating the Silva system into low-risk (pattern A + B without LVI) and high-risk (pattern B with LVI and pattern C) categories.
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Adenocarcinoma , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Papillomavirus Humano , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/patologia , Adenocarcinoma/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Biomarcadores Tumorais , Prognóstico , Invasividade NeoplásicaRESUMO
OBJECTIVE: UKCTOCS provides an opportunity to explore symptoms in preclinical invasive epithelial ovarian cancer (iEOC). We report on symptoms in women with pre-clinical (screen-detected) cancers (PC) compared to clinically diagnosed (CD) cancers. METHODS: In UKCTOCS, 202638 postmenopausal women, aged 50-74 were randomly allocated (April 17, 2001-September 29, 2005) 2:1:1 to no screening or annual screening till Dec 31,2011, using a multimodal or ultrasound strategy. Follow-up was through national registries. An outcomes committee adjudicated on OC diagnosis, histotype, stage. Eligible women were those diagnosed with iEOC at primary censorship (Dec 31, 2014). Symptom details were extracted from trial clinical-assessment forms and medical records. Descriptive statistics were used to compare symptoms in PC versus CD women with early (I/II) and advanced (III/IV/unable to stage) stage high-grade-serous (HGSC) cancer. ISRCTN-22488978; ClinicalTrials.gov-NCT00058032. RESULTS: 1133 (286PC; 847CD) women developed iEOC. Median age (years) at diagnosis was earlier in PC compared to CD (66.8PC, 68.7CD, p = 0.0001) group. In the PC group, 48% (112/234; 90%, 660/730CD) reported symptoms when questioned. Half PC (50%, 13/26PC; 36%, 29/80CD; p = 0.213) women with symptomatic HGSC had >1symptom, with abdominal symptoms most common, both in early (62%, 16/26, PC; 53% 42/80, CD; p = 0.421) and advanced (57%, 49/86, PC; 74%, 431/580, CD; p = 0.001) stages. In symptomatic early-stage HGSC, compared to CD, PC women reported more gastrointestinal (change in bowel habits and dyspepsia) (35%, 9/26PC; 9%, 7/80CD; p = 0.001) and systemic (mostly lethargy/tiredness) (27%, 7/26PC; 9%, 7/80CD; p = 0.017) symptoms. CONCLUSIONS: Our findings, add to the growing evidence, that we should reconsider what constitutes alert symptoms for early tubo-ovarian cancer. We need a more nuanced complex of key symptoms which is then evaluated and refined in a prospective trial.
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Detecção Precoce de Câncer , Neoplasias Ovarianas , Feminino , Humanos , Carcinoma Epitelial do Ovário/diagnóstico , Estudos Prospectivos , Neoplasias Ovarianas/diagnóstico , Reino Unido/epidemiologiaRESUMO
BACKGROUND: Attractive toxic sugar bait (ATSB) is a promising "attract and kill"-based approach for mosquito control. It is a combination of flower nectar/fruit juice to attract the mosquitoes, sugar solution to stimulate feeding, and a toxin to kill them. Selecting an effective attractant and optimizing concentration of toxicant is significant in the formulation of ATSB. METHODS: Current study formulated an ATSB using fruit juice, sugar and deltamethrin, a synthetic pyrethroid. It was evaluated against two laboratory strains of Anopheles stephensi. Initial studies evaluated comparative attractiveness of nine different fruit juices to An. stephensi adults. Nine ASBs were prepared by adding fermented juices of plum, guava, sweet lemon, orange, mango, pineapple, muskmelon, papaya, and watermelon with 10% sucrose solution (w/v) in 1:1 ratio. Cage bioassays were conducted to assess relative attraction potential of ASBs based on the number of mosquito landings on each and the most effective ASB was identified. Ten ATSBs were prepared by adding the identified ASB with different deltamethrin concentrations (0.015625-8.0 mg/10 mL) in 1:9 ratio. Each ATSB was assessed for the toxic potential against both the strains of An. stephensi. The data was statistically analysed using PASW (SPSS) software 19.0 program. RESULTS: The cage bioassays with nine ASBs revealed higher efficacy (p < 0.05) of Guava juice-ASB > Plum juice-ASB > Mango juice-ASB in comparison to rest of the six ASB's. The bioassay with these three ASB's ascertained the highest attractancy potential of guava juice-ASB against both the strains of An. stephensi. The ATSB formulations resulted in 5.1-97.9% mortality in Sonepat (NIMR strain) with calculated LC30, LC50, and LC90 values of 0.17 mg deltamethrin/10 mL, 0.61 mg deltamethrin/10 mL, and 13.84 mg deltamethrin/10 mL ATSB, respectively. Whereas, 6.12-86.12% mortality was recorded in the GVD-Delhi (AND strain) with calculated LC30, LC50, and LC90 values of 0.25 mg deltamethrin/10 mL, 0.73 mg deltamethrin/10 mL and 10.22 mg deltamethrin/10 mL ATSB, respectively. CONCLUSION: The ATSB formulated with guava juice-ASB and deltamethrin (0.0015625-0.8%) in 9:1 ratio showed promising results against two laboratory strains of An. stephensi. Field assessment of these formulations is being conducted to estimate their feasibility for use in mosquito control.
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Anopheles , Inseticidas , Piretrinas , Animais , Açúcares/toxicidade , Anopheles/fisiologia , Carboidratos , Controle de Mosquitos/métodosRESUMO
Approximately 1% to 1.5% of uterine leiomyomas are fumarate hydratase (FH)-deficient (FHd). A subset of these are associated with germline FH mutations. However, the prevalence and clinicopathologic characteristics of FHd uterine leiomyosarcoma (uLMS) remain unknown. Clinicopathologic data were collected for 348 uLMS. Morphologic features associated with FH deficiency (staghorn-type vessels, alveolar-pattern edema, macronucleoli with perinucleolar clearing, eosinophilic cytoplasmic inclusions, and chain-like nuclear arrangement) were documented. All 348 tumors were studied by FH immunohistochemistry. Eighty-nine were also studied by S-(2-succinyl)-cysteine (2SC) immunohistochemistry. Seven (2%) FHd uLMS were identified. Five showed uniformly negative FH and diffusely positive 2SC immunostaining; 1 showed variably negative to weak to strong FH and diffusely positive 2SC immunostaining; and 1 showed retained FH staining alongside positive 2SC confined to a morphologically distinct subclone. Three of 7 patients had extrauterine disease at presentation, and 3 of 6 had persistent disease or died from disease. Macronucleoli with perinucleolar clearing were significantly more common in FHd uLMS (7/7) than in uLMS with retained FH (182/341; P =0.017). Disease-specific survival, disease-free survival, and other morphologic features of FH deficiency did not differ significantly between FHd and FH-retained tumors. Our data emphasize that immunohistochemical FH deficiency does not preclude malignancy in uterine smooth muscle tumors. However, the biological significance and molecular basis of FH deficiency in uLMS, including any relationship to germline FH mutation, remain unknown, and a larger multi-institutional effort is necessary to gather sufficient FHd uLMS for more robustly powered clinicopathologic and for molecular characterization.
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Carcinoma de Células Renais , Neoplasias Renais , Leiomiomatose , Leiomiossarcoma , Neoplasias Pélvicas , Neoplasias Uterinas , Feminino , Humanos , Fumarato Hidratase/genética , Cisteína , Estudos de Coortes , Imuno-Histoquímica , Neoplasias Uterinas/patologia , Leiomiomatose/genética , Neoplasias Renais/patologia , Carcinoma de Células Renais/patologiaRESUMO
Most low-grade, early-stage endometrial endometrioid carcinomas (EEC) have an excellent prognosis; however, recurrences occur in a small subset with several studies reporting an increase in CTNNB1 exon 3 mutations in this population. Herein we evaluated 10 recurrent low-grade (FIGO 1 or 2), early-stage (FIGO IA) EECs matched to 10 nonrecurrent EECs to further characterize their clinicopathologic features and molecular phenotype. Cases were matched to controls based on size, grade, and depth of invasion. All tumors were evaluated for specific clinicopathologic parameters followed by next-generation sequencing using a 1213 gene panel. Recurrent EECs demonstrated no significant clinicopathologic differences when compared with nonrecurrent EECs, in terms of age, body mass index, pattern of invasion, presence of endometrial atypical hyperplasia/endometrioid intraepithelial neoplasia, associated metaplastic changes, peritumoral lymphocytes, mitoses, and tumor-infiltrating lymphocytes. Both cohorts also showed a similar number of pathogenic mutations, including CTNNB1 exon 3 mutations, as well as tumor mutational burden and microsatellite profiles. Although in this particular study, the lack of correlation between CTNNB1 exon 3 mutation and recurrence might be secondary to a small sample size, it also suggests the presence of other contributing factors. Thus, it helps set the foundation for larger series incorporating whole genome, transcriptome, proteome, and epigenome analyses to answer this clinically important question.
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Carcinoma Endometrioide , Hiperplasia Endometrial , Neoplasias do Endométrio , Feminino , Humanos , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patologia , Estudos de Casos e Controles , Estadiamento de Neoplasias , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Hiperplasia Endometrial/patologiaRESUMO
BACKGROUND: The physiological interactions of MBL suggest its contribution towards the pathogenesis of COPD. OBJECTIVE: The present case-control study was undertaken to elucidate the role of MBL with COPD risk and clinical outcomes in north Indian cohort. METHODS: Patients were enrolled as per GOLD criteria. MBL2 variants were selected based on the literature and their putative functional significance. Genotyping of six single nucleotide polymorphisms of MBL2 comprising of two coding (rs1800450, rs1800451) and four non-coding variants (rs11003125, rs7096206, rs11003123 and rs7095891) was done by using PCR-RFLP and ARMS-PCR. Serum MBL levels were analysed by sandwich ELISA. RESULTS: Overall findings of the molecular genetic analysis of MBL2 indicated significant difference in frequency of three of the six studied variants, between patients and controls or among different disease severity stages. Heterozygous genotype of rs7095891 showed significant protective association towards severity of disease. Linkage disequilibrium (LD) analysis indicated a strong LD between rs1800450 and rs7095891 while intermediate LD was observed for rs11003123/rs11003125 and rs7096206/rs11003125. Haplotype analysis revealed 17.14-fold risk of developing exacerbations conferred by GGGTGG haplotype. Significantly low serum MBL levels observed in COPD patients as compared to controls. Significant difference in MBL deficiency levels were also observed for homozygous wild and variant genotypes of rs11003125 and rs7096206 respectively, as well as for all genotypes of rs11003123 than respective controls. CONCLUSION: The present study reinforces the role played by MBL in the susceptibility, protection and clinical outcomes of COPD. Therefore, including the reported associations at diagnostic, prognostic and therapeutic interventions may prove helpful.
Assuntos
Lectina de Ligação a Manose , Doença Pulmonar Obstrutiva Crônica , Humanos , Genótipo , Polimorfismo de Nucleotídeo Único/genética , Haplótipos/genética , Doença Pulmonar Obstrutiva Crônica/genética , Lectina de Ligação a Manose/genética , Estudos de Casos e Controles , Predisposição Genética para DoençaRESUMO
STK11 adnexal tumor is a recently described entity with less than 25 cases reported to date. These aggressive tumors typically occur in paratubal/paraovarian soft tissues, have characteristically striking morphologic and immunohistochemical heterogeneity, and harbor pathognomonic alterations in STK11. These occur almost exclusively in adult patients, with only one reported in a pediatric patient (to our knowledge). A previously healthy 16-year-old female presented with acute abdominal pain. Imaging studies revealed large bilateral solid and cystic adnexal masses, ascites, and peritoneal nodules. Following frozen section evaluation of a left ovarian surface nodule, bilateral salpingo-oophorectomy and tumor debulking were performed. Histologically, the tumor demonstrated distinctively variable cytoarchitecture, myxoid stroma, and mixed immunophenotype. A next generation sequencing-based assay identified a pathogenic STK11 mutation. We report the youngest patient to date with an STK11 adnexal tumor, highlighting key clinicopathologic and molecular features in order to contrast them with those of other pediatric intra-abdominal malignancies. This rare and unfamiliar tumor poses a considerable diagnostic challenge and requires a multidisciplinary integrated approach to diagnosis.
Assuntos
Adenoma , Neoplasias Cutâneas , Adolescente , Feminino , Humanos , Quinases Proteína-Quinases Ativadas por AMP , Proteínas Serina-Treonina Quinases/genéticaRESUMO
Bone and soft tissue lesions in the head and neck encompass not only a broad morphologic spectrum but also significant inherent clinicopathologic overlap. Epidemiology, radiology, and location - similar to the diagnostic assessment in other sites - are especially important considerations in the context of an established mesenchymal proliferation. Herein, the approach towards diagnosis is stratified by morphology (spindle, sarcomatoid, epithelioid, round cell), cellular lineage (fibroblastic, nerve sheath, rhabdomyogenic), and tumor grade (benign, low- to high-grade malignant) as the basis of further immunohistochemical or molecular investigation.
Assuntos
Sarcoma , Neoplasias de Tecidos Moles , Humanos , Neoplasias de Tecidos Moles/patologia , Biópsia , Biomarcadores TumoraisRESUMO
BACKGROUND: Ovarian cancer continues to have a poor prognosis with the majority of women diagnosed with advanced disease. Therefore, we undertook the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) to determine if population screening can reduce deaths due to the disease. We report on ovarian cancer mortality after long-term follow-up in UKCTOCS. METHODS: In this randomised controlled trial, postmenopausal women aged 50-74 years were recruited from 13 centres in National Health Service trusts in England, Wales, and Northern Ireland. Exclusion criteria were bilateral oophorectomy, previous ovarian or active non-ovarian malignancy, or increased familial ovarian cancer risk. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computer generated random numbers to annual multimodal screening (MMS), annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. Follow-up was through national registries. The primary outcome was death due to ovarian or tubal cancer (WHO 2014 criteria) by June 30, 2020. Analyses were by intention to screen, comparing MMS and USS separately with no screening using the versatile test. Investigators and participants were aware of screening type, whereas the outcomes review committee were masked to randomisation group. This study is registered with ISRCTN, 22488978, and ClinicalTrials.gov, NCT00058032. FINDINGS: Between April 17, 2001, and Sept 29, 2005, of 1 243 282 women invited, 202 638 were recruited and randomly assigned, and 202 562 were included in the analysis: 50 625 (25·0%) in the MMS group, 50 623 (25·0%) in the USS group, and 101 314 (50·0%) in the no screening group. At a median follow-up of 16·3 years (IQR 15·1-17·3), 2055 women were diagnosed with tubal or ovarian cancer: 522 (1·0%) of 50 625 in the MMS group, 517 (1·0%) of 50 623 in the USS group, and 1016 (1·0%) of 101 314 in the no screening group. Compared with no screening, there was a 47·2% (95% CI 19·7 to 81·1) increase in stage I and 24·5% (-41·8 to -2·0) decrease in stage IV disease incidence in the MMS group. Overall the incidence of stage I or II disease was 39·2% (95% CI 16·1 to 66·9) higher in the MMS group than in the no screening group, whereas the incidence of stage III or IV disease was 10·2% (-21·3 to 2·4) lower. 1206 women died of the disease: 296 (0·6%) of 50 625 in the MMS group, 291 (0·6%) of 50 623 in the USS group, and 619 (0·6%) of 101 314 in the no screening group. No significant reduction in ovarian and tubal cancer deaths was observed in the MMS (p=0·58) or USS (p=0·36) groups compared with the no screening group. INTERPRETATION: The reduction in stage III or IV disease incidence in the MMS group was not sufficient to translate into lives saved, illustrating the importance of specifying cancer mortality as the primary outcome in screening trials. Given that screening did not significantly reduce ovarian and tubal cancer deaths, general population screening cannot be recommended. FUNDING: National Institute for Health Research, Cancer Research UK, and The Eve Appeal.
Assuntos
Carcinoma Epitelial do Ovário , Detecção Precoce de Câncer , Neoplasias Ovarianas , Idoso , Antígeno Ca-125/sangue , Feminino , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/mortalidade , Sistema de Registros , Medicina Estatal , Ultrassonografia , Reino Unido/epidemiologiaRESUMO
Uterine leiomyosarcoma is the most common uterine mesenchymal malignancy. The majority present at stage I, and clinical outcomes vary widely. However, no widely accepted risk stratification system for stage I uterine leiomyosarcoma is currently available. We studied 17 routinely evaluated clinicopathologic parameters in 203 stage I uterine leiomyosarcoma from three institutions to generate a novel risk stratification model for these tumors. Mitoses >25 per 2.4 mm2 (10 high-power fields), atypical mitoses, coagulative necrosis, lymphovascular invasion, and serosal abutment were significantly associated with disease-free and disease-specific survival in univariate and multivariate analyses. These prognostic parameters were each scored as binary ("yes" or "no") variables and fitted to a single optimized algebraic risk model:Risk score = (coagulative necrosis)(1) + (mitoses > 25 per 2.4 mm2)(2) + (atypical mitoses)(2) + (lymphovascular invasion)(3) + (serosal abutment)(5)By logistic regression, the risk model was significantly associated with 5-year disease-free (AUC = 0.9270) and 5-year disease-specific survival (AUC = 0.8517). Internal and external validation substantiated the model. The continuous score (range, 0-13) was optimally divided into 3 risk groups with distinct 5-year disease-free and disease-specific survival: low risk (0-2 points), intermediate risk (3-5 points), and high risk (6-13 points) groups. Our novel risk model performed significantly better than alternative uterine leiomyosarcoma risk stratification systems in predicting 5-year disease-free and disease-specific survival in stage I tumors. A simplified risk model, omitting terms for serosal abutment and lymphovascular invasion, can be accurately applied to myomectomy or morcellated specimens. We advocate routine application of this novel risk model in stage I uterine leiomyosarcoma to facilitate patient counseling and proper risk stratification for clinical trials.
Assuntos
Leiomiossarcoma , Neoplasias Testiculares , Neoplasias Uterinas , Feminino , Humanos , Leiomiossarcoma/patologia , Masculino , Necrose/patologia , Estadiamento de Neoplasias , Prognóstico , Medição de Risco , Neoplasias Testiculares/patologia , Neoplasias Uterinas/patologiaRESUMO
BACKGROUND: There is level 1 evidence for cerebral thrombectomy with thrombolysis in acute large vessel occlusion. Many hospitals are now contemplating setting up this life-saving service. For the hospital, however, the first treatment is associated with an initial high cost to cover the procedure. Whilst the health economic benefit of treating stroke is documented, this is the only study to date performing matched-pair, patient-level costing to determine treatment cost within the first hospital episode and up to 90 days post-event. METHODS: We conducted a retrospective coarsened exact matched-pair analysis of 50 acute stroke patients eligible for thrombectomy. RESULTS: Thrombectomy resulted in significantly more good outcomes (mRS 0-2) compared to matched controls (56% vs 8%, p = 0.001). More patients in the thrombectomy group could be discharged home (60% vs 28%), fewer were discharged to nursing homes (4% vs 16%), residential homes (0% vs 12%) or rehabilitation centres (8% vs 20%). Thrombectomy patients had fewer serious adverse events (n = 30 vs 86) and were, on average, discharged 36 days earlier. They required significantly fewer physiotherapy sessions (18.72 vs 46.49, p = 0.0009) resulting in a median reduction in total rehabilitation cost of £4982 (p = 0.0002) per patient. The total cost of additional investigations was £227 lower (p = 0.0369). Overall, the median cost without thrombectomy was £39,664 per case vs £22,444, resulting in median savings of £17,221 (p = 0.0489). CONCLUSIONS: Mechanical thrombectomy improved patient outcome, reduced length of hospitalisation and, even without procedural reimbursement, significantly reduced cost to the thrombectomy providing hospital.
RESUMO
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder marked by social and communication deficits as well as repetitive behaviour. Several studies have found that overactivation of the PI3K/AKT/mTOR signalling pathways during brain development plays a significant role in autism pathogenesis. Overexpression of the PI3K/AKT/mTOR signalling pathway causes neurological disorders by increasing cell death, neuroinflammation, and oxidative stress. Chrysophanol, also known as chrysophanic acid, is a naturally occurring chemical obtained from the plant Rheum palmatum. This study aimed to examine the neuroprotective effect of CPH on neurobehavioral, molecular, neurochemical, and gross pathological alterations in ICV-PPA induced experimental model of autism in adult rats. The effects of ICV-PPA on PI3K/AKT/mTOR downregulation in the brain were studied in autism-like rats. Furthermore, we investigated how CPH affected myelin basic protein (MBP) levels in rat brain homogenate and apoptotic biomarkers such as caspase-3, Bax, and Bcl-2 levels in rat brain homogenate and blood plasma samples. Rats were tested for behavioural abnormalities such as neuromuscular dysfunction using an actophotometer, motor coordination using a beam crossing task (BCT), depressive behaviour using a forced swim test (FST), cognitive deficiency, and memory consolidation using a Morris water maze (MWM) task. In PPA-treated rats, prolonged oral CPH administration from day 12 to day 44 of the experimental schedule reduces autistic-like symptoms. Furthermore, in rat brain homogenates, blood plasma, and CSF samples, cellular, molecular, and cell death markers, neuroinflammatory cytokines, neurotransmitter levels, and oxidative stress indicators were investigated. The recent findings imply that CPH also restores abnormal neurochemical levels and may prevent autism-like gross pathological alterations, such as demyelination volume, in the rat brain.