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BACKGROUND: One of the most common sporadic homozygous deletions in cancers is 9p21 loss, which includes the genes methylthioadenosine phosphorylase (MTAP), CDKN2A, and CDKN2B, and has been correlated with worsened outcomes and immunotherapy resistance. MTAP-loss is a developing drug target through synthetic lethality with MAT2A and PMRT5 inhibitors. The purpose of this study is to investigate the prevalence and genomic landscape of MTAP-loss in advanced gastrointestinal (GI) tumors and investigate its role as a prognostic biomarker. MATERIALS AND METHODS: We performed next-generation sequencing and comparative genomic and clinical analysis on an extensive cohort of 64 860 tumors comprising 5 GI cancers. We compared the clinical outcomes of patients with GI cancer harboring MTAP-loss and MTAP-intact tumors in a retrospective study. RESULTS: The prevalence of MTAP-loss in GI cancers is 8.30%. MTAP-loss was most prevalent in pancreatic ductal adenocarcinoma (PDAC) at 21.7% and least in colorectal carcinoma (CRC) at 1.1%. MTAP-loss tumors were more prevalent in East Asian patients with PDAC (4.4% vs 3.2%, Pâ =â .005) or intrahepatic cholangiocarcinoma (IHCC; 6.4% vs 4.3%, Pâ =â .036). Significant differences in the prevalence of potentially targetable genomic alterations (ATM, BRAF, BRCA2, ERBB2, IDH1, PIK3CA, and PTEN) were observed in MTAP-loss tumors and varied according to tumor type. MTAP-loss PDAC, IHCC, and CRC had a lower prevalence of microsatellite instability or elevated tumor mutational burden. Positive PD-L1 tumor cell expression was less frequent among MTAP-loss versus MTAP-intact IHCC tumors (23.2% vs 31.2%, Pâ =â .017). CONCLUSION: In GI cancers, MTAP-loss occurs as part of 9p21 loss and has an overall prevalence of 8%. MTAP-loss occurs in 22% of PDAC, 15% of IHCC, 8.7% of gastroesophageal adenocarcinoma, 2.4% of hepatocellular carcinoma, and 1.1% of CRC and is not mutually exclusive with other targetable mutations.
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Neoplasias Gastrointestinais , Purina-Núcleosídeo Fosforilase , Humanos , Purina-Núcleosídeo Fosforilase/genética , Masculino , Feminino , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Biomarcadores Tumorais/genética , Adulto , Prognóstico , Genômica/métodosRESUMO
SIGNIFICANCE: Suspected clinically significant macular edema (SCSME) from exudates differed among ethnic groups in our underserved population. African American and Asian subjects had higher prevalence than Hispanics and non-Hispanic Caucasians, from the same clinics. Men had higher prevalence than women. Highly elevated blood glucose was frequent and associated with SCSME. PURPOSE: We investigated the association between the presence of SCSME from exudates and hemoglobin A1c (HbA1c), as well as demographic factors such as age, sex, and ethnic group. Our population was underserved diabetic patients from the same geographic locations. Ethnic groups were White Hispanic, non-Hispanic Caucasian, African American, and Asian, with a high proportion of underrepresented minorities. METHODS: In a diabetic retinopathy screening study at four community clinics in Alameda County, California, nonmydriatic 45° color fundus images were collected from underserved diabetic subjects following the EyePACS imaging protocol. Images were analyzed for SCSME from exudates by two certified graders. Logistic regression assessed the association between SCSME from exudates and age, sex, ethnic group, and HbA1c. RESULTS: Of 1997 subjects, 147 (7.36%) had SCSME from exudates. The mean ± standard deviation age was 53.4 ± 10.5 years. The mean ± standard deviation HbA1c level was 8.26 ± 2.04. Logistic regression analysis indicated a significant association between presence of SCSME from exudates and HbA1c levels (p<0.001), sex (p=0.027), and ethnicity (p=0.030). African Americans (odds ratio [OR], 1.63; 95% confidence interval [CI], 1.06 to 2.50; p=0.025) and Asians (OR, 1.63; 95% CI, 1.05 to 2.54; p=0.029) had a higher risk than Hispanics. After adjusting for ethnicity, sex, and age, the odds of developing SCSME from exudates increased by 26.5% with every 1% increase in HbA1c level (OR, 1.26; 95% CI, 1.18 to 1.36; p<0.001). CONCLUSIONS: In our underserved population, many diabetic patients had very high HbA1c values. Ethnic background (African American > Asians > Hispanics), sex (male > female), and HbA1c level were strong indicators for identifying who is at increased risk of developing SCSME from exudates.
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Diabetes Mellitus , Edema Macular , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Hemoglobinas Glicadas , Edema Macular/diagnóstico , Edema Macular/epidemiologia , Populações Vulneráveis , Demografia , Fatores de RiscoRESUMO
BACKGROUND: In 2020, pembrolizumab was approved as a therapy for triple-negative breast cancer (TNBC) with the companion diagnostic DAKO 22C3 programmed death ligand-1 (PD-L1) immunohistochemistry assay. The study aimed to determine the landscape of PD-L1 expression as detected by the DAKO 22C3 PD-L1 assay in breast cancer subtypes and compare the clinicopathologic and genomic characteristics of PD-L1 positive and negative TNBC. METHODS: PD-L1 expression using the DAKO 22C3 antibody was scored using a combined positive score (CPS) and positive status was defined as CPS ≥10. Comprehensive genomic profiling was performed using the FoundationOne CDx assay. RESULTS: Of the 396 BC patients stained with DAKO 22C3, the majority were HR+/HER2- and TNBC (42% and 36%, respectively). Median PD-L1 expression and frequency of CPS ≥10 was highest in TNBC cases (median: 7.5, 50% CPS ≥10) and lowest in the HR+/HER2- group (median: 1.0, 15.5% CPS ≥10) (P < .0001). A comparison of PD-L1 positive and PD-L1 negative TNBC demonstrated no significant differences in clinicopathologic or genomic characteristics. TNBC tissue samples from the breast did have an observed enrichment for PD-L1 positivity compared to TNBC tissue samples from a metastatic site (57% vs. 44%), but this was not statistically significant (P = .1766). In the HR+/HER2- group, genomic alterations in TP53, CREBBP, and CCNE1 were more prevalent and genomic loss of heterozygosity was higher in the PD-L1(+) group compared to the PD-L1(-) group. CONCLUSIONS: The subtypes of breast cancer have distinct patterns of PD-L1 expression, supporting that further research of immunotherapies may include specific evaluation of optimum cutoffs for non-TNBC patients. In TNBC, PD-L1 positivity is not associated with other clinicopathologic or genomic features and should be integrated into future studies of immunotherapy efficacy.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Neoplasias de Mama Triplo Negativas , Humanos , Imuno-Histoquímica , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismoRESUMO
AIMS: Small cell bladder carcinoma (SCBC) is a rare, divergent form of urothelial carcinoma (UC). We aimed to determine whether pure (n = 16) and mixed (SCBC and UC; n = 30) tumours differed in pathology, gene expression characteristics, genetic alterations, and clinical outcomes. METHODS AND RESULTS: Forty (87%) patients received first-line chemotherapy. Twenty-nine patients had no metastatic disease at diagnosis and underwent radical cystectomy. There were no differences in age, sex, race distribution, tumour size, stage at presentation, therapy response with pathological downstaging to ≤ypT1N0, or overall or progression-free survival (PFS) between pure and mixed tumours. There was a longer PFS among downstaged chemotherapy-responding tumours ≤ypT2N0M0 than among unresponsive tumours ≥ypT2 ≥ yN1M1 (P = 0.001). Patients who achieved pathological downstaging with neoadjuvant chemotherapy (n = 10) were stage cT2N0M0 at the time of diagnosis and were alive at the last follow-up (median 37 months), while 46% of patients who failed to achieve pathological downstaging were alive at the last follow-up (median 38 months; P = 0.008). RNA sequencing showed that the UC of mixed SCBC had similar neural expression signatures to pure SCBC. DNA sequencing revealed alterations in TERT (83%), P53 (56%), ARID1A (28%), RB1 (22%), and BRCA2 (11%). Immunohistochemistry for RB1 showed loss of expression in 18/19 (95%) patients, suggesting frequent pathway downregulation despite a low prevalence of RB1 mutation. CONCLUSION: Patients with pure and mixed SCBC have similar outcomes and these outcomes are determined by the pathological stage at RC and are best among patients who have pathological downstaging after NAC.
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Carcinoma de Células Pequenas , Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/terapia , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/terapia , Bexiga Urinária/patologia , Transcriptoma , Resultado do Tratamento , Terapia Neoadjuvante/métodos , Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/terapia , Estudos RetrospectivosRESUMO
BACKGROUND: In the current study, we examined the real-world prevalence of highly pigmented advanced melanomas (HPMel) and the clinicopathologic, genomic, and ICPI biomarker signatures of this class of tumors. MATERIALS AND METHODS: Our case archive of clinical melanoma samples for which the ordering physician requested testing for both PD-L1 immunohistochemistry (IHC) and comprehensive genomic profiling (CGP) was screened for HPMel cases, as well as for non-pigmented or lightly pigmented advanced melanoma cases (LPMel). RESULTS: Of the 1268 consecutive melanoma biopsies in our archive that had been submitted for PD-L1 IHC, 13.0% (165/1268) were HPMel and 87.0% (1103/1268) were LPMel. In the HPMel cohort, we saw a significantly lower tumor mutational burden (TMB, median 8.8 mutations/Mb) than in the LPMel group (11.4 mut/Mb), although there was substantial overlap. In examining characteristic secondary genomic alterations (GA), we found that the frequencies of GA in TERTp, CDKN2A, TP53, and PTEN were significantly lower in the HPMel cases than in LPMel. A higher rate of GA in CTNNB1, APC, PRKAR1A, and KIT was identified in the HPMel cohort compared with LPMel. CONCLUSIONS: In this study, we quantified the failure rates of melanoma samples for PD-L1 testing due to high melanin pigmentation and showed that CGP can be used in these patients to identify biomarkers that can guide treatment decisions for HPMel patients. Using this practical clinical definition for tumor pigmentation, our results indicate that HPMel are frequent at 13% of melanoma samples, and in general appear molecularly less developed, with a lower TMB and less frequent secondary GA of melanoma progression.
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Antígeno B7-H1 , Melanoma , Antígeno B7-H1/genética , Biomarcadores Tumorais/genética , Genômica , Humanos , Melanoma/genética , Melanoma/patologia , Mutação , Pigmentação/genéticaRESUMO
Adult granulosa cells tumors (AGCTs) are typically low-grade indolent tumors. On rare occasions, they undergo high-grade/sarcomatous transformation and behave aggressively. This transformation is postulated to occur as the result of acquired genetic alterations, some of which may be eligible for targeted therapy. Here we report a rare case of AGCT with sarcomatous transformation that harbored distinct molecular alterations from those typically seen with AGCTs supporting a molecularly driven approach to these malignancies. The patient is a 56-yr-old G3P3 woman with a history of multiple recurrences of ovarian AGCT for which the first diagnosis was made at the age of 25 when she was evaluated for infertility. The ovarian tumor displayed typical features of AGCT with low-grade, bland morphology. The first extraovarian spread of tumor involving the cul-de-sac was reported at the age of 39. After that, recurrences occurred every 2 to 3 yr with involvement of multiple anatomic sites and repeated surgical resections. At the age of 55 she developed a symptomatic recurrence in the pelvis and underwent resection of an isolated lesion (specimen 1) to no gross residual disease. Within 4 wk of resection she developed significant pelvic pain and imaging showed recurrence of the mass. Therefore, in 5 mo after the initial resection she underwent repeat excision of the lesion (specimen 2) and associated bowel. The sections from specimen 1 showed a biphasic morphology: a low-grade component with morphology and immunophenotype consistent with a typical AGCT and a high-grade spindle cell component with features consistent with a high-grade sarcoma. Specimen 2 featured a pure high-grade sarcoma characterized by coagulative tumor cell necrosis, readily recognizable mitoses, highly atypical cells with vesicular nuclei and prominent nucleoli. SF-1 positivity and the presence of FOXL2 C134W mutation in the sarcomatous component support the notion of transformation of typical AGCT. While detected TERT promoter C228T mutation may play a role in this process, we further identified genetic alterations affecting PI3K/AKT/mTOR pathway, including mutations in PIK3CA , PIK3R1 , AKT1 , and NF2 , which may also contribute to tumor progression/transformation. These findings provide rationale for molecular/pathway-based targeted therapy for patients with advanced AGCT.
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Tumor de Células da Granulosa , Neoplasias Ovarianas , Sarcoma , Neoplasias de Tecidos Moles , Adulto , Feminino , Humanos , Tumor de Células da Granulosa/patologia , Fosfatidilinositol 3-Quinases , Neoplasias Ovarianas/patologia , Sarcoma/genéticaRESUMO
Endometrium-related malignancies including uterine endometrioid carcinoma, ovarian clear cell carcinoma and ovarian endometrioid carcinoma are major types of gynecologic cancer, claiming more than 13,000 women's lives annually in the United States. In vitro cell models that recapitulate "normal" endometrial epithelial cells and their malignant counterparts are critically needed to facilitate the studies of pathogenesis in endometrium-related carcinomas. To achieve this objective, we have established a human endometrial epithelial cell line, hEM3, through immortalization and clonal selection from a primary human endometrium culture. hEM3 exhibits stable growth in vitro without senescence. hEM3 expresses protein markers characteristic of the endometrial epithelium, and they include PAX8, EpCAM, cytokeratin 7/8, and ER. hEM3 does not harbor pathogenic germline mutations in genes involving DNA mismatch repair (MMR) or homologous repair (HR) pathways. Despite its unlimited capacity of in vitro proliferation, hEM3 cells are not transformed, as they are not tumorigenic in immunocompromised mice. The cell line is amenable for gene editing, and we have established several gene-specific knockout clones targeting ARID1A, a tumor suppressor gene involved in the SWI/SNF chromatin remodeling. Drug screening demonstrates that both HDAC inhibitor and PARP inhibitor are effective in targeting cells with ARID1A deletion. Together, our data support the potential of hEM3 as a cell line model for studying the pathobiology of endometrium-related diseases and for developing effective precision therapies.
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Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Endométrio/citologia , Células Epiteliais , Animais , Feminino , Humanos , Camundongos , Receptores de Estrogênio/metabolismoRESUMO
Risk biomarkers for estrogen receptor (ER)-negative breast cancer have clear value for breast cancer prevention. We previously reported a set of lipid metabolism (LiMe) genes with high expression in the contralateral unaffected breasts (CUBs) of ER-negative cancer cases. We now further examine LiMe gene expression in both tumor and CUB, and investigate the role of Pre-B-cell leukemia homeobox-1 (PBX1) as a candidate common transcription factor for LiMe gene expression. mRNA was extracted from laser-capture microdissected epithelium from tumor and CUB of 84 subjects (28 ER-positive cases, 28 ER-negative cases, 28 healthy controls). Gene expression was quantitated by qRT-PCR. Logistic regression models were generated to predict ER status of the contralateral cancer. Protein expression of HMGCS2 and PBX1 was measured using immunohistochemistry. The effect of PBX1 on LiMe gene expression was examined by overexpressing PBX1 in MCF10A cells with or without ER, and by suppressing PBX1 in MDA-MB-453 cells. The expression of DHRS2, HMGCS2, UGT2B7, UGT2B11, ALOX15B, HPGD, UGT2B28 and GLYATL1 was significantly higher in ER-negative versus ER-positive CUBs, and predicted ER status of the tumor in test and validation sets. In contrast, LiMe gene expression was significantly lower in ER-negative than ER-positive tumors. PBX1 overexpression in MCF10A cells up-regulated most LiMe genes, but not in MCF10A cells overexpressing ER. Suppressing PBX1 in MDA-MB-453 cells resulted in decrease of LiMe gene expression. Four binding sites of PBX1 and cofactor were identified in three lipid metabolism genes using ChIP-qPCR. These data suggest a novel role for PBX1 in the regulation of lipid metabolism genes in benign breast, which may contribute to ER-negative tumorigenesis.
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Neoplasias da Mama/genética , Proteínas de Ligação a DNA/genética , Metabolismo dos Lipídeos/genética , Proteínas Proto-Oncogênicas/genética , Receptores de Estrogênio/genética , Adulto , Idoso , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Pessoa de Meia-Idade , Fator de Transcrição 1 de Leucemia de Células Pré-B , RNA Mensageiro/genética , Regulação para Cima/genéticaRESUMO
BACKGROUND: GL261 cells are murine glioma cells that demonstrate proliferation, invasion, and angiogenesis when implanted in syngeneic C57BL/6 mice, providing a highly useful immunocompetent animal model of glioblastoma. Modification of tumor cells for luciferase expression enables non-invasive monitoring of orthotopic tumor growth, and has proven useful for studying glioblastoma response to novel therapeutics. However, tumor modification for luciferase has the potential for evoking host immune response against otherwise syngeneic tumor cells, thereby mitigating the tumor cells' value for tumor immunology and immunotherapy studies. METHODS: GL261 cells were infected with lentivirus containing a gene encoding firefly luciferase (GL261.luc). In vitro proliferation of parental (unmodified) GL261 and GL261.luc was measured on days 0, 1, 2, 4, and 7 following plating, and the expression of 82 mouse cytokines and chemokines were analyzed by RT-PCR array. Cell lines were also evaluated for differences in invasion and migration in modified Boyden chambers. GL261 and GL261.luc cells were then implanted intracranially in C57BL/6 mice, with GL261.luc tumor growth monitored by quantitative bioluminescence imaging, and all mice were followed for survival to compare relative malignancy of tumor cells. RESULTS: No difference in proliferation was indicated for GL261 vs. GL261.luc cells (p>0.05). Of the 82 genes examined by RT-PCR array, seven (9%) exhibited statistically significant change after luciferase modification. Of these, only three changed by greater than 2-fold: BMP-2, IL-13, and TGF-ß2. No difference in invasion (p=0.67) or migration (p=0.26) was evident between modified vs. unmodified cells. GL261.luc cell luminescence was detectable in the brains of C57BL/6 mice at day 5 post-implantation, and tumor bioluminescence increased exponentially to day 19. Median overall survival was 20.2 days versus 19.7 days for mice receiving implantation with GL261 and GL261.luc, respectively (p=0.62). Histopathologic analysis revealed no morphological difference between tumors, and immunohistochemical analysis showed no significant difference for staining of CD3, Ki67, or CD31 (p>0.05 for all). CONCLUSIONS: Luciferase expression in GL261 murine glioma cells does not affect GL261 proliferation, invasion, cytokine expression, or in vivo growth. Luciferase modification increases their utility for studying tumor immunology and immunotherapeutic approaches for treating glioblastoma.
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Neoplasias Encefálicas/patologia , Glioma/patologia , Luciferases/genética , Animais , Neoplasias Encefálicas/imunologia , Divisão Celular , Linhagem Celular Tumoral , Citocinas/imunologia , Glioma/imunologia , CamundongosRESUMO
We demonstrate a free-space, trolley-mounted potential vision tester (PVT), designed to study and improve the accuracy of visual acuity (VA) measurements in the aging eye. Key features include a high-resolution visual display presented in Maxwellian view, a 3 mm pupil to limit wavefront (WF) aberrations, and a moderate cost deformable mirror to induce or correct higher order optical aberrations. The visual display supported accurate measurement of visual acuities down to 20/5. The moderate cost, piezo deformable mirror induced seven nominal aberrations, calibrated as 0, -0.32, -0.23, + 0.27, and +0.39 microns spherical aberration; + 0.49 microns Y coma; and -0.51 microns X coma. A custom Hartmann Shack (HS) calibration (HSc) system demonstrated that induced aberrations were repeatable and stable. A Badal optometer provided the coarse focus. WF aberrations were measured for five normal subjects with a commercially available HS device (HSP) (OCULUS Pentacam AXL Wave), providing estimates of WF errors for 3 mm and other pupil sizes. VA was measured using four alternative forced-choice for a single black on white E stimulus in each trial. Using the method of constant stimuli yielded robust standard deviation measurements. The 50% fit for VA plotted against induced aberration resulted in linear functions for each subject for the range of our positive and negative spherical aberration data. Subjects differed, but higher order terms were unnecessary to describe data across spherical aberrations.
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In this study, we report the clinicopathologic and genomic profiles of 891 patients with RET fusion driven advanced solid tumors. All patient samples were tested using a tissue-based DNA hybrid capture next generation sequencing (NGS) assay and a subset of the samples were liquid biopsies tested using a liquid-based hybrid capture NGS assay. RET fusions were found in 523 patients with NSCLC and in 368 patients with other solid tumors. The two tumor types with the highest number of RET fusion were lung adenocarcinoma and thyroid papillary carcinoma, and they had a prevalence rate 1.14% (455/39,922) and 9.09% (109/1199), respectively. A total of 61 novel fusions were discovered in this pan-tumor cohort. The concordance of RET fusion detection across tumor types among tissue and liquid-based NGS was 100% (8/8) in patients with greater than 1% composite tumor fraction (cTF). Herein, we present the clinicopathologic and genomic landscape of a large cohort of RET fusion positive tumors and we observed that liquid biopsy-based NGS is highly sensitive for RET fusions at cTF ≥1%.
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Lapatinib, a dual kinase inhibitor against epidermal growth factor receptor (EGFR) and human epidermal receptor two (HER2) has shown efficacy in treating HER2 positive breast cancer. Nanoparticle albumin bound (nab) paclitaxel was developed to reduce toxicities from paclitaxel and improve its efficacy. Thirty patients with stage I-III HER2 positive breast cancer were treated in the neoadjuvant setting with lapatinib 1,000 mg/day and nab-paclitaxel 260 mg/m(2) every 3 weeks for four cycles. The primary end point of the trial was clinical response rate (cRR) with secondary end points including pathologic complete response rate (pCR), tolerability of the combination, and marker response. The cRR was 82.8% (24 patients) with six (20.7%) patients having complete clinical response, 18 (62.1%) having partial clinical response, and five (17.2%) stable disease. A pCR was observed in five of the 28 patients (17.9%). The most frequent grade 2 toxicities were neuropathy in nine patients (30%), fatigue in seven patients (23.3%), rash in 11 patients (36.7%), and bone pain in 10 patients (33.3%). There was no significant drop in the left ventricular ejection fraction (LVEF). Of the tissue markers examined, we were not able to find a predictor of response. The combination of lapatinib and nab-paclitaxel was well tolerated and provided good efficacy in women with HER2 positive breast cancer. This combination offers an alternative non-anthracycline-containing regimen for women with HER2 positive breast cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Terapia Neoadjuvante , Receptor ErbB-2/metabolismo , Adulto , Idoso , Albuminas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/mortalidade , Diarreia/induzido quimicamente , Feminino , Testes de Função Cardíaca , Humanos , Estimativa de Kaplan-Meier , Lapatinib , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Projetos Piloto , Quinazolinas/administração & dosagem , Resultado do TratamentoRESUMO
Purpose: Cones in diabetic patients are at risk due to metabolic and vascular changes. By imaging retinal vessel modeling at high magnification, we reduced its impact on cone distribution measurements. The retinal vessel images and retinal thickness measurements provided information about cone microenvironment. Methods: We compared cone data in 10 diabetic subjects (28-78 yr) to our published norms from 36 younger and 10 older controls. All subjects were consented and tested in a manner approved by the Indiana University Institutional Review Board, which adhered to the Declaration of Helsinki. Custom adaptive optics scanning laser ophthalmoscopy (AOSLO) was used to image cones and retinal microcirculation. We counted cones in a montage of foveal and temporal retina, using four non-contiguous samples within 0.9-7 deg that were selected for best visibility of cones and least pathology. The data were fit with a two parameter exponential model: ln(cone density) = a * microns eccentricity + b. These results were compared to retinal thickness measurements from SDOCT. Results: Diabetic cone maps were more variable than in controls and included patches, or unusually bright and dark cones, centrally and more peripherally. Model parameters and total cones within the central 14 deg of the macula differed across diabetic patients. Total cones fell into two groups: similar to normal for 5 vs. less than normal for 2 of 2 younger diabetic subjects and 3 older subjects, low but not outside the confidence limits. Diabetic subjects had all retinal vascular remodeling to varying degrees: microaneurysms; capillary thickening, thinning, or bends; and vessel elongation including capillary loops, tangles, and collaterals. Yet SD-OCT showed that no diabetic subject had a Total Retinal Thickness in any quadrant that fell outside the confidence limits for controls. Conclusions: AOSLO images pinpointed widespread retinal vascular remodeling in all diabetic eyes, but the SDOCT showed no increased retinal thickness. Cone reflectivity changes were found in all diabetic patients, but significantly low cone density in only some. These results are consistent with early changes to neural, glial, or vascular components of the retinal without significant retinal thickening due to exudation.
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Thyroid hormones (TH) regulate growth, nervous system myelination, metabolism, and physiologic functions in nearly every organ system. Congenital hypothyroidism (CH) is one of the most common endocrinopathies in children and has potentially devastating neurologic and developmental consequences. The etiology and clinical manifestations of hypothyroidism in children differ from adults. And hence, pediatric medical care requires a detailed understanding of thyroid function and dysfunction in children. The perinatal risk factors include female sex, preterm birth, low birth weight, postmature birth, additional birth abnormalities, and being delivered in multiple births. In countries where newborn screening is practiced, CH is detected after birth through screening tests. It aids in determining the underlying cause, though some patients may be able to start treatment without these tests. Early detection and treatment prevent irreversible and permanent nervous system damage. Thus, in addition to exploring the development of CH, this article has also covered the epidemiological data, clinical aspects, and management stemming from pediatric hypothyroidism.
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Pancreatic cancer (PC) is the primary cause of cancer death in the United States and Europe. Despite remarkable advances in the molecular understanding of PC and advances in new therapeutic approaches, PC remains a disease with a poor prognosis. Although evidence indicates that long-term smoking is a major cause of PC, the molecular pathways behind smoking-induced PC pathogenesis are not fully understood. Smoking cessation can significantly reduce the occurrence of PC. This review explores the processes underpinning the influence of smoking-related chemicals on fibrosis and inflammation and provides insight into the etiology of PC. In the future, a thorough exploration of the effects of smoking chemicals on the activity of pancreatic stem cells and then on the essential mediators of the association with cancer cells would likely yield new diagnostic targets.
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Depression is a psychiatric disorder characterized by various symptoms that can impact one's quality of life. Vitamin D, a fat-soluble vitamin, is well-known for its role in bone health, and research on its effects on mental health has only recently emerged. Vitamin D deficiency is widespread worldwide, and it has been linked to an increased risk of depression. In this article, we have discussed different hypotheses that explain the role of vitamin D in gene expression and its effects on neurotransmitters and different brain functions. We have reviewed literature that shows us that Vitamin D deficiency is a risk factor for depression and explored studies that show us the effects of using or supplementing Vitamin D in preventing depression among various populations.
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A neurodegenerative disorder, Alzheimer's disease (AD), is characterized by dementia in which there is an age-related decline in cognition and higher functions. Stroke is a cerebrovascular disorder that frequently presents in old age and is a known risk factor for AD development. However, the association that AD can be a risk factor for stroke is not well-studied. This review article compiled various studies that pointed out the association between stroke development in patients with dementia, particularly AD-related dementia. The pathophysiological progression of stroke in AD cases and the genetic makeup possibly affecting the interrelation between these disorders were analyzed in detail using currently available data and studies. Therapeutic and management modalities already in use for AD were put together, and the possibility of early intervention in such patients benefitting cerebrovascular pathologies, particularly stroke-related, was explored. Prognostic differences between patients of stroke with and without AD were also reviewed, and how appropriate management can reduce the burden on health care settings when both present simultaneously was emphasized.
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Colorectal carcinoma is the third most malignant and second leading cause of death from cancer. The cruelty of this entity is that it takes decades to be symptomatic and is known to be detected late in its timeline by a screening technique. The fatality of this carcinoma only means heightened importance of screening guidelines to be laid down and strict follow-ups by the healthcare providers. A novel method, a potential competitor that could now replace the present screening techniques for colorectal carcinoma, is computed tomographic colonography (CTC) or virtual colonoscopy. Though it first came into existence in 1994, this method is yet to be deeply studied and scrutinized for it to be the next benchmark modality. This review has mainly focused on the various features of CTC. It is contrasted against the gold standard colonoscopy for its superiority, efficacy, cost-effectiveness, patient logistics, and role in detecting extra-colonic lesions. The main focus would be laid on CTC being a screening modality. The review also emphasized why there is a need for the current healthcare providers to incorporate this modality into their practice widely. Although much has been said about CTC and its various aspects of cost-effectiveness, about it being replaced or supplemented for cancer screening, a collaborative effort has to be made by both the fields of radiology and gastroenterology to investigate the outcomes of this not so new technique in daily practice and to avoid misinterpretation of the results due to lack of skill and proficiency.
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Noninvasive low-grade papillary urothelial carcinoma is a papillary neoplasm with orderly appearance and mild nuclear pleomorphism. Some cases show significant nuclear pleomorphism with degenerative atypia leading to grading difficulties. A retrospective review of the pathology files identified 16 cases diagnosed as noninvasive low-grade papillary urothelial carcinoma with degenerative atypia. Fifteen cases were consults. The average age was 46 years (range 19-78). The average size was 1.7 cm (range: 0.3-3.5). The submitting diagnoses in consults were noninvasive high-grade papillary urothelial carcinoma (n = 6), condyloma (n = 1), atypical papillary lesion (n = 1), prominent umbrella cells (n = 1), and not given (n = 6). Ki-67 proliferation rate was <5% in 10 of 10 cases (100%), and the cells with large atypical nuclei were negative. Microscopically, there were scattered cells with nuclei larger than 5 times the size of stromal lymphocytes but displayed smudgy chromatin and occasional multinucleation and intranuclear vacuoles. Next-generation sequencing identified the following mutations: HRAS (n = 4), FGFR3 (n = 3), KRAS (n = 3), BRAF (n = 1), PDGFRA (n = 1), and PIK3CA (n = 1). Other deleterious mutations were identified, but none in genes characteristic of high-grade tumors. Follow-up was available in 6 patients (median 32 months). One patient recurred with a noninvasive low-grade papillary urothelial carcinoma 20 months after the index case. All the remaining patients had no evidence of disease at the last follow-up. No patient died or had disease progression. The combination of preservation of polarity, low mitotic activity, Ki-67 <5% with the larger atypical nuclei negative for Ki-67, along with nuclear atypia that is degenerative are features used to classify these tumors as low grade.
Assuntos
Carcinoma Papilar/patologia , Núcleo Celular/patologia , Neoplasias Urológicas/patologia , Urotélio/patologia , Adulto , Idoso , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Carcinoma Papilar/química , Carcinoma Papilar/genética , Núcleo Celular/química , Proliferação de Células , Análise Mutacional de DNA , Feminino , Humanos , Imuno-Histoquímica , Antígeno Ki-67/análise , Masculino , Pessoa de Meia-Idade , Índice Mitótico , Mutação , Gradação de Tumores , Invasividade Neoplásica , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos Retrospectivos , Neoplasias Urológicas/química , Neoplasias Urológicas/genética , Urotélio/química , Adulto JovemRESUMO
The antibody-drug conjugate enfortumab-vedotin acts by targeting nectin-4, a protein that is nearly ubiquitously expressed in conventional urothelial cancer. However, expression of nectin-4 in morphologic variants of urothelial carcinoma and nonurothelial histotypes was unknown. Immunohistochemistry for nectin-4 using was performed on 169 patients including 83 with nonmuscle invasive bladder cancer and 86 patients with muscle invasive bladder cancer. Staining was scored for intensity (0 to 3) and extent (% positive cells) using the histological score system, where >15 was considered positive. Overall, 72/83 (87%) samples of nonmuscle invasive urothelial carcinoma were positive, including 29/30 (97%) noninvasive papillary urothelial carcinomas, 7/8 (87.5%) carcinomas in situ, 36/45 (80%) papillary urothelial carcinomas invading the lamina propria. Overall, 50/86 muscle invasive tumors were positive, including 15/22 (68.2%) urothelial carcinomas, 7/10 (70%) squamous cell carcinomas, 3/11 (28%) micropapillary tumors, 4/6 (66%) adenocarcinomas, 2/4 (50%) nested carcinomas, 5/8 (63%) plasmacytoid, 1/10 (10%) sarcomatoid carcinomas, and 0/15 (0%) small cell carcinomas. Whole transcriptome RNA sequencing revealed that compared with conventional urothelial carcinomas, most sarcomatoid carcinomas and all but 2 small cell carcinomas expressed very low levels of nectin-4 mRNA but expressed significant levels of either trop2 or ERBB2, which are the molecular targets of 2 other antibody-drug conjugates-sacituzumab gavitecan (trop2) or trastuzumab deruxtecan (ERBB2/HER2). In summary, our study demonstrates that there is heterogeneity of expression of nectin-4 in morphologic variants of urothelial cancer and nonurothelial histotypes, and suggests that testing expression of nectin-4 should be considered in morphologic variants or nonurothelial histotypes found to have lower expression.