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Lung cancer heterogeneity is a major barrier to effective treatments and encompasses not only the malignant epithelial cell phenotypes and genetics but also the diverse tumor-associated cell types. Current techniques used to investigate the tumor microenvironment can be time-consuming, expensive, complicated to interpret, and often involves destruction of the sample. Here we use standard hematoxylin and eosin-stained tumor sections and the HALO AI nuclear phenotyping software to characterize 6 distinct cell types (epithelial, mesenchymal, macrophage, neutrophil, lymphocyte, and plasma cells) in both murine lung cancer models and human lung cancer samples. CD3 immunohistochemistry and lymph node sections were used to validate lymphocyte calls, while F4/80 immunohistochemistry was used for macrophage validation. Consistent with numerous prior studies, we demonstrated that macrophages predominate the adenocarcinomas, whereas neutrophils predominate the squamous cell carcinomas in murine samples. In human samples, we showed a strong negative correlation between neutrophils and lymphocytes as well as between mesenchymal cells and lymphocytes and that higher percentages of mesenchymal cells correlate with poor prognosis. Taken together, we demonstrate the utility of this AI software to identify, quantify, and compare distributions of cell types on standard hematoxylin and eosin-stained slides. Given the simplicity and cost-effectiveness of this technique, it may be widely beneficial for researchers designing new therapies and clinicians working to select favorable treatments for their patients.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Animales , Ratones , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Hematoxilina , Inteligencia Artificial , Microambiente Tumoral , Eosina Amarillenta-(YS)RESUMEN
BACKGROUND: Solitary fibrous tumour (SFT) is a unique mesenchymal neoplasm with classic features on histology and is characterised by the NAB2-STAT6 gene fusion. There are rare reports of SFTs with pancreatic involvement and only two cases in the literature reporting its features by preoperative fine needle aspiration (FNA). Herein, we characterise the cytomorphological features of four SFTs involving the pancreas by FNA to establish a preoperative diagnostic approach. METHODS: The anatomic pathology archives of two academic medical centres were searched to identify patients with a pancreatic FNA cytology specimen and a confirmed diagnosis of SFT by surgical resection. The clinical history, pathological diagnosis, cytomorphological findings, and results of immunohistochemistry (IHC) were reviewed. RESULTS: Four SFTs were identified from four patients with a median age of 59 years. The morphological features were variable but most frequently showed a bland spindled-to-epithelioid proliferation in fragments and single cells with small, oval, elongated, and hypochromatic nuclei in a haphazard arrangement with or without dense collagen. One tumour presented with a concurrent metastasis and showed a pure epithelioid component with necrosis and enlarged, hyperchromatic nuclei with conspicuous nucleoli and scattered mitoses. IHC was necessary for all diagnoses which were confirmed by surgical resection. CONCLUSIONS: SFTs with pancreatic involvement are rare, and non-specific features and tumour heterogeneity can pose a diagnostic challenge on FNA; however, IHC can be used to make a definitive diagnosis. As a result, FNA is a simple, safe, cost-effective, and accurate approach that can be used to diagnose SFT in the pancreas.
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Tumores Fibrosos Solitarios , Biopsia con Aguja Fina/métodos , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Páncreas/patología , Tumores Fibrosos Solitarios/diagnóstico , Tumores Fibrosos Solitarios/patologíaRESUMEN
OBJECTIVE. The purpose of this study was to investigate whether MRI-typical and MRI-atypical intraosseous vascular malformations are associated with familial cerebral cavernous malformation (FCCM). MATERIALS AND METHODS. In a retrospective matched case-control study, two radiologists reviewed the spinal imaging, both CT and MRI, of 22 patients with FCCM seen between 2006 and 2017 and of age- and sex-matched control subjects for MRI-typical and MRI-atypical intraosseous vascular malformations. Quantitative analysis of lesions identified included vertebral level, size, and number of lesions. Pathologic samples from two lesions were analyzed for histologic and immunohistochemical features. Whether the presence of typical, atypical, and total intraosseous vascular malformations differed between patients and control subjects was tested. For patients with complete spinal imaging, whether intraosseous vascular malformations were associated with age, sex, brain lesion count, and spinal lesion count was also tested. RESULTS. MRI-atypical intraosseous vertebral malformations were more commonly present in patients with FCCM (p = 0.003). Sixteen lesions were found in nine patients and none in the control group. The numbers of MRI-typical intraosseous vascular malformations were similar between patients and control subjects (p = 0.480). Age was associated with typical intraosseous vascular malformations (p = 0.027), though not with atypical malformations. MRI-atypical malformations were larger (mean diameter double) than MRI-typical malformations (p = 0.023). Histologic analysis of two lesions from different patients with pathologic collapse revealed the same histologic features consistent with combined capillary-venous malformations. CONCLUSION. Vertebral capillary-venous malformations (MRI-atypical intraosseous vascular malformations) are common in patients with FCCM and may have a more aggressive clinical course than MRI-typical malformations.
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Hemangioma Cavernoso del Sistema Nervioso Central/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Columna Vertebral/anomalías , Columna Vertebral/irrigación sanguínea , Tomografía Computarizada por Rayos X/métodos , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Prevalencia , Estudios RetrospectivosRESUMEN
Nuclear Protein in Testis (NUT)-rearranged tumors comprise predominantly NUT carcinoma but also include certain lymphomas, leukemias, skin appendage tumors, and sarcomas. Although histologically diverse, all are genetically identified by oncogenic rearrangement in the NUTM1 gene. Many fusion partners occur, and NSD3 is NUT carcinoma's third most common partner. Herein, we present a case of a 26-year-old man with an NSD3::NUTM1 fusion sarcoma. The patient presented at the age of 13 months with a scalp nodule. Over the next 24 years, he experienced five local recurrences and ultimately expired of a rapidly progressive recurrence. His treatment included surgical resections, radiation, and various chemotherapies. Deceptively, the clinical presentation and histopathology aligned with a malignant peripheral nerve sheath tumor, a diagnosis rendered at initial resection with concurrence by a national soft tissue tumor expert. The patient's exceptionally long survival could be due to NSD3 as the fusion partner, aided by the initial small tumor size and young patient age. Thus, this case expands NUT fusion sarcomas' histologic and immunohistochemical profile to include mimicking a malignant peripheral nerve sheath tumor (MPNST). Additionally, it indicates that the NSD3::NUTM1 fusion can drive sarcoma genesis.
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Abemaciclib was originally FDA approved for patients with ER-positive/HER2-negative breast cancer with Ki-67 expression ≥20%. However, there were no guidelines provided on which specimen to test or which scoring method to use. We performed a comprehensive study evaluating the variation in Ki-67 expression in breast specimens from 50 consecutive patients who could have been eligible for abemaciclib therapy. Three pathologists with breast expertise each performed a blinded review with 3 different manual scoring methods [estimated (EST), unweighted (UNW), and weighted (WT) (WT recommended by the International Ki-67 in Breast Cancer Working Group)]. Quantitative image analysis (QIA) using the HALO platform was also performed. Three different specimen types [core needle biopsy (CNB) (n=63), resection (RES) (n=52), and axillary lymph node metastasis (ALN) (n=50)] were evaluated for each patient. The average Ki-67 for all specimens was 14.68% for EST, 14.46% for UNW, 14.15% for WT, and 11.15% for QIA. For the manual methods, the range between the lowest and highest Ki-67 for each specimen between the 3 pathologists was 8.44 for EST, 5.94 for WT, and 5.93 for UNW. The WT method limited interobserver variability with ICC1=0.959 (EST ICC1=0.922 and UNW=0.949). Using the aforementioned cutoff of Ki-67 ≥20% versus <20% to determine treatment eligibility, the averaged EST method yields 20 of 50 patients (40%) who would have been treatment-eligible, versus 15 (30%) for the UNW, 17 (34%) for the WT, and 12 (24%) for the QIA. There was no statistically significant difference in Ki-67 among the 3 specimen types. The average Ki-67 difference was 4.36 for CNB vs RES, 6.95 for CNB versus ALN, and RES versus ALN (P=0.93, 0.99, and 0.94, respectively). Our study concludes that further refinement in Ki-67 scoring is advisable to reduce clinically significant variation.
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Bencimidazoles , Neoplasias de la Mama , Proyectos de Investigación , Humanos , Femenino , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/tratamiento farmacológico , Antígeno Ki-67 , AminopiridinasRESUMEN
Soft tissue tumors (STTs) pose diagnostic and therapeutic challenges due to their rarity, complexity, and morphological overlap. Accurate differentiation between benign and malignant STTs is important to set treatment directions, however, this task can be difficult. The integration of machine learning and artificial intelligence (AI) models can potentially be helpful in classifying these tumors. The aim of this study was to investigate AI and machine learning tools in the classification of STT into benign and malignant categories. This study consisted of three components: (1) Evaluation of whole-slide images (WSIs) to classify STT into benign and malignant entities. Five specialized soft tissue pathologists from different medical centers independently reviewed 100 WSIs, representing 100 different cases, with limited clinical information and no additional workup. The results showed an overall concordance rate of 70.4% compared to the reference diagnosis. (2) Identification of cell-specific parameters that can distinguish benign and malignant STT. Using an image analysis software (QuPath) and a cohort of 95 cases, several cell-specific parameters were found to be statistically significant, most notably cell count, nucleus/cell area ratio, nucleus hematoxylin density mean, and cell max caliper. (3) Evaluation of machine learning library (Scikit-learn) in differentiating benign and malignant STTs. A total of 195 STT cases (156 cases in the training group and 39 cases in the validation group) achieved approximately 70% sensitivity and specificity, and an AUC of 0.68. Our limited study suggests that the use of WSI and AI in soft tissue pathology has the potential to enhance diagnostic accuracy and identify parameters that can differentiate between benign and malignant STTs. We envision the integration of AI as a supportive tool to augment the pathologists' diagnostic capabilities.
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PURPOSE: Patients with cancer frequently undergo research-grade germline sequencing but clinically actionable results are not routinely disclosed. The objective of this study is to evaluate the feasibility of reporting clinically relevant secondary findings (SF) identified in germline research sequencing using the institutional molecular tumor board (MTB) and the treating oncology physician. METHODS: This prospective, interventional cohort study enrolled Total Cancer Care participants with any cancer diagnosis at a single institution. Patients underwent research-grade germline whole-exome sequencing, with bioinformatic analysis in a Clinical Laboratory Improvement Amendments-certified laboratory to verify pathogenic/likely pathogenic germline variants (PGVs) in any American College of Medical Genomics and Genetics SF v2.0 genes. After a protocol modification in consenting patients, the MTB reported PGVs to treating oncology physicians with recommendations for referral to a licensed genetic counselor and clinical confirmatory testing. RESULTS: Of the 781 enrolled participants, 32 (4.1%) harbored cancer predisposition PGVs, 24 (3.1%) were heterozygous carriers of an autosomal recessive cancer predisposition syndrome, and 14 (1.8%) had other hereditary disease PGVs. Guideline-directed testing would have missed 37.5% (12/32) of the inherited cancer predisposition PGVs, which included BRCA1, BRCA2, MSH6, SDHAF2, SDHB, and TP53 variants. Three hundred fifteen participants consented to reporting results; results for all living patients were reported to the clinical team with half referred to a licensed genetic counselor. There was concordance between all research variants identified in patients (n = 9) who underwent clinical confirmatory sequencing. CONCLUSION: MTB reporting of research-grade germline sequencing to the clinical oncology team is feasible. Over a third of PGVs identified using a universal testing strategy would have been missed by guideline-based approach, suggesting a role for expanding germline testing.
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Neoplasias , Humanos , Estados Unidos , Estudios Prospectivos , Estudios de Cohortes , Estudios de Factibilidad , Neoplasias/diagnóstico , Neoplasias/genética , Predisposición Genética a la Enfermedad/genética , Células GerminativasRESUMEN
Adenosquamous proliferation (ASP) is known to occur in the central nidus of radial sclerosing lesions (RSL) of the breast. However, their significance is debated and remains largely unknown. In addition, there is a histologic overlap between ASP and low-grade adenosquamous carcinomas (LGASC). We conducted a large retrospective review of 247 RSLs to evaluate the prevalence of ASP and quantitatively analyze associated histologic features of RSLs including size, stromal cellularity, and presence of chronic inflammation. The central nidus of RSLs were classified as hyalinized in 121 cases (49%), cellular in 37 cases (15%), and equally mixed hyalinized and cellular in 89 (36%). ASP occurred in 92 of 247 RSLs (37.2%). Cases with ASP were significantly associated with a cellular stroma; 78.4% of RSLS with cellular stroma had ASP versus just 11.6% of hyalinized RSLs. In our large cohort, inflammation is commonly found in RSLs with ASP (p= <0.001). In conclusion, we confirm that ASP is statistically more likely to be found in RSLs with a cellular stroma. In addition, ASP is commonly associated with chronic inflammation. The finding challenges the notion that prominent lymphocytes are a diagnostic clue to LGASC on limited biopsy material.
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Neoplasias de la Mama , Carcinoma Adenoescamoso , Enfermedad Fibroquística de la Mama , Femenino , Humanos , Neoplasias de la Mama/patología , Mama/patología , Enfermedad Fibroquística de la Mama/patología , Carcinoma Adenoescamoso/patología , Inflamación/patología , Proliferación CelularRESUMEN
OBJECTIVES: The presence of nodal metastases in patients with papillary thyroid carcinoma (PTC) has both staging and treatment implications. However, lymph nodes are often not removed during thyroidectomy. Prior work has demonstrated the capability of artificial intelligence (AI) to predict the presence of nodal metastases in PTC based on the primary tumor histopathology alone. This study aimed to replicate these results with multi-institutional data. METHODS: Cases of conventional PTC were identified from the records of 2 large academic institutions. Only patients with complete pathology data, including at least 3 sampled lymph nodes, were included in the study. Tumors were designated "positive" if they had at least 5 positive lymph node metastases. First, algorithms were trained separately on each institution's data and tested independently on the other institution's data. Then, the data sets were combined and new algorithms were developed and tested. The primary tumors were randomized into 2 groups, one to train the algorithm and another to test it. A low level of supervision was used to train the algorithm. Board-certified pathologists annotated the slides. HALO-AI convolutional neural network and image software was used to perform training and testing. Receiver operator characteristic curves and the Youden J statistic were used for primary analysis. RESULTS: There were 420 cases used in analyses, 45% of which were negative. The best performing single institution algorithm had an area under the curve (AUC) of 0.64 with a sensitivity and specificity of 65% and 61% respectively, when tested on the other institution's data. The best performing combined institution algorithm had an AUC of 0.84 with a sensitivity and specificity of 68% and 91% respectively. CONCLUSION: A convolutional neural network can produce an accurate and robust algorithm that is capable of predicting nodal metastases from primary PTC histopathology alone even in the setting of multi-institutional data.
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Carcinoma Papilar , Neoplasias de la Tiroides , Humanos , Inteligencia Artificial , Carcinoma Papilar/cirugía , Carcinoma Papilar/patología , Ganglios Linfáticos/patología , Metástasis Linfática/patología , Disección del Cuello , Redes Neurales de la Computación , Estudios Retrospectivos , Cáncer Papilar Tiroideo/patología , Neoplasias de la Tiroides/patología , Tiroidectomía/métodosAsunto(s)
Medios de Contraste , Óxido Ferrosoférrico , Aumento de la Imagen/métodos , Imagen por Resonancia Magnética/métodos , Osteomielitis/diagnóstico por imagen , Adulto , Anciano , Hematínicos , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Dedos del Pie/diagnóstico por imagenRESUMEN
In this report, we present a high-grade thyroid carcinoma with an NSD3::NUTM1 fusion detected on expanded next-generation sequencing testing. Nuclear protein of the testis (NUT) carcinomas comprise high-grade, aggressive tumors characterized by rearrangements of the NUTM1 gene with various partner genes, most commonly the bromodomain protein genes BRD4 and BRD3. Approximately 10% of NUT carcinomas contain an NSD3::NUTM1 fusion. NUT carcinomas manifest as poorly differentiated or undifferentiated squamous carcinomas, and 33% show areas of mature squamous differentiation. Only exceptionally have NUT carcinomas shown histology discordant from poorly differentiated/undifferentiated squamous carcinoma, and a thyroid NUT carcinoma with histologic thyrocyte differentiation has not been described to date. Our patient's tumor exhibited mixed cytologic features suggestive of squamoid cells or papillary thyroid carcinoma cells. Overt squamous differentiation was absent, and the tumor produced colloid in poorly formed follicles. Immunophenotypically, the carcinoma was consistent with thyrocyte differentiation with expression of monoclonal PAX8, TTF1, and thyroglobulin (the last predominantly in extracellular colloid). There was zero to < 2% reactivity for proteins typically diffusely expressed in NUT carcinoma: p40, p63, and cytokeratins 5/6. NUT protein expression was equivocal, but fluorescence in situ hybridization confirmed a NUTM1 rearrangement. This exceptional case suggests that NUTM1 fusions may occur in an unknown number of aggressive thyroid carcinomas, possibly with distinctive histologic features but with thyrocyte differentiation. Recognition of this entity potentially has significant prognostic implications. Moreover, thyroid carcinomas with NUTM1 fusions may be amenable to treatment with NUT carcinoma-targeted therapy such as a bromodomain and extraterminal domain protein small molecular inhibitor (BETi).
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Carcinoma de Células Escamosas , Células Epiteliales Tiroideas , Neoplasias de la Tiroides , Proteínas de Ciclo Celular , Coloides , Humanos , Hibridación Fluorescente in Situ , Masculino , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/genética , Células Epiteliales Tiroideas/metabolismo , Neoplasias de la Tiroides/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
PURPOSE: Large-scale genomic sequencing studies are driving oncology drug development. However, rural populations, like those residing in Appalachian Kentucky, are underrepresented in these efforts. In this study, we determined the frequency of participation, reasons for nonparticipation, and factors predicting the decision to participate in the Total Cancer Care (TCC) prospective genomic cohort study. METHODS: A total of 1,188 patients were invited to enroll in the TCC prospective cohort from December 2018 to May 2019. Declining patients were queried for their rationale for nonparticipation and their patient data were obtained from the Kentucky Cancer Registry (KCR). Logistic regression was used to assess the association between characteristics and study participation. The association of study participation with survival was modeled with Cox proportional-hazards regression. RESULTS: 90.9% (1,081) patients consented to participate. In multivariate analysis, factors significantly associated with participation were age, gender, treatment status, and race. Though overall more women participated in the study, men were more likely to participate than women when invited (OR 1.57). Younger, Caucasian individuals who had received chemotherapy, but not surgery, were also more likely to participate. Patients in the Kentucky Appalachian cohort were primarily rural, had less educational attainment, and lower socioeconomic status. Kentucky Appalachian patients were no less likely to enroll in TCC than non-Appalachian patients. Consented individuals had higher overall survival compared to those who declined. CONCLUSION: Though minorities, those with low socioeconomic status, and rural populations are underrepresented in genomic studies, they were no less likely to participate when given the opportunity, and participation was associated with better clinical outcomes.
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Neoplasias , Región de los Apalaches , Estudios de Cohortes , Femenino , Genómica , Humanos , Kentucky/epidemiología , Masculino , Neoplasias/genética , Neoplasias/terapia , Estudios ProspectivosRESUMEN
Background: Lymphatic malformations (LMs) often pose treatment challenges due to a large size or a critical location that could lead to disfigurement, and there are no standardized treatment approaches for either refractory or unresectable cases. Methods: We examined the genomic landscape of a patient cohort of LMs (n = 30 cases) that underwent comprehensive genomic profiling using a large-panel next-generation sequencing assay. Immunohistochemical analyses were completed in parallel. Results: These LMs had low mutational burden with hotspot PIK3CA mutations (n = 20) and NRAS (n = 5) mutations being most frequent, and mutually exclusive. All LM cases with Kaposi sarcoma-like (kaposiform) histology had NRAS mutations. One index patient presented with subacute abdominal pain and was diagnosed with a large retroperitoneal LM harboring a somatic PIK3CA gain-of-function mutation (H1047R). The patient achieved a rapid and durable radiologic complete response, as defined in RECIST1.1, to the PI3Kα inhibitor alpelisib within the context of a personalized N-of-1 clinical trial (NCT03941782). In translational correlative studies, canonical PI3Kα pathway activation was confirmed by immunohistochemistry and human LM-derived lymphatic endothelial cells carrying an allele with an activating mutation at the same locus were sensitive to alpelisib treatment in vitro, which was demonstrated by a concentration-dependent drop in measurable impedance, an assessment of cell status. Conclusions: Our findings establish that LM patients with conventional or kaposiform histology have distinct, yet targetable, driver mutations. Funding: R.P. and W.A. are supported by awards from the Levy-Longenbaugh Fund. S.G. is supported by awards from the Hugs for Brady Foundation. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of Arizona Cancer Center (CA023074), the University of New Mexico Comprehensive Cancer Center (CA118100), and the Rutgers Cancer Institute of New Jersey (CA072720). B.K.M. was supported by National Science Foundation via Graduate Research Fellowship DGE-1143953. Clinical trial number: NCT03941782.
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Antineoplásicos , Fosfatidilinositol 3-Quinasa Clase I , GTP Fosfohidrolasas , Linfangioma , Anomalías Linfáticas , Proteínas de la Membrana , Tiazoles , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Fosfatidilinositol 3-Quinasa Clase Ia/metabolismo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , GTP Fosfohidrolasas/genética , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica , Linfangioma/tratamiento farmacológico , Linfangioma/genética , Anomalías Linfáticas/tratamiento farmacológico , Anomalías Linfáticas/genética , Proteínas de la Membrana/genética , Mutación , Análisis de Secuencia de ADN , Tiazoles/farmacología , Tiazoles/uso terapéuticoRESUMEN
Importance: Obesity is associated with increased risk of colorectal cancer (CRC) and a more aggressive disease course. Tumor budding (TB) is an important prognostic factor for CRC, but its association with obesity is unknown. Objective: To evaluate the association of TB with obesity and other prognostic factors in colon cancer. Design, Setting, and Participants: This cohort study involved a histological review of colon cancer specimens obtained during 7 years (January 2008 to December 2015) at the University of Kentucky Medical Center; data analysis was conducted from February 2020 to January 2021. Specimens came from 200 patients with stage I to III colon cancer; patients with stage 0, stage IV, or incomplete data were excluded. Main Outcomes and Measures: TB was defined as 1 to 4 malignant cells at the invasive edge of the tumor, independently assessed by 2 academic pathologists. The primary outcome was the association of TB with obesity (defined as body mass index [BMI] of 30 or greater). Secondary outcomes include the association of TB with clinical features (ie, age, race, sex, TNM stage, tumor location) and pathological features (ie, poorly differentiated tumor clusters [PDCs], Klintrup-Mäkinen inflammatory score, desmoplasia, infiltrative tumor border, tumor necrosis, and tumor-to-stroma ratio). Results: A total of 200 specimens were reviewed. The median (interquartile range) age of patients was 62 (55-72) years, 102 (51.0%) were women, and the mean (SD) BMI was 28.5 (8.4). A total of 57 specimens (28.5%) were from stage I tumors; 74 (37.0%), stage II; and 69 (34.5%), stage III. Of these, 97 (48.5%) had low-grade (<5 buds), 36 (18.0%) had intermediate-grade (5-9 buds), and 67 (33.5%) had high-grade (≥10 buds) TB. Multivariable analysis adjusting for clinical and histological factors demonstrated that higher TB grade was associated with obesity (odds ratio [OR], 4.25; 95% CI, 1.95-9.26), higher PDC grade (grade 2 vs 1: OR, 9.14; 95% CI, 3.49-23.93; grade 3 vs 1: OR, 5.10; 95% CI, 2.30-11.27), increased infiltrative tumor border (OR, 1.03; 95% CI, 1.01-1.04), cecal location (OR, 2.55; 95% CI, 1.09-5.97), and higher stage (eg, stage III vs stage I for high-grade or intermediate-grade vs low-grade TB: OR, 2.91; 95% CI, 1.00-8.49). Additionally, patients with a higher TB grade had worse overall survival (intermediate vs low TB: hazard ratio, 2.20; 95% CI, 1.11-4.35; log-rank P = .02; high vs low TB: hazard ratio, 2.67; 95% CI, 1.45-4.90; log-rank P < .001). Conclusions and Relevance: In this cohort study, a novel association between high TB grade and obesity was found. The association could reflect a systemic condition (ie, obesity) locally influencing aggressive growth (ie, high TB) in colon cancer.
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Biomarcadores de Tumor/sangre , Neoplasias del Colon/patología , Invasividad Neoplásica/patología , Obesidad/patología , Anciano , Estudios de Cohortes , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Obesidad/complicaciones , Estudios RetrospectivosRESUMEN
OBJECTIVE: National pathology guidelines recommend full pathologic analysis for all adult tonsillectomy specimens. We evaluated the available data on occult malignancy in adult tonsillectomy for benign indication, and created a screening system to reduce the risk of missed malignancies if routine histopathologic examination were to be discontinued. STUDY DESIGN: Retrospective chart review and systematic review of the literature. SETTING: Tertiary care academic hospital and multi-hospital private healthcare system. SUBJECTS AND METHODS: A systematic literature review identified case series of adult tonsillectomy. Retrospective chart review at our institutions from 2000 to 2016 produced an additional case series. The pooled rate of occult malignancy was determined, and re-analyzed using criteria based on preoperative risk factors designed to identify patients requiring full pathologic analysis. The predicted effects of prospective application of the proposed criteria were calculated. Pooled occult malignancy prevalence was estimated. RESULTS: Literature review and our own case series yielded 12,094 total cases. Occult malignancy prevalence in the combined data was 0.033%, representing four occult malignancies. Three out of the four would have been selected for full pathology preoperatively with use of the proposed criteria. Statistical analysis indicates that the predicted frequency of occult malignancy incidence in cases negative for the criteria is 0.01%, or 1/10,000. CONCLUSION: Application of the proposed criteria to adults undergoing tonsillectomy for benign indication identifies a subset of patients with an estimated incidence of occult malignancy similar to that reported for pediatric tonsillectomy, and potentially may permit safe elimination of pathologic analysis of their tonsil specimens. LEVEL OF EVIDENCE: Pooled analysis of case series from the literature and a single institution, level 4.
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Biopsia/métodos , Neoplasias Primarias Desconocidas , Tonsila Palatina , Neoplasias Tonsilares , Tonsilectomía , Adulto , Humanos , Incidencia , Neoplasias Primarias Desconocidas/diagnóstico , Neoplasias Primarias Desconocidas/epidemiología , Neoplasias Primarias Desconocidas/patología , Tonsila Palatina/patología , Tonsila Palatina/cirugía , Neoplasias Tonsilares/diagnóstico , Neoplasias Tonsilares/epidemiología , Neoplasias Tonsilares/patología , Tonsilectomía/métodos , Tonsilectomía/estadística & datos numéricos , Tonsilitis/cirugía , Procedimientos Innecesarios/métodosRESUMEN
Regulatory properties of macrophages associated with alternative activation serve to limit the exaggerated inflammatory response during pneumonia caused by Pseudomonas aeruginosa infection. Arginase-1 is an important effector of these macrophages believed to play an essential role in decreasing injury and promoting repair. We investigated the role of arginase-1 in the control of inflammatory immune responses to P. aeruginosa pneumonia in mice that exhibit different immunologic phenotypes. C57BL/6 mice with conditional knockout of the arginase-1 (Arg1) gene from myeloid cells (Arg1ΔM) or BALB/c mice treated with small molecule inhibitors of arginase were infected intratracheally with P. aeruginosa. Weight loss, mortality, bacterial clearance, and lung injury were assessed and compared, as were the characterization of immune cell populations over time post-infection. Myeloid arginase-1 deletion resulted in greater morbidity along with more severe inflammatory responses compared to littermate control mice. Arg1ΔM mice had greater numbers of neutrophils, macrophages, and lymphocytes in their airways and lymph nodes compared to littermate controls. Additionally, Arg1ΔM mice recovered from inflammatory lung injury at a significantly slower rate. Conversely, treatment of BALB/c mice with the arginase inhibitor S-(2-boronoethyl)-l-cysteine hydrochloride (BEC) did not change morbidity as defined by weight loss, but mice at day 10 post-infection treated with BEC had gained significantly more weight back than controls. Neutrophil and macrophage infiltration were similar between groups in the lung parenchyma, and neutrophil migration into the airways was reduced by BEC treatment. Differences seem to lie in the impact on T cell subset disposition. Arg1ΔM mice had increased total CD4+ T cell expansion in the lymph nodes, and increased T cell activation, IFNγ production, and IL-17 production in the lymph nodes, lung interstitium, and airways, while treatment with BEC had no impact on T cell activation or IL-17 production, but reduced the number of T cells producing IFNγ in the lungs. Lung injury scores were increased in the Arg1ΔM mice, but no differences were observed in the mice treated with pharmacologic arginase inhibitors. Overall, myeloid arginase production was demonstrated to be essential for control of damaging inflammatory responses associated with P. aeruginosa pneumonia in C57BL/6 mice, in contrast to a protective effect in the Th2-dominant BALB/c mice when arginase activity is globally inhibited.
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Arginasa/metabolismo , Linfocitos T CD4-Positivos/inmunología , Inflamación/inmunología , Pulmón/metabolismo , Neutrófilos/inmunología , Neumonía Bacteriana/inmunología , Infecciones por Pseudomonas/inmunología , Pseudomonas aeruginosa/fisiología , Subgrupos de Linfocitos T/inmunología , Animales , Arginasa/antagonistas & inhibidores , Arginasa/genética , Ácidos Borónicos/farmacología , Citocinas/metabolismo , Femenino , Antecedentes Genéticos , Predisposición Genética a la Enfermedad , Humanos , Inmunomodulación , Pulmón/patología , Activación de Linfocitos , Activación de Macrófagos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Balance Th1 - Th2RESUMEN
Although Pembrolizumab-based immunotherapy has significantly improved lung cancer patient survival, many patients show variable efficacy and resistance development. A better understanding of the drug's action is needed to improve patient outcomes. Functional heterogeneity of the tumor microenvironment (TME) is crucial to modulating drug resistance; understanding of individual patients' TME that impacts drug response is hampered by lack of appropriate models. Lung organotypic tissue slice cultures (OTC) with patients' native TME procured from primary and brain-metastasized (BM) non-small cell lung cancer (NSCLC) patients were treated with Pembrolizumab and/or beta-glucan (WGP, an innate immune activator). Metabolic tracing with 13C6-Glc/13C5,15N2-Gln, multiplex immunofluorescence, and digital spatial profiling (DSP) were employed to interrogate metabolic and functional responses to Pembrolizumab and/or WGP. Primary and BM PD-1+ lung cancer OTC responded to Pembrolizumab and Pembrolizumab + WGP treatments, respectively. Pembrolizumab activated innate immune metabolism and functions in primary OTC, which were accompanied by tissue damage. DSP analysis indicated an overall decrease in immunosuppressive macrophages and T cells but revealed microheterogeneity in immune responses and tissue damage. Two TMEs with altered cancer cell properties showed resistance. Pembrolizumab or WGP alone had negligible effects on BM-lung cancer OTC but Pembrolizumab + WGP blocked central metabolism with increased pro-inflammatory effector release and tissue damage. In-depth metabolic analysis and multiplex TME imaging of lung cancer OTC demonstrated overall innate immune activation by Pembrolizumab but heterogeneous responses in the native TME of a patient with primary NSCLC. Metabolic and functional analysis also revealed synergistic action of Pembrolizumab and WGP in OTC of metastatic NSCLC.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunidad Innata , Neoplasias Pulmonares/inmunología , Linfocitos T CD8-positivos/inmunología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Inmunoterapia/métodos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Macrófagos/inmunología , Metástasis de la Neoplasia , Receptor de Muerte Celular Programada 1/inmunología , Microambiente TumoralRESUMEN
INTRODUCTION: Kentucky is recognized as the state with the highest lung cancer burden for more than 2 decades, but how lung cancer differs in Kentucky relative to other US populations is not fully understood. PATIENTS AND METHODS: We examined lung cancer reported to the Surveillance, Epidemiology, and End Results (SEER) Program by Kentucky and the other SEER regions for patients diagnosed between 2012 and 2016. Our analyses included histologic types, incidence rates, stage at diagnosis, and survival in Kentucky and Appalachian Kentucky relative to other SEER regions. RESULTS: We found that both squamous cell carcinomas and small-cell lung cancers represent larger proportions of lung cancer diagnoses in Kentucky and Appalachian Kentucky than they do in the SEER registries. Furthermore, age-adjusted cancer incidence rates were higher in Kentucky for every subtype of lung cancer examined. Most notably, for Appalachian women the rate of small-cell carcinomas was 3.5-fold higher, and for Appalachian men the rate of squamous cell carcinoma was 3.1-fold higher, than the SEER rates. In Kentucky, lung cancers were diagnosed at later stages and lung cancer survival was lower for adenocarcinoma and neuroendocrine carcinomas than in SEER registries. Squamous cell carcinomas and small-cell carcinomas were most lethal in Appalachian Kentucky. CONCLUSION: Together, these data highlight the considerable disparities among lung cancer cases in the United States and demonstrate the continuing high burden and poor survival of lung cancer in Kentucky and Appalachian Kentucky. Strategies to identify and rectify causes of these disparities are discussed.
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Disparidades en el Estado de Salud , Disparidades en Atención de Salud , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/fisiopatología , Sobrevida , Región de los Apalaches/epidemiología , Femenino , Humanos , Kentucky/epidemiología , MasculinoRESUMEN
Venous thromboembolism (VTE) occurs at an increased incidence in cancer patients. A cancer-related hypercoagulable state has been considered to play role in this phenomenon. Preclinical data suggest an association between tumor expression of MET proto-oncogene (MET) and a hypercoagulable state, resulting in VTE. We investigated this association in this retrospective study. Thirty-five cancer patients with documented VTE and no relevant predisposing factors were compared with 35 matched cancer patients without VTE who served as controls. Pathology specimens of all patients and controls were stained by immunohistochemistry (IHC) for MET protein. Intensity of reactivity to the MET antibody was read as 0 (negative), 1+ (equivocal), and 2+ (positive). The pathologists were blinded to the patient VTE status. The MET reactivity in tissue sections were compared between the two cohorts. No significant difference was observed between the two groups for MET expression. This study's findings indicate no association between the reactivity for MET protein as measured through an immunohistochemical technique, and the incidence of VTE in cancer patients.
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Neoplasias/complicaciones , Proteínas Proto-Oncogénicas c-met/análisis , Receptores de Factores de Crecimiento/análisis , Tromboembolia Venosa/etiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inmunohistoquímica , Incidencia , Masculino , Persona de Mediana Edad , Neoplasias/patología , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas c-met/fisiología , Receptores de Factores de Crecimiento/fisiología , Estudios Retrospectivos , Factores de Riesgo , Tromboembolia Venosa/epidemiologíaRESUMEN
Chronic plasmacytic endometritis (CPE) is an infectious or reactive process with multiple etiologies. The lesion is reportedly often associated with pelvic inflammatory disease and intermenstrual bleeding. However, the clinical significance of the diagnosis when found incidentally and whether particular pathologic findings are associated with clinically important CPE have not been evaluated. We reviewed 105 chronic endometritis cases that had been diagnosed earlier and 130 controls to examine the pathologic and clinical associations in a diverse population.A pathology database was searched for endometrial biopsies diagnosed as CPE, and 105 cases were found. Systematic randomized sampling identified 130 control cases (biopsies not diagnosed as CPE). Slides were carefully reviewed to assess 10 histopathologic features. Clinical records were reviewed for 15 clinical parameters. Analysis was performed using chi tests and SAS software.Few patients (3%) received antibiotics or further clinical intervention after the diagnosis of CPE was rendered. The clinical data trended toward fewer menstrual abnormalities as plasma cells increased. The intensity of inflammation showed no association with patient age or symptom duration. Evaluation of controls revealed 17 cases with missed diagnosis of CPE, representing an overall 16% underdiagnosis rate.In CPE, there are no specific clinical features that correlate with the intensity of pathologic findings; the most specific histologic feature is the presence of plasma cells, and it is predominantly identified in weakly proliferative endometrium. There is a clinically insignificant 16% pathologic underdiagnosis rate. In contrast to the findings of past studies, only a small percentage of patients had pelvic inflammatory disease (4%).