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BACKGROUND: Intraductal oncocytic papillary neoplasms (IOPNs) of the pancreas are now considered a separate entity to intraductal papillary mucinous neoplasms (IPMN). Invasive IOPNs are extremely rare, and their recurrence patterns, response to adjuvant chemotherapy and long-term survival outcomes are unknown. METHODS: Consecutive patients undergoing pancreatic resection (2010-2020) for invasive IOPNs or adenocarcinoma arising from IPMN (A-IPMN) from 18 academic pancreatic centers worldwide were included. Outcomes of invasive IOPNs were compared with A-IPMN invasive subtypes (ductal and colloid A-IPMN). RESULTS: 415 patients were included: 20 invasive IOPN, 331 ductal A-IPMN and 64 colloid A-IPMN. After a median follow-up of 6-years, 45% and 60% of invasive IOPNs had developed recurrence and died, respectively. There was no significant difference in recurrence or overall survival between invasive IOPN and ductal A-IPMN. Overall survival of invasive IOPNs was inferior to colloid A-IPMNs (median time of survival 24.4 months vs. 86.7, months, p = 0.013), but the difference in recurrence only showed borderline significance (median time to recurrence, 22.5 months vs. 78.5 months, p = 0.132). Adjuvant chemotherapy, after accounting for high-risk features, did not reduce rates of recurrence in invasive IOPN (p = 0.443), ductal carcinoma (p = 0.192) or colloid carcinoma (p = 0.574). CONCLUSIONS: Invasive IOPNs should be considered an aggressive cancer with a recurrence rate and prognosis consistent with ductal type A-IPMN.
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BACKGROUND: Expression of programmed death ligand-1 (PD-L1) guides the use of immune checkpoint inhibitors (ICI) in several cancers. In colorectal cancer (CRC), ICI are only approved for metastatic CRC, while several studies suggest high efficacy even in operable CRC. The aim of this study was to investigate the inter-rater agreement of PD-L1 as a companion diagnostic marker. METHODS: Specimens from resected stage I-III CRC (n = 166 tumors) were stained with PD-L1 22C3 clone. PD-L1 expression was scored by two pathologists as tumor proportion score (TPS), combined positive score (CPS) and immune cell score (IC). Inter-rater agreement was tested using three different agreement coefficients. RESULTS: Raw scores of the two pathologists had 'good' to 'excellent' correlation. Spearman's rho for TPS=0.917 (95 %CI 0.839-0.995), for CPS=0.776 (95 %CI 0.726-0.826) and IC=0.818 (95 %CI 0.761-0.875). For TPS, kappa (κ)-agreements for both the ≥1 % and ≥10 % cutoffs had excellent correlation. For CPS the ≥1 % and ≥10 % cutoffs demonstrated κ=0.32 (95 %CI 0.12-0.51) and κ=0.36 (95 %CI 0.25-0.48) respectively. Cutoffs for IC showed κ=0.53 (95 %CI 0.18-0.79) for the ≥1 % cutoff, and κ=0.61 (95 %CI 0.48-0.73) for the ≥10 % cutoff. Gwet's agreement coefficient (AC1) showed higher agreement coefficients than κ-values for most, but not all cut-offs. CONCLUSION: Agreement for PD-L1 was good to excellent for raw scores. Agreement variation across several criteria and cut-offs suggests the need for more robust criteria for PD-L1 as a companion diagnostic marker.
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Neoplasias Colorrectales , Neoplasias Pulmonares , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunohistoquímica , Antígeno B7-H1/metabolismo , Ligandos , Neoplasias Pulmonares/patología , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genéticaRESUMEN
BACKGROUND: The overall poor prognosis in pancreatic cancer is related to late clinical detection. Early diagnosis remains a considerable challenge in pancreatic cancer. Unfortunately, the onset of clinical symptoms in patients usually indicate advanced disease or presence of metastasis. ANALYSIS AND RESULTS: Currently, there are no designated diagnostic or screening tests for pancreatic cancer in clinical use. Thus, identifying risk groups, preclinical risk factors or surveillance strategies to facilitate early detection is a target for ongoing research. Hereditary genetic syndromes are a obvious, but small group at risk, and warrants close surveillance as suggested by society guidelines. Screening for pancreatic cancer in asymptomatic individuals is currently associated with the risk of false positive tests and, thus, risk of harms that outweigh benefits. The promise of cancer biomarkers and use of 'omics' technology (genomic, transcriptomics, metabolomics etc.) has yet to see a clinical breakthrough. Several proposed biomarker studies for early cancer detection lack external validation or, when externally validated, have shown considerably lower accuracy than in the original data. Biopsies or tissues are often taken at the time of diagnosis in research studies, hence invalidating the value of a time-dependent lag of the biomarker to detect a pre-clinical, asymptomatic yet operable cancer. New technologies will be essential for early diagnosis, with emerging data from image-based radiomics approaches, artificial intelligence and machine learning suggesting avenues for improved detection. CONCLUSIONS: Early detection may come from analytics of various body fluids (eg 'liquid biopsies' from blood or urine). In this review we present some the technological platforms that are explored for their ability to detect pancreatic cancer, some of which may eventually change the prospects and outcomes of patients with pancreatic cancer.
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Detección Precoz del Cáncer , Neoplasias Pancreáticas , Humanos , Inteligencia Artificial , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/genética , Factores de Riesgo , Neoplasias PancreáticasRESUMEN
Almost half of all patients with colorectal cancer present with or eventually develop metastasis, most frequently in the liver. Understanding the histopathological growth patterns and tumor immune microenvironment of colorectal liver metastases may help determine treatment strategies and assess prognosis. A literature search was conducted to gather information on cancer biology, histopathological growth patterns, and the tumor immune microenvironment in colorectal liver metastases, including their mechanisms and their impact on clinical outcomes. A first consensus on histopathological growth patterns emerged in 2017, identifying five growth patterns. Later studies found benefits from a two-tier system, desmoplastic and non-desmoplastic, incorporated into the updated 2022 consensus. Furthermore, the tumor immune microenvironment shows additional characteristic features with relevance to cancer biology. This includes density of T-cells (CD8+), expression of claudin-2, presence of vessel co-option versus angiogenesis, as well as several other factors. The relation between histopathological growth patterns and the tumor immune microenvironment delineates distinct subtypes of cancer biology. The distinct subtypes are found to correlate with risk of metastasis or relapse, and hence to clinical outcome and long-term survival in each patient. In order to optimize personalized and precision therapy for patients with colorectal liver metastases, further investigation into the mechanisms of cancer biology and their translational aspects to novel treatment targets is warranted.
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Background and Objectives: Endometrial hyperplasia (EH) is a precursor lesion to endometrial cancer (EC), and when cellular atypia is present, in 40% of cases, they are diagnosed with EC on hysterectomy. Usually, EH is clinically manifested by uterine bleeding. In patients with oral anticoagulant therapy (OAT), the uterus is the second most common source of bleeding. The aim of the study was to show that uterine bleeding in postmenopausal patients undergoing OAT may reveal precancerous endometrial lesions with atypia, or neoplastic lesions in patients with an initial diagnosis of endometrial hyperplasia without atypia (non-atypical endometrial hyperplasia, NAEH) on dilation and curettage (D&C). We will be able to estimate the risk of a postmenopausal female patient with uterine bleeding during an OAT to have a precancerous endometrial lesion. Materials and Methods: The subjects of the study were 173 female patients with uterine bleeding, who have had total hysterectomy with bilateral salpingoovarectomy, of whom 99 underwent an OAT. There were 101 female patients initially diagnosed with NAEH, of which 60 did not have anticoagulant treatment (mean age 57.36 ± 6.51) and 41 had anticoagulant treatment (mean age 60.39 ± 7.35) (p = 0.006). From the pathology diagnosis moment, the surgery was performed at 42.09 ± 14.54 days in patients without OAT and after 35.39 ± 11.29 days in those who received such treatment (p = 0.724). Results: Initial diagnosis of NAEH established at D&C was changed at the final diagnosis after hysterectomy in EH with cellular atypia (atypical endometrial hyperplasia AEH) or EC in 18.18% of patients without OAT, and in 40.54% of patients who received this treatment. Conclusions: Based on a logistic regression model, it is estimated that female patients with an initial histopathological diagnosis of NAEH and who underwent OAT have, on average, 4.85 times greater odds (OR = 4.85, 95% CI 1.79-14.06) than the others of being identified postoperatively with more advanced lesions.
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Hiperplasia Endometrial , Neoplasias Endometriales , Anciano , Anticoagulantes/efectos adversos , Hiperplasia Endometrial/diagnóstico , Hiperplasia Endometrial/cirugía , Femenino , Humanos , Histerectomía , Persona de Mediana Edad , Posmenopausia , Estudios Retrospectivos , Hemorragia Uterina/etiología , Hemorragia Uterina/cirugíaRESUMEN
The long-term survival of a species requires, among other things, gene flow between populations. Approaches for the evaluation of fragmentation in the frame of freshwater habitats consider only a small amount of the information that combined demography and geography are currently able to provide. This study addresses two species of Austropotamobius crayfish in the light of population genetics, spatial ecology and protected areas of the Carpathians. Advancing the classical approaches, we defined ecological distances upon the rasterised river network as a surrogate of habitat resistance to migration, quantifying the deviations from the species´ suitability range for a set of relevant geospatial variables in each cell of the network. Molecular analyses revealed the populations of the two Austropotamobius crayfish species are clearly distinct, lacking hybridisation. Comparing pairs of populations, we found, in some cases, a strong disagreement regarding genetic and ecological distances, potentially due to human-mediated translocations or the geophysical phenomena of regressive erosion, which may have led to unexpected colonisation routes. Protected areas were found to offer appropriate local habitat conditions but failed to ensure connectivity. The methodology applied in this study allowed us to quantify the contribution of each geospatial (environmental) variable to the overall effect of fragmentation, and we found that water quality was the most important variable. A multilevel approach proved to reveal a better understanding of drivers behind the distribution patterns, which can lead to more adequate conservation measures.
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Astacoidea/clasificación , Astacoidea/genética , Conservación de los Recursos Naturales/métodos , Ecosistema , Especies en Peligro de Extinción , Animales , Genética de Población , Geografía , Ríos , Especificidad de la EspecieRESUMEN
Crayfish can be used as model organisms in phylogeographic and divergence time studies if reliable calibrations are available. This study presents a comprehensive investigation into the phylogeography of the European stone crayfish (Austropotamobius torrentium) and includes samples from previously unstudied sites. Two mitochondrial markers were used to reveal evolutionary relationships among haplogroups throughout the species' distributional range and to estimate the divergence time by employing both substitution rates and geological calibration methods. Our haplotype network reconstruction and phylogenetic analyses revealed the existence of a previously unknown haplogroup distributed in Romania's Apuseni Mountains. This haplogroup is closely related to others that are endemic in the Dinarides, despite their vast geographical separation (~600 km). The separation is best explained by the well-dated tectonic displacement of the Tisza-Dacia microplate, which started in the Miocene (~16 Ma) and possibly carried part of the A. torrentium population to the current location of the Apuseni Mountains. This population may thus have been isolated from the Dinarides for a period of ca. 11 m.y. by marine and lacustrine phases of the Pannonian Basin. The inclusion of this geological event as a calibration point in divergence time analyses challenges currently accepted crayfish evolutionary time frames for the region, constraining the evolution of this area's crayfish to a much earlier date. We discuss why molecular clock calibrations previously employed to date European crayfish species divergences should therefore be reconsidered.
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Enfermedad de Whipple/diagnóstico , Anciano , Artralgia/microbiología , Artritis Reumatoide/diagnóstico , Diagnóstico Diferencial , Diarrea/microbiología , Femenino , Humanos , Persona de Mediana Edad , Tropheryma/aislamiento & purificación , Enfermedad de Whipple/complicaciones , Enfermedad de Whipple/tratamiento farmacológico , Enfermedad de Whipple/patologíaRESUMEN
The present study was undertaken to investigate the expression of prostate-specific membrane antigen (PSMA) in normal breast tissues, in cancerous breast tissues and in distant metastases from patients with breast cancer. Immunohistochemical analysis was performed to determine PSMA expression and angiogenic activity using anti-PSMA mAb and anti-CD31 mAb respectively. Immunofluorescence staining was applied to confirm the exact co-localization of PSMA and CD31. We observed different patterns of PSMA expression between normal and cancerous tissues. Normal breast tissues showed PSMA expression only in normal glandular cells. However, primary breast tumors and distant metastases showed PSMA expression in tumor cells and in tumor-associated neovasculature. PSMA score group status in primary breast tumors was significantly associated with histologic type and tumor grade (p = 0.026 and p = 0.004 respectively). Distant metastases showed higher PSMA expression in tumor-associated neovasculature comparing with primary tumors. Moreover, brain tumor-associated neovasculture had significantly higher expression of PSMA comparing with bone tumor-associated neovasculture. The localized binding of PSMA mAb to the neovasculature endothelium was confirmed with the double Immunofluorescence staining. 68Ga-PSAM imaging of a patient with metastatic breast cancer showed strong tracer uptake in all known skeletal metastases. To the best of our knowledge, this study is the second one that has assessed PSMA expression in a large number of breast cancer patients. Our findings showed that PSMA is particularly expressed in tumor-associated neovasculature of breast tumors and its distant metastases, thus enhancing the evidence on the potential usefulness of PSMA as a therapeutic vascular target.
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Antígenos de Superficie/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias Óseas/secundario , Neoplasias Encefálicas/secundario , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Carcinoma Lobular/patología , Glutamato Carboxipeptidasa II/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Óseas/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/metabolismo , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Persona de Mediana Edad , Invasividad Neoplásica , PronósticoRESUMEN
Invasion is one of the most consequential phenomena affecting the distribution of native species. Few in number of species, European crayfish are losing the competition with introduced North American crayfish. The spiny-cheek crayfish, Orconectes limosus, is an outstanding example, successfully competing against the native narrow-clawed crayfish, Astacus leptodactylus. For four years, we collected data regarding crayfish occurrences, their relative abundance, and the structure of populations in the ongoing colonisation process of O. limosus in the lower Danube. The mature females of both invasive and indigenous crayfish species were analysed with respect to biometry and production of oocytes in relation to the dynamics of invasion. The interspecific comparisons showed no significant differences regarding body size, with an average of approximately 102 mm total length and 31 g wet weight for both species. However, the fecundity of the indigenous species was found to be constant throughout the investigated area, whereas the number of eggs produced by the invasive females was significantly increased at the active front of the invasion. The maximum number of ovarian eggs found was 887 and 1156 in the indigenous species and the invasive species, respectively. We propose the scenario that the invasive species, which carries the deadly crayfish plague, creates an ecological advantage by reducing the populations of indigenous crayfish. Subsequently, the invasive females opportunistically use the available resources to enhance their fecundity, resulting in the acute growth of populations. However, the long-term competitiveness and colonisation success of O. limosus still remain in question.