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Introduction: Younger patients with non-small cell lung cancer (NSCLC) (<50 years) represent a significant patient population with distinct clinicopathological features and enriched targetable genomic alterations compared to older patients. However, previous studies of younger NSCLC suffer from inconsistent findings, few studies have incorporated sex into their analyses, and studies targeting age-related differences in the tumor immune microenvironment are lacking. Methods: We performed a retrospective analysis of 8,230 patients with NSCLC, comparing genomic alterations and immunogenic markers of younger and older patients while also considering differences between male and female patients. We defined older patients as those ≥65 years and used a 5-year sliding threshold from <45 to <65 years to define various groups of younger patients. Additionally, in an independent cohort of patients with NSCLC, we use our observations to inform testing of the combinatorial effect of age and sex on survival of patients given immunotherapy with or without chemotherapy. Results: We observed distinct genomic and immune microenvironment profiles for tumors of younger patients compared to tumors of older patients. Younger patient tumors were enriched in clinically relevant genomic alterations and had gene expression patterns indicative of reduced immune system activation, which was most evident when analyzing male patients. Further, we found younger male patients treated with immunotherapy alone had significantly worse survival compared to male patients ≥65 years, while the addition of chemotherapy reduced this disparity. Contrarily, we found younger female patients had significantly better survival compared to female patients ≥65 years when treated with immunotherapy plus chemotherapy, while treatment with immunotherapy alone resulted in similar outcomes. Discussion: These results show the value of comprehensive genomic and immune profiling (CGIP) for informing clinical treatment of younger patients with NSCLC and provides support for broader coverage of CGIP for younger patients with advanced NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Microambiente Tumoral , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/terapia , Masculino , Femenino , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/terapia , Persona de Mediana Edad , Anciano , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Factores de Edad , Estudios Retrospectivos , Factores Sexuales , Adulto , Genómica/métodos , Biomarcadores de Tumor/genética , Perfilación de la Expresión Génica , InmunoterapiaRESUMEN
Background: KEYNOTE-522 resulted in FDA approval of the immune checkpoint inhibitor pembrolizumab in combination with neoadjuvant chemotherapy for patients with early-stage, high-risk, triple-negative breast cancer (TNBC). Unfortunately, pembrolizumab is associated with several immune-related adverse events (irAEs). We aimed to identify potential tumor microenvironment (TME) biomarkers which could predict patients who may attain pathological complete response (pCR) with chemotherapy alone and be spared the use of anti-PD-1 immunotherapy. Methods: Comprehensive immune profiling, including RNA-seq gene expression assessment of 395 immune genes, was performed on matched FFPE tumor samples from 22 stage I-III TNBC patients (14 patients treated with neoadjuvant chemotherapy alone (NAC) and 8 treated with neoadjuvant chemotherapy combined with pembrolizumab (NAC+I)). Results: Differential gene expression analysis revealed that in the NAC group, IL12B and IL13 were both significantly associated with pCR. In the NAC+I group, LCK and TP63 were significantly associated with pCR. Patients in both treatment groups exhibiting pCR tended to have greater tumor inflammation than non-pCR patients. In the NAC+I group, patients with pCR tended to have greater cell proliferation and higher PD-L1 expression, while in the NAC group, patients with pCR tended to have lower cancer testis antigen expression. Additionally, the NAC+I group trended toward a lower relative dose intensity averaged across all chemotherapy drugs, suggesting that more dose reductions or treatment delays occurred in the NAC+I group than the NAC group. Conclusions: A comprehensive understanding of immunologic factors could potentially predict pCR to chemotherapy alone, enabling the avoidance of the unnecessary treatment of these patients with checkpoint inhibitors.
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INTRODUCTION: Tissue-based broad molecular profiling of guideline-recommended biomarkers is advised for the therapeutic management of patients with non-small cell lung cancer (NSCLC). However, practice variation can affect whether all indicated biomarkers are tested. We aimed to evaluate the impact of common single-gene testing (SGT) on subsequent comprehensive genomic profiling (CGP) test outcomes and results in NSCLC. METHODS: Oncologists who ordered SGT for guideline-recommended biomarkers in NSCLC patients were prospectively contacted (May-December 2022) and offered CGP (DNA and RNA sequencing), either following receipt of negative SGT findings, or instead of SGT for each patient. We describe SGT patterns and compare CGP completion rates, turnaround time, and recommended biomarker detection for NSCLC patients with and without prior negative SGT results. RESULTS: Oncologists in > 80 community practices ordered CGP for 561 NSCLC patients; 135 patients (27%) first had negative results from 30 different SGT combinations; 84% included ALK, EGFR and PD-L1, while only 3% of orders included all available SGTs for guideline-recommended genes. Among patients with negative SGT results, CGP was attempted using the same tissue specimen 90% of the time. There were also significantly more CGP order cancellations due to tissue insufficiency (17% vs. 7%), DNA sequencing failures (13% vs. 8%), and turnaround time > 14 days (62% vs. 29%) than among patients who only had CGP. Forty-six percent of patients with negative prior SGT had positive CGP results for recommended biomarkers, including targetable genomic variants in genes beyond ALK and EGFR, such as ERBB2, KRAS (non-G12C), MET (exon 14 skipping), NTRK2/3, and RET . CONCLUSION: For patients with NSCLC, initial use of SGT increases subsequent CGP test cancellations, turnaround time, and the likelihood of incomplete molecular profiling for guideline-recommended biomarkers due to tissue insufficiency.
Patients with non-small cell lung cancer (NSCLC) should have their tumor tissue tested for all recommended biomarkers that can help identify their best treatment options. Traditional tests look at gene biomarkers one by one (single-gene testing), and doctors can order some or all these tests individually or in a group. However, some recommended biomarkers cannot be tested by traditional single-gene tests at all. Newer technology (next-generation sequencing) covers all current recommended treatment biomarkers in one test (comprehensive genomic profiling), but this testing is more expensive and can take more time. Our study shows that NSCLC patients do not get all recommended treatment biomarkers tested when a single-gene testing approach is taken. Single-gene testing also used up some patients' tumor tissue entirely, such that further testing by comprehensive genomic profiling could not be done at all (17% vs. 7% for patients with no prior single-gene tests), resulted in more sequencing failures (13% vs. 8%), and had turnaround time for results greater than 14 days for more patients (62% vs. 29%). When comprehensive genomic profiling was completed, 46% of patients with negative results from prior single-gene testing had positive results for recommended treatment biomarkers that were not included in the initial single-gene tests. To ensure that NSCLC patients receive testing for all recommended biomarkers, comprehensive genomic profiling must be performed first.
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BACKGROUND: Cancer-testis antigens (CTAs) are tumor antigens that are normally expressed in the testes but are aberrantly expressed in several cancers. CTA overexpression drives the metastasis and progression of lung cancer, and is associated with poor prognosis. To improve lung cancer diagnosis, prognostic prediction, and drug discovery, robust CTA identification and quantitation is needed. In this study, we examined and quantified the co-expression of CTAs in lung cancer to derive cancer testis antigen burden (CTAB), a novel biomarker of immunotherapy response. METHODS: Formalin fixed paraffin embedded (FFPE) tumor samples in discovery cohort (n = 5250) and immunotherapy and combination therapy treated non-small cell lung cancer (NSCLC) retrospective (n = 250) cohorts were tested by comprehensive genomic and immune profiling (CGIP), including tumor mutational burden (TMB) and the mRNA expression of 17 CTAs. PD-L1 expression was evaluated by IHC. CTA expression was summed to derive the CTAB score. The median CTAB score for the discovery cohort of 170 was applied to the retrospective cohort as cutoff for CTAB "high" and "low". Biomarker and gene expression correlation was measured by Spearman correlation. Kaplan-Meier survival analyses were used to detect overall survival (OS) differences, and objective response rate (ORR) based on RECIST criteria was compared using Fisher's exact test. RESULTS: The CTAs were highly co-expressed (p < 0.05) in the discovery cohort. There was no correlation between CTAB and PD-L1 expression (R = 0.011, p = 0.45) but some correlation with TMB (R = 0.11, p = 9.2 × 10-14). Kaplan-Meier survival analysis of the immunotherapy-treated NSCLC cohort revealed better OS for the pembrolizumab monotherapy treated patients with high CTAB (p = 0.027). The combination group demonstrated improved OS compared to pembrolizumab monotherapy group (p = 0.04). The pembrolizumab monotherapy patients with high CTAB had a greater ORR than the combination therapy group (p = 0.02). CONCLUSIONS: CTA co-expression can be reliably measured using CGIP in solid tumors. As a biomarker, CTAB appears to be independent from PD-L1 expression, suggesting that CTAB represents aspects of tumor immunogenicity not measured by current standard of care testing. Improved OS and ORR for high CTAB NSCLC patients treated with pembrolizumab monotherapy suggests a unique underlying aspect of immune response to these tumor antigens that needs further investigation.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Masculino , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Antígeno B7-H1/metabolismo , Cetrimonio/uso terapéutico , Estudios Retrospectivos , Testículo/química , Testículo/metabolismo , Testículo/patología , Antígenos de Neoplasias , Biomarcadores de Tumor/genéticaRESUMEN
OBJECTIVE: This multi-center cohort study assessed associations between race, TP53 mutations, p53 expression, and histology to investigate racial survival disparities in endometrial cancer (EC). METHODS: Black and White patients with advanced or recurrent EC with Next Generation Sequencing data in the Endometrial Cancer Molecularly Targeted Therapy Consortium database were identified. Clinicopathologic and treatment variables were summarized by race and compared. Overall survival (OS) and progression-free survival (PFS) among all patients were estimated by the Kaplan-Meier method. Cox proportional hazards models estimated the association between race, TP53 status, p53 expression, histology, and survival outcomes. RESULTS: Black patients were more likely than White patients to have TP53-mutated (N = 727, 71.7% vs 49.7%, p < 0.001) and p53-abnormal (N = 362, 71.1% vs 53.2%, p = 0.003) EC. Patients with TP53-mutated EC had worse PFS (HR 2.73 (95% CI 1.88-3.97)) and OS (HR 2.20 (95% CI 1.77-2.74)) compared to those with TP53-wildtype EC. Patients with p53-abnormal EC had worse PFS (HR 2.01 (95% CI 1.22-3.32)) and OS (HR 1.61 (95% CI 1.18-2.19)) compared to those with p53-wildtype EC. After adjusting for TP53 mutation and p53 expression, race was not associated with survival outcomes. The most frequent TP53 variants were at nucleotide positions R273 (n = 54), R248 (n = 38), and R175 (n = 23), rates of which did not differ by race. CONCLUSIONS: Black patients are more likely to have TP53-mutated and p53-abnormal EC, which are associated with worse survival outcomes than TP53- and p53-wildtype EC. The higher frequency of these subtypes among Black patients may contribute to survival disparities.
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Neoplasias Endometriales , Proteína p53 Supresora de Tumor , Femenino , Humanos , Estudios de Cohortes , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Mutación , Recurrencia Local de Neoplasia , Pronóstico , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Población Negra/genética , Población Blanca/genéticaRESUMEN
BACKGROUND: Studies conflict on how acute versus chronic placental pathology impacts outcomes after neonatal encephalopathy from presumed hypoxic-ischemic encephalopathy (HIE). We examine how outcomes after presumed HIE vary by placental pathology categories. METHODS: We performed retrospective chart review for neonates with presumed HIE, regardless of severity, focusing on 50 triads for whom placental specimens were available for re-review. Placentas were categorized as having only acute, any chronic, or no lesions. Primary outcomes included in-hospital morbidity/mortality and long-term neurodevelopmental symptoms. Secondary outcomes assessed neonatal MRI and EEG. RESULTS: Demographics did not differ between groups. Forty-seven neonates were treated with therapeutic hypothermia. Placental acuity category was not associated with primary or secondary outcomes, but clinical and/or histopathological chorioamnionitis was associated with abnormal EEG background and post-neonatal epilepsy (16.7%, n = 3 with chorioamnionitis versus 0%, n = 0 without chorioamnionitis, p = 0.04). CONCLUSIONS: When grouped by acute, chronic, or absent placental lesions, we observed no association with in-hospital, neurodevelopmental, MRI, or EEG outcomes. When reanalyzed by the presence of chorioamnionitis, we found that chorioamnionitis appeared to be associated with a higher risk of EEG alterations and post-neonatal epilepsy. Despite our limited sample size, our results emphasize the critical role of placental examination for neuroprognostication in presumed HIE. IMPACT: Neonatal encephalopathy presumed to result from impaired fetal cerebral oxygenation or blood flow is called hypoxic ischemic encephalopathy (HIE). Prior studies link placental pathology to various outcomes after HIE but disagree on the impact of acute versus chronic pathology. Our study determines that neurodevelopmental outcomes, in-hospital outcomes, injury on MRI, and EEG findings in patients with HIE are not differentially associated with acute versus chronic placental pathology. Chorioamnionitis is associated with an increased risk of abnormal EEG patterns and post-neonatal epilepsy. Histopathologic chorioamnionitis without clinical symptoms is common in HIE, emphasizing the crucial role of placental pathology for neuroprognostication.
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Corioamnionitis , Epilepsia , Hipotermia Inducida , Hipoxia-Isquemia Encefálica , Enfermedades del Recién Nacido , Recién Nacido , Humanos , Femenino , Embarazo , Placenta/patología , Corioamnionitis/patología , Estudios Retrospectivos , Enfermedades del Recién Nacido/terapia , Enfermedades del Recién Nacido/patología , Hipoxia-Isquemia Encefálica/complicaciones , Hipoxia-Isquemia Encefálica/diagnóstico por imagen , Hipoxia-Isquemia Encefálica/terapia , Epilepsia/patologíaRESUMEN
Triple-negative breast cancers (TNBC) tend to become invasive and metastatic at early stages in their development. Despite some treatment successes in early-stage localized TNBC, the rate of distant recurrence remains high, and long-term survival outcomes remain poor. In a search for new therapeutic targets for this disease, we observed that elevated expression of the serine/threonine kinase calcium/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) is highly correlated with tumor invasiveness. In validation studies, genetic disruption of CaMKK2 expression or inhibition of its activity with small molecule inhibitors disrupted spontaneous metastatic outgrowth from primary tumors in murine xenograft models of TNBC. High-grade serous ovarian cancer (HGSOC), a high-risk, poor prognosis ovarian cancer subtype, shares many features with TNBC, and CaMKK2 inhibition effectively blocked metastatic progression in a validated xenograft model of this disease. Mechanistically, CaMKK2 increased the expression of the phosphodiesterase PDE1A, which hydrolyzed cyclic guanosine monophosphate (cGMP) to decrease the cGMP-dependent activity of protein kinase G1 (PKG1). Inhibition of PKG1 resulted in decreased phosphorylation of vasodilator-stimulated phosphoprotein (VASP), which in its hypophosphorylated state binds to and regulates F-actin assembly to facilitate cell movement. Together, these findings establish a targetable CaMKK2-PDE1A-PKG1-VASP signaling pathway that controls cancer cell motility and metastasis by impacting the actin cytoskeleton. Furthermore, it identifies CaMKK2 as a potential therapeutic target that can be exploited to restrict tumor invasiveness in patients diagnosed with early-stage TNBC or localized HGSOC. SIGNIFICANCE: CaMKK2 regulates actin cytoskeletal dynamics to promote tumor invasiveness and can be inhibited to suppress metastasis of breast and ovarian cancer, indicating CaMKK2 inhibition as a therapeutic strategy to arrest disease progression.
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Neoplasias Ováricas , Neoplasias de la Mama Triple Negativas , Animales , Femenino , Humanos , Ratones , Actinas/metabolismo , Movimiento Celular , Neoplasias Ováricas/tratamiento farmacológico , Proteínas QuinasasRESUMEN
Triple-negative breast cancers (TNBCs) tend to become highly invasive early during cancer development. Despite some successes in the initial treatment of patients diagnosed with early-stage localized TNBC, the rate of metastatic recurrence remains high with poor long-term survival outcomes. Here we show that elevated expression of the serine/threonine-kinase, Calcium/Calmodulin (CaM)-dependent protein kinase kinase-2 (CaMKK2), is highly correlated with tumor invasiveness. We determined that genetic disruption of CaMKK2 expression, or inhibition of its activity, disrupted spontaneous metastatic outgrowth from primary tumors in murine xenograft models of TNBC. High-grade serous ovarian cancer (HGSOC), a high-risk, poor-prognosis ovarian cancer subtype, shares many genetic features with TNBC, and importantly, CaMKK2 inhibition effectively blocked metastatic progression in a validated xenograft model of this disease. Probing the mechanistic links between CaMKK2 and metastasis we defined the elements of a new signaling pathway that impacts actin cytoskeletal dynamics in a manner which increases cell migration/invasion and metastasis. Notably, CaMKK2 increases the expression of the phosphodiesterase PDE1A which decreases the cGMP-dependent activity of protein kinase G1 (PKG1). This inhibition of PKG1 results in decreased phosphorylation of Vasodilator-Stimulated Phosphoprotein (VASP), which in its hypophosphorylated state binds to and regulates F-actin assembly to facilitate contraction/cell movement. Together, these data establish a targetable CaMKK2-PDE1A-PKG1-VASP signaling pathway that controls cancer cell motility and metastasis. Further, it credentials CaMKK2 as a therapeutic target that can be exploited in the discovery of agents for use in the neoadjuvant/adjuvant setting to restrict tumor invasiveness in patients diagnosed with early-stage TNBC or localized HGSOC.
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Background: Uterine serous carcinomas represent 10% of uterine carcinomas but account for nearly 40% of deaths from the disease. Improved molecular characterization of these tumors is instrumental in guiding targeted treatment and improving outcomes. This study assessed the genomic instability score (GIS), tumor mutational burden (TMB), and tumor-infiltrating lymphocytes (TILs) in patients with USC. Methods: A retrospective cohort study evaluated patients with USC following staging surgery. The GIS and TMB were determined from archived specimens. We evaluated the tumoral expression of CD3, CD4, CD8, FOXP3, and CD68 using immunohistochemistry. T-tests were used to assess associations of TILs with the GIS. Results: We evaluated 53 patients with USC. The median GIS was 31 (range: 0−52) and a higher GIS was not associated with progression-free (PFS) or overall survival (OS). The median TMB was 1.35 mt/Mb; patients with TMB > 1.35 mt/Mb had improved PFS and OS (p = 0.005; p = 0.002, respectively). Tumors with increased CD3+ and CD4+ immune cells had a higher mean GIS (p = 0.013, p = 0.002). Conclusions: TMB > 1.35 mt/Mb was associated with improved survival in USC patients, whereas the GIS was not. Lower TMB thresholds may provide prognostic value for less immunogenic tumors such as USC. In this limited cohort, we observed that increased TIL populations were correlated with a higher GIS.
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The BRCA1-associated protein 1 ( BAP1 ) gene encodes a tumor suppressor that functions as a ubiquitin hydrolase involved in DNA damage repair. BAP1 germline mutations are associated with increased risk of multiple solid malignancies, including mesothelioma, uveal melanoma, renal cell carcinoma, and high-grade rhabdoid meningiomas. Here, we describe the case of a 52-yr-old woman who experienced multiple abdominal recurrences of an ovarian sex cord-stromal tumor that was originally diagnosed at age 25 and who was found to have a germline mutation in BAP1 and a family history consistent with BAP1 tumor predisposition syndrome. Recurrence of the sex cord-stromal tumor demonstrated loss of BAP1 expression by immunohistochemistry. Although ovarian sex cord-stromal tumors have been described in mouse models of BAP1 tumor predisposition syndrome, this relationship has not been previously described in humans and warrants further investigation. The case presentation, tumor morphology, and immunohistochemical findings have overlapping characteristics with peritoneal mesotheliomas, and this case represents a potential pitfall for surgical pathologists.
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Neoplasias Meníngeas , Mesotelioma , Síndromes Neoplásicos Hereditarios , Neoplasias Ováricas , Tumores de los Cordones Sexuales y Estroma de las Gónadas , Neoplasias de la Úvea , Ratones , Femenino , Animales , Humanos , Adulto , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/metabolismo , Neoplasias de la Úvea/diagnóstico , Neoplasias de la Úvea/genética , Síndromes Neoplásicos Hereditarios/genética , Mesotelioma/genética , Mesotelioma/metabolismo , Mesotelioma/patología , Mutación de Línea Germinal , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genética , Tumores de los Cordones Sexuales y Estroma de las Gónadas/diagnóstico , Tumores de los Cordones Sexuales y Estroma de las Gónadas/genética , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patología , Predisposición Genética a la Enfermedad , Proteínas Supresoras de Tumor/genéticaRESUMEN
Patients with early-onset lysosomal storage diseases are ideal candidates for prenatal therapy because organ damage starts in utero. We report the safety and efficacy results of in utero enzyme-replacement therapy (ERT) in a fetus with CRIM (cross-reactive immunologic material)-negative infantile-onset Pompe's disease. The family history was positive for infantile-onset Pompe's disease with cardiomyopathy in two previously affected deceased siblings. After receiving in utero ERT and standard postnatal therapy, the current patient had normal cardiac and age-appropriate motor function postnatally, was meeting developmental milestones, had normal biomarker levels, and was feeding and growing well at 13 months of age.
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Enfermedad del Almacenamiento de Glucógeno Tipo II , Humanos , Lactante , Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológicoRESUMEN
Locally advanced pancreatic tumours are highly resistant to conventional radiochemotherapy. Here we show that such resistance can be surmounted by an injectable depot of thermally responsive elastin-like polypeptide (ELP) conjugated with iodine-131 radionuclides (131I-ELP) when combined with systemically delivered nanoparticle albumin-bound paclitaxel. This combination therapy induced complete tumour regressions in diverse subcutaneous and orthotopic mouse models of locoregional pancreatic tumours. 131I-ELP brachytherapy was effective independently of the paclitaxel formulation and dose, but external beam radiotherapy (EBRT) only achieved tumour-growth inhibition when co-administered with nanoparticle paclitaxel. Histological analyses revealed that 131I-ELP brachytherapy led to changes in the expression of intercellular collagen and junctional proteins within the tumour microenvironment. These changes, which differed from those of EBRT-treated tumours, correlated with the improved delivery and accumulation of paclitaxel nanoparticles within the tumour. Our findings support the further translational development of 131I-ELP depots for the synergistic treatment of localized pancreatic cancer.
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Braquiterapia , Nanopartículas , Neoplasias Pancreáticas , Animales , Ratones , Elastina , Paclitaxel Unido a Albúmina , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Radioisótopos de Yodo/uso terapéutico , Biopolímeros , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/radioterapia , Péptidos , Microambiente TumoralRESUMEN
OBJECTIVE: This study compares the number of units of red blood cells (RBCs) transfused in patients with placenta accreta spectrum (PAS) treated with or without a multidisciplinary algorithm that includes placental uterine arterial embolization (P-UAE) and selective use of either immediate or delayed hysterectomy. STUDY DESIGN: This is a retrospective study of deliveries conducted at a tertiary care hospital from 2001 to 2018 with pathology-confirmed PAS. Those with previable pregnancies or microinvasive histology were excluded. To improve the equity of comparison, analyses were made separately among scheduled and unscheduled cases, therefore patients were assigned to one of four cohorts as follows: (1) scheduled/per-algorithm, (2) scheduled/off-algorithm, (3) unscheduled/per-algorithm, or (4) unscheduled/off-algorithm. Primary outcomes included RBCs transfused and estimated blood loss (EBL). Secondary outcomes included perioperative complications and disposition. RESULTS: Overall, 95 patients were identified, with 87 patients meeting inclusion criteria: 36 treated per-algorithm (30 scheduled and 6 unscheduled) and 51 off-algorithm patients (24 scheduled and 27 unscheduled). Among scheduled deliveries, 9 (30.0%) patients treated per-algorithm received RBCs compared with 20 (83.3%) patients treated off-algorithm (p < 0.01), with a median (interquartile range [IQR]) of 3.0 (2.0, 4.0) and 6.0 (2.5, 7.5) units transfused (p = 0.13), respectively. Among unscheduled deliveries, 5 (83.3%) per-algorithm patients were transfused RBCs compared with 25 (92.6%) off-algorithm patients (p = 0.47) with a median (IQR) of 4.0 (2.0, 6.0) and 8.0 (3.0, 10.0) units transfused (p = 0.47), respectively. Perioperative complications were similar between cohorts. CONCLUSION: A multidisciplinary algorithm including P-UAE and selective use of delayed hysterectomy is associated with a lower rate of blood transfusion in scheduled but not unscheduled cases. KEY POINTS: · An algorithm with delayed hysterectomy had less transfusion in scheduled, but not unscheduled, cases.. · Over time, more cases were managed per algorithm; among scheduled cases, the transfusion rate and volume transfused decreased.. · There were similar transfusion outcomes among off-algorithm cases, regardless if delivery was scheduled..
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Placenta Accreta , Pérdida de Sangre Quirúrgica , Transfusión Sanguínea , Cesárea , Femenino , Humanos , Histerectomía , Placenta , Placenta Accreta/cirugía , Embarazo , Estudios RetrospectivosRESUMEN
We describe outcomes of patients with suspected placenta percreta treated with placental uterine artery embolization (P-UAE) followed by delayed hysterectomy. This is a prospective case series of subjects from 2005 to 2018 with suspected placenta percreta who underwent P-UAE at the time of cesarean delivery followed by delayed hysterectomy. Both scheduled and unscheduled surgical cases were included. Maternal characteristics, surgical approaches, intra- and postoperative outcomes were abstracted from medical records. In total, twenty-two subjects were included. Median (interquartile range, IQR) delivery gestational age was 34.6 (31.9, 35.7) weeks, occurring as scheduled in 17 (77.3%) subjects and unscheduled in 5 (22.7%). Delayed hysterectomy was performed as scheduled in 17 (77.3%) subjects at a median (IQR) 40.5 (38.0, 44.0) days after delivery, and 5 (22.7%) subjects had a hysterectomy prior to scheduled date, median (IQR) 27.0 (17.0, 35.0) days after delivery. Indications for the 5 unscheduled hysterectomies included bleeding (n = 3) and suspected endometritis (n = 2). Three subjects (13.6%) received a blood transfusion (1, 3, 3 units) during delivery, and 7 (31.8%) were transfused during delayed hysterectomy (median [IQR] 2 [1,3] units). Three (13.6%) subjects had bladder resection at the time of hysterectomy; 1 (4.5%) had an unintentional cystotomy and 1 (4.5%) had a ureteral injury. P-UAE followed by delayed hysterectomy appears to be a safe and feasible, although appropriate patient selection and close surveillance are imperative, as 22.7% of patients underwent unscheduled hysterectomy.
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Cytosolic 10-formyltetrahydrofolate dehydrogenase (ALDH1L1) is commonly downregulated in human cancers through promoter methylation. We proposed that ALDH1L1 loss promotes malignant tumor growth. Here, we investigated the effect of the Aldh1l1 mouse knockout (Aldh1l1-/-) on hepatocellular carcinoma using a chemical carcinogenesis model. Fifteen-day-old male Aldh1l1 knockout mice and their wild-type littermate controls (Aldh1l1+/+) were injected intraperitoneally with 20 µg/g body weight of DEN (diethylnitrosamine). Mice were sacrificed 10, 20, 28, and 36 weeks post-DEN injection, and livers were examined for tumor multiplicity and size. We observed that while tumor multiplicity did not differ between Aldh1l1-/- and Aldh1l1+/+ animals, larger tumors grew in Aldh1l1-/- compared to Aldh1l1+/+ mice at 28 and 36 weeks. Profound differences between Aldh1l1-/- and Aldh1l1+/+ mice in the expression of inflammation-related genes were seen at 10 and 20 weeks. Of note, large tumors from wild-type mice showed a strong decrease of ALDH1L1 protein at 36 weeks. Metabolomic analysis of liver tissues at 20 weeks showed stronger differences in Aldh1l1+/+ versus Aldh1l1-/- metabotypes than at 10 weeks, which underscores metabolic pathways that respond to DEN in an ALDH1L1-dependent manner. Our study indicates that Aldh1l1 knockout promoted liver tumor growth without affecting tumor initiation or multiplicity.
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BACKGROUND: The aim of this study was to evaluate whether molecular classification prognosticates treatment response in women with endometrial cancers and endometrial intraepithelial neoplasia (EIN) treated with levonorgestrel intrauterine system (LNG-IUS). METHODS: Patients treated with LNG-IUS for endometrial cancer or EIN from 2013 to 2018 were evaluated. Using immunohistochemistry and single gene sequencing of POLE, patients were classified into four groups as per the Proactive Molecular Risk Classifier for Endometrial cancer (ProMisE): POLE-mutated, mismatch repair-deficient (MMRd), p53 wild type (p53wt), and p53-abnormal (p53abn). Groups were assessed relative to the primary outcome of progression or receipt of definitive treatment. RESULTS: Fifty-eight subjects with endometrioid endometrial cancer or EIN treated with LNG-IUS were included. Of these, 22 subjects (37.9%) had endometrial cancer and 36 subjects (62.1%) had EIN. Per the ProMisE algorithm, 44 patients (75.9%) were classified as p53wt, 6 (10.3%) as MMRd, 4 (6.9%) as p53abn, and 4 (6.9%) as POLE-mutated. Of the 58 patients, 11 (19.0%) progressed or opted for definitive therapy. Median time to progression or definitive therapy was 7.5 months, with p53abn tumors having the shortest time to progression or definitive therapy. CONCLUSIONS: Molecular classification of endometrial cancer and EIN prior to management with LNG-IUS is feasible and may predict patients at risk of progression.
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Management of breast cancer in limited-resource settings is hindered by a lack of low-cost, logistically sustainable approaches toward molecular and cellular diagnostic pathology services that are needed to guide therapy. To address these limitations, we have developed a multimodal cellphone-based platform-the EpiView-D4-that can evaluate both cellular morphology and molecular expression of clinically relevant biomarkers directly from fine-needle aspiration (FNA) of breast tissue specimens within 1 h. The EpiView-D4 is comprised of two components: (1) an immunodiagnostic chip built upon a "non-fouling" polymer brush-coating (the "D4") which quantifies expression of protein biomarkers directly from crude cell lysates, and (2) a custom cellphone-based optical microscope ("EpiView") designed for imaging cytology preparations and D4 assay readout. As a proof-of-concept, we used the EpiView-D4 for assessment of human epidermal growth factor receptor-2 (HER2) expression and validated the performance using cancer cell lines, animal models, and human tissue specimens. We found that FNA cytology specimens (prepared in less than 5 min with rapid staining kits) imaged by the EpiView-D4 were adequate for assessment of lesional cellularity and tumor content. We also found our device could reliably distinguish between HER2 expression levels across multiple different cell lines and animal xenografts. In a pilot study with human tissue (n = 19), we were able to accurately categorize HER2-negative and HER2-positve tumors from FNA specimens. Taken together, the EpiView-D4 offers a promising alternative to invasive-and often unavailable-pathology services and may enable the democratization of effective breast cancer management in limited-resource settings.
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Pancreatic adenocarcinoma commonly presents as metastatic disease and harbors a dire prognosis due to its aggressive behavior, propensity for resistance to therapies, and lack of targetable driver mutations. Additionally, despite advances in other cancers, immunotherapy has been ineffective in this disease thus far and treatment remains centered around cytotoxic chemotherapy. Here, we present a case of a patient with pancreatic adenocarcinoma harboring both high microsatellite instability (MSI-H) and HER2 amplification. After an initial response to standard-of-care chemotherapy with FOLFIRINOX followed by progression, she was treated with dual immune checkpoint blockade, which resulted in a period of disease control. This was complicated by the development of autoimmune hypophysitis and an incidental finding of brain metastasis on magnetic resonance imaging (MRI). Her extracranial disease progressed while receiving stereotactic radiosurgery, with findings of lymphangitic spread in her lungs, and her treatment was changed to gemcitabine/nab-paclitaxel with trastuzumab. This resulted in a degree of extracranial disease control, though she experienced progressive brain metastases despite radiation and therapeutic switch to lapatinib and trastuzumab. Ultimately, the patient developed leptomeningeal disease which was not controlled by intrathecal trastuzumab. Given the rarity of central nervous system metastasis, HER2 amplification, and MSI in pancreatic cancer, this patient's presentation represents a confluence of multiple unique features. This case highlights the clinical value of up-front next-generation sequencing in metastatic pancreatic cancer and the ability of pancreatic cancer with actionable molecular variants to develop atypical sites of disease and adaptive resistance.