RESUMEN
Adoptive T cell therapies have produced exceptional responses in a subset of patients with cancer. However, therapeutic efficacy can be hindered by poor T cell persistence and function1. In human T cell cancers, evolution of the disease positively selects for mutations that improve fitness of T cells in challenging situations analogous to those faced by therapeutic T cells. Therefore, we reasoned that these mutations could be co-opted to improve T cell therapies. Here we systematically screened the effects of 71 mutations from T cell neoplasms on T cell signalling, cytokine production and in vivo persistence in tumours. We identify a gene fusion, CARD11-PIK3R3, found in a CD4+ cutaneous T cell lymphoma2, that augments CARD11-BCL10-MALT1 complex signalling and anti-tumour efficacy of therapeutic T cells in several immunotherapy-refractory models in an antigen-dependent manner. Underscoring its potential to be deployed safely, CARD11-PIK3R3-expressing cells were followed up to 418 days after T cell transfer in vivo without evidence of malignant transformation. Collectively, our results indicate that exploiting naturally occurring mutations represents a promising approach to explore the extremes of T cell biology and discover how solutions derived from evolution of malignant T cells can improve a broad range of T cell therapies.
Asunto(s)
Evolución Molecular , Inmunoterapia Adoptiva , Linfoma Cutáneo de Células T , Mutación , Linfocitos T , Humanos , Proteínas Adaptadoras de Señalización CARD/genética , Proteínas Adaptadoras de Señalización CARD/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Citocinas/biosíntesis , Citocinas/inmunología , Citocinas/metabolismo , Guanilato Ciclasa/genética , Guanilato Ciclasa/metabolismo , Inmunoterapia Adoptiva/métodos , Linfoma Cutáneo de Células T/genética , Linfoma Cutáneo de Células T/inmunología , Linfoma Cutáneo de Células T/patología , Linfoma Cutáneo de Células T/terapia , Fosfatidilinositol 3-Quinasas , Transducción de Señal/genética , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/trasplanteRESUMEN
Systemic lupus erythematosus (SLE) is prototypical autoimmune disease driven by pathological T cell-B cell interactions1,2. Expansion of T follicular helper (TFH) and T peripheral helper (TPH) cells, two T cell populations that provide help to B cells, is a prominent feature of SLE3,4. Human TFH and TPH cells characteristically produce high levels of the B cell chemoattractant CXCL13 (refs. 5,6), yet regulation of T cell CXCL13 production and the relationship between CXCL13+ T cells and other T cell states remains unclear. Here, we identify an imbalance in CD4+ T cell phenotypes in patients with SLE, with expansion of PD-1+/ICOS+ CXCL13+ T cells and reduction of CD96hi IL-22+ T cells. Using CRISPR screens, we identify the aryl hydrocarbon receptor (AHR) as a potent negative regulator of CXCL13 production by human CD4+ T cells. Transcriptomic, epigenetic and functional studies demonstrate that AHR coordinates with AP-1 family member JUN to prevent CXCL13+ TPH/TFH cell differentiation and promote an IL-22+ phenotype. Type I interferon, a pathogenic driver of SLE7, opposes AHR and JUN to promote T cell production of CXCL13. These results place CXCL13+ TPH/TFH cells on a polarization axis opposite from T helper 22 (TH22) cells and reveal AHR, JUN and interferon as key regulators of these divergent T cell states.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Linfocitos T CD4-Positivos , Quimiocina CXCL13 , Interferón Tipo I , Lupus Eritematoso Sistémico , Proteínas Proto-Oncogénicas c-jun , Receptores de Hidrocarburo de Aril , Femenino , Humanos , Masculino , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Diferenciación Celular , Quimiocina CXCL13/metabolismo , Epigenómica , Perfilación de la Expresión Génica , Interferón Tipo I/inmunología , Interferón Tipo I/metabolismo , Interleucina-22/inmunología , Interleucina-22/metabolismo , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/metabolismo , Lupus Eritematoso Sistémico/genética , Proteínas Proto-Oncogénicas c-jun/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismoRESUMEN
Adult T-cell leukemia-lymphoma (ATLL) is an aggressive Human T-cell Leukemia Virus Type 1 (HTLV-1)-driven malignancy. Although Western hemisphere (Afro-Caribbean and South American) patients face worse prognoses, our understanding of ATLL molecular drivers derives mostly from Japanese studies. We performed multi-omic analyses to elucidate the genomic landscape of ATLL in Western cohorts. Recurrent deletion and/or damaging mutations involving FOXO3, ANKRD11, DGKZ, and PTPN6 implicate these genes as potential tumor suppressors. RNA-seq, published functional data and in vitro assays support the roles of ANKRD11 and FOXO3 as regulators of T-cell proliferation and apoptosis in ATLL, respectively. Survival data suggest ANKRD11 mutation may confer a worse prognosis. Japanese and Western cohorts, in addition to acute and lymphomatous subtypes, demonstrated distinct molecular patterns. GATA3 deletion was associated with unfavorable chronic cases. IRF4 and CARD11 mutations frequently emerged in relapses after interferon therapy. Our findings reveal novel putative ATLL driver genes and clinically relevant differences between Japanese and Western ATLL patients.
RESUMEN
BACKGROUND: Approximately 15% of patients experience post-hepatectomy liver failure after major hepatectomy. Poor hepatocyte uptake of gadoxetate disodium, a magnetic resonance imaging contrast agent, may be a predictor of post-hepatectomy liver failure. METHODS: A retrospective cohort study of patients undergoing major hepatectomy (≥3 segments) with a preoperative gadoxetate disodium-enhanced magnetic resonance imaging was conducted. The liver signal intensity (standardized to the spleen) and the functional liver remnant was calculated to determine if this can predict post-hepatectomy liver failure after major hepatectomy. RESULTS: In 134 patients, low signal intensity of the remnant liver standardized by signal intensity of the spleen in post-contrast images was associated with post-hepatectomy liver failure in multiple logistic regression analysis (Odds Ratio 0.112; 95% CI 0.023-0.551). In a subgroup of 33 patients with lower quartile of functional liver remnant, area under the curve analysis demonstrated a diagnostic accuracy of functional liver remnant to predict post-hepatectomy liver failure of 0.857 with a cut-off value for functional liver remnant of 1.4985 with 80.0% sensitivity and 89.3% specificity. CONCLUSION: Functional liver remnant determined by gadoxetate disodium-enhanced magnetic resonance imaging is a predictor of post-hepatectomy liver failure which may help identify patients for resection, reducing morbidity and mortality.
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Medios de Contraste , Gadolinio DTPA , Hepatectomía , Fallo Hepático , Imagen por Resonancia Magnética , Valor Predictivo de las Pruebas , Humanos , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Fallo Hepático/etiología , Fallo Hepático/diagnóstico por imagen , Anciano , Factores de Riesgo , Resultado del Tratamiento , AdultoRESUMEN
Cutaneous T-cell lymphomas (CTCLs) are a clinically heterogeneous collection of lymphomas of the skin-homing T cell. To identify molecular drivers of disease phenotypes, we assembled representative samples of CTCLs from patients with diverse disease subtypes and stages. Via DNA/RNA-sequencing, immunophenotyping, and ex vivo functional assays, we identified the landscape of putative driver genes, elucidated genetic relationships between CTCLs across disease stages, and inferred molecular subtypes in patients with stage-matched leukemic disease. Collectively, our analysis identified 86 putative driver genes, including 19 genes not previously implicated in this disease. Two mutations have never been described in any cancer. Functionally, multiple mutations augment T-cell receptor-dependent proliferation, highlighting the importance of this pathway in lymphomagenesis. To identify putative genetic causes of disease heterogeneity, we examined the distribution of driver genes across clinical cohorts. There are broad similarities across disease stages. Many driver genes are shared by mycosis fungoides (MF) and Sezary syndrome (SS). However, there are significantly more structural variants in leukemic disease, leading to highly recurrent deletions of putative tumor suppressors that are uncommon in early-stage skin-centered MF. For example, TP53 is deleted in 7% and 87% of MF and SS, respectively. In both human and mouse samples, PD1 mutations drive aggressive behavior. PD1 wild-type lymphomas show features of T-cell exhaustion. PD1 deletions are sufficient to reverse the exhaustion phenotype, promote a FOXM1-driven transcriptional signature, and predict significantly worse survival. Collectively, our findings clarify CTCL genetics and provide novel insights into pathways that drive diverse disease phenotypes.
Asunto(s)
Linfoma Cutáneo de Células T/genética , Transcriptoma , Animales , Células Cultivadas , Proteína Forkhead Box M1/genética , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor , Humanos , Ratones , Mutación , Oncogenes , Proteína p53 Supresora de Tumor/genéticaRESUMEN
BACKGROUND: Pancreaticoduodenectomy is the only curative option for patients with pancreatic cancer; however, pain remains a considerable problem postoperatively. With many centres moving away from using epidural analgesia, there is the need to evaluate alternative opiate sparing techniques for postoperative analgesia. We sought to determine if rectus sheath catheters (RSCs) had an opiate sparing and analgesic effect compared with standard care alone (opiate analgesia). METHODS: We conducted a retrospective pre- and postintervention cohort study of patients undergoing pancreaticoduodenectomy at a single tertiary academic hospital in Toronto, Canada, between April 2018 and December 2019. All patients undergoing a pancreaticoduodenectomy were eligible for inclusion. Among the 101 patients identified, 84 (61 control, 23 RSCs) were analyzed after exclusion criteria were applied (epidural analgesia, admission to intensive care intubated or reintubated within the first 96 hours). The pre-intervention group received a semi-standardized course of analgesics, including intravenous hydromorphone, acetaminophen, ketamine, with or without nonsteroidal anti-inflammatory, and with or without intravenous lidocaine; the latter 2 drugs were at the individual anesthesiologist and surgeon's preference. For the postintervention group, the same course of analgesics were used, with the addition of RSCs. These were inserted at the end of the operation, with a loading dose of ropivacaine administered and followed by a programmed intermittent bolus regime for 72-96 hours. The primary outcome measure was total postoperative opiate consumption (oral morphine equivalents). Secondary outcomes included pain scores (numeric rating scale) and treatment-related adverse effects. RESULTS: Opiate consumption (oral morphine equivalents) at 96 hours was significantly lower (median 188 mg, interquartile range [IQR] 112-228 v. 242.4 mg, IQR 166.8-352) with and without RSC, respectively (p = 0.01). The RSC group used significantly less opiates at each time point from 24 hours postoperatively, with no significant difference in pain scores between the groups and no significant catheter-related complications. CONCLUSION: The use of RSCs was associated with significant reductions in postoperative opiate consumption. Given the ease of placement and management, with minimal complications, RSCs should be incorporated into a course of postoperative multimodal analgesia. A large scale randomized controlled trial should be conducted to further investigate these findings.
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Alcaloides Opiáceos , Humanos , Alcaloides Opiáceos/uso terapéutico , Analgésicos Opioides , Estudios Retrospectivos , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/etiología , Estudios de Cohortes , Pancreaticoduodenectomía/efectos adversos , Resultado del Tratamiento , Analgésicos , Morfina/uso terapéutico , Complicaciones Posoperatorias , Catéteres/efectos adversosRESUMEN
OBJECTIVE: We examined the impact of upfront small bowel resection (USBR) for metastatic small bowel neuroendocrine (SB-NET) compared to nonoperative management (NOM) on long-term healthcare utilization and survival outcomes. SUMMARY OF BACKGROUND DATA: The role of early resection of the primary tumor in metastatic SB-NET remains controversial. Conflicting data exist regarding its clinical and survival benefits. METHODS: This is a population-based retrospective matched comparative cohort study of adults diagnosed with synchronous metastatic SB-NET between 2001 and 2017 in Ontario. USBR was defined as resection within 6 months of diagnosis. Primary outcomes were subsequent unplanned acute care admissions and small bowel-related surgery. Secondary outcome was overall survival. USBR and NOM patients were matched 2:1 using a propensity-score. We used time-to-event analyses with cumulative incidencefunctions and univariate Andersen-Gill regression for primary outcomes. E value methods assessed the potential for residual confounding. RESULTS: Of 1000 patients identified, 785 had USBR. The matched cohort included 348 patients with USBR and 174 with NOM. Patients with USBR had lower 3-year risk of subsequent admissions (72.6% vs 86.4%, P < 0.001) than those with NOM, with hazard ratio 0.72 (95% confidence interval 0.570.91). USBR was associated with lower risk of subsequent small bowel-related surgery (15.4% vs 40.3%, P < 0.001), with hazard ratio 0.44 (95% confidence interval 0.29-0.67). E -values indicated it was unlikely that the observed risk estimates could be explained by an unmeasured confounder. Sensitivity analysis excluding emergent resections to define USBR did not alter the results. CONCLUSIONS: USBR for SB-NETs in the presence of metastatic disease was associated with better patient-oriented outcomes of decreased subsequent admissions and interventions, compared to NOM. USBR should be considered for metastatic SB-NETs.
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Neoplasias Intestinales , Tumores Neuroendocrinos , Adulto , Estudios de Cohortes , Humanos , Neoplasias Intestinales/cirugía , Neoplasias Pancreáticas , Estudios Retrospectivos , Neoplasias GástricasRESUMEN
INTRODUCTION: Liver metastases are common in patients with neuroendocrine neoplasms. The role of stereotactic ablative radiotherapy (SABR) is not well understood in this population. OBJECTIVE: The objective of this study was to evaluate the safety and efficacy of SABR in treating well-differentiated neuroendocrine liver metastases (WD-NELM). METHODS: A retrospective review of patients with WD-NELM treated with SABR was conducted between January 2015 and July 2019. Demographic, treatment, and clinical/radiographic follow-up data were abstracted. RECIST 1.1 criteria were applied to each individual target to evaluate the response to treatment. Local control (LC) and progression-free survival (PFS) were determined using the Kaplan-Meier methodology. Toxicity was reported according to the CTCAE v5.0. RESULTS: Twenty-five patients with a total of 53 liver metastases treated with SABR were identified. Most patients (68%) had midgut tumors, were grade 2 (80%), and had high-volume intrahepatic and/or extrahepatic disease (76%). The median number of liver metastases treated was 2, with a median size of 2.5 cm. The median radiation dose delivered was 50 Gy/5 fractions. The median follow-up was 14 months; 24 of the 25 patients were alive at the time of analysis. The objective response rate was 32%, with improvement or stability in 96% of lesions treated. The median time to best response was 9 months. The 1-year LC and PFS were 92 and 44%, respectively. No grade 3/4 acute or late toxicity was identified. CONCLUSIONS: Liver SABR is a safe and promising means of providing LC for WD-NELM. This treatment modality should be evaluated in selected patients in concert with strategies to manage systemic disease.
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Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/secundario , Tumores Neuroendocrinos/patología , Ablación por Radiofrecuencia , Técnicas Estereotáxicas , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Ablación por Radiofrecuencia/efectos adversos , Ablación por Radiofrecuencia/métodos , Ablación por Radiofrecuencia/normas , Estudios RetrospectivosRESUMEN
Pancreatic cancer, a highly aggressive tumour type with uniformly poor prognosis, exemplifies the classically held view of stepwise cancer development. The current model of tumorigenesis, based on analyses of precursor lesions, termed pancreatic intraepithelial neoplasm (PanINs) lesions, makes two predictions: first, that pancreatic cancer develops through a particular sequence of genetic alterations (KRAS, followed by CDKN2A, then TP53 and SMAD4); and second, that the evolutionary trajectory of pancreatic cancer progression is gradual because each alteration is acquired independently. A shortcoming of this model is that clonally expanded precursor lesions do not always belong to the tumour lineage, indicating that the evolutionary trajectory of the tumour lineage and precursor lesions can be divergent. This prevailing model of tumorigenesis has contributed to the clinical notion that pancreatic cancer evolves slowly and presents at a late stage. However, the propensity for this disease to rapidly metastasize and the inability to improve patient outcomes, despite efforts aimed at early detection, suggest that pancreatic cancer progression is not gradual. Here, using newly developed informatics tools, we tracked changes in DNA copy number and their associated rearrangements in tumour-enriched genomes and found that pancreatic cancer tumorigenesis is neither gradual nor follows the accepted mutation order. Two-thirds of tumours harbour complex rearrangement patterns associated with mitotic errors, consistent with punctuated equilibrium as the principal evolutionary trajectory. In a subset of cases, the consequence of such errors is the simultaneous, rather than sequential, knockout of canonical preneoplastic genetic drivers that are likely to set-off invasive cancer growth. These findings challenge the current progression model of pancreatic cancer and provide insights into the mutational processes that give rise to these aggressive tumours.
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Carcinogénesis/genética , Carcinogénesis/patología , Reordenamiento Génico/genética , Genoma Humano/genética , Modelos Biológicos , Mutagénesis/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Carcinoma in Situ/genética , Cromotripsis , Variaciones en el Número de Copia de ADN/genética , Progresión de la Enfermedad , Evolución Molecular , Femenino , Genes Relacionados con las Neoplasias/genética , Humanos , Masculino , Mitosis/genética , Mutación/genética , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Poliploidía , Lesiones Precancerosas/genéticaRESUMEN
PURPOSE: Diversion of tryptophan to tumoral hormonal production has been suggested to result in psychiatric illnesses in neuroendocrine tumors (NET). We measured the occurrence of psychiatric illness after NET diagnosis and compare it to colon cancer (CC). METHODS: We conducted a population-based retrospective cohort study. Adults with NET were matched 1:1 to CC (2000-2019). Psychiatric illness was defined by mental health diagnoses and mental health care use after a cancer diagnosis, categorized as severe, other, and none. Cumulative incidence functions accounted for death as a competing risk. RESULTS: A total of 11,223 NETs were matched to CC controls. Five-year cumulative incidences of severe psychiatric illness for NETs vs. CC was 7.7% (95%CI 7.2-8.2%) vs 7.6% (95%CI 7.2-8.2%) (p = 0.50), and that of other psychiatric illness was 32.9% (95%CI 32.0-33.9%) vs 31.6% (95%CI 30.8-32.6%) (p = 0.005). In small bowel and lung NETs, 5-year cumulative incidences of severe (8.1% [95%CI 7.3-8.9%] vs. 7.0% [95%CI 6.3-7.8%]; p = 0.01) and other psychiatric illness (34.7% [95%CI 33.3-36.1%] vs. 31.1% [95%CI 29.7-32.5%]; p < 0.01) were higher than for matched CC. The same was observed for serotonin-producing NETs for both severe (7.9% [95%CI 6.5-9.4%] vs. 6.8% [95%CI 5.5-8.2%]; p = 0.02) and other psychiatric illness (35.4% [95%CI 32.8-38.1%] vs. 31.9% [95%CI 29.3-34.4%]; p = 0.02). CONCLUSIONS: In all NETs, there was no difference observed in the incidence of psychiatric illness compared to CC. For sub-groups of small bowel and lung NETs and of serotonin-producing NETs, the incidence of psychiatric illness was higher than for CC. These data suggest a signal towards a relationship between those sub-groups of NETs and psychiatric illness.
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Neoplasias del Colon , Trastornos Mentales , Tumores Neuroendocrinos , Adulto , Humanos , Tumores Neuroendocrinos/epidemiología , Tumores Neuroendocrinos/diagnóstico , Incidencia , Estudios Retrospectivos , Serotonina , Trastornos Mentales/epidemiologíaRESUMEN
BACKGROUND: Post-operative pancreatic fistula (POPF) is the most significant cause of morbidity following distal pancreatectomy. Hemopatch™ is a thin, bovine collagen-based hemostatic sealant. We hypothesized that application of Hemopatch™ to the pancreatic stump following distal pancreatectomy would decrease the incidence of clinically-significant POPF. METHODS: We conducted a prospective, single-arm, multicentre phase II study of application of Hemopatch™ to the pancreatic stump following distal pancreatectomy. The primary outcome was clinically-significant POPF within 90 days of surgery. A sample size of 52 patients was required to demonstrate a 50% relative reduction in Grade B/C POPF from a baseline incidence of 20%, with a type I error of 0.2 and power of 0.75. Secondary outcomes included incidence of POPF (all grades), 90-day mortality, 90-day morbidity, re-interventions, and length of stay. RESULTS: Adequate fixation Hemopatch™ to the pancreatic stump was successful in all cases. The rate of grade B/C POPF was 25% (95%CI: 14.0-39.0%). There was no significant difference in the incidence of grade B/C POPF compared to the historical baseline (p = 0.46). The 90-day incidence of Clavien-Dindo grade ≥3 complications was 26.9% (95%CI: 15.6-41.0%). CONCLUSION: The use of Hemopatch™ was not associated with a decreased incidence of clinically-significant POPF compared to historical rates. (NCT03410914).
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Pancreatectomía , Fístula Pancreática , Animales , Bovinos , Humanos , Páncreas , Pancreatectomía/efectos adversos , Fístula Pancreática/epidemiología , Fístula Pancreática/etiología , Fístula Pancreática/prevención & control , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/prevención & control , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
BACKGROUND: Administration of chemotherapy to patients with colorectal liver metastases may result in disappearing liver metastases (DLM). This poses a therapeutic dilemma due to the uncertainty of true complete (pathological) response. OBJECTIVE: We aimed to examine the diagnostic performance of imaging modalities in detecting true complete response in patients with DLM after chemotherapy. METHODS: We performed a systematic search for articles assessing the diagnostic performance of imaging modalities in evaluating DLM following chemotherapy. True complete response was defined as 1-year recurrence-free survival in non-resected patients or complete pathological response on histologic examination in resected patients. We calculated the negative predictive value (NPV) for detecting true complete response of each imaging modality using a random effects model. RESULTS: Thirteen studies comprising 332 patients with at least one DLM were included. The number of DLMs after chemotherapy was 955 with computed tomography (CT), 104 with positron emission tomography (PET), 50 with intraoperative ultrasound (IOUS), 585 with magnetic resonance imaging (MRI), and 175 with contrast-enhanced IOUS (CEIOUS). Substantial variation in study design, patient characteristics, and imaging features was observed. Pooled NPV was 0.79 (95% confidence interval [CI] 0.53-0.96), 0.73 (95% CI 0.58-0.85), 0.54 (95% CI 0.37-0.7), 0.47 (95% CI 0.34-0.61), and 0.22 (95% CI 0.11-0.39) for CEIOUS, MRI, IOUS, CT, and PET, respectively. CONCLUSION: After chemotherapy, MRI or CEIOUS are the most accurate imaging modalities for assessment of DLM and should be used routinely in this context. Given the high NPV of these two modalities, surgical resection of visible CRLM is warranted if technically possible, even if DLM remain.
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Neoplasias Colorrectales , Neoplasias Hepáticas , Neoplasias Colorrectales/diagnóstico por imagen , Neoplasias Colorrectales/tratamiento farmacológico , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/tratamiento farmacológico , Imagen por Resonancia Magnética , Tomografía Computarizada por Rayos X , UltrasonografíaRESUMEN
BACKGROUND: Although patients with neuroendocrine tumors (NETs) are known to have prolonged overall survival, the contribution of cancer-specific and noncancer deaths is undefined. This study examined cancer-specific and noncancer death after NET diagnosis. METHODS: We conducted a population-based retrospective cohort study of adult patients with NETs from 2001 through 2015. Using competing risks methods, we estimated the cumulative incidence of cancer-specific and noncancer death and stratified by primary NET site and metastatic status. Subdistribution hazard models examined prognostic factors. RESULTS: Among 8,607 included patients, median follow-up was 42 months (interquartile range, 17-82). Risk of cancer-specific death was higher than that of noncancer death, at 27.3% (95% CI, 26.3%-28.4%) and 5.6% (95% CI, 5.1%-6.1%), respectively, at 5 years. Cancer-specific deaths largely exceeded noncancer deaths in synchronous and metachronous metastatic NETs. Patterns varied by primary tumor site, with highest risks of cancer-specific death in bronchopulmonary and pancreatic NETs. For nonmetastatic gastric, small intestine, colonic, and rectal NETs, the risk of noncancer death exceeded that of cancer-specific deaths. Advancing age, higher material deprivation, and metastases were independently associated with higher hazards, and female sex and high comorbidity burden with lower hazards of cancer-specific death. CONCLUSIONS: Among all NETs, the risk of dying of cancer was higher than that of dying of other causes. Heterogeneity exists by primary NET site. Some patients with nonmetastatic NETs are more likely to die of noncancer causes than of cancer causes. This information is important for counseling, decision-making, and design of future trials. Cancer-specific mortality should be included in outcomes when assessing treatment strategies.
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Neoplasias Primarias Secundarias , Tumores Neuroendocrinos , Adulto , Estudios de Cohortes , Femenino , Humanos , Incidencia , Tumores Neuroendocrinos/epidemiología , Tumores Neuroendocrinos/patología , Estudios RetrospectivosRESUMEN
While small bowel resection is well established as standard of care for curative-intent management of localized and loco-regional small bowel neuroendocrine tumors (SB-NETs), resection of the primary tumor in the setting of metastatic disease is debated. This review addresses the role of primary tumor resection for stage IV well-differentiated grade 1 and 2 SB-NETs. While survival benefits have been reported for primary tumor resection in the setting of metastatic disease, these studies are limited by selection bias and thus controversial. The main clinical benefits of primary tumor resection for stage IV disease involve the prevention of potentially debilitating complications associated with mesenteric fibrosis, including intestinal obstruction, mesenteric ischemia and angina, venous congestion, malabsorption, and malnutrition. Patients with metastases undergoing initial resection of the primary SB-NETs appear to have fewer episodes of care and re-intervention for loco-regional complications than those who do not undergo resection. As recommended by the NANETS and ENETS guidelines, resection of the primary tumor for stage IV SB-NETs should be strongly considered to avoid future loco-regional complications and potentially to improve survival. All patients with stage IV SB-NETs should be assessed by a surgeon experienced in the management of NETs to consider surgical therapies, including resection of the primary tumor despite metastatic disease.
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Neoplasias Intestinales , Tumores Neuroendocrinos , Procedimientos Quirúrgicos del Sistema Digestivo , Humanos , Neoplasias Intestinales/cirugía , Intestino Delgado , Tumores Neuroendocrinos/cirugía , Neoplasias Pancreáticas , Neoplasias GástricasRESUMEN
The management of nodal disease remains controversial for small bowel neuroendocrine tumors (SB-NETs). Debates remain regarding the therapeutic role and extent of routine lymph node dissection (LND) for localized SB-NETs, as well as the need for aggressive resection of advanced loco-regional SB-NETs with mesenteric nodal masses. This review will address these questions regarding lymph node dissection for well-differentiated WHO grade 1 and 2 SB-NETs. In general, the aggressiveness and radicality of resection should be balanced against the length of bowel resected and post-operative functional outcomes. In localized SB-NETs with clinically negative lymph nodes, a nodal harvest of ≥ 8 lymph nodes provides accurate staging, but has not been shown to confer survival benefit. For loco-regional SB-NETs with clinically positive lymph nodes identified on imaging, 4 stages of nodal extent have been described: stage 1 nodes are located near to the intestinal border, stage 2 on arterial branches close to the origin of the SMA, stage 3 along the SMA itself, and stage 4 extend in the retroperitoneum under the pancreatic neck. In SB-NETs, every attempt should be made at resection of the primary tumor and the nodal mesenteric mass for curative-intent management and to prevent debilitating complications from mesenteric fibrosis. A mesenteric-sparing approach is favored to allow for resection for complex proximal nodal masses while preserving intestinal length and function. All patients with SB-NETs with nodal mesenteric mass should be assessed by a surgeon for resection; if deemed unresectable, consideration should be given to assessment in high-volume NETs centres to confirm proximal mesenteric-sparing resection is not feasible.
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Neoplasias Intestinales , Intestino Delgado/cirugía , Escisión del Ganglio Linfático/métodos , Tumores Neuroendocrinos , Humanos , Neoplasias Intestinales/patología , Neoplasias Intestinales/cirugía , Intestino Delgado/patología , Ganglios Linfáticos/patología , Ganglios Linfáticos/cirugía , Estadificación de Neoplasias , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/cirugíaRESUMEN
BACKGROUND: Red blood cell transfusions (RBCT) remain a concern for patients undergoing hepatectomy. The effect of tranexamic acid (TXA), an anti-fibrinolytic, on receipt of RBCT in colorectal liver metastases (CRLM) resection was examined. METHODS: Hepatectomies for CRLM over 2009-2014 were included. Primary outcome was 30-day receipt of RBCT. Secondary outcomes were 30-day major morbidity (Clavien-Dindo III-V) and 90-day mortality. Multivariable modelling examined the adjusted association between TXA and outcomes. RESULTS: Of 433 included patients, 146 (34%) received TXA. TXA patients were more likely to have inflow occlusion (41.8% vs. 23.1%; p < 0.01) and major hepatectomies (56.1% vs. 45.6%; p = 0.0193). TXA was independently associated with lower risk of RBCT (Relative risk (RR) 0.59; 95% confidence interval (95%CI): 0.42-0.85), but not with 30-day major morbidity (adjusted RR 1.02; 95%CI: 0.64-1.60) and 90-day mortality (univariable RR 0.99; 95%CI: 0.95-1.03). CONCLUSION: Intraoperative TXA was associated with a 41% reduction in risk of 30 -day receipt of RBCT after hepatectomy for CRLM. This finding is important to potentially improve healthcare resource allocation and patient outcomes. Pending further evidence, intraoperative TXA may be an effective method of reducing RBCT in hepatectomy for CRLM.
Asunto(s)
Antifibrinolíticos , Neoplasias Colorrectales , Neoplasias Hepáticas , Ácido Tranexámico , Antifibrinolíticos/efectos adversos , Pérdida de Sangre Quirúrgica/prevención & control , Transfusión de Eritrocitos/efectos adversos , Hepatectomía/efectos adversos , Humanos , Neoplasias Hepáticas/cirugía , Ácido Tranexámico/efectos adversosRESUMEN
BACKGROUND: Although pancreatic adenocarcinoma (PA) surgery performed by high-volume (HV) providers yields better outcomes, volume-outcome relationships are unknown for medical oncologists. This study examined variation in practice and outcomes in noncurative management of PA based on medical oncology provider volume. METHODS: This population-based cohort study linked administrative healthcare datasets and included nonresected PA from 2005 through 2016. The volume of PA consultations per medical oncology provider per year was divided into quintiles, with HV providers (≥16 patients/year) constituting the fifth quintile and low-volume (LV) providers the first to fourth quintiles. Outcomes were receipt of chemotherapy and overall survival (OS). The Brown-Forsythe-Levene (BFL) test for equality of variances was performed to assess outcome variability between provider-volume quintiles. Multivariate regression models were used to examine the association between management by HV provider and outcomes. RESULTS: A total of 7,062 patients with noncurable PA consulted with medical oncology providers. Variability was seen in receipt of chemotherapy and median survival based on provider volume (BFL, P<.001 for both), with superior 1-year OS for HV providers (30.1%; 95% CI, 27.7%-32.4%) compared with LV providers (19.7%; 95% CI, 18.5%-20.6%) (P<.001). After adjustment for age at diagnosis, sex, comorbidity burden, rural residence, income, and diagnosis period, HV provider care was independently associated with higher odds of receiving chemotherapy (odds ratio, 1.19; 95% CI, 1.05-1.34) and with superior OS (hazard ratio, 0.79; 95% CI, 0.74-0.84). CONCLUSIONS: Significant variation was seen in noncurative management and outcomes of PA based on provider volume, with management by an HV provider being independently associated with superior OS and higher odds of receiving chemotherapy. This information is important to inform disease care pathways and care organization. Cancer care systems could consider increasing the number of HV providers to reduce variation and improve outcomes.
Asunto(s)
Adenocarcinoma/terapia , Oncología Médica/métodos , Neoplasias Pancreáticas/terapia , Femenino , Humanos , Masculino , Resultado del TratamientoRESUMEN
Trinucleotide repeat (TNR) expansions in the genome cause a number of degenerative diseases. A prominent TNR expansion involves the triplet CAG in the huntingtin (HTT) gene responsible for Huntington's disease (HD). Pathology is caused by protein and RNA generated from the TNR regions including small siRNA-sized repeat fragments. An inverse correlation between the length of the repeats in HTT and cancer incidence has been reported for HD patients. We now show that siRNAs based on the CAG TNR are toxic to cancer cells by targeting genes that contain long reverse complementary TNRs in their open reading frames. Of the 60 siRNAs based on the different TNRs, the six members in the CAG/CUG family of related TNRs are the most toxic to both human and mouse cancer cells. siCAG/CUG TNR-based siRNAs induce cell death in vitro in all tested cancer cell lines and slow down tumor growth in a preclinical mouse model of ovarian cancer with no signs of toxicity to the mice. We propose to explore TNR-based siRNAs as a novel form of anticancer reagents.
Asunto(s)
Proteína Huntingtina/genética , Neoplasias/genética , ARN Interferente Pequeño/farmacología , Repeticiones de Trinucleótidos/genética , Animales , Línea Celular Tumoral , Proliferación Celular/genética , Modelos Animales de Enfermedad , Humanos , Proteína Huntingtina/antagonistas & inhibidores , Enfermedad de Huntington/genética , Enfermedad de Huntington/patología , Ratones , Neoplasias/patología , Neoplasias/terapia , Sistemas de Lectura Abierta , ARN Interferente Pequeño/genética , Expansión de Repetición de Trinucleótido/genética , Repeticiones de Trinucleótidos/efectos de los fármacosRESUMEN
BACKGROUND: How to best support patients with neuroendocrine tumors (NETs) remains unclear. Improving quality of care requires an understanding of symptom trajectories. Objective validated assessments of symptoms burden over the course of disease are lacking. This study examined patterns and risk factors of symptom burden in NETs, using patient-reported outcomes. SUBJECTS, MATERIALS, AND METHODS: A retrospective, population-based, observational cohort study of patients with NETs diagnosed from 2004 to 2015, who survived at least 1 year, was conducted. Prospectively collected patient-reported Edmonton Symptom Assessment System scores were linked to provincial administrative health data sets. Moderate-to-severe symptom scores were presented graphically for both the 1st year and 5 years following diagnosis. Multivariable Poisson regression identified factors associated with record of moderate-to-severe symptom scores during the 1st year after diagnosis. RESULTS: Among 2,721 included patients, 7,719 symptom assessments were recorded over 5 years following diagnosis. Moderate-to-severe scores were most frequent for tiredness (40%-51%), well-being (37%-49%), and anxiety (30%-40%). The proportion of moderate-to-severe symptoms was stable over time. Proportion of moderate-to-severe anxiety decreased by 10% within 6 months of diagnosis, followed by stability thereafter. Changes were below 5% for other symptoms. Similar patterns were observed for the 1st year after diagnosis. Primary tumor site, metastatic disease, younger age, higher comorbidity burden, lower socioeconomic status, and receipt of therapy within 30 days of assessment were independently associated with higher risk of elevated symptom burden. CONCLUSION: Patients with NETs have a high prevalence of moderate-to-severe patient-reported symptoms, with little change over time. Patients remain at risk of prolonged symptom burden following diagnosis, highlighting potential unmet needs. Combined with identified patient and disease factors associated with moderate-to-severe symptom scores, this information is important to support symptom management strategies to improve patient-centered care. IMPLICATIONS FOR PRACTICE: This study used population-level, prospectively collected, validated, patient-reported outcome measures to appraise the symptoms burden and trajectory of patients with neuroendocrine tumors (NETs) after diagnosis. It is the largest and most detailed analysis of patient-reported symptoms for NETs. Patients with NETs present a high burden of symptoms at diagnosis that persists up to 5 years later, highlighting unmet needs. Early and comprehensive symptom screening and management programs are needed. This information should serve to devise pathways and policies to better support patients, evaluate supportive interventions, and assess the effectiveness of symptom management at the provider, institutional, and system levels.