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BACKGROUND: Discontinuation of the Codman 3000 pump in 2018 left no Food and Drug Administration (FDA)-approved hepatic artery infusion (HAI) device for unresectable colorectal liver metastases (uCLM) and intrahepatic cholangiocarcinoma (uIHC). Historically, HAI has been performed at academic medical centers in large metropolitan areas, which are often inaccessible to rural patients. Consequently, feasibility of dissemination of HAI to rural populations is unknown. PATIENTS AND METHODS: Under an FDA investigational device exemption, we opened the only HAI program in Kentucky and enrolled patients with uCLM and uIHC in a phase I clinical trial. The trial examined the safety of the hybrid Codman catheter/Medtronic SynchroMed II pump (hCMP) combination, defined as successful completion of one cycle of HAI chemotherapy. Rural feasibility was assessed by number of missed pump fills appointments. RESULTS: A total of 21 patients (n = 17 uCLM, n = 4 uIHC) underwent hCMP implantation before accrual was stopped early owing to FDA approval of the Intera 3000 pump. 20/21 (95%) patients met the primary safety endpoint. Serious adverse events (AEs) included a grade 5 coronavirus disease 2019 (COVID-19) infection (n = 1) and a grade 3 catheter erosion into the bowel (n = 1). Biliary sclerosis developed in two patients (9.5%). Median distance to infusion center was 47.6 miles (2-138 miles), and 62% were from Appalachia, yet there were no missed pump fill appointments. The 2-year overall survival was 82.4% (uCLM) and 50% (uIHC). CONCLUSIONS: The hCMP device had an acceptable safety profile. Despite the complexity of starting a new HAI program, early results showed feasibility for HAI delivery in a rural catchment area and comparable outcomes to larger urban-based HAI centers.
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Neoplasias de los Conductos Biliares , Neoplasias Colorrectales , Neoplasias Hepáticas , Dispositivos de Acceso Vascular , Humanos , Neoplasias Colorrectales/patología , Arteria Hepática/patología , Estudios de Factibilidad , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Hepáticas/secundario , Infusiones Intraarteriales , Conductos Biliares Intrahepáticos/patología , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/etiologíaRESUMEN
BACKGROUND: An increasing number of hepatic artery infusion (HAI) programs have been established worldwide. Practice patterns for this complex therapy across these programs have not been reported. This survey aimed to identify current practice patterns in HAI therapy with the long-term goal of defining best practices and performing prospective studies. METHODS: Using SurveyMonkeyTM, a 28-question survey assessing current practices in HAI was developed by 12 HAI Consortium Research Network (HCRN) surgical oncologists. Content analysis was used to code textual responses, and the frequency of categories was calculated. Scores for rank-order questions were generated by calculating average ranking for each answer choice. RESULTS: Thirty-six (72%) HCRN members responded to the survey. The most common intended initial indications for HAI at new programs were unresectable colorectal liver metastases (uCRLM; 100%) and unresectable intrahepatic cholangiocarcinoma (uIHC; 56%). Practice patterns evolved such that uCRLM (94%) and adjuvant therapy for CRLM (adjCRLM; 72%) have become the most common current indications for HAI at established centers. Referral patterns for pump placement differed between uCRLM and uIHC, with most patients referred while receiving second- and first-line therapy, respectively, with physicians preferring to evaluate patients for HAI while receiving first-line therapy for CRLM. Concern for extrahepatic disease was ranked as the most important factor when considering a patient for HAI. CONCLUSIONS: Indication and patient selection factors for HAI therapy are relatively uniform across most HCRN centers. The increasing use of adjuvant HAI therapy and overall consistency of practice patterns among HCRN centers provides a robust environment for prospective data collection and randomized clinical trials.
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OBJECTIVE: To characterize the results of surgery for gastrointestinal stromal tumor (GIST) in the pre and post-imatinib eras at a single institution and to identify current prognostic clinicopathologic factors. BACKGROUND: Imatinib has radically changed the management of GIST, yet the magnitude of impact on outcome across the spectrum of GIST presentation and relevance of historical prognostic factors are not well defined. METHODS: We retrospectively analyzed 1000 patients who underwent surgery for GIST at our institution from 1982 to 2016. Patients were stratified by presentation status as primary tumor only (PRIM), primary with synchronous metastasis (PRIMâ+âMET), or metachronous recurrence/metastases (MET), and also imatinib era (before and after it became available). Cox proportional-hazard models and Kaplan-Meier methods were used to model and estimate overall survival (OS) and recurrence-free survival (RFS). RESULTS: OS was longer in the imatinib era compared with the pre-imatinib era in each presentation group, including in Miettinen high-risk primary tumors. Among PRIM patients from the pre-imatinib era, tumor site, size, and mitotic rate were independently associated with OS and RFS on multivariate analysis. PRIM patients in the imatinib era who received imatinib (neoadjuvant and/or adjuvant) had higher risk tumors, but after adjusting for treatment, only size >10âcm remained independently prognostic of RFS [hazard ratio (HR) 3.85, 95% confidence interval (CI) 2.00-7.40, P < 0.0001) and OS (HR 3.37, 95% CI 1.60-7.13, P = 0.001)]. CONCLUSIONS: Patients treated in the imatinib era had prolonged OS across all presentations. In the imatinib era, among site, size, and mitotic rate, high-risk features were associated with treatment with the drug, but only size >10âcm correlated with outcome. Imatinib should still be prescribed for patients with high-risk features.
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Antineoplásicos/uso terapéutico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/cirugía , Mesilato de Imatinib/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Femenino , Tumores del Estroma Gastrointestinal/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Adulto JovenAsunto(s)
Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Arteria Hepática , Infusiones Intraarteriales , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Fluorouracilo/uso terapéutico , Protocolos de Quimioterapia Combinada AntineoplásicaAsunto(s)
Neoplasias de la Corteza Suprarrenal , Carcinoma Corticosuprarrenal , Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Floxuridina , Arteria Hepática/diagnóstico por imagen , Arteria Hepática/patología , Carcinoma Corticosuprarrenal/diagnóstico por imagen , Carcinoma Corticosuprarrenal/tratamiento farmacológico , Carcinoma Corticosuprarrenal/cirugía , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Neoplasias Colorrectales/patología , Neoplasias de la Corteza Suprarrenal/diagnóstico por imagen , Neoplasias de la Corteza Suprarrenal/tratamiento farmacológicoRESUMEN
BACKGROUND: Approximately 5% of gastrointestinal stromal tumors (GISTs) originate in the rectum, and historically, radical resection was commonly performed. Little is known about the outcome for rectal GIST in the era of imatinib. METHODS: Using a prospectively maintained database, this study retrospectively analyzed 47 localized primary rectal GISTs treated at our center from 1982 to 2016, stratified by when imatinib became available in 2000. Overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) were analyzed by the Kaplan-Meier method. RESULTS: Rectal GISTs represented 7.1% of 663 primary GISTs. The findings showed 17 patients in the pre-imatinib era and 30 patients in the imatinib era. The two groups had similar follow-up evaluation, age, gender, Miettinen risk, and distance to the anal verge. In the imatinib era, tumors were smaller at diagnosis (median 4 vs. 5 cm; p = 0.029), and 24 of the 30 patients received perioperative imatinib. In the high-risk patients, organ preservation and negative margins were more common among the 13 patients treated with neoadjuvant imatinib than among the 21 patients treated directly with surgery. High-risk patients who received perioperative imatinib (n = 15) had greater (or nearly significantly greater) 5-year OS, DSS, local RFS, and distant RFS than those who did not (n = 19) (91, 100, 100, and 71% vs. 47, 65, 74, and 41%; p = 0.049, 0.052, 0.077, 0.051, respectively). In the imatinib era, no patient has had a local recurrence or death due to GIST. CONCLUSIONS: The use of imatinib is associated with organ preservation and improved oncologic outcome for patients with rectal GIST.
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Neoplasias Gastrointestinales/mortalidad , Tumores del Estroma Gastrointestinal/mortalidad , Mesilato de Imatinib/uso terapéutico , Terapia Neoadyuvante/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Neoplasias del Recto/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Femenino , Estudios de Seguimiento , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/patología , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/patología , Humanos , Masculino , Oncología Médica , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Preservación de Órganos , Pronóstico , Estudios Prospectivos , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/patología , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Tumor-associated macrophages (TAMs) support growth in most human cancers, with the notable exception of colorectal adenocarcinoma, in which TAM infiltration of primary tumors is correlated with a better outcome. The importance of TAMs in colorectal liver metastases (CLM) is unknown. METHODS: Using a tissue microarray of CLM resected at their institution from 1998 to 2000, the authors quantified immune marker expression by immunohistochemistry (IHC) using Metamorph Image Analysis software. Findings showed that CD68, CD3, CD4, CD8, FoxP3, and MHC-I were correlated with overall survival (OS) and disease-free survival (DFS). RESULTS: Tumor cores from 158 patients were analyzed. The median follow-up period was 117 months for survivors (n = 39). The univariate analysis showed a significant positive association between DFS and CD4+ (p = 0.025) and CD68+ (p = 0.007). The findings showed a significant positive correlation of OS with CD4+ (p = 0.042), whereas the correlation with CD68+ was not significant (p = 0.17). Cutoffs were determined to dichotimize each marker for the highest log-rank statistic. Patients with CD4high had a median OS of 115 months and DFS of 41 months (p = 0.007 compared with 40 and 16 months, respectively, for patients with CD4low (p = 0.022). Patients with CD68high had a median OS of 50 months and a median DFS of 25 months (p = 0.67) compared with 43 and 15 months (p = 0.028). In the multivariate analysis of factors affecting DFS, high CD68 was associated with longer DFS (hazard ratio [HR], 0.63, 95% confidence interval [CI], 0.43-0.94; p = 0.02), independently of clinicopathologic variables and CD4. CONCLUSIONS: High TAM infiltration in resected CLM is associated with better outcome, independently of known clinicopathologic and immune predictors. This suggests that TAM depletion, which is being tested clinically in other cancers, may be detrimental in CLM.
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Adenocarcinoma/mortalidad , Neoplasias Colorrectales/mortalidad , Neoplasias Hepáticas/mortalidad , Linfocitos Infiltrantes de Tumor/inmunología , Macrófagos/inmunología , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de SupervivenciaRESUMEN
PURPOSE: Patients with cancer frequently undergo research-grade germline sequencing but clinically actionable results are not routinely disclosed. The objective of this study is to evaluate the feasibility of reporting clinically relevant secondary findings (SF) identified in germline research sequencing using the institutional molecular tumor board (MTB) and the treating oncology physician. METHODS: This prospective, interventional cohort study enrolled Total Cancer Care participants with any cancer diagnosis at a single institution. Patients underwent research-grade germline whole-exome sequencing, with bioinformatic analysis in a Clinical Laboratory Improvement Amendments-certified laboratory to verify pathogenic/likely pathogenic germline variants (PGVs) in any American College of Medical Genomics and Genetics SF v2.0 genes. After a protocol modification in consenting patients, the MTB reported PGVs to treating oncology physicians with recommendations for referral to a licensed genetic counselor and clinical confirmatory testing. RESULTS: Of the 781 enrolled participants, 32 (4.1%) harbored cancer predisposition PGVs, 24 (3.1%) were heterozygous carriers of an autosomal recessive cancer predisposition syndrome, and 14 (1.8%) had other hereditary disease PGVs. Guideline-directed testing would have missed 37.5% (12/32) of the inherited cancer predisposition PGVs, which included BRCA1, BRCA2, MSH6, SDHAF2, SDHB, and TP53 variants. Three hundred fifteen participants consented to reporting results; results for all living patients were reported to the clinical team with half referred to a licensed genetic counselor. There was concordance between all research variants identified in patients (n = 9) who underwent clinical confirmatory sequencing. CONCLUSION: MTB reporting of research-grade germline sequencing to the clinical oncology team is feasible. Over a third of PGVs identified using a universal testing strategy would have been missed by guideline-based approach, suggesting a role for expanding germline testing.
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Neoplasias , Humanos , Estados Unidos , Estudios Prospectivos , Estudios de Cohortes , Estudios de Factibilidad , Neoplasias/diagnóstico , Neoplasias/genética , Predisposición Genética a la Enfermedad/genética , Células GerminativasRESUMEN
BACKGROUND: The immune system has been shown to play an important role in gastrointestinal stromal tumor (GIST). The neutrophil-to-lymphocyte ratio (NLR) in blood is an easily assessable parameter of systemic inflammatory response. The aim of this study was to determine whether the NLR is prognostic in GIST. METHODS: A total of 339 previously untreated patients with primary, localized GIST operated at our institution between 1995 and 2010 were identified from a prospectively collected sarcoma database. NLR was assessed preoperatively. Patients who received adjuvant imatinib treatment were excluded from the analysis (n = 64). Cox regression models were calculated and correlation analyses were performed. RESULTS: On univariate analysis, NLR was associated with recurrence-free survival (RFS) (P = 0.003, hazard ratio 3.3, 95 % confidence interval 1.5-7.4). Patients with a low NLR had a 1- and 5-year RFS of 98 and 91 %, compared with 89 and 76 % in those with a high NLR. The median RFS was not reached. Positive correlations were found between NLR and mitotic rate (Pearson correlation coefficient [r] = 0.15, P = 0.03), and NLR and tumor size (r = 0.36, P = 0.0001). RFS in patients with a GIST >5 cm with low NLR was significantly longer compared to patients with high NLR (P = 0.002). Flow cytometry analysis of freshly obtained GISTs revealed that neutrophils constituted a minimal percentage of intratumoral immune cells. CONCLUSIONS: NLR is a surrogate for high-risk tumor features. Elevated blood NLR appears to represent systemic inflammation in patients with high-risk GIST.
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Tumores del Estroma Gastrointestinal/mortalidad , Linfocitos/patología , Recurrencia Local de Neoplasia/mortalidad , Neutrófilos/patología , Anciano , Femenino , Estudios de Seguimiento , Tumores del Estroma Gastrointestinal/sangre , Tumores del Estroma Gastrointestinal/patología , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
Investigator-initiated trials (IITs) are designed by principal investigators who identify important, unaddressed clinical gaps and opportunities to answer these questions through clinical trials. Surgical oncologists are poised to lead IITs due to their multidisciplinary clinical practice and substantial research background. The process of developing, organizing, and implementing IITs is multifaceted and involves important steps including (but not limited to) navigating regulatory requirements, obtaining funding, and meeting enrollment targets. Here, the authors explore the steps, methodology, and barriers of IIT development by surgical oncologists and highlight the importance of IITs in oncology.
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Oncólogos , Oncología Quirúrgica , Humanos , Investigadores , Oncología MédicaRESUMEN
Implementation of a successful hepatic artery infusion pump program requires numerous factors to be in place, and the lack of any of these may lead to program failure. First and foremost, hepatic artery infusion pump programs must have adequate surgical expertise in the complex technical aspects of hepatic artery infusion pump implantation and postoperative management. Most new hepatic artery infusion pump programs are initiated by a surgeon and led in conjunction with a medical oncologist. Medical oncology experience in floxuridine dosing is critical in maximizing the treatment doses and the number of cycles administered while avoiding biliary toxicity. This is facilitated by collaboration with an engaged pharmacy team. To have adequate patient volume for a successful program, internal and external stakeholders must have buy-in, including surgical and medical oncology colleagues unfamiliar with hepatic artery infusion pumps, colorectal surgery, and other referring providers. Programmatic support must be obtained from the hospital, cancer center, and department administration. Day-to-day pump access for chemotherapy and maintenance saline fills must be performed by appropriately trained infusion nurses to avoid complications. Nuclear and diagnostic radiology experience is key to identifying extrahepatic perfusion and hepatic artery infusion pump-specific complications. Additionally, skilled interventional radiologists and gastroenterologists are necessary to identify and treat rare complications rapidly. Finally, given the current rapid expansion of hepatic artery infusion pump programs, new programs must identify engaged mentors to help guide patient selection, navigate the nuanced issues that may arise, and provide advice in the case of complications. Although hepatic artery infusion pump dissemination outside of several major tertiary centers previously had stalled, establishing a successful and active hepatic artery infusion pump is feasible with appropriate training, mentorship, and thoughtful assembly of a dedicated multidisciplinary team.
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Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Arteria Hepática , Neoplasias Hepáticas/cirugía , Floxuridina/uso terapéutico , Bombas de Infusión Implantables , Infusiones IntraarterialesRESUMEN
Gastric adenocarcinoma (GAd) is the third leading cause of cancer-related deaths worldwide. Most patients require perioperative chemotherapy, yet methods to accurately predict responses to therapy are lacking. Thus, patients may be unnecessarily exposed to considerable toxicities. Here, we present a novel methodology using patient-derived organoids (PDOs) that rapidly and accurately predicts the chemotherapy efficacy for GAd patients. Methods:Endoscopic GAd biopsies were obtained from 19 patients, shipped overnight, and PDOs were developed within 24 h. Drug sensitivity testing was performed on PDO single-cells with current standard-of-care systemic GAd regimens and cell viability was measured. Whole exome sequencing was used to confirm the consistency of tumor-related gene mutations and copy number alterations between primary tumors, PDOs, and PDO single-cells. Results:Overall, 15 of 19 biopsies (79%) were appropriate for PDO creation and single-cell expansion within 24 h of specimen collection and overnight shipment. With our PDO single-cell technique, PDOs (53%) were successfully developed. Subsequently, two PDO lines were subjected to drug sensitivity testing within 12 days from initial biopsy procurement. Drug sensitivity assays revealed unique treatment response profiles for combination drug regimens in both of the two unique PDOs, which corresponded with the clinical response. Conclusions:The successful creation of PDOs within 24 h of endoscopic biopsy and rapid drug testing within 2 weeks demonstrate the feasibility of our novel approach for future applications in clinical decision making. This proof of concept sets the foundation for future clinical trials using PDOs to predict clinical responses to GAd therapies.
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BACKGROUND & AIMS: The mitogen-activated protein kinases (MAPKs), c-Jun N-terminal kinase (JNK), and p38, mediate liver ischemia/reperfusion (I/R) injury via cell death and inflammatory cytokine expression, respectively. Nilotinib is an orally available receptor tyrosine kinase inhibitor used for chronic myelogenous leukemia that also has in vitro activity against JNK and p38. In this study, we examine its therapeutic potential against hepatic I/R injury. METHODS: The effects of nilotinib on liver I/R injury were tested using a murine model of warm, segmental liver I/R. Serum ALT was measured and livers were analyzed by histology, RT-PCR, Western blot, and flow cytometry. The in vitro effects of nilotinib on hepatocyte and non-parenchymal cell (NPC) MAPK activation and cytokine production were also tested. RESULTS: Mice receiving nilotinib had markedly lower serum ALT levels and less histologic injury and apoptosis following liver I/R. Nilotinib did not inhibit its known receptor tyrosine kinases. Nilotinib lowered intrahepatic expression of IL-1ß, IL-6, MCP-1, and MIP-2 and systemic levels of IL-6, MCP-1, and TNF. Nilotinib reduced NPC activation of p38 MAPK signaling and decreased the recruitment of inflammatory monocytes and their production of TNF. Nilotinib attenuated JNK phosphorylation and hepatocellular apoptosis. In vitro, nilotinib demonstrated direct inhibition of JNK activation in isolated hepatocytes cultured under hypoxic conditions, and blocked activation of p38 MAPK and cytokine production by stimulated NPCs. CONCLUSIONS: Nilotinib lowers both liver JNK activation and NPC p38 MAPK activation and may be useful for ameliorating liver I/R injury in humans.
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Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Daño por Reperfusión/metabolismo , Daño por Reperfusión/prevención & control , Alanina Transaminasa/sangre , Animales , Apoptosis/efectos de los fármacos , Benzamidas , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Quimiocina CCL2/metabolismo , Quimiocina CXCL2/metabolismo , Activación Enzimática/efectos de los fármacos , Hepatocitos , Mesilato de Imatinib , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Monocitos/fisiología , Fosforilación/efectos de los fármacos , Piperazinas/uso terapéutico , Proteínas Proto-Oncogénicas c-abl/metabolismo , Proteínas Proto-Oncogénicas c-kit/metabolismo , Receptor de Factor Estimulante de Colonias de Macrófagos/metabolismo , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Daño por Reperfusión/patologíaRESUMEN
We recently demonstrated that immune checkpoint PD-1 was endogenously expressed in pancreatic ductal adenocarcinoma (PDAC) cells. Our data indicated that PD-1 proteins are not exclusive to immune cells and have unrecognized signal transduction cascades intrinsic to cancer cells. Building on this paradigm shift, we sought to further characterize PD-1 expression in PDAC. We utilized a phospho-explorer array to identify pathways upregulated by PD-1 signaling. We discovered PD-1-mediated activation of the proto-oncogene MET in PDAC cells, which was dependent on hepatocyte growth factor (MET ligand) and not secondary to direct protein interaction. We then discovered that the PD-1/MET axis in PDAC cells regulated growth, migration, and invasion. Importantly, the PD-1/MET axis induced epithelial-to-mesenchymal transition (EMT), a well-established early oncogenic process in PDAC. We observed that combined targeting of PDAC cell PD-1 and MET resulted in substantial direct tumor cell cytotoxicity and growth inhibition in PDAC cell lines, patient-derived organoids, and patient-derived xenografts independent of cytotoxic immune responses. This is the first report of PDAC-endogenous PD-1 expression regulating MET signaling, which builds upon our growing body of work showing the oncogenic phenotype of PD-1 expression in PDAC cells is distinct from its immunogenic role. These results highlight a paradigm shift that the tumor-specific PD-1 axis is a novel target to effectively kill PDAC cells by antagonizing previously unrecognized PD-1-dependent oncogenic pathways.
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Despite recent therapeutic advances, pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease with limited therapeutic options. Immune checkpoint inhibitors (ICIs) have demonstrated promising results in many cancers, but thus far have yielded little clinical benefit in PDAC. Based on recent combined targeting of programmed cell death protein-1 (PD-1) and C-X-C chemokine receptor 4 (CXCR4) in patient-derived xenografts (PDXs) and a pilot clinical trial, we sought to elucidate potential interactions between PD-1 and CXCR4. We observed concomitant expression and direct interaction of PD-1 and CXCR4 in PDAC cells. This interaction was disrupted upon CXCR4 antagonism with AMD3100 and led to increased cell surface expression of PD-1. Importantly, CXCR4-mediated PDAC cell migration was also blocked by PD-1 inhibition. Our work provides a possible mechanism by which prior studies have demonstrated that combined CXCR4 and PD-1 inhibition leads to decreased tumor growth. This is the first report investigating PD-1 and CXCR4 interactions in PDAC cells and our results can serve as the basis for further investigation of combined therapeutic targeting of CXCR4 and PD-1.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/patología , Humanos , Neoplasias Pancreáticas/patología , Fenotipo , Receptor de Muerte Celular Programada 1 , Receptores CXCR4 , Microambiente Tumoral , Neoplasias PancreáticasRESUMEN
Serous cystadenocarcinoma (SCAC) of the pancreas is rare, with only 35 cases reported in the literature. We present a case of SCAC, comparing the clinical presentation, management and molecular features of this case to a series of serous cystadenoma (SCA), which may be a precursor. Compared with SCAs (n = 5), SCAC was larger (11.5 vs median 3.6 cm). The case of SCAC invaded the spleen and exhibited distant metastasis, a requirement for diagnosis since pathologic features are otherwise indistinguishable from SCA. VHL mutations have been reported in about half of SCA in the literature. Accordingly, we identified either somatic or germline VHL mutations in 3 of 5 SCAs (60%), yet no pathogenic mutation was identified in the SCAC. A somatic mutation in IDH1 was found in SCAC only. This has been associated with multiple malignancies, is targetable with the drug ivosidenib and should be studied as a progression factor in SCAC.
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PURPOSE: Large-scale genomic sequencing studies are driving oncology drug development. However, rural populations, like those residing in Appalachian Kentucky, are underrepresented in these efforts. In this study, we determined the frequency of participation, reasons for nonparticipation, and factors predicting the decision to participate in the Total Cancer Care (TCC) prospective genomic cohort study. METHODS: A total of 1,188 patients were invited to enroll in the TCC prospective cohort from December 2018 to May 2019. Declining patients were queried for their rationale for nonparticipation and their patient data were obtained from the Kentucky Cancer Registry (KCR). Logistic regression was used to assess the association between characteristics and study participation. The association of study participation with survival was modeled with Cox proportional-hazards regression. RESULTS: 90.9% (1,081) patients consented to participate. In multivariate analysis, factors significantly associated with participation were age, gender, treatment status, and race. Though overall more women participated in the study, men were more likely to participate than women when invited (OR 1.57). Younger, Caucasian individuals who had received chemotherapy, but not surgery, were also more likely to participate. Patients in the Kentucky Appalachian cohort were primarily rural, had less educational attainment, and lower socioeconomic status. Kentucky Appalachian patients were no less likely to enroll in TCC than non-Appalachian patients. Consented individuals had higher overall survival compared to those who declined. CONCLUSION: Though minorities, those with low socioeconomic status, and rural populations are underrepresented in genomic studies, they were no less likely to participate when given the opportunity, and participation was associated with better clinical outcomes.
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Neoplasias , Región de los Apalaches , Estudios de Cohortes , Femenino , Genómica , Humanos , Kentucky/epidemiología , Masculino , Neoplasias/genética , Neoplasias/terapia , Estudios ProspectivosRESUMEN
Sarcomas are rare mesenchymal tumors with a propensity for hematogenous metastasis. Gastrointestinal stromal tumor (GIST) is the most common histologic subtype and the most common source of hepatic metastases. In the case of metastatic GIST, neoadjuvant imatinib can be used as a selection tool for the judicious application of surgery, where treatment-responsive patients who undergo resection to prevent the development of treatment-resistant clones have associated 10-year actuarial survival of 40%. Further advances for many of the non-GIST sarcoma subtypes will depend on the development of improved systemic therapies and evaluation of their activity in subtype or molecularly defined trials.
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Antineoplásicos , Neoplasias Gastrointestinales , Tumores del Estroma Gastrointestinal , Sarcoma , Antineoplásicos/uso terapéutico , Neoplasias Gastrointestinales/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/cirugía , Humanos , Hígado , Sarcoma/tratamiento farmacológico , Sarcoma/cirugíaRESUMEN
Colorectal cancer was the third most common malignancy worldwide in 2018, and most patients present with or develop distant metastases. Colorectal liver metastases are most commonly observed because of the vascular drainage of the colon and superior rectum. Current guidelines recommend surgical resection as first-line treatment; however, 80% to 90% of patients with colorectal liver metastases are ineligible for primary resection. For patients with unresectable disease, a multidisciplinary treatment approach is favored, incorporating systemic therapy and a toolbox of local ablative therapies. These treatments either aim at cytoreduction to enable a conversion to surgical resectability or control of disease progression and spread. Each of these treatments carries unique outcomes and risk profiles, thereby contributing to an individualized treatment strategy for patients with colorectal liver metastases. This review summarizes evidence on hepatic artery infusion, stereotactic body radiation therapy, thermal ablation, transarterial chemoembolization with drug-eluding beads, and transarterial radioembolization for treatment of colorectal liver metastases. Results of large-scale prospective and retrospective studies and international guidelines are discussed to provide detailed background on the current and prospective use of local ablative techniques in management of colorectal liver metastases.