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1.
Foods ; 13(14)2024 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-39063309

RESUMEN

Increased food production and consumption patterns have resulted in higher urban food phosphorus footprints, leading to a series of resource and environmental problems worldwide. We quantified the food phosphorus footprint of the African city of Kisumu using substance flow analysis. Our aim was to develop Kisumu's sustainable phosphorus management framework so that the city would reduce phosphorus losses into the food system. Our results show that in the year 2023, the import and export of food phosphorus in the Kisumu food system was 2730.26 ± 2.7% t P yr-1 and 3297.05 ± 2.4% t P yr-1, respectively. There was -566.79 ± -18% t P yr-1 food phosphorus deficit in the Kisumu food system. Crop planting subsystem runoff/leaching/erosion loss, household consumption subsystem waste loss, and pit latrine subsystem blackwater loss are the major pathways of phosphorus losses into the environment and the main contributors to the food phosphorus footprint in the city. The 2030 scenario analysis shows that implementing a comprehensive scenario scheme throughout the entire lifecycle process from phosphorus input to waste disposal is the best choice for reducing phosphorus losses and suppressing the growth of food phosphorus footprint in the future. Our study shows that the food phosphorus footprint in the Kisumu food system was 0.67 kg P cap-1yr-1 in 2023, which is still at a low level but may enter a continuous upward trend with the improvement of socio-economic development of the city. In our framework, we have proposed a few essential measures that include urine separation, installation of septic tank, adjustment of dietary structure, flexible layout of sanitary disposal facilities, and separation of organic waste streams to reduce food phosphorus footprints in Kisumu. Given the similarity of cities along the shores of Lake Victoria, our calculation methods and management strategies can be applied to other cities in the region.

2.
Cureus ; 16(5): e61438, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38953081

RESUMEN

Background There has been an explosion of commentary and discussion about the ethics and utility of using artificial intelligence in medicine, and its practical use in medical education is still being debated. Through qualitative research methods, this study aims to highlight the advantages and pitfalls of using ChatGPT in the development of clinical reasoning cases for medical student education. Methods Five highly experienced faculty in medical education were provided instructions to create unique clinical reasoning cases for three different chief concerns using ChatGPT 3.0. Faculty were then asked to reflect on and review the created cases. Finally, a focus group was conducted to further analyze and describe their experiences with the new technology. Results Overall, faculty found the use of ChatGPT in the development of clinical reasoning cases easy to use but difficult to get to certain objectives and largely incapable of being creative enough to create complexity for student use without heavy editing. The created cases did provide a helpful starting point and were extremely efficient; however, faculty did experience some medical inaccuracies and fact fabrication. Conclusion There is value to using ChatGPT to develop curricular content, especially for clinical reasoning cases, but it needs to be comprehensively reviewed and verified. To efficiently and effectively utilize the tool, educators will need to develop a framework that can be easily translatable into simple prompts that ChatGPT can understand. Future work will need to strongly consider the risks of recirculating biases and misinformation.

3.
Med Sci Educ ; 34(2): 455-461, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38686159

RESUMEN

Medical students will become educators teaching peers, healthcare students, patients, and families. At Rutgers New Jersey Medical School, the "Teaching Assistants in Medical Education" program provides fourth-year medical students with the skills and experiences needed to prepare them as medical educators. The program goes beyond the near peer teaching model to support student development in curricular design, assessment, and communication skills through a Clinical Skills or Anatomy track. Investment in the development of medical students as future educators will yield immediate and long-term rewards.

4.
Adv Healthc Mater ; 13(19): e2304186, 2024 Jul.
Artículo en Catalán | MEDLINE | ID: mdl-38676697

RESUMEN

In viral infections, natural killer (NK) cells exhibit anti-viral activity by inducing apoptosis in infected host cells and impeding viral replication through heightened cytokine release. Extracellular vesicles derived from NK cells (NK-EVs) also contain the membrane composition, homing capabilities, and cargo that enable anti-viral activity. These characteristics, and their biocompatibility and low immunogenicity, give NK-EVs the potential to be a viable therapeutic platform. This study characterizes the size, EV-specific protein expression, cell internalization, biocompatibility, and anti-viral miRNA cargo to evaluate the anti-viral properties of NK-EVs. After 48 h of NK-EV incubation in inflamed A549 lung epithelial cells, or conditions that mimic lung viral infections such as during COVID-19, cells treated with NK-EVs exhibit upregulated anti-viral miRNA cargo (miR-27a, miR-27b, miR-369-3p, miR-491-5p) compared to the non-treated controls and cells treated with control EVs derived from lung epithelial cells. Additionally, NK-EVs effectively reduce expression of viral RNA and pro-inflammatory cytokine (TNF-α, IL-8) levels in SARS-CoV-2 infected Vero E6 kidney epithelial cells and in infected mice without causing tissue damage while significantly decreasing pro-inflammatory cytokine compared to non-treated controls. Herein, this work elucidates the potential of NK-EVs as safe, anti-viral nanomaterials, offering a promising alternative to conventional NK cell and anti-viral therapies.


Asunto(s)
COVID-19 , Vesículas Extracelulares , Células Asesinas Naturales , MicroARNs , SARS-CoV-2 , Vesículas Extracelulares/química , Vesículas Extracelulares/metabolismo , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Animales , Humanos , Ratones , MicroARNs/metabolismo , MicroARNs/genética , Células A549 , COVID-19/virología , COVID-19/inmunología , COVID-19/metabolismo , Nanoestructuras/química , Antivirales/farmacología , Antivirales/química , Citocinas/metabolismo
5.
Blood ; 144(2): 171-186, 2024 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-38579288

RESUMEN

ABSTRACT: Multiple myeloma is a plasma cell malignancy that is currently incurable with conventional therapies. Following the success of CD19-targeted chimeric antigen receptor (CAR) T cells in leukemia and lymphoma, CAR T cells targeting B-cell maturation antigen (BCMA) more recently demonstrated impressive activity in relapsed and refractory myeloma patients. However, BCMA-directed therapy can fail due to weak expression of BCMA on myeloma cells, suggesting that novel approaches to better address this antigen-low disease may improve patient outcomes. We hypothesized that engineered secretion of the proinflammatory cytokine interleukin-18 (IL-18) and multiantigen targeting could improve CAR T-cell activity against BCMA-low myeloma. In a syngeneic murine model of myeloma, CAR T cells targeting the myeloma-associated antigens BCMA and B-cell activating factor receptor (BAFF-R) failed to eliminate myeloma when these antigens were weakly expressed, whereas IL-18-secreting CAR T cells targeting these antigens promoted myeloma clearance. IL-18-secreting CAR T cells developed an effector-like T-cell phenotype, promoted interferon-gamma production, reprogrammed the myeloma bone marrow microenvironment through type-I/II interferon signaling, and activated macrophages to mediate antimyeloma activity. Simultaneous targeting of weakly-expressed BCMA and BAFF-R with dual-CAR T cells enhanced T-cell:target-cell avidity, increased overall CAR signal strength, and stimulated antimyeloma activity. Dual-antigen targeting augmented CAR T-cell secretion of engineered IL-18 and facilitated elimination of larger myeloma burdens in vivo. Our results demonstrate that combination of engineered IL-18 secretion and multiantigen targeting can eliminate myeloma with weak antigen expression through distinct mechanisms.


Asunto(s)
Antígeno de Maduración de Linfocitos B , Inmunoterapia Adoptiva , Interleucina-18 , Mieloma Múltiple , Animales , Mieloma Múltiple/inmunología , Mieloma Múltiple/terapia , Mieloma Múltiple/patología , Ratones , Interleucina-18/inmunología , Inmunoterapia Adoptiva/métodos , Antígeno de Maduración de Linfocitos B/inmunología , Humanos , Receptores Quiméricos de Antígenos/inmunología , Modelos Animales de Enfermedad , Antígenos de Neoplasias/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Línea Celular Tumoral
6.
World J Surg ; 48(3): 701-712, 2024 03.
Artículo en Inglés | MEDLINE | ID: mdl-38342773

RESUMEN

BACKGROUND: The decriminalization of cannabis across the United States has led to an increased number of patients reporting cannabis use prior to surgery. However, it is unknown whether preoperative cannabis use disorder (CUD) increases the risk of postoperative complications among adult colectomy patients. METHODS: Adult patients undergoing an elective colectomy were retrospectively analyzed from the National Inpatient Sample database (2004-2018). To control for potential confounders, patients with CUD, defined using ICD-9/10 codes, were propensity score matched to patients without CUD in a 1:1 ratio. The association between preoperative CUD and composite morbidity, the primary outcome of interest, was assessed. Subgroup analyses were performed after stratification by age (≥50 years). RESULTS: Among 432,018 adult colectomy patients, 816 (0.19%) reported preoperative CUD. The prevalence of CUD increased nearly three-fold during the study period from 0.8/1000 patients in 2004 to 2.0/1000 patients in 2018 (P-trend<0.001). After propensity score matching, patients with CUD exhibited similar rates of composite morbidity (140 of 816; 17.2%) as those without CUD (151 of 816; 18.5%) (p = 0.477). Patients with CUD also had similar anastomotic leak rates (CUD: 5.64% vs. No CUD: 6.25%; p = 0.601), hospital lengths of stay (CUD: 5 days, IQR 4-7 vs. No CUD: 5 days, IQR 4-7) (p = 0.415), and hospital charges as those without CUD. Similar findings were seen among patients aged ≥50 years in the subgroup analysis. CONCLUSIONS: Though the prevalence of CUD has increased drastically over the past 15 years, preoperative CUD was not associated with an increased risk of composite morbidity among adult patients undergoing an elective colectomy.


Asunto(s)
Colectomía , Abuso de Marihuana , Adulto , Humanos , Estados Unidos/epidemiología , Prevalencia , Estudios Retrospectivos , Puntaje de Propensión , Colectomía/efectos adversos , Abuso de Marihuana/epidemiología
7.
Colorectal Dis ; 26(3): 497-507, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38302723

RESUMEN

AIM: The purpose of this study is to assess US operative trends and outcomes of ulcerative colitis (UC) patients undergoing total proctocolectomy with ileal pouch-anal anastomosis (TPC-IPAA) or completion proctectomy with IPAA (CP-IPAA). METHODS: Adult UC patients who underwent TPC-IPAA or CP-IPAA were analysed retrospectively using the 2016-2020 American College of Surgeons National Surgical Quality Improvement Program database. Factors associated with 30-day overall and serious morbidity were identified using multivariable logistic regression. RESULTS: A total of 1696 patients were identified, with 958 patients (56.5%) undergoing TPC-IPAA and 738 (43.5%) undergoing CP-IPAA. A greater proportion of TPC-IPAAs were performed each year (except in 2019) compared to CP-IPAAs over the study period (P trend <0.001). Unadjusted analysis showed comparable rates of overall (20.8% vs. 24.4%, P = 0.076) and serious morbidity (14.3% vs. 12.7%, P = 0.352) between TPC-IPAA and CP-IPAA patients. Robotic TPC-IPAA had no differences in complications compared to laparoscopic and open approaches. Robotic CP-IPAA had higher anastomotic leak rates and longer hospital length of stay compared to laparoscopic and open approaches. Obesity was associated with increased odds of overall and serious morbidity for patients who underwent TPC-IPAA. Steroid/immunosuppressive therapy was associated with increased odds of overall and serious morbidity for patients who underwent CP-IPAA. CONCLUSIONS: Obese patients should be informed of their increased morbidity risk and offered counselling on weight loss prior to surgery when feasible. Patients on steroid/immunosuppressive therapy within 30 days preoperatively should not undergo CP-IPAA or should delay surgery until they can be safely off those medications.


Asunto(s)
Colitis Ulcerosa , Reservorios Cólicos , Proctocolectomía Restauradora , Adulto , Humanos , Proctocolectomía Restauradora/efectos adversos , Proctocolectomía Restauradora/métodos , Colitis Ulcerosa/cirugía , Colitis Ulcerosa/complicaciones , Estudios Retrospectivos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/cirugía , Esteroides , Obesidad/complicaciones , Anastomosis Quirúrgica/efectos adversos , Resultado del Tratamiento , Reservorios Cólicos/efectos adversos
8.
J Am Coll Surg ; 238(2): 172-181, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-37937826

RESUMEN

BACKGROUND: Advances in surgical practices have decreased hospital length of stay (LOS) after surgery. This study aimed to determine the safety of short-stay (≤24-hour) left colectomy for colon cancer patients in the US. STUDY DESIGN: Adult colon cancer patients who underwent elective left colectomies were identified using the American College of Surgeons NSQIP database (2012 to 2021). Patients were categorized into 4 LOS groups: LOS 1 day or less (≤24-hour short stay), 2 to 4, 5 to 6, and 7 or more. Primary outcomes were 30-day postoperative overall and serious morbidity. Secondary outcomes were 30-day mortality and readmission. Multivariable logistic regression was performed to explore the association between LOS and overall and serious morbidity. RESULTS: A total of 15,745 patients who underwent left colectomies for colon cancer were identified with 294 (1.87%) patients undergoing short stay. Short-stay patients were generally younger and healthier with lower 30-day overall morbidity rates (LOS ≤1 day: 3.74%, 2 to 4: 7.38%, 5 to 6: 16.12%, and ≥7: 37.64%, p < 0.001). Compared with patients with LOS 2 to 4 days, no differences in mortality and readmission rates were observed. On adjusted analysis, there was no statistical difference in the odds of overall (LOS 2 to 4 days: odds ratio 1.90, 95% CI 1.01 to 3.60, p = 0.049) and serious morbidity (LOS 2 to 4 days: odds ratio 0.86, 95% CI 1.42 to 1.76, p = 0.672) between the short-stay and LOS 2 to 4 days groups. CONCLUSIONS: Although currently performed at low rates in the US, short-stay left colectomy is safe for a select group of patients. Attention to patient selection, refinement of clinical pathways, and close follow-up may enable short-stay colectomies to become a more feasible reality.


Asunto(s)
Neoplasias del Colon , Adulto , Humanos , Estudios Retrospectivos , Neoplasias del Colon/cirugía , Colectomía , Tiempo de Internación , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/cirugía
9.
Water Res ; 249: 120975, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38096728

RESUMEN

Microplastic (MP) dynamics can reflect history of plastic production and waste management in nearby areas. However, the stratigraphy of MPs in coastal wetlands and their link to policy and economic pattern changes are currently unclear. Here, MP stratigraphic records in sediment core from coastal wetlands in Yancheng, China, were used to reconstruct plastic pollution history. Neural network models simulated how policy intervention and economic development affected MP accumulation over time. We showed that MP abundance curves with boundaries from 1920 to 2019 had four stages. MP growth slowed or even decreased in the mid-to-late 1980s due to improved waste management and wastewater treatment since the late 1980s. Human activities were the primary factor affecting MP abundance and shape, followed by sediment properties. We predict that the environmental impact of MPs will continue to increase in the next decade. Current plastic policy measures focus on predictable waste emissions, but hidden sources like clothing fibers and tire wear that significantly contribute to MP pollution require further attention.


Asunto(s)
Microplásticos , Contaminantes Químicos del Agua , Humanos , Plásticos , Humedales , Contaminantes Químicos del Agua/análisis , Monitoreo del Ambiente , China
10.
Nature ; 623(7987): 653-655, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37957385
11.
Nature ; 623(7989): 964-971, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-38030779

RESUMEN

Plasmas can generate ultra-high-temperature reactive environments that can be used for the synthesis and processing of a wide range of materials1,2. However, the limited volume, instability and non-uniformity of plasmas have made it challenging to scalably manufacture bulk, high-temperature materials3-8. Here we present a plasma set-up consisting of a pair of carbon-fibre-tip-enhanced electrodes that enable the generation of a uniform, ultra-high temperature and stable plasma (up to 8,000 K) at atmospheric pressure using a combination of vertically oriented long and short carbon fibres. The long carbon fibres initiate the plasma by micro-spark discharge at a low breakdown voltage, whereas the short carbon fibres coalesce the discharge into a volumetric and stable ultra-high-temperature plasma. As a proof of concept, we used this process to synthesize various extreme materials in seconds, including ultra-high-temperature ceramics (for example, hafnium carbonitride) and refractory metal alloys. Moreover, the carbon-fibre electrodes are highly flexible and can be shaped for various syntheses. This simple and practical plasma technology may help overcome the challenges in high-temperature synthesis and enable large-scale electrified plasma manufacturing powered by renewable electricity.

12.
J Robot Surg ; 17(6): 2929-2936, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37837599

RESUMEN

Multivisceral robotic surgery may be an alternative to sequential procedures in select patients with colorectal cancer who are diagnosed with synchronous lesions or in those who require additional procedures at the time of resection. The aim of this study was to assess utilization of the robot for multivisceral resections and compare the surgical outcomes of this approach to laparoscopic resections. Adult colorectal surgery patients who underwent a colectomy or proctectomy and a concurrent abdominal surgery procedure in the American College of Surgeons NSQIP database (2016-2021) were included. The primary outcomes were 30-day postoperative overall and serious morbidity. Factors associated with morbidity were assessed using a multivariable logistic regression. Of the 3875 patients who underwent simultaneous multivisceral resections, 397 (10.3%) underwent a robotic approach and 962 (24.8%) a laparoscopic approach. Gynecological procedures (38%) comprised the largest proportion of concurrent procedures followed by hepatic resections (18%). On unadjusted analysis, rates of overall morbidity (25.4% vs. 30.0%) and serious morbidity (12.1% vs 12.0%) did not differ between the robotic and laparoscopic approach groups, respectively. The rate of conversion to open was lower for the robotic compared to laparoscopic approach (9.3% vs. 28.8%, p < 0.001), and length of stay was shorter (4 vs. 5, p < 0.001). On adjusted analysis, there was no significant difference in overall (OR 0.87, 95% CI 0.65-1.16, p = 0.34) or serious morbidity (OR 1.12, 95% CI 0.75-1.65, p = 0.59) between the two approaches even after concurrent procedure risk stratification. Robotic multivisceral resections can be performed with acceptable overall and serious morbidity in select patients with colorectal cancer. Rates of conversion and length of stay may be decreased with a robotic approach, and future research is needed to determine the optimal operative approach in this patient population.


Asunto(s)
Neoplasias Colorrectales , Laparoscopía , Procedimientos Quirúrgicos Robotizados , Robótica , Adulto , Humanos , Procedimientos Quirúrgicos Robotizados/métodos , Estudios de Factibilidad , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/cirugía , Laparoscopía/métodos , Colectomía/métodos , Neoplasias Colorrectales/cirugía , Estudios Retrospectivos , Resultado del Tratamiento
13.
Surgery ; 174(6): 1323-1333, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37852832

RESUMEN

BACKGROUND: The traditional treatment paradigm for patients with locally advanced rectal cancers has been neoadjuvant chemoradiation followed by curative intent surgery and adjuvant chemotherapy. This study aimed to assess surgery trends for locally advanced rectal cancers, factors associated with forgoing surgery, and overall survival outcomes. METHODS: Adults with locally advanced rectal cancers were retrospectively analyzed using the National Cancer Database (2004-2019). Propensity score matching was performed. Factors associated with not undergoing surgery were identified using multivariable logistic regression. Kaplan-Meier and log-rank tests were used for 5-year overall survival analysis, stratified by stage and treatment type. RESULTS: A total of 72,653 patients were identified, with 64,396 (88.64%) patients undergoing neoadjuvant + surgery ± adjuvant therapy, 579 (0.80%) chemotherapy only, 916 (1.26%) radiation only, and 6,762 (9.31%) chemoradiation only. The proportion of patients who underwent surgery declined over the study period (95.61% in 2006 to 92.29% in 2019, P trend < .001), whereas the proportion of patients who refused surgery increased (1.45%-4.48%, P trend < .001). Factors associated with not undergoing surgery for locally advanced rectal cancers included older age, Black race (odds ratio 1.47, 95% CI 1.35-1.60, P < .001), higher Charlson-Deyo score (score ≥3: 1.79, 1.58-2.04, P < .001), stage II cancer (1.22, 1.17-1.28, P < .001), lower median household income, and non-private insurance. Neoadjuvant + surgery ± adjuvant therapy was associated with the best 5-year overall survival, regardless of stage, in unmatched and matched cohorts. CONCLUSION: Despite surgery remaining an integral component in the management of locally advanced rectal cancers, there is a concerning decline in guideline-concordant surgical care for rectal cancer in the United States, with evidence of persistent socioeconomic disparities. Providers should seek to understand patient perspectives/barriers and guide them toward surgery if appropriate candidates. Continued standardization, implementation, and evaluation of rectal cancer care through national accreditation programs are necessary to ensure that all patients receive optimal treatment.


Asunto(s)
Neoplasias Primarias Secundarias , Neoplasias del Recto , Adulto , Humanos , Estudios Retrospectivos , Neoplasias del Recto/cirugía , Terapia Combinada , Terapia Neoadyuvante , Adyuvantes Inmunológicos
14.
Lab Chip ; 23(20): 4552-4564, 2023 10 10.
Artículo en Inglés | MEDLINE | ID: mdl-37771308

RESUMEN

Several methods have been developed for generating 3D, in vitro, organ-on-chip models of human vasculature to study vascular function, transport, and tissue engineering. However, many of these existing models lack the hierarchical nature of the arterial-to-capillary-to-venous architecture that is key to capturing a more comprehensive view of the human microvasculature. Here, we present a perfusable, multi-compartmental model that recapitulates the three microvascular compartments to assess various physiological properties such as vessel permeability, vasoconstriction dynamics, and circulating cell arrest and extravasation. Viscous finger patterning and passive pumping create the larger arterial and venular lumens, while the smaller diameter capillary bed vessels are generated through self-assembly. These compartments anastomose and form a perfusable, hierarchical system that portrays the directionality of blood flow through the microvasculature. The addition of collagen channels reduces the apparent permeability of the central capillary region, likely by reducing leakage from the side channels, enabling more accurate measurements of vascular permeability-an important motivation for this study. Furthermore, the model permits modulation of fluid flow and shear stress conditions throughout the system by using hydrostatic pressure heads to apply pressure differentials across either the arteriole or the capillary. This is a pertinent system for modeling circulating tumor or T cell dissemination and extravasation. Circulating cells were found to arrest in areas conducive to physical trapping or areas with the least amount of shear stress, consistent with hemodynamic or mechanical theories of metastasis. Overall, this model captures more features of human microvascular beds and is capable of testing a broad variety of hypotheses.


Asunto(s)
Microvasos , Neoplasias , Humanos , Ingeniería de Tejidos/métodos , Colágeno , Dispositivos Laboratorio en un Chip
15.
Cancer Lett ; 573: 216366, 2023 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-37640197

RESUMEN

Tumor antigens are crucial targets for T-cell-based therapy to induce tumor-specific rejection. However, identifying pancreatic ductal adenocarcinoma (PDAC)-specific T-cell epitopes has been challenging. Using advanced mass spectrometry (MS) analysis, we previously identified cancer-associated, class I MHC-bound epitopes shared by multiple PDAC patients with different HLA-A types. Here, we investigated one of these epitopes, LAMC2203-211, a naturally occurring nonmutated epitope on the LAMC2 protein. Following stimulation with the LAMC2203-211 peptide, we cloned T-cell receptors (TCRs) and transduced them into the Jurkat human T-cell line using a lentiviral vector. We found that Jurkat cells expressing LAMC2203-211-specific TCRs resulted in potent, LAMC2 specific, in vitro cytotoxic effects on PDAC cells. Furthermore, in mice that harbored either subcutaneously or orthotopically implanted tumors originating from both HLA-A allele-matched and unmatched PDAC patients, tumor growth was suppressed in a LAMC2-dependent manner following the infusion of LAMC2-targeting T cells. We have therefore developed a LAMC2-specific TCR-based T-cell therapy strategy likely suitable for many PDAC patients. This is the first study to adopt MS analysis to identify natural CD8+ T-cell epitopes in PDAC that could potentially serve as targets for PDAC immunotherapy.


Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Animales , Ratones , Epítopos de Linfocito T , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/terapia , Receptores de Antígenos de Linfocitos T/genética , Espectrometría de Masas , Tratamiento Basado en Trasplante de Células y Tejidos , Antígenos HLA-A
16.
J Gastrointest Surg ; 27(11): 2380-2387, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37468732

RESUMEN

BACKGROUND: Preoperative chemotherapy, or neoadjuvant therapy (NAC) can be used to improve resectability but can also have hepatotoxic effects on the future liver remnant. The purpose of this study was to investigate the impact of NAC on 30-day morbidity among patients undergoing a resection of primary colon cancer and synchronous liver metastases (sLM). METHODS: This was a retrospective study using the National Surgical Quality Improvement Program database (2012-2020). The association between NAC and 30-day overall morbidity, the primary outcome, was assessed. Subgroup analyses for low and high-risk procedures were performed. RESULTS: Among 968 patients who underwent the combined resection, 571 (58.99%) received NAC. There was a lower rate of 30-day overall morbidity among patients who received NAC (34.50% vs. 41.56%, p = 0.026) and no difference in rates of postoperative liver failure, bile leak, need for invasive intervention for hepatic procedure, and anastomotic leak. On adjusted analyses, patients who received NAC had decreased odds of overall morbidity (OR 0.73, 95% CI 0.55-0.97, p = 0.031) compared to patients who did not receive NAC. On subgroup analyses, patients who received NAC prior to a low risk combined resection had lower rates of overall morbidity on both adjusted and unadjusted analyses. Among those undergoing high-risk combined resections, there was no difference in overall morbidity. DISCUSSION AND CONCLUSION: Patients who are deemed to be candidates for preoperative chemotherapy can proceed with planned neoadjuvant chemotherapy prior to combined resection of primary colon cancer and sLM as preoperative neoadjuvant chemotherapy does not appear to be associated with increased postoperative morbidity.


Asunto(s)
Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Neoplasias Colorrectales/patología , Estudios Retrospectivos , Hepatectomía/métodos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/cirugía , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/cirugía , Morbilidad , Terapia Neoadyuvante
17.
J Surg Oncol ; 128(7): 1095-1105, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37448259

RESUMEN

BACKGROUND AND OBJECTIVES: Over 25% of patients diagnosed with colorectal cancer (CRC) will develop colorectal liver metastases (CRLM). Controversy exists over the surgical management of these patients. This study aims to investigate the safety of a simultaneous surgical approach by stratifying patients based on procedure risk and operative approach. METHODS: Using ACS-NSQIP (2016-2020), patients with CRC who underwent isolated colorectal, isolated hepatic, or simultaneous resections were identified. Colorectal and hepatic procedures were stratified by morbidity risk (high vs. low) and operative approach (open vs. minimally invasive). Thirty-day overall morbidity was compared between risk matched isolated and simultaneous resection groups. RESULTS: A total of 65 417 patients were identified, with 1550 (2.4%) undergoing simultaneous resections. A total of 1207 (77.9%) underwent a low-risk colorectal and low-risk liver resection. On multivariate analysis, there was no significant difference in overall morbidity between patients who had a simultaneous open high-risk colorectal/low-risk hepatic procedure compared to patients who had an isolated open high-risk colorectal procedure (odds ratio: 1.19; 95% confidence interval: 0.94-1.50; p = 0.148). All other combinations of simultaneous procedures had statistically significant higher rates of morbidity than the isolated group. CONCLUSIONS: Simultaneous resection of colorectal and synchronous CRLM is associated with an increased risk of morbidity in most circumstances in a risk stratified analysis, although rates of readmission and reoperation were not increased. Minimally invasive surgical approaches may significantly mitigate this morbidity.

18.
J Robot Surg ; 17(5): 2555-2558, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37436675

RESUMEN

An estimated 25% of patients with colorectal cancer (CRC) present with distant metastases at the time of diagnosis, the most common site being the liver. Although prior studies have reported that a simultaneous approach to resections in these patients can lead to increased rates of complications, emerging literature shows that minimally invasive surgical (MIS) approaches can mitigate this additional morbidity. This is the first study utilizing a large national database to investigate colorectal and hepatic procedure-specific risks in robotic simultaneous resections for CRC and colorectal liver metastases (CRLM). Utilizing the ACS-NSQIP targeted colectomy, proctectomy, and hepatectomy files, 1,721 patients were identified who underwent simultaneous resections of CRC and CRLM from 2016 to 2021. Of these patients, 345 (20%) underwent resections by an MIS approach, defined as either laparoscopic (n = 266, 78%) or robotic (n = 79, 23%). Patients who underwent robotic resections had lower rates of ileus compared to those who had open surgeries. The robotic group had similar rates of 30-day anastomotic leak, bile leak, hepatic failure, and post-operative invasive hepatic procedures compared to both the open and laparoscopic groups. The rate of conversion to open (8% vs. 22%, p = 0.004) and median LOS (5 vs. 6 days, p = 0.022) was significantly lower for robotic compared to laparoscopic group. This study, which is the largest national cohort of simultaneous CRC and CRLM resections, supports the safety and potential benefits of a robotic approach in these patients.


Asunto(s)
Neoplasias Colorrectales , Laparoscopía , Neoplasias Hepáticas , Procedimientos Quirúrgicos Robotizados , Humanos , Procedimientos Quirúrgicos Robotizados/métodos , Neoplasias Colorrectales/cirugía , Neoplasias Colorrectales/patología , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/cirugía , Hepatectomía/efectos adversos , Hepatectomía/métodos , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/secundario , Colectomía/efectos adversos , Colectomía/métodos , Laparoscopía/efectos adversos , Laparoscopía/métodos , Estudios Retrospectivos , Resultado del Tratamiento
19.
Gastroenterology ; 165(5): 1219-1232, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37507075

RESUMEN

BACKGROUND & AIMS: BiTE (bispecific T-cell engager) immune therapy has demonstrated clinical activity in multiple tumor indications, but its influence in the tumor microenvironment remains unclear. CLDN18.2 is overexpressed in solid tumors including gastric cancer (GC) and pancreatic ductal adenocarcinoma (PDAC), both of which are characterized by the presence of immunosuppressive cells, including regulatory T cells (Tregs) and few effector T cells (Teffs). METHODS: We evaluated the activity of AMG 910, a CLDN18.2-targeted half-life extended (HLE) BiTE molecule, in GC and PDAC preclinical models and cocultured Tregs and Teffs in the presence of CLDN18.2-HLE-BiTE. RESULTS: AMG 910 induced potent, specific cytotoxicity in GC and PDAC cell lines. In GSU and SNU-620 GC xenograft models, AMG 910 engaged human CD3+ T cells with tumor cells, resulting in significant antitumor activity. AMG 910 monotherapy, in combination with a programmed death-1 (PD-1) inhibitor, suppressed tumor growth and enhanced survival in an orthotopic Panc4.14 PDAC model. Moreover, Treg infusion enhanced the antitumor efficacy of AMG 910 in the Panc4.14 model. In syngeneic KPC models of PDAC, treatment with a mouse surrogate CLDN18.2-HLE-BiTE (muCLDN18.2-HLE-BiTE) or the combination with an anti-PD-1 antibody significantly inhibited tumor growth. Tregs isolated from mice bearing KPC tumors that were treated with muCLDN18.2-HLE-BiTE showed decreased T cell suppressive activity and enhanced Teff cytotoxic activity, associated with increased production of type I cytokines and expression of Teff gene signatures. CONCLUSIONS: Our data suggest that BiTE molecule treatment converts Treg function from immunosuppressive to immune enhancing, leading to antitumor activity in immunologically "cold" tumors.


Asunto(s)
Anticuerpos Biespecíficos , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Animales , Ratones , Linfocitos T Reguladores/metabolismo , Anticuerpos Biespecíficos/genética , Anticuerpos Biespecíficos/farmacología , Neoplasias Pancreáticas/tratamiento farmacológico , Moléculas de Adhesión Celular , Carcinoma Ductal Pancreático/tratamiento farmacológico , Inmunidad , Microambiente Tumoral , Claudinas
20.
Res Sq ; 2023 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-37292634

RESUMEN

An estimated 25% of patients with colorectal cancer (CRC) present with distant metastases at the time of diagnosis, the most common site being the liver. Controversy exists regarding the safety of a simultaneous versus staged approach to resections in these patients, but reports have shown that minimally invasive surgery (MIS) approaches can mitigate morbidity. This is the first study utilizing a large national database to investigate colorectal and hepatic procedure-specific risks in robotic simultaneous resections for CRC and colorectal liver metastases (CRLM). Utilizing the ACS-NSQIP targeted colectomy, proctectomy, and hepatectomy files, 1,550 patients were identified who underwent simultaneous resections of CRC and CRLM from 2016-2020. Of these patients, 311 (20%) underwent resections by an MIS approach, defined as an either laparoscopic (n = 241, 78%) or robotic (n = 70, 23%). Patients who underwent robotic resections had lower rates of ileus compared to those who had an open surgery. The robotic group had similar rates of 30-day anastomotic leak, bile leak, hepatic failure, and post operative invasive hepatic procedures compared to both the open and laparoscopic groups. The rate of conversion to open was significantly lower for robotic compared to laparoscopic group (9% vs. 22%, p = 0.012). This report is the largest study to date of robotic simultaneous CRC and CRLM resections reported in the literature and supports the safety and potential benefits of this approach.

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