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In strawberry cultivation, precise disease management is crucial for maximizing yields and reducing unnecessary fungicide use. Traditional methods for measuring leaf wetness duration (LWD), a critical factor in assessing the risk of fungal diseases such as botrytis fruit rot and anthracnose, have been reliant on sensors with known limitations in accuracy and reliability and difficulties with calibrating. To overcome these limitations, this study introduced an innovative algorithm for leaf wetness detection systems employing high-resolution imaging and deep learning technologies, including convolutional neural networks (CNNs). Implemented at the University of Florida's Plant Science Research and Education Unit (PSREU) in Citra, FL, USA, and expanded to three additional locations across Florida, USA, the system captured and analyzed images of a reference plate to accurately determine the wetness and, consequently, the LWD. The comparison of system outputs with manual observations across diverse environmental conditions demonstrated the enhanced accuracy and reliability of the artificial intelligence-driven approach. By integrating this system into the Strawberry Advisory System (SAS), this study provided an efficient solution to improve disease risk assessment and fungicide application strategies, promising significant economic benefits and sustainability advances in strawberry production.
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Inteligencia Artificial , Fragaria , Enfermedades de las Plantas , Hojas de la Planta , Fragaria/microbiología , Enfermedades de las Plantas/microbiología , Redes Neurales de la Computación , Algoritmos , BotrytisRESUMEN
MOTIVATION: A fluorescence emission-guided microscope used to monitor the outcome of cancer removal surgery is highly effective when employing a manipulator to motorize and switch the observation direction. It is necessary to minimize the alignment of looper tension between the stands for pull/push to change the direction of the manipulator and reduce the error rate caused by tension differences. This paper presents a method to minimize the error rate of looper tension between the stands. METHODS: \The looper is inserted between the stands of the manipulator to minimize the difference in tension and make the stress on the pull and push of the looper constant. The constant stress allows the manipulator to move stably in left/right, up/down, and left/right movements, which will be effective for full-camera observation and close-up shots of the end effector. RESULTS: Reducing the tolerance for differences in the manipulator's looper tension (angle and tension) is crucial. When the input value of the looper tension angle is 50°, the output should closely match 50°. Consequently, the measured response has a tolerance of ±49.98%, resulting in an error rate of .02% (1/50th level). CONCLUSION: A method is proposed to minimize the error rate of the manipulator's looper tension in a robot-based fluorescence emission-guided microscope used to observe the status of cancer surgery. As a result, a stable manipulator with a minimal error rate can achieve a 3.986x magnification for close-up observation by switching between high and low orientations.
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Procedimientos Quirúrgicos Robotizados , Humanos , Procedimientos Quirúrgicos Robotizados/métodos , Procedimientos Quirúrgicos Robotizados/instrumentación , Microscopía Fluorescente/métodos , Diseño de Equipo , Cirugía Asistida por Computador/métodos , Cirugía Asistida por Computador/instrumentaciónRESUMEN
Background: Until now, studies on colorectal cancer (CRC) have focused on clinicopathological characteristics based on location without considering sex differences. However, as men and women have fundamentally different physiological characteristics, research results in the clinical field are limited. We aimed to elucidate the differences in the clinicopathological characteristics between right-sided CRC (RCC) and left-sided CRC (LCC) according to sex. Methods: We classified 1492 South Korean patients with no history of colon surgery between July 2005 and June 2015 based on tumor location and sex. For these patients, differences in the clinical characteristics according to sex were compared using univariate and multivariate analyses. Results: Of the 1269 patients, 951 (74.9%) had LCC, and 318 (25.1%) had RCC, making LCC approximately three times more common than RCC. When sex was not taken into account, patients with RCC had significantly higher rates of anemia and undifferentiated cancers than the rates in those with LCC. Even considering sex, anemia and undifferentiated cancer were more prevalent in RCC than in LCC in both men and women. In contrast, age over 65 years and abnormal white blood cell count differed between RCC and LCC only in women. Conclusions: The clinicopathologic characteristics of CRC vary according to the location and sex. Therefore, sex must be considered as a fundamental characteristic of personalized treatment.
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Purpose: Since 2020, Atezolizumab plus bevacizumab (Ate/Bev) has been the standard first-line therapy for unresectable hepatocellular carcinoma (HCC), but long-term treatment studies are limited. This study evaluated the clinical characteristics and effects of Ate/Bev for over 1 year. Materials and Methods: This study included patients with unresectable HCC treated with first-line Ate/Bev between May 2020 and April 2022. Those receiving Ate/Bev for 1 year or more were classified as the long-term treatment group. Results: Of 246 patients, 69 (28.0%) were in the long-term treatment group, which comprised more proportions of intrahepatic tumor burden <25%, ECOG 0, and a lower proportion of portal vein tumor thrombosis than the short-term treatment group. The long-term treatment group had a higher incidence of atezolizumab-related thyroid dysfunction (31.9% vs. 10.7%, p<0.001; median time to onset [mTTO]: 2.8 months), dermatologic toxicity (29.0% vs. 14.7%, p=0.017; mTTO: 3.3 months), bevacizumab-related hypertension (44.9% vs. 22.0%, p=0.001; mTTO: 4.2 months), and proteinuria (69.6% vs. 38.4%, p<0.001; mTTO: 6.8 months), compared to the short-term treatment group. Regarding liver function in the long-term treatment group, patients initially classified as Child-Pugh class A decreased from 87% to 75.4%, and albumin-bilirubin grade 1 decreased from 68.1% to 50.7% after 1 year of treatment. Conclusion: The Ate/Bev long-term treatment group had a lower intrahepatic tumor burden, less portal vein tumor thrombosis, and better performance status and liver function at baseline. Atezolizumab-related immunological adverse events emerged relatively early in treatment compared to the bevacizumab-related. Additionally, some patients demonstrated liver function deterioration during long-term Ate/Bev treatment.
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BACKGROUND: Malignant triton tumors (MTTs) comprise a subgroup of malignant peripheral nerve sheath tumors (MPNSTs) that exhibits rhabdomyosarcomatous differentiation and follow an aggressive course. MTTs are primarily located along peripheral nerves. Cases of MTTs in the abdominal wall have not been reported. MTT has a poorer prognosis than classic MPNSTs, and accurate diagnosis necessitates a keen understanding of the clinical history and knowledge of its differential diagnosis intricacies. Treatment for MTTs mirrors that for MPNSTs and is predominantly surgical. CASE SUMMARY: A 49-year-old woman presented with a subcutaneous mass in her lower abdominal wall and a pre-existing surgical scar that had grown slowly over 3-4 months before the consultation. She had previously undergone radical hysterectomy and concurrent chemo-radiotherapy for cervical cancer approximately 5 years prior to the consultation. Abdominal computed tomography (CT) showed a 1.3 cm midline mass in the lower abdomen with infiltration into the rectus abdominis muscle. There was no sign of metastasis (T1N0M0). An incisional biopsy identified sporadic MTT of the lower abdomen. A comprehensive surgical excision with a 3 cm margin inclusive of the peritoneum was executed. Subsequently, the general surgeon utilized an approach akin to the open peritoneal onlay mesh technique. The patient underwent additional treatment with an excision shaped as a mini-abdominoplasty for the skin defect. No complications arose, and annual follow-up CTs did not show signs of recurrence or metastasis. CONCLUSION: An abdominal MTT was efficaciously treated with extensive excision and abdominal wall reconstruction, eliminating the need for postoperative radiotherapy.
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Introduction: Atezolizumab and bevacizumab (Ate/Bev) combination has become the new first-line systemic therapy for unresectable hepatocellular carcinoma (HCC). Although several studies reported thyroid dysfunction after treatment with immune checkpoint inhibitors, the clinical and immunological significance of thyroid dysfunction in patients treated with Ate/Bev has not been comprehensively addressed. We aimed to comprehensively evaluate the clinical and immunological implications of thyroid dysfunction in unresectable HCC patients treated with Ate/Bev. Methods: We enrolled 208 patients with unresectable HCC treated with Ate/Bev from three Korean cancer centers. Thyroid adverse events (AEs) were reviewed, and cytokines and T cells in the blood samples were analyzed at baseline. For external validation, we analyzed clinical outcomes according to thyroid AEs in patients treated with Ate/Bev in the IMbrave150 study. Results: Forty-one (19.7%) out of 208 patients experienced thyroid dysfunction (hypothyroidism [17.3%] and thyrotoxicosis [5.8%]) after Ate/Bev treatment. Median time to onset of hypothyroidism and thyrotoxicosis after Ate/Bev treatment was 3.5 and 1.3 months, respectively. Patients with thyroid AEs demonstrated significantly better progression-free survival, overall survival, and objective response rate than those without thyroid AEs. These findings were still consistent even after adjusting for confounding factors. Furthermore, favorable survival outcomes in patients with thyroid AEs were also validated in a cohort of IMbrave150 patients. While patients with thyrotoxicosis showed a significantly lower level of baseline IL-6, those with hypothyroidism did not show significant differences in circulating cytokine levels and CD8+ T-cell fractions. Conclusions: A fraction of patients with HCC treated with Ate/Bev experienced thyroid dysfunction, and the development of thyroid AEs was associated with favorable clinical outcomes.
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MOTIVATION: Typical surgical microscopes used for fluorescence-based lymph node detection experience limitations such as weight and restricted adjustability of the integrated light emitting diode (LED) and camera. This restricts the capture of detailed images of specific regions within the lesion. RESEARCH GOAL: This study proposes a miniature observation robot design that offers adjustable working distance (WD) and rotational radius, along with zoom-in/zoom-out functionality. METHODS: A five-degree-of-freedom manipulator was designed, with the end effector incorporating an LED and concave lens to widen the beam width for comprehensive lesion illumination. Additionally, a long-pass filter was integrated into the camera system to enhance image resolution. EXPERIMENTAL RESULTS: Experiments were conducted using a fluorescence-expressing phantom to evaluate the performance of the robot. Results demonstrated a captured image resolution of 9600 × 3240 pixels and a zoom-in/zoom-out capacity of up to 3.68 times. CONCLUSION: The proposed robot design is cost-effective and highly adjustable, enabling suitability for rapid and accurate detection of fresh lymph nodes during surgeries. The robot's capability to detect small lesions (<1 cm), as validated by phantom tests, holds promise for the detection of minute lymph nodes.
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Verde de Indocianina , Robótica , Biopsia del Ganglio Linfático Centinela/métodos , Quirófanos , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/patologíaRESUMEN
Antiangiogenic therapy is a recognized method for countering the immunosuppressive tumor microenvironment (TME) and improving anti-tumor immunity. PB101 is a glycosylated decoy receptor that binds to VEGF-A and PlGF with high affinity, based on the VEGFR1 backbone. Here, we elucidated PB101-induced remodeling of tumor angiogenesis and immunity, which enhances anti-PD-L1 immune checkpoint blockade. PB101 inhibited tumor growth by suppressing angiogenesis and enhancing CD8+ T cell infiltration into the tumors. PB101 induced robust reprogramming of antitumor immunity and activates intratumoral CD8+ T cells. Anti-tumor efficacy of PB101 is mostly dependent on CD8+ T cells and IFN-γ. PB101 reprograms tumor immunity in a manner distinct from that of the conventional VEGF decoy receptor, VEGF-trap. With its potent immune-modulating capability, PB101 synergizes with an anti-PD-L1, triggering strengthened antitumor immunity. Combining PB101 and anti-PD-L1 could establish durable protective immunity against tumor recurrence and metastasis. The findings of this study offer scientific rationales for further clinical development of PB101, particularly when used in combination with immune checkpoint inhibitors, as a potential treatment for advanced cancers.
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Linfocitos T CD8-positivos , Neoplasias , Factor A de Crecimiento Endotelial Vascular , Inhibidores de Puntos de Control Inmunológico , Neoplasias/inmunología , Metástasis de la NeoplasiaRESUMEN
Although stimulator of interferon genes (STING) agonists has shown great promise in preclinical studies, the clinical development of STING agonist therapy is challenged by its limited systemic delivery. Here, positively charged fusogenic liposomes loaded with a STING agonist (PoSTING) are designed for systemic delivery and to preferentially target the tumor microenvironment. When PoSTING is administered intravenously, it selectively targets not only tumor cells but also immune and tumor endothelial cells (ECs). In particular, delivery of STING agonists to tumor ECs normalizes abnormal tumor vasculatures, induces intratumoral STING activation, and elicits robust anti-tumor T cell immunity within the tumor microenvironment. Therefore, PoSTING can be used as a systemic delivery platform to overcome the limitations of using STING agonists in clinical trials.
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Liposomas , Neoplasias , Humanos , Microambiente Tumoral , Células Endoteliales , Neoplasias/patología , Neovascularización Patológica/tratamiento farmacológico , InmunoterapiaRESUMEN
Immune checkpoint inhibitor (ICI) became a standard treatment for advanced renal cell carcinoma (RCC). However, clinically valid biomarkers of therapeutic outcome are lacking. We investigated the role of interleukin-10 (IL-10) as a predictive biomarker for first-line ICI therapy in patients with advanced RCC. Baseline serum samples were prospectively collected and analyzed using a cytometric bead assay. Patients were divided into two groups according to their serum IL-10 levels using maximally selected rank statistics. A fraction (13.0%) of patients had high levels of serum IL-10 at baseline. High serum IL-10 levels (> 4.3 ng/mL) were associated with a significantly shorter progression-free (median: 5.2 months vs. not reached, P = 0.007) and overall survival (median: 13.9 months vs. not reached, P < 0.001). Multivariate Cox regression analysis confirmed the independent association between high serum IL-10 levels and poor survival outcomes. Effector cytokine production and the proliferative response of CD8+ T cells were significantly lower in patients with high serum IL-10 levels, who also had a shorter duration of response to first-line ICI therapy (4.6 months vs. not reached, P < 0.001). In conclusion, elevated serum IL-10 levels at baseline were associated with reduced clinical benefit from first-line ICI therapy in patients with advanced RCC.
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Background: Surgical site infections (SSIs) are the most common nosocomial infections suffered by surgical patients. They increase medical costs and prolong hospital stay. With respect to gastrointestinal surgery, SSIs are reported to have an incidence of up to 30%, and they frequently cause morbidity. The aim of this study was to prospectively investigate whether use of triclosan-coated sutures for abdominal incision closure during colorectal surgery reduces the incidence of SSI. Patients and Methods: This was a double-blinded randomized controlled trial in a single academic surgical hospital. Patients who underwent laparoscopic or open colorectal surgery were included. Patients were pre-operatively randomly assigned to either the Vicryl® Plus (VP) or Vicryl® (Ethicon Inc., Somerville, NJ) group. The patients and medical staff were blinded. Results: The primary end point was overall SSI rate and SSI at 30 days. Over a six-year period, 811 patients who underwent colorectal surgery and provided informed consent were randomly assigned (VP group, 396 patients; Vicryl group, 415 patients). No differences in baseline demographics were observed between the groups. The overall incidence of SSI was 4.8% (39/811 patients). There were no statistically significant differences in mean length of post-operative hospital stay between the groups (VP group, 9.3 days; Vicryl group, 9.6 days; p = 0.587). Statistically significant differences in SSI rate after post-operative day 30 were observed between the groups (VP group, 1 patient [7.1%]; Vicryl group, 7 patients [28.0%]; p = 0.039). Conclusions: Although use of triclosan-coated sutures did not reduce incidence of SSI within 30 days post-operatively, it is associated with reduced SSI rate after post-operative day 30.
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Antiinfecciosos Locales , Infecciones Intraabdominales , Triclosán , Humanos , Infección de la Herida Quirúrgica/epidemiología , Incidencia , Poliglactina 910 , Infecciones Intraabdominales/complicaciones , SuturasRESUMEN
Background & Aims: We elucidated the clinical and immunologic implications of serum IL-6 levels in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (Ate/Bev). Methods: We prospectively enrolled 165 patients with unresectable HCC (discovery cohort: 84 patients from three centres; validation cohort: 81 patients from one centre). Baseline blood samples were analysed using a flow cytometric bead array. The tumour immune microenvironment was analysed using RNA sequencing. Results: In the discovery cohort, clinical benefit 6 months (CB6m) was defined as complete or partial response, or stable disease for ≥6 months. Among various blood-based biomarkers, serum IL-6 levels were significantly higher in participants without CB6m than in those with CB6m (mean 11.56 vs. 5.05 pg/ml, p = 0.02). Using maximally selected rank statistics, the optimal cut-off value for high IL-6 was determined as 18.49 pg/ml, and 15.2% of participants were found to have high IL-6 levels at baseline. In both the discovery and validation cohorts, participants with high baseline IL-6 levels had a reduced response rate and worse progression-free and overall survival after Ate/Bev treatment compared with those with low baseline IL-6 levels. In multivariable Cox regression analysis, the clinical implications of high IL-6 levels persisted, even after adjusting for various confounding factors. Participants with high IL-6 levels showed reduced interferon-γ and tumour necrosis factor-α secretion from CD8+ T cells. Moreover, excess IL-6 suppressed cytokine production and proliferation of CD8+ T cells. Finally, participants with high IL-6 levels exhibited a non-T-cell-inflamed immunosuppressive tumour microenvironment. Conclusions: High baseline IL-6 levels can be associated with poor clinical outcomes and impaired T-cell function in patients with unresectable HCC after Ate/Bev treatment. Impact and implications: Although patients with hepatocellular carcinoma who respond to treatment with atezolizumab and bevacizumab exhibit favourable clinical outcomes, a fraction of these still experience primary resistance. We found that high baseline serum levels of IL-6 correlate with poor clinical outcomes and impaired T-cell response in patients with hepatocellular carcinoma treated with atezolizumab and bevacizumab.
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The dynamic behaviors of brain glial cells in various neuroinflammatory conditions and neurological disorders have been reported; however, little is known about the underlying intracellular signaling pathways. Here, we developed a multiplexed kinome-wide siRNA screen to identify the kinases regulating several inflammatory phenotypes of mouse glial cells in culture, including inflammatory activation, migration, and phagocytosis of glia. Subsequent proof-of-concept experiments involving genetic and pharmacological inhibitions indicated the importance of T-cell receptor signaling components in microglial activation and a metabolic shift from glycolysis to oxidative phosphorylation in astrocyte migration. This time- and cost-effective multiplexed kinome siRNA screen efficiently provides exploitable drug targets and novel insight into the mechanisms underlying the phenotypic regulation of glial cells and neuroinflammation. Moreover, the kinases identified in this screen may be relevant in other inflammatory diseases and cancer, wherein kinases play a critical role in disease signaling pathways.
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Encéfalo , Neuroglía , Animales , Ratones , ARN Interferente Pequeño/genética , Transducción de Señal , Movimiento CelularRESUMEN
BACKGROUND: The relationship between autophagy and diabetic peripheral neuropathy (DPN) has been highlighted in few reports. Using an animal model, the authors investigated the relationship between autophagy and DPN, focused particularly on changes in autophagy in Schwann cells. METHODS: The ultrastructural features of DPN mice were evaluated in vivo using transmission electron microscopy. Dysfunction of autophagy in DPN was evaluated using immunofluorescence microscopy and Western blot analysis of proteins related to autophagy, including Beclin1, LC3, and p62. Reactive oxygen species levels were measured in vitro in glucose-treated Schwann cells. Dysfunction of autophagy in glucose-treated Schwann cells was examined by immunofluorescence microscopy and Western blot analysis. RESULTS: Reduced myelin thickness and axonal shrinkage were observed in the sciatic nerves of DPN mice. Reactive oxygen species levels were increased in Schwann cells treated with high glucose ( P < 0.05). The expression of Beclin1 was increased in DPN mice and Schwann cells treated with high glucose ( P < 0.05), whereas the expression of LC3-II/LC3-I ratio and p62 were decreased in DPN mice and Schwann cells treated with high glucose ( P < 0.05). CONCLUSIONS: These results suggest that increased levels of reactive oxygen species induced by high glucose may contribute to autophagy dysfunction in Schwann cells. Autophagy dysfunction especially in Schwann cells may be an underlying cause of DPN. CLINICAL RELEVANCE STATEMENT: This study presents the pathological mechanism of diabetic peripheral neuropathy.
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Diabetes Mellitus , Neuropatías Diabéticas , Ratones , Animales , Neuropatías Diabéticas/etiología , Especies Reactivas de Oxígeno/metabolismo , Beclina-1/metabolismo , Células de Schwann/metabolismo , Glucosa/metabolismo , Glucosa/farmacología , Glucosa/uso terapéutico , Autofagia/fisiologíaRESUMEN
Renal cell carcinoma (RCC) is the most common type of kidney malignancy worldwide with Pembrolizumab and axitinib treatment (Pembro/Axi) amongst the most effective first-line immunotherapies for advanced RCC. However, it remains difficult to predict treatment response and early resistance. Therefore, we evaluated whether baseline serum interleukin-6 (IL-6) could be a predictive biomarker. Between November 2019 and December 2021, 58 patients with advanced RCC were enrolled, administered first-line Pembro/Axi, and baseline blood samples were analyzed using flow cytometry. The mean baseline serum IL-6 concentration was 8.6 pg/mL in responders and 84.1 pg/mL in patients with progressive disease. The IL-6 cut-off value was set at 6.5 pg/mL using time-dependent receiver operating characteristic curves, with 37.9% of patients having high baseline serum IL-6 levels and 62.1% having low levels. Objective response rates were 58.3% and 36.4% in low and high IL-6 groups, respectively. Overall survival and progression-free survival were longer in patients with low IL-6 levels than in those with high levels. High IL-6 levels were related to reduced interferon-γ and tumor necrosis factor-α production from CD8+ T cells. Overall, high baseline serum IL-6 levels were associated with worse survival outcomes and reduced T-cell responses in Pembro/Axi-treated advanced RCC patients.
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The Strawberry Advisory System (SAS) is a tool developed to help Florida strawberry growers determine the risk of common fungal diseases and the need for fungicide applications. Leaf wetness duration (LWD) is one of the important parameters in SAS disease risk modeling. By accurately measuring the LWD, disease risk can be better assessed, leading to less fungicide use and more economic benefits to the farmers. This research aimed to develop and test a more accurate leaf wetness detection system than traditional leaf wetness sensors. In this research, a leaf wetness detection system was developed and tested using color imaging of a reference surface and a convolutional neural network (CNN), which is one of the artificial-intelligence-based learning methods. The system was placed at two separate field locations during the 2021-2022 strawberry-growing season. The results from the developed system were compared against manual observation to determine the accuracy of the system. It was found that the AI- and imaging-based system had high accuracy in detecting wetness on a reference surface. The developed system can be used in SAS for determining accurate disease risks and fungicide recommendations for strawberry production and allows the expansion of the system to multiple locations.
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Aprendizaje Profundo , Fragaria , Fungicidas Industriales , Agua , Hojas de la PlantaRESUMEN
Importance: Administration of atezolizumab could be immunogenic and induce undesirable antidrug antibody (ADA) responses. This may interfere with atezolizumab-mediated actions, affecting drug clearance and serum concentration or inducing antibody neutralization. Objective: To determine the clinical and immunological associations of highly elevated ADA levels with clinical outcomes after atezolizumab/bevacizumab (Atezo/Bev) treatment in patients with advanced hepatocellular carcinoma (HCC). Design, Setting, and Participants: This cohort study prospectively enrolled 174 patients with advanced HCC treated with first-line Atezo/Bev (discovery cohort: 61 patients from 1 center; validation cohort: 113 patients from 4 centers). Exposures: Serum ADA levels at pretreatment and 3 weeks (cycle 2 day 1 [C2D1]) were analyzed using competitive enzyme-linked immunosorbent assays. In addition, samples were subjected to serological and flow cytometric analyses. Main Outcomes and Measures: Overall, ADA positivity was associated with treatment outcomes and T-cell functions. Results: After excluding patients with inadequate samples, follow-up loss, or consent withdrawal, 132 patients (discovery cohort: 50 patients; 41 [82.0%] men; median age [IQR], 61 [55-70] years; validation cohort: 82 patients; 70 [85.4%] men; median age [IQR], 61 [53-68] years) were analyzed, and robust ADA (≥1000 ng/mL) responses at C2D1 were identified in 23 (17.4%) of the patients. Patients with progressive disease exhibited higher ADA levels (median [IQR], 65.2 [0-520.4] ng/mL) at C2D1 than in responders (median [IQR], 0 [0-117.5] ng/mL). In both discovery and validation cohorts, patients with high ADA levels at C2D1 were associated with a reduced response rate (discovery cohort: 34% vs 11%; validation cohort: 29% vs. 7%) and worse progression-free survival (discovery cohort: hazard ratio [HR], 2.84; 95% CI, 1.31-6.13; P = .005; validation cohort: HR, 2.52; 95% CI, 1.27-5.01; P = .006) and overall survival (discovery cohort: HR, 3.30; 95% CI, 1.43-7.64; P = .003; validation cohort: HR, 5.81, 95% CI, 2.70-12.50; P = .001) with Atezo/Bev compared with those with low ADA levels. In multivariable Cox regression, the clinical implication of high ADA levels persisted even after adjusting for various confounding factors and was most significant at 1000 ng/mL or greater. Compared with patients with low ADA levels, patients with high ADA levels exhibited reduced serum atezolizumab concentrations, impaired CD8-positive T-cell proliferation, and had decreased interferon-γ and tumor necrosis factor-α from CD8-positive T cells compared with patients with low ADA levels. Conclusions and Relevance: This cohort study found that highly elevated ADA levels at C2D1 may be associated with poor clinical outcomes in patients with advanced HCC treated with Atezo/Bev. High ADA levels may reduce atezolizumab exposure and attenuate the anticancer efficacy of the drug.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Masculino , Humanos , Persona de Mediana Edad , Femenino , Carcinoma Hepatocelular/tratamiento farmacológico , Estudios de Cohortes , Neoplasias Hepáticas/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéuticoRESUMEN
During laparoscopic surgery for colorectal or gastric cancers, locating the tumor for excision is difficult owing to it being obscured by mucous membranes. Therefore, a clip can be installed around the tumor, which can be located using a sensor. Most of the clip-detectors developed thus far can only detect tumors in either the colon or stomach and require a wire to connect the clip and detector. This study designs a clip and detector that can locate a tumor in the stomach and colon. The clip contains a neodymium magnet that generates a magnetic field, and the detector includes a Colpitts oscillator that allows magnetic coupling of the clip and detector. After installing the prepared clip at the tumor location, the detector is used to locate the clip. To test the clip and detector, we conducted animal experiments, during which four clips were installed in the colon and stomach of a mini pig. We succeeded in locating the clips within 2.17 and 3.14 s in the stomach and colon, respectively, which were shorter than the detection times reported in previous studies. The demand for laparoscopic surgery and endoscopes is predicted to increase owing to this method.
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Laparoscopía , Neoplasias Gástricas , Animales , Imanes , Neodimio , Instrumentos Quirúrgicos , Porcinos , Porcinos EnanosRESUMEN
BACKGROUND: Toll-like receptors (TLRs) are critical innate immune sensors that elicit antitumor immune responses in cancer immunotherapy. Although a few TLR agonists have been approved for the treatment of patients with early-stage superficial cancers, their therapeutic efficacy is limited in patient with advanced invasive cancers. Here, we identified the therapeutic role of a TLR2/3 agonist, L-pampo (LP), which promotes antitumor immunity and enhances the immune checkpoint blockade. METHODS: We generated LP by combining a TLR2 agonist, Pam3CSK4, with a TLR3 agonist, Poly (I:C). Immune responses to stimulation with various TLR agonists were compared. Tumor-bearing mice were intratumorally treated with LP, and their tumor sizes were measured. The antitumor effects of LP treatment were determined using flow cytometry, multiplexed imaging, and NanoString nCounter immune profiling. The immunotherapeutic potential of LP in combination with α-programmed cell death protein-1 (PD-1) or α-cytotoxic T-lymphocytes-associated protein 4 (CTLA-4) was evaluated in syngeneic MC38 colon cancer and B16F10 melanoma. RESULTS: The LP treatment induced a potent activation of T helper 1 (Th1) and 2 (Th2)-mediated immunity, tumor cell apoptosis, and immunogenic tumor cell death. Intratumoral LP treatment effectively inhibited tumor progression by activating tumor-specific T cell immunity. LP-induced immune responses were mediated by CD8+ T cells and interferon-γ, but not by CD4+ T cells and CD25+ T cells. LP simultaneously activated TLR2 and TLR3 signaling, thereby extensively changing the immune-related gene signatures within the tumor microenvironment (TME). Moreover, intratumoral LP treatment led to systemic abscopal antitumor effects in non-injected distant tumors. Notably, LP treatment combined with ÉPD-1 and ÉCTLA-4 further enhanced the efficacy of monotherapy, resulting in complete tumor regression and prolonged overall survival. Furthermore, LP-based combination immunotherapy elicited durable antitumor immunity with tumor-specific immune memory in colon cancer and melanoma. CONCLUSIONS: Our study demonstrated that intratumoral LP treatment improves the innate and adaptive antitumor immunity within the TME and enhances the efficacy of αPD-1 and αCTLA-4 immune checkpoint blockade.