RESUMEN
Severity of neurobehavioral deficits in children born from adverse pregnancies, such as maternal alcohol consumption and diabetes, does not always correlate with the adversity's duration and intensity. Therefore, biological signatures for accurate prediction of the severity of neurobehavioral deficits, and robust tools for reliable identification of such biomarkers, have an urgent clinical need. Here, we demonstrate that significant changes in the alternative splicing (AS) pattern of offspring lymphocyte RNA can function as accurate peripheral biomarkers for motor learning deficits in mouse models of prenatal alcohol exposure (PAE) and offspring of mother with diabetes (OMD). An aptly trained deep-learning model identified 29 AS events common to PAE and OMD as superior predictors of motor learning deficits than AS events specific to PAE or OMD. Shapley-value analysis, a game-theory algorithm, deciphered the trained deep-learning model's learnt associations between its input, AS events, and output, motor learning performance. Shapley values of the deep-learning model's input identified the relative contribution of the 29 common AS events to the motor learning deficit. Gene ontology and predictive structure-function analyses, using Alphafold2 algorithm, supported existing evidence on the critical roles of these molecules in early brain development and function. The direction of most AS events was opposite in PAE and OMD, potentially from differential expression of RNA binding proteins in PAE and OMD. Altogether, this study posits that AS of lymphocyte RNA is a rich resource, and deep-learning is an effective tool, for discovery of peripheral biomarkers of neurobehavioral deficits in children of diverse adverse pregnancies.
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Diabetes Mellitus , Trastornos del Espectro Alcohólico Fetal , Efectos Tardíos de la Exposición Prenatal , Ratones , Animales , Niño , Humanos , Embarazo , Femenino , Empalme Alternativo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Etanol , Diabetes Mellitus/inducido químicamente , Biomarcadores/metabolismo , ARN/metabolismo , Trastornos del Espectro Alcohólico Fetal/genéticaRESUMEN
Matrix metalloproteinase-9 (MMP-9) is a secreted zinc-dependent endopeptidase that degrades the extracellular matrix and basement membrane of neurons, and then contributes to synaptic plasticity by remodeling the extracellular matrix. Inhibition of MMP-9 activity has therapeutic potential for neurodegenerative diseases such as fragile X syndrome. This paper reports the molecular design, synthesis, and in vitro studies of novel indole derivatives as inhibitors of proMMP-9 activation. High-throughput screening (HTS) of our internal compound library and subsequent merging of hit compounds 1 and 2 provided compound 4 as a bona-fide lead. X-ray structure-based design and subsequent lead optimization led to the discovery of compound 33, a highly potent and selective inhibitor of proMMP-9 activation.
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Precursores Enzimáticos , Metaloproteinasa 9 de la Matriz , Metaloproteinasa 9 de la Matriz/metabolismo , Precursores Enzimáticos/metabolismo , Matriz Extracelular/metabolismo , Indoles/farmacología , Indoles/metabolismo , Metaloendopeptidasas/metabolismo , Inhibidores de la Metaloproteinasa de la MatrizRESUMEN
Mesonephric-like adenocarcinoma (MLA) has recently been described as a tumor of the endometrium or ovaries, which, morphologically and immunohistochemically, resembles mesonephric adenocarcinoma arising mostly in the uterine cervix. Herein, we report, to our knowledge, the first case of ovarian MLA that developed into an extremely rapidly growing recurrent mesonephric-like carcinosarcoma, as confirmed by a genomic profiling test. A 51-year-old woman underwent chemotherapy with complete debulking surgery for ovarian carcinoma. Pathologically, the patient was diagnosed with stage IVB ovarian MLA. Subsequent to 15 months of complete remission, an enhanced computed tomography scan revealed a solid tumor of 10 cm diameter in the abdominal cavity. Secondary surgery was terminated with a 2 cm 2 tumor biopsy specimen collection considering perioperative complications. Histologically, the tumor consisted of short spindle cells, and immunohistochemical staining revealed a rhabdomyosarcomatous profile without an epithelial component. Despite treatment for the sarcoma, she died 3 months after the detection of the tumor. The genomic profiling of the primary ovarian carcinoma and secondary resected tumor biopsy specimens revealed an identical KRAS mutation in both. Therefore, we concluded that the ovarian MLA recurred with a rhabdomyosarcoma component.
RESUMEN
The developing brain is under the risk of exposure to a multitude of environmental stressors. While perinatal exposure to excessive levels of environmental stress is responsible for a wide spectrum of neurological and psychiatric conditions, the developing brain is equipped with intrinsic cell protection, the mechanisms of which remain unknown. Here we show, using neonatal mouse as a model system, that primary cilia, hair-like protrusions from the neuronal cell body, play an essential role in protecting immature neurons from the negative impacts of exposure to environmental stress. More specifically, we found that primary cilia prevent the degeneration of dendritic arbors upon exposure to alcohol and ketamine, two major cell stressors, by activating cilia-localized insulin-like growth factor 1 receptor and downstream Akt signaling. We also found that activation of this pathway inhibits Caspase-3 activation and caspase-mediated cleavage/fragmentation of cytoskeletal proteins in stress-exposed neurons. These results indicate that primary cilia play an integral role in mitigating adverse impacts of environmental stressors such as drugs on perinatal brain development.
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Cilios/metabolismo , Células-Madre Neurales/metabolismo , Prosencéfalo/embriología , Animales , Animales Recién Nacidos/metabolismo , Encéfalo/metabolismo , Dendritas/metabolismo , Femenino , Factor I del Crecimiento Similar a la Insulina/metabolismo , Ratones/embriología , Ratones Endogámicos C57BL , Neuronas/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal , Prosencéfalo/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de SeñalRESUMEN
AIM: Minimally invasive surgeries for endometrial cancer are increasing worldwide. In Japan, some articles have examined surgical outcomes, but only a few have addressed oncological outcomes. This study aims to compare robot surgery, laparoscopic surgery, and laparotomy in terms of surgical and oncological outcomes within a low-risk group for endometrial cancer recurrence. METHODS: This study included patients with endometrial cancer deemed to be at low risk of recurrence and who underwent surgery between January 2011 and December 2020. We studied 99 patients who underwent robot surgery, 85 patients who underwent laparotomy, and 77 patients who underwent laparoscopic surgery. Surgical and oncological outcomes were compared retrospectively for these groups of patients. RESULTS: The median follow-up period was 47, 61, and 60 months in the laparotomy, laparoscopy, and robotic groups, respectively. The three groups had similar perioperative and pathological data. No significant differences in overall survival and disease-free survival were observed among the groups. Univariate and multivariate analyses conducted on the overall study population for disease-free survival and overall survival showed that the surgical approach did not have any influence. Minimally invasive surgery groups had longer operating times compared to the laparotomy group, but they had significantly less blood loss. The number of resected pelvic lymph nodes was similar, and the complication rate was not significant. CONCLUSIONS: Robot-assisted surgery and laparoscopic surgery were found to be less invasive and showed similar oncologic outcomes compared to laparotomy surgery for endometrial cancer in patients with a low risk of recurrence.
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Neoplasias Endometriales , Laparoscopía , Laparotomía , Procedimientos Quirúrgicos Robotizados , Femenino , Humanos , Neoplasias Endometriales/patología , Neoplasias Endometriales/cirugía , Histerectomía , Laparoscopía/efectos adversos , Laparotomía/efectos adversos , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Complicaciones Posoperatorias/epidemiología , Estudios Retrospectivos , Procedimientos Quirúrgicos Robotizados/efectos adversosRESUMEN
BACKGROUND: Itai-itai disease is the most severe case of chronic cadmium (Cd) toxicity, which was endemic in Cd-polluted areas in the Jinzu River basin in Toyama prefecture, Japan. Akita prefecture also has Cd-polluted areas, but there have been no cases of "itai-itai disease". CASE PRESENTATION: An elderly female farmer with Cd nephropathy residing in a Cd-polluted area in the northern part of the Akita prefecture was identified through hospital-based screening at Akita Rosai Hospital in Odate city. She had chronic renal failure with a high Cd exposure level and advanced renal tubular dysfunction. The shortening of height, bone deformities and fractures, abnormal bone metabolism suggesting osteomalacia, and renal anemia were also noted. Therefore, "itai-itai disease", similar to cases in the Jinzu River basin, was suspected. CONCLUSION: This is the first case of "itai-itai disease" in a Cd-polluted area in Akita prefecture.
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Cadmio , Japón/epidemiología , Femenino , Humanos , Anciano , Intoxicación por Cadmio/epidemiología , Intoxicación por Cadmio/etiología , Agricultores , Contaminantes AmbientalesRESUMEN
The case was a 70-year-old man of highly advanced gastric cancer with 2 liver metastases(S3, S8)and pancreatic invasion. Three courses of S-1 plus L-OHP(SOX therapy)were performed, and total gastrectomy and combined resection of the spleen and body and tail of the pancreas and partial resection of the liver S3 and S8 were performed after reduction of primary tumor and liver metastasis. S-1 therapy was continued for 1 year as postoperative adjuvant chemotherapy. Left adrenal metastasis was detected by CT, 1 year and 6 months after the operation. PET-CT revealed no other areas suspected of recurrence, so left adrenalectomy was performed through the retroperitoneal space. Radical resection was not achieved because adhesions and scarring from the previous surgery were severe. Paclitaxel plus Ramucirumab was started and after 10 courses, the disappearance of the tumor shadow was observed on enhanced CT, and PET-CT. Three years and 3 months after the initial surgery and 1 year and 8 months after resection of adrenal metastasis, the patient is alive without recurrence.
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Neoplasias Hepáticas , Neoplasias Gástricas , Anciano , Humanos , Adrenalectomía , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia Adyuvante , Gastrectomía , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/secundario , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/cirugía , Neoplasias Gástricas/patología , MasculinoRESUMEN
The patient was a 79-year-old man who underwent robot-assisted gastrectomy for esophagogastric junction cancer. pT4aN1M0, pStage â ¢A. Nine months after surgery, he had emergency visit to the hospital due to abdominal pain and vomiting, and contrast CT scan showed a small intestine with poor contrast effect above the left diaphragm. He was diagnosed as a diaphragmatic hernia with small intestinal strangulation and underwent emergency surgery. Under laparotomy, 2 fb hernia orifice were observed on the ventral side of the esophageal hiatus, and a 50 cm jejunum was incarcerated and became necrotic. A partial jejunectomy was performed, and the esophageal hiatus was closed by suturing the stomach with 3-0 absorbable suture. He was discharged from the hospital with good postoperative course. But one month after the operation, the patient was seen in the hospital again with abdominal pain. Under laparotomy, it was found that one suture was dropped off the esophageal hiatus at the previous surgery, and a 100 cm jejunum was incarcerated, which was not necrotic. The hiatal hernia was closed by suturing the stomach and the hiatal hernia with 3-0 non-absorbable suture. Diaphragmatic hernia is a rare late complication of esophagogastric junction cancer.
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Hernia Diafragmática , Hernia Hiatal , Neoplasias , Masculino , Humanos , Anciano , Hernia Hiatal/cirugía , Hernia Diafragmática/cirugía , Unión Esofagogástrica/cirugía , Necrosis , Dolor AbdominalRESUMEN
Our patient was a 72-year-old man in whom a liver mass was identified on abdominal ultrasonography at the examination for which he was referred to our hospital. Contrast-enhanced CT showed that the liver mass was a hemangioma with a surrounding AP shunt. Gallbladder wall thickening could not be ruled out as gallbladder cancer; however, a high possibility of adenomyomatosis was considered. EOB-MRI determined that the gallbladder wall thickening was adenomyomatosis and liver mass was a metastatic malignant tumor of unknown primary origin. Our policy was to resect gallbladder adenomyomatosis and the liver tumor for diagnostic purposes. Cholecystectomy plus hepatic S4a subsegmental resection and hepatoduodenal mesenteric lymph node dissection were performed. The histopathological diagnosis was neuroendocrine cancer of the gallbladder. A similar histology of the liver mass suggested continuity from the gallbladder tumor and was considered direct infiltration. Fifteen months after the operation, no recurrence was observed.
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Carcinoma Neuroendocrino , Neoplasias de la Vesícula Biliar , Masculino , Humanos , Anciano , Neoplasias de la Vesícula Biliar/diagnóstico por imagen , Neoplasias de la Vesícula Biliar/cirugía , Vesícula Biliar/patología , Colecistectomía , Carcinoma Neuroendocrino/cirugía , Carcinoma Neuroendocrino/diagnóstico , Hígado/patologíaRESUMEN
We experienced a case of rapidly progressing transverse colon NEC that was treated with laparoscopic right hemispherectomy. A 72-year-old man underwent a follow-up lower gastrointestinal endoscopy at another hospital after a polyp resection. The examination showed a surrounding mass with stenosis of the intestinal tract of the transverse colon. A biopsy led to a diagnosis of poorly differentiated adenocarcinoma. A laparoscopic right hemicolectomy was performed of the transverse colon tumor. He was discharged on postoperative day 13 without complications, and NEC was diagnosed. We decided to administer postoperative adjuvant chemotherapy, starting with cisplatin plus etoposide. Four courses of postoperative adjuvant chemotherapy were completed. Approximately 1 year has passed since the operation, and progress has been observed in the outpatient department without recurrence.
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Colon Transverso , Neoplasias del Colon , Laparoscopía , Masculino , Humanos , Anciano , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/cirugía , Neoplasias del Colon/diagnóstico , Colon Transverso/cirugía , ColectomíaRESUMEN
BACKGROUND: Pharyngolaryngectomy with total esophagectomy (PLTE) is often indicated for patients with synchronous head and neck cancer and thoracic esophageal cancer or those with head and neck cancer extending to the upper mediastinum. A long conduit is required for the reconstruction, and the blood flow at the tip of the conduit is not always sufficient. Thus, reconstructive surgery after PLTE remains challenging, and optimal reconstruction methods have not been elucidated to date. METHODS: This analysis investigated 65 patients who underwent PLTE. The short-term outcomes among the procedures were compared to explore the optimal digestive reconstruction methods. RESULTS: We used a simple gastric conduit for 7 patients, a gastric conduit with microvascular anastomosis (MVA) for 10 patients, an elongated gastric conduit with an MVA for 20 patients, a gastric conduit combined with a free jejunum transfer (FJT) for 25 patients, and other procedures for 3 patients. Postoperatively, 17 (26.2%) of the patients experienced severe complications, classified as Clavien-Dindo grade 3b or higher, including graft failure for 3 patients (6.2%). Anastomotic leakage was found in six patients (9.2%), and all leakages occurred at the pharyngogastric anastomosis. The reoperation rate was 15.4% (n = 10), and three patients (4.6%) died of massive bleeding from major vessels. The patients who underwent simple gastric conduit more frequently had graft failure (P = 0.04), anastomotic leakage (P < 0.01), and reoperation (P = 0.04) than the patients treated with the other reconstructive methods. CONCLUSION: Additional procedures such as MVA, gastric tube elongation, and FJT contribute to improving the outcomes of reconstruction after PLTE.
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Esofagectomía , Anastomosis Quirúrgica , Neoplasias Esofágicas/cirugía , Esofagectomía/efectos adversos , Humanos , Laringectomía , Faringectomía , Estómago/cirugíaRESUMEN
The development of the cerebral cortex is directed by a series of methodically precise events, including progenitor cell proliferation, neural differentiation, and cell positioning. Over the past decade, many studies have demonstrated the critical contributions of Notch signaling in neurogenesis, including that in the developing telencephalon. However, in vivo evidence for the role of Notch signaling in cortical development still remains limited partly due to the redundant functions of four mammalian Notch paralogues and embryonic lethality of the knockout mice. Here, we utilized the conditional deletion and in vivo gene manipulation of Rbpj, a transcription factor that mediates signaling by all four Notch receptors, to overcome these challenges and examined the specific roles of Rbpj in cortical development. We report severe structural abnormalities in the embryonic and postnatal cerebral cortex in Rbpj conditional knockout mice, which provide strong in vivo corroboration of previously reported functions of Notch signaling in neural development. Our results also provide evidence for a novel dual role of Rbpj in cell type-specific regulation of two key developmental events in the cerebral cortex: the maintenance of the undifferentiated state of neural progenitor cells, and the radial and tangential allocation of neurons, possibly through stage-dependent differential regulation of Ngn1.
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Movimiento Celular , Corteza Cerebral/crecimiento & desarrollo , Proteína de Unión a la Señal Recombinante J de las Inmunoglobulinas/fisiología , Células-Madre Neurales/fisiología , Neuronas/fisiología , Animales , Diferenciación Celular , Corteza Cerebral/citología , Proteína de Unión a la Señal Recombinante J de las Inmunoglobulinas/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Células-Madre Neurales/citologíaRESUMEN
The development of effective respiratory syncytial virus (RSV) fusion glycoprotein (F protein) inhibitors against both wild-type and the D486N-mutant F protein is urgently required. We recently reported a 15-membered macrocyclic pyrazolo[1,5-a]pyrimidine derivative 4 that exhibited potent anti-RSV activities against not only wild-type, but also D486N-mutant F protein. However, NMR studies revealed that the 15-membered derivative 4 existed as a mixture of atropisomers. An optimization study of the linker moiety between the 2-position of the benzoyl moiety and the 7-position of the pyrazolo[1,5-a]pyrimidine scaffold identified a 16-membered derivative 42c with an amide linker that showed a rapid interconversion of atropisomers. Subsequent optimization of the 5-position of the pyrazolo[1,5-a]pyrimidine scaffold and the 5-position of the benzoyl moiety resulted in the discovery of a potent clinical candidate 60b for the treatment of RSV infections.
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Antivirales/química , Virus Sincitial Respiratorio Humano/metabolismo , Proteínas Virales de Fusión/antagonistas & inhibidores , Animales , Antivirales/metabolismo , Antivirales/farmacología , Sitios de Unión , Línea Celular , Permeabilidad de la Membrana Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Isomerismo , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/química , Ratones , Simulación de Dinámica Molecular , Mutación , Pirazoles/química , Pirazoles/metabolismo , Pirazoles/farmacología , Pirimidinas/química , Pirimidinas/metabolismo , Pirimidinas/farmacología , Relación Estructura-Actividad , Proteínas Virales de Fusión/genética , Proteínas Virales de Fusión/metabolismo , Internalización del Virus/efectos de los fármacosRESUMEN
BACKGROUND: Globally, the use of single DTaP-IPV/Hib vaccines that combine DTaP-IPV and Hib is widespread, but in Japan vaccination is usually concomitant at separate sites. The immunogenicity and safety of a primary vaccination series and booster of a combined pentavalent DTaP-IPV/Hib vaccine were evaluated and compared to separate administration of DTaP-IPV and Hib in Japanese infants. METHODS: Healthy Japanese infants were administered DTaP-IPV/Hib (Group A: N = 207) or DTaP-IPV + Hib (Group B: N = 207) by the subcutaneous (SC) or DTaP-IPV/Hib by the intramuscular (IM) route (Group C: N = 10). All subjects received a 3-dose primary vaccination series and a booster. Non-inferiority (Group A versus Group B) was tested post-primary series and subsequent post hoc analyses were performed for anti-Hib. Safety was assessed by parental reports. RESULTS: Non-inferiority for SC administration of Group A versus Group B for the primary series was demonstrated for antibody responses to all antigens except Hib using the threshold of 1.0 µg/mL. Post hoc analyses for anti-Hib demonstrated non-inferiority for the primary series response using 0.15 µg/mL, and for pre-booster antibody persistence and the booster response using 0.15 µg/mL and 1.0 µg/mL. The immune response was similar for each antigen following SC or IM administration. There were no safety concerns in any group, and a lower incidence of injection sites for the IM route was observed as expected. CONCLUSIONS: These data show the good immunogenicity and safety profile of the DTaP-IPV/Hib vaccine as a 3-dose infant primary series followed by a booster in the second year of life in Japan.
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Cápsulas Bacterianas/inmunología , Vacuna contra Difteria, Tétanos y Tos Ferina/inmunología , Vacunas contra Difteria, Tétanos y Tos Ferina Acelular/inmunología , Vacunas contra Haemophilus/inmunología , Inmunización Secundaria/métodos , Inmunogenicidad Vacunal , Vacuna Antipolio de Virus Inactivados/inmunología , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunología , Niño , Preescolar , Difteria/inmunología , Difteria/microbiología , Difteria/prevención & control , Vacuna contra Difteria, Tétanos y Tos Ferina/administración & dosificación , Vacuna contra Difteria, Tétanos y Tos Ferina/efectos adversos , Vacunas contra Difteria, Tétanos y Tos Ferina Acelular/administración & dosificación , Vacunas contra Difteria, Tétanos y Tos Ferina Acelular/efectos adversos , Femenino , Vacunas contra Haemophilus/administración & dosificación , Vacunas contra Haemophilus/efectos adversos , Haemophilus influenzae tipo b/inmunología , Voluntarios Sanos , Humanos , Esquemas de Inmunización , Incidencia , Lactante , Reacción en el Punto de Inyección/epidemiología , Reacción en el Punto de Inyección/inmunología , Inyecciones Intramusculares , Inyecciones Subcutáneas , Japón , Masculino , Meningitis por Haemophilus/inmunología , Meningitis por Haemophilus/microbiología , Meningitis por Haemophilus/prevención & control , Poliomielitis/inmunología , Poliomielitis/microbiología , Poliomielitis/prevención & control , Vacuna Antipolio de Virus Inactivados/administración & dosificación , Vacuna Antipolio de Virus Inactivados/efectos adversos , Tétanos/inmunología , Tétanos/microbiología , Tétanos/prevención & control , Vacunas Conjugadas/administración & dosificación , Vacunas Conjugadas/efectos adversos , Vacunas Conjugadas/inmunología , Tos Ferina/inmunología , Tos Ferina/microbiología , Tos Ferina/prevención & controlRESUMEN
Respiratory syncytial virus (RSV) is one of the most common causes of lower respiratory tract infections and a significant pathogen for both adults and children. Although two drugs have been approved for the treatment of RSV infections, the low therapeutic index of these drugs have led pharmaceutical companies to develop safe and effective small-molecule anti-RSV drugs. The pyrazolo[1,5-a]pyrimidine series of compounds containing a piperidine ring at the 2-position of the pyrazolo[1,5-a]pyrimidine scaffold are known as candidate RSV fusion (F) protein inhibitor drugs, such as presatovir and P3. The piperidine ring has been revealed to facilitate the formation of an appropriate dihedral angle between the pyrazolo[1,5-a]pyrimidine scaffold and the plane of the amide bond for exertion of anti-RSV activity. A molecular-dynamic study on newly designed compounds with an acyclic chain instead of the piperidine ring proposed and demonstrated a new series of pyrazolo[1,5-a]pyrimidine derivatives, such as 9c with a 1-methyaminopropyl moiety, showing similar dihedral angle distributions to those in presatovir. Compound 9c exhibited potent anti-RSV activity with an EC50 value of below 1 nM, which was similar to that of presatovir. A subsequent optimization study on the benzene ring of 9c led to the potent RSV F protein inhibitor 14f with an EC50 value of 0.15 nM. The possibility of improving the biological properties of anti-RSV agents by modification at the 7-position of pyrazolo[1,5-a]pyrimidine is also discussed.
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Antivirales/farmacología , Diseño de Fármacos , Pirazoles/farmacología , Pirimidinas/farmacología , Virus Sincitial Respiratorio Humano/efectos de los fármacos , Antivirales/síntesis química , Antivirales/química , Relación Dosis-Respuesta a Droga , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Pirimidinas/síntesis química , Pirimidinas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
OBJECTIVES: The prognosis for pharyngeal cancer is relatively poor. It is usually diagnosed in an advanced stage. Although the recent development of narrow-band imaging (NBI) and increased awareness among endoscopists have enabled detection of superficial pharyngeal cancer, these techniques are still not prevalent worldwide. Nevertheless, artificial intelligence (AI)-based deep learning has led to significant advancements in various medical fields. Here, we demonstrate the diagnostic ability of AI-based detection of pharyngeal cancer from endoscopic images in esophagogastroduodenoscopy. METHODS: We retrospectively collected 5403 training images of pharyngeal cancer from 202 superficial cancers and 45 advanced cancers from the Cancer Institute Hospital, Tokyo, Japan. Using these images, we developed an AI-based diagnostic system with convolutional neural networks. We prepared 1912 validation images from 35 patients with 40 pharyngeal cancers and 40 patients without pharyngeal cancer to evaluate our system. RESULTS: Our AI-based diagnostic system correctly detected all pharyngeal cancer lesions (40/40) in the patients with cancer, including three small lesions smaller than 10 mm. For each image, the AI-based system correctly detected pharyngeal cancers in images obtained via NBI with a sensitivity of 85.6%, much higher sensitivity than that for images obtained via white light imaging (70.1%). The novel diagnostic system took only 28 s to analyze 1912 validation images. CONCLUSIONS: The novel AI-based diagnostic system detected pharyngeal cancer with high sensitivity. It could facilitate early detection, thereby leading to better prognosis and quality of life for patients with pharyngeal cancers in the near future.
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Inteligencia Artificial , Neoplasias Faríngeas , Humanos , Japón , Redes Neurales de la Computación , Neoplasias Faríngeas/diagnóstico por imagen , Calidad de Vida , Estudios RetrospectivosRESUMEN
Research into hand-sensing is the focus of various fields, such as medical engineering and ergonomics. The thumb is essential in these studies, as there is great value in assessing its opposition function. However, evaluation methods in the medical field, such as physical examination and computed tomography, and existing sensing methods in the ergonomics field have various shortcomings. Therefore, we conducted a comparative study using a carbon nanotube-based strain sensor to assess whether opposition movement and opposition impairment can be detected in 20 hands of volunteers and 14 hands of patients with carpal tunnel syndrome while avoiding existing shortcomings. We assembled a measurement device with two sensors and attached it to the dorsal skin of the first carpometacarpal joint. We measured sensor expansion and calculated the correlation coefficient during thumb motion. The average correlation coefficient significantly increased in the patient group, and intrarater and interrater reliability were good. Thus, the device accurately detected thumb opposition impairment due to carpal tunnel syndrome, with superior sensitivity and specificity relative to conventional manual inspection, and may also detect opposition impairment due to various diseases. Additionally, in the future, it could be used as an easy, affordable, and accurate sensor in sensor gloves.
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Síndrome del Túnel Carpiano/diagnóstico , Nanotubos de Carbono , Pulgar/fisiopatología , Anciano , Femenino , Mano/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los ResultadosRESUMEN
Aflibercept plus 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) is a second-line treatment for metastatic colorectal cancer. This ancillary exploratory analysis of data in Japanese people was aimed at exploring the relationship between a set of potential prognostic biomarkers and efficacy endpoints following aflibercept plus FOLFIRI therapy. Sixty-two patients with metastatic colorectal cancer received aflibercept (4 mg/kg) plus FOLFIRI every 2 weeks. Seventy-eight potential protein biomarkers were chosen for analysis based on their roles in angiogenesis, tumor progression, and tumor-stroma interaction. Plasma levels of biomarkers at baseline and at pre-dose 3 (day 1 of treatment cycle 3) were measured in all patients by ELISA. Relationships between these levels and efficacy endpoints were assessed. Ten potential biomarkers had a ±30% change from baseline to pre-dose 3 (adjusted P < .001), with the greatest changes occurring in placental growth factor (median: +4716%) and vascular endothelial growth factor receptor 1 (+2171%). Baseline levels of eight potential biomarkers correlated with overall survival in a univariate Cox regression analysis: extracellular newly identified receptor for advanced glycation end-products binding protein, insulin-like growth factor-binding protein 1, interleukin-8, kallikrein 5, pulmonary surfactant-associated protein D, tissue inhibitor of metalloproteinases 1, tenascin-C, and tumor necrosis factor receptor 2. None correlated with progression-free survival or maximum tumor shrinkage. Pre-dose 3 levels did not correlate with any efficacy endpoints. Preliminary data show that these eight biomarkers could be associated with overall survival. ClinicalTrials.gov identifier: NCT01882868.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/sangre , Camptotecina/análogos & derivados , Neoplasias del Colon/tratamiento farmacológico , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Neoplasias del Recto/tratamiento farmacológico , Pueblo Asiatico , Camptotecina/uso terapéutico , Neoplasias del Colon/sangre , Neoplasias del Colon/mortalidad , Neoplasias del Colon/patología , Fluorouracilo/uso terapéutico , Humanos , Proteína 1 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Interleucina-8/sangre , Japón , Calicreínas/sangre , Leucovorina/uso terapéutico , Factor de Crecimiento Placentario/sangre , Pronóstico , Supervivencia sin Progresión , Estudios Prospectivos , Proteína D Asociada a Surfactante Pulmonar/sangre , Receptor para Productos Finales de Glicación Avanzada/sangre , Receptores Tipo II del Factor de Necrosis Tumoral/sangre , Neoplasias del Recto/sangre , Neoplasias del Recto/mortalidad , Neoplasias del Recto/patología , Análisis de Regresión , Tenascina/sangre , Inhibidor Tisular de Metaloproteinasa-1/sangre , Receptor 1 de Factores de Crecimiento Endotelial Vascular/sangreRESUMEN
Aflibercept targets vascular endothelial growth factor. The present study involved assessing the efficacy, safety and pharmacokinetics of aflibercept plus 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) as a second-line treatment for metastatic colorectal cancer (mCRC) in Japanese patients. Aflibercept (4 mg/kg) plus FOLFIRI was administered every 2 weeks in 62 patients with mCRC until disease progression, unacceptable toxicity or patient withdrawal. Tumors were imaged every 6 weeks. The primary endpoint was objective response rate (ORR); secondary endpoints were progression-free survival, overall survival, safety, and pharmacokinetics of aflibercept, irinotecan and 5-fluorouracil. A total of 60 patients were evaluated for ORR; 50 had received prior bevacizumab. The ORR was 8.3% (95% confidence interval [CI]: 1.3%-15.3%), and the disease control rate (DCR) was 80.0% (69.9%-90.1%). The median progression-free survival was 5.42 months (4.14-6.70 months) and the median overall survival was 15.59 months (11.20-19.81 months). No treatment-related deaths were observed, and no significant drug-drug interactions were found. The most common treatment-emergent adverse events were neutropenia and decreased appetite. Free aflibercept had a mean maximum concentration (coefficient of variation) of 73.2 µg/mL (15%), clearance of 0.805 L/d (22%) and volume of distribution of 6.2 L (18%); aflibercept bound with vascular endothelial growth factor had a clearance of 0.162 L/d (9%) (N = 62). Aflibercept did not significantly affect the pharmacokinetics of irinotecan or 5-fluorouracil: The clearance was 11.1 L/h/m2 (28%) for irinotecan and, at steady state, 72.6 L/h/m2 (56%) for 5-fluorouracil (N = 10). Adding aflibercept to FOLFIRI was shown to be beneficial and well-tolerated in Japanese patients with mCRC. ClinicalTrials.gov Identifier: NCT01882868.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Pueblo Asiatico , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Neoplasias Colorrectales/metabolismo , Supervivencia sin Enfermedad , Fluorouracilo/administración & dosificación , Humanos , Leucovorina/administración & dosificación , Masculino , Estudios Prospectivos , Receptores de Factores de Crecimiento Endotelial Vascular/administración & dosificación , Proteínas Recombinantes de Fusión/administración & dosificación , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: In health examinations for local inhabitants in cadmium-polluted areas, only healthy people are investigated, suggesting that patients with severe cadmium nephropathy or itai-itai disease may be overlooked. Therefore, we performed hospital-based screening to detect patients with cadmium nephropathy in two core medical institutes in cadmium-polluted areas in Akita prefecture, Japan. METHODS: Subjects for this screening were selected from patients aged 60 years or older with elevated serum creatinine levels and no definite renal diseases. We enrolled 35 subjects from a hospital in Odate city and 22 from a clinic in Kosaka town. Urinary ß2-microglobulin and blood and urinary cadmium levels were measured. RESULTS: The criteria for renal tubular dysfunction and the over-accumulation of cadmium were set as a urinary ß2-microglobulin level higher than 10,000 µg/g cr. and a blood cadmium level higher than 6 µg/L or urinary cadmium level higher than 10 µg/g cr., respectively. Subjects who fulfilled both criteria were diagnosed with cadmium nephropathy. Six out of 57 patients (10.5% of all subjects) had cadmium nephropathy. CONCLUSIONS: This hospital-based screening is a very effective strategy for detecting patients with cadmium nephropathy in cadmium-polluted areas, playing a complementary role in health examinations for local inhabitants. REGISTRATION NUMBER: No. 6, date of registration: 6 June, 2010 (Akita Rosai Hospital), and No. 1117, date of registration: 26 December, 2013 (Akita University).