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The accumulation of α-synuclein (α-syn) aggregates in specific brain regions is a hallmark of synucleinopathies including Parkinson disease (PD). α-Syn aggregates propagate in a "prion-like" manner and can be transferred inside lysosomes to recipient cells through tunneling nanotubes (TNTs). However, how lysosomes participate in the spreading of α-syn aggregates is unclear. Here, by using super-resolution (SR) and electron microscopy (EM), we find that α-syn fibrils affect the morphology of lysosomes and impair their function in neuronal cells. In addition, we demonstrate that α-syn fibrils induce peripheral redistribution of lysosomes, likely mediated by transcription factor EB (TFEB), increasing the efficiency of α-syn fibrils' transfer to neighboring cells. We also show that lysosomal membrane permeabilization (LMP) allows the seeding of soluble α-syn in cells that have taken up α-syn fibrils from the culture medium, and, more importantly, in healthy cells in coculture, following lysosome-mediated transfer of the fibrils. Moreover, we demonstrate that seeding occurs mainly at lysosomes in both donor and acceptor cells, after uptake of α-syn fibrils from the medium and following their transfer, respectively. Finally, by using a heterotypic coculture system, we determine the origin and nature of the lysosomes transferred between cells, and we show that donor cells bearing α-syn fibrils transfer damaged lysosomes to acceptor cells, while also receiving healthy lysosomes from them. These findings thus contribute to the elucidation of the mechanism by which α-syn fibrils spread through TNTs, while also revealing the crucial role of lysosomes, working as a Trojan horse for both seeding and propagation of disease pathology.
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Lisosomas/metabolismo , Nanotubos , Pliegue de Proteína , alfa-Sinucleína/metabolismo , Animales , Permeabilidad de la Membrana Celular , Técnicas de Cocultivo , Humanos , Lisosomas/ultraestructura , Microscopía ElectrónicaRESUMEN
TDP-43-positive inclusions in neurons are a hallmark of several neurodegenerative diseases including familial amyotrophic lateral sclerosis (fALS) caused by pathogenic TARDBP variants as well as more common non-Mendelian sporadic ALS (sALS). Here we report a G376V-TDP-43 missense variant in the C-terminal prion-like domain of the protein in two French families affected by an autosomal dominant myopathy but not fulfilling diagnostic criteria for ALS. Patients from both families presented with progressive weakness and atrophy of distal muscles, starting in their 5th-7th decade. Muscle biopsies revealed a degenerative myopathy characterized by accumulation of rimmed (autophagic) vacuoles, disruption of sarcomere integrity and severe myofibrillar disorganization. The G376â V variant altered a highly conserved amino acid residue and was absent in databases on human genome variation. Variant pathogenicity was supported by in silico analyses and functional studies. The G376â V mutant increased the formation of cytoplasmic TDP-43 condensates in cell culture models, promoted assembly into high molecular weight oligomers and aggregates in vitro, and altered morphology of TDP-43 condensates arising from phase separation. Moreover, the variant led to the formation of cytoplasmic TDP-43 condensates in patient-derived myoblasts and induced abnormal mRNA splicing in patient muscle tissue. The identification of individuals with TDP-43-related myopathy but not ALS implies that TARDBP missense variants may have more pleiotropic effects than previously anticipated and support a primary role for TDP-43 in skeletal muscle pathophysiology. We propose to include TARDBP screening in the genetic work-up of patients with late-onset distal myopathy. Further research is warranted to examine the precise pathogenic mechanisms of TARDBP variants causing either a neurodegenerative or myopathic phenotype.
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PURPOSE: Pulmonary complications (PC) are a serious condition with a 20% mortality rate. However, few reports have examined risk factors for PC after colorectal surgery. This study investigated the frequency, characteristics, and risk factors for PC after colorectal cancer surgery. METHODS: Between January 2016 and December 2022, we retrospectively reviewed 3979 consecutive patients who underwent colorectal cancer surgery in seven participating hospitals. Patients were divided into patients who experienced PC (PC group, n = 54) and patients who did not (non-PC group, n = 3925). Clinical and pathological features were compared between groups. RESULTS: Fifty-four patients (1.5%) developed PC, of whom 2 patients (3.7%) died due to PC. Age was greater (80 years vs 71 years; p < 0.001), frequency of chronic obstructive pulmonary distress was greater (9.3% vs 3.2%; p = 0.029), performance status was poorer (p < 0.001), the proportion of underweight was higher (42.6% vs 13.4%, p < 0.001), frequency of open surgery was greater (24.1% vs 9.3%; p < 0.001), and blood loss was greater (40 mL vs 22 mL; p < 0.001) in the PC group. Multivariate analysis revealed male sex (odds ratio (OR) 2.165, 95% confidence interval (CI) 1.176-3.986; p = 0.013), greater age (OR 3.180, 95%CI 1.798-5.624; p < 0.001), underweight (OR 3.961, 95%CI 2.210-7.100; p < 0.001), and poorer ASA-PS (OR 3.828, 95%CI 2.144-6.834; p < 0.001) as independent predictors of PC. CONCLUSION: Our study revealed male sex, greater age, underweight, and poorer ASA-PS as factors associated with development of PC, and suggested that pre- and postoperative rehabilitation and pneumonia control measures should be implemented for patients at high risk of PC.
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Neoplasias Colorrectales , Complicaciones Posoperatorias , Humanos , Masculino , Factores de Riesgo , Femenino , Anciano , Neoplasias Colorrectales/cirugía , Neoplasias Colorrectales/patología , Japón/epidemiología , Anciano de 80 o más Años , Complicaciones Posoperatorias/etiología , Persona de Mediana Edad , Enfermedades Pulmonares/etiología , Enfermedades Pulmonares/epidemiología , Estudios Retrospectivos , Cirugía Colorrectal/efectos adversos , Pueblos del Este de AsiaRESUMEN
PURPOSE: Positive pathologic lymph nodes in colorectal cancer represent an important prognostic indicator. Whether lymph node distribution or the number of metastatic nodes is more strongly associated with survival prediction remains controversial. METHODS: Among 3449 colorectal cancer surgeries performed at Nagasaki University Hospital and five affiliated institutions from April 2016 to March 2022, we investigated 604 patients who underwent laparoscopic radical resection and were diagnosed with pathological stage III cancer. Patients were divided into two groups according to whether they had central vessel metastasis (LND3 group, n=42) or not (LND1/2 group, n=562). After adjusting for background factors using propensity score matching, the LND3 group included 42 patients and the LND1/2 group included 40 patients. Patient background characteristics and prognosis were compared between these two groups. RESULTS: Before matching, frequencies of right-side colon cancer (64.3% vs 38.1%, p=0.001), multivisceral resection (11.9% vs 4.4%, p=0.039), clinical N2 status (40.5% vs 22.6%, p=0.032), and pathological N2 (73.8% vs 22.6%, p<0.001) were all greater, and the number of lymph nodes retrieved was higher (24 vs 19, p=0.042) in the LND3 group. After matching, no differences in any clinical factors were evident between groups. Five-year RFS (44.8% vs 77.1%, p=0.004) and OS (43.1% vs 83.2%, p<0.001) were worse in the LND3 group. Adjuvant chemotherapy improved RFS (adjuvant chemotherapy (+) vs adjuvant chemotherapy (-): 62.1% vs 27.7%, p=0.047) in the LND3 group. CONCLUSION: LND3-positive patients show poorer prognosis than LND1/2 patients and should be treated with an appropriate perioperative treatment strategy.
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Neoplasias Colorrectales , Laparoscopía , Humanos , Pronóstico , Japón , Colectomía , Ganglios Linfáticos , Neoplasias Colorrectales/cirugíaRESUMEN
PURPOSE: The Endoscopic Surgical Skill Qualification System was established in Japan to evaluate safe endoscopic surgical techniques and teaching skills. Trainee surgeons obtaining this certification in rural hospitals are disadvantaged by the limited number of surgical opportunities. To address this problem, we established a surgical training system to educate trainee surgeons. METHODS: Eighteen certified expert surgeons affiliated with our department were classified into an experienced training system group (E group, n = 9) and a non-experienced group (NE group, n = 9). Results of the training system were then compared between the groups. RESULTS: The number of years required to become board certified was shorter in the E group (14 years) than that in the NE group (18 years). Likewise, the number of surgical procedures performed before certification was lower in the E group (n = 30) than that in the NE group (n = 50). An expert surgeon was involved in the creation of the certification video of all the E group participants. A questionnaire to board-certified surgeons revealed that guidance by a board-certified surgeon and trainee education (surgical training system) was useful for obtaining certification. CONCLUSIONS: Continuous surgical training, starting with trainee surgeons, appears useful for expediting their acquisition of technical certification in rural areas.
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Laparoscopía , Cirujanos , Humanos , Japón , Competencia Clínica , Certificación , Cirujanos/educaciónRESUMEN
PURPOSE: Colorectal cancer is not common in patients under 40 years old, and its associations with clinical features and the prognosis remain uncertain. METHODS: Using a multicenter database, we retrospectively reviewed 3015 patients who underwent colorectal surgery between 2016 and 2021. Patients were divided by age into those < 40 years old (young; n = 52), 40-54 years old (middle-aged; n = 254) and > 54 years old (old; n = 2709). We then investigated age-related differences in clinicopathological features, perioperative outcomes and the prognosis. RESULTS: The proportion of young patients increased annually from 0.63% in 2016 to 2.10% in 2021. Female patients were more frequent, the performance status was better, tumors were larger, clinically node-positive and poorly differentiated adenocarcinomas were more frequent, postoperative complications were less frequent, and the hospital stay was shorter in young patients than in older patients. Young age was an independent predictor of a low risk of postoperative complications (odds ratio, 0.204; 95% confidence interval, 0.049-0.849; p = 0.028). With pathologically node-positive status, adjuvant chemotherapy was more frequent in young patients (100%) than in middle-aged (73.7%) or old (51.8%) patients (p < 0.001), and the 3-year relapse-free survival was better in the young group than in others. CONCLUSION: Despite higher rates of advanced tumors in younger patients, adequate adjuvant chemotherapy appears to improve the relapse-free survival.
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Neoplasias Colorrectales , Recurrencia Local de Neoplasia , Persona de Mediana Edad , Humanos , Femenino , Anciano , Adulto , Estudios Retrospectivos , Japón/epidemiología , Recurrencia Local de Neoplasia/patología , Pronóstico , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/patología , Neoplasias Colorrectales/patología , Estadificación de Neoplasias , Factores de EdadRESUMEN
PURPOSE: The C-reactive protein-albumin-lymphocyte (CALLY) index is a novel score that offers a good reflection of nutritional status, inflammatory response, and immune system status. The CALLY index is reported to correlate with the prognosis of various carcinomas. The purpose of the present study was to investigate the association between the CALLY index and the short-term prognosis of obstructive colorectal cancer managed with a colonic stent. METHODS: The subjects of this retrospective study were 263 patients who underwent colorectal resection after colonic stenting for obstructive colorectal cancer between 2016 and 2023. Patients were classified into a group with a low CALLY index (CALLY-L group, n = 85) and a group with a high (CALLY-H group, n = 178) CALLY index. RESULTS: The CALLY-L group had greater blood loss (53 mL vs 20 mL, p = 0.002) and higher poor performance status (PS3; 20% vs 10.1%, p = 0.033), open surgery (21.2% vs 7.3%, p = 0.001), distant metastases (41.2% vs 20.8%, p = 0.01), and postoperative complications (30.6% vs. 18.5%, p = 0.039) than the CALLY-H group. Multivariate analysis identified a prolonged operative time (odds ratio 1.983, 95% confidence interval 1.013-3.881; p = 0.045), greater blood loss (odds ratio 2.572, 95% confidence interval 1.291-5.129; p = 0.007) and a low CALLY index (odds ratio 1.961, 95% confidence interval 1.013-3.795; p = 0.045) as independent predictors of complications. CONCLUSION: The CALLY index may be a useful predictor of postoperative complications of obstructive colorectal cancer.
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PURPOSE: The prognostic value of the lymphocyte-to-monocyte (LMR) ratio has been reported for various cancers, including colorectal cancer (CRC). The insertion of colonic stents is considered effective for patients with surgically indicated obstructive CRC, but their LMR can vary depending on factors such as inflammation associated with stent dilation and improvement of obstructive colitis. However, the usefulness of the LMR in patients with obstructive CRC and colonic stents and the optimal timing for its measurement remain unclear. We conducted this study to investigate the relationship between the pre-stent LMR and the mid-term prognosis of patients with obstructive CRC and stents as a bridge to surgery (BTS). METHODS: The subjects of this retrospective multicenter study were 175 patients with pathological stage 2 or 3 CRC. Patients were divided into a low pre-stent LMR group (n = 87) and a high pre-stent LMR group (n = 83). RESULTS: Only 3-year relapse-free survival differed significantly between the low and high pre-stent LMR groups (39.9% vs. 63.6%, respectively; p = 0.015). The pre-stent LMR represented a prognostic factor for relapse-free survival in multivariate analyses (hazard ratio 2.052, 95% confidence interval 1.242-3.389; p = 0.005), but not for overall survival. CONCLUSIONS: A low pre-stent LMR is a prognostic factor for postoperative recurrence in patients with obstructive CRC and a colonic stent as a BTS.
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BACKGROUND: The effect of laparoscopic surgery on short-term outcomes in colorectal cancer patients over 90 years old has remained unclear. METHODS: We reviewed 87 colorectal cancer patients aged over 90 years who underwent surgery between 2016 and 2022. Patients were divided into an open surgery group (n = 22) and a laparoscopic surgery group (n = 65). The aim of this study was to investigate the effect of laparoscopic surgery on postoperative outcome in elderly colorectal cancer patients, as compared to open surgery. RESULTS: Seventy-eight patients (89.7%) had comorbidities. Frequency of advanced T stage was lower with laparoscopic surgery (p = 0.021). Operation time was longer (open surgery 146 min vs. laparoscopic surgery 203 min; p = 0.002) and blood loss was less (105 mL vs. 20 mL, respectively; p < 0.001) with laparoscopic surgery. Length of hospitalization was longer with open surgery (22 days vs. 18 days, respectively; p = 0.007). Frequency of infectious complications was lower with laparoscopic surgery (18.5%) than with open surgery (45.5%; p = 0.021). Multivariate analysis revealed open surgery (p = 0.026; odds ratio, 3.535; 95% confidence interval, 1.159-10.781) as an independent predictor of postoperative infectious complications. CONCLUSIONS: Laparoscopic colorectal resection for patients over 90 years old is a useful procedure that reduces postoperative infectious complications.
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Neoplasias Colorrectales , Laparoscopía , Anciano de 80 o más Años , Humanos , Colectomía/efectos adversos , Colectomía/métodos , Neoplasias Colorrectales/cirugía , Japón/epidemiología , Laparoscopía/efectos adversos , Laparoscopía/métodos , Complicaciones Posoperatorias/epidemiología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Aberrant cytoplasmic accumulation of an RNA-binding protein, fused in sarcoma (FUS), characterizes the neuropathology of subtypes of ALS and frontotemporal lobar degeneration, although the effects of post-translational modifications of FUS, especially phosphorylation, on its neurotoxicity have not been fully characterized. Here, we show that casein kinase 1δ (CK1δ) phosphorylates FUS at 10 serine/threonine residues in vitro using mass spectrometric analyses. We also show that phosphorylation by CK1δ or CK1ε significantly increased the solubility of FUS in human embryonic kidney 293 cells. In transgenic Drosophila that overexpress wt or P525L ALS-mutant human FUS in the retina or in neurons, we found coexpression of human CK1δ or its Drosophila isologue Dco in the photoreceptor neurons significantly ameliorated the observed retinal degeneration, and neuronal coexpression of human CK1δ extended fly life span. Taken together, our data suggest a novel regulatory mechanism of the assembly and toxicity of FUS through CK1δ/CK1ε-mediated phosphorylation, which could represent a potential therapeutic target in FUS proteinopathies.
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Esclerosis Amiotrófica Lateral , Caseína Cinasa 1 épsilon , Quinasa Idelta de la Caseína , Proteínas de Drosophila , Degeneración Lobar Frontotemporal , Sarcoma , Esclerosis Amiotrófica Lateral/metabolismo , Animales , Caseína Cinasa 1 épsilon/genética , Quinasa Idelta de la Caseína/genética , Quinasa Idelta de la Caseína/metabolismo , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Degeneración Lobar Frontotemporal/metabolismo , Humanos , Mutación , Proteína FUS de Unión a ARN/genética , Proteína FUS de Unión a ARN/metabolismoRESUMEN
Tunneling nanotubes (TNTs) are actin-based transient tubular connections that allow direct communication between distant cells. TNTs play an important role in several physiological (development, immunity, and tissue regeneration) and pathological (cancer, neurodegeneration, and pathogens transmission) processes. Here, we report that the Wnt/Ca2+ pathway, an intracellular cascade that is involved in actin cytoskeleton remodeling, has a role in TNT formation and TNT-mediated transfer of cargoes. Specifically, we found that Ca2+ /calmodulin-dependent protein kinase II (CaMKII), a transducer of the Wnt/Ca2+ pathway, regulates TNTs in a neuronal cell line and in primary neurons. We identified the ß isoform of CaMKII as a key molecule in modulating TNT formation and transfer, showing that this depends on the actin-binding activity of the protein. Finally, we found that the transfer of vesicles and aggregated α-synuclein between primary neurons can be regulated by the activation of the Wnt/Ca2+ pathway. Our findings suggest that Wnt/Ca2+ pathway could be a novel promising target for therapies designed to impair TNT-mediated propagation of pathogens.
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Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/fisiología , Calcio/metabolismo , Comunicación Celular , Membrana Celular/metabolismo , Nanotubos/química , Neuronas/fisiología , Proteínas Wnt/metabolismo , Actinas/metabolismo , Animales , Señalización del Calcio , Células Cultivadas , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/citología , Transducción de SeñalRESUMEN
The phenomenon of 'prion-like propagation' in which aggregates of abnormal amyloid-fibrilized protein propagate between neurons and spread pathology, is attracting attention as a new mechanism in neurodegenerative diseases. There is a strong correlation between the accumulation or spread of abnormal tau aggregates and the clinical symptoms of tauopathies. Microtubule-associated protein tau (MAPT) contains a microtubule-binding domain that consists of three or four repeats (3R/4R) due to alternative mRNA splicing of transcripts for the MAPT gene. Although a number of models for tau propagation have been reported, most use 4R human tau transgenic mice or adult wild-type mice expressing only endogenous 4R tau and these models have not been able to reproduce the pathology of Alzheimer's disease in which 3R and 4R tau accumulate simultaneously, or that of Pick's disease in which only 3R tau is aggregated. These deficiencies may reflect differences between human and rodent tau isoforms in the brain. To overcome this problem, we used genome editing techniques to generate mice that express an equal ratio of endogenous 3R and 4R tau, even after they become adults. We injected these mice with sarkosyl-insoluble fractions derived from the brains of human tauopathy patients such as those afflicted with Alzheimer's disease (3R and 4R tauopathy), corticobasal degeneration (4R tauopathy) or Pick's disease (3R tauopathy). At 8-9 months following intracerebral injection of mice, histopathological and biochemical analyses revealed that the abnormal accumulation of tau was seed-dependent, with 3R and 4R tau in Alzheimer's disease-injected brains, 4R tau only in corticobasal degeneration-injected brains and 3R tau only in Pick disease-injected brains, all of which contained isoforms related to those found in the injected seeds. The injected abnormal tau was seeded, and accumulated at the site of injection and at neural connections, predominantly within the same site. The abnormal tau newly accumulated was found to be endogenous in these mice and to have crossed the species barrier. Of particular importance, Pick's body-like inclusions were observed in Pick's disease-injected mice, and accumulations characteristic of Pick's disease were reproduced, suggesting that we have developed the first model that recapitulates the pathology of Pick's disease. These models are not only useful for elucidating the mechanism of propagation of tau pathology involving both 3R and 4R isoforms, but can also reproduce the pathology of tauopathies, which should lead to the discovery of new therapeutic agents.
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Enfermedad de Alzheimer , Enfermedad de Pick , Tauopatías , Enfermedad de Alzheimer/patología , Animales , Encéfalo/patología , Humanos , Ratones , Ratones Transgénicos , Enfermedad de Pick/patología , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Tauopatías/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismoRESUMEN
PURPOSE: Several guidelines have recommended surgical resection for localized peritoneal metastases, but the prognosis remains poor. In addition, the efficacy of adjuvant chemotherapy (AC) after curative resection is under debate. The present study compared long-term outcomes between curative and non-curative resection and evaluated the effects of AC after curative resection. METHODS: Using a multicenter database, we retrospectively reviewed 123 colorectal cancer patients with peritoneal metastases between April 2016 and December 2021. Of these patients, 49 underwent curative resection, and 74 underwent non-curative resection. RESULTS: The frequency of broad metastases was lower in the curative resection group (8.2%) than in the non-curative resection group (43.2%, p < 0.001). Among all patients, 5-year overall survival rate was higher in the curative resection group (43.0%) than in the non-curative resection group (7.3%, p = 0.004). Among patients who underwent curative resection, 5-year overall survival rate was significantly higher in the AC group (48.2%) than in the non-AC group (38.1%, p = 0.037). Multivariate analysis of all patients revealed pathological N status and non-curative resection as independent predictors of overall survival. In patients who underwent curative resection, advanced age was an independent predictor of relapse-free survival, and AC was an independent predictor of overall survival. CONCLUSION: This multicenter study of colorectal cancer patients with peritoneal metastases revealed that prognosis was more favorable for curable cases than for non-curable cases. Prognosis was more favorable in the AC group than in the non-AC group after curative resection.
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Neoplasias Colorrectales , Neoplasias Peritoneales , Humanos , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/cirugía , Neoplasias Peritoneales/secundario , Estudios Retrospectivos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/cirugía , Neoplasias Colorrectales/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Pronóstico , Quimioterapia Adyuvante , Tasa de SupervivenciaRESUMEN
PURPOSE: Laparoscopic colectomy for transverse colon cancer (TCC) can be technically demanding due to the anatomical complexity of the region. In Japan, the Endoscopic Surgical Skill Qualification System (ESSQS) was established to improve the skill of laparoscopic surgeons and further develop surgical teams. We examined the safety and feasibility of laparoscopic colectomy for TCC and evaluated the effects of the Japanese ESSQS in facilitating this approach. METHODS: We retrospectively reviewed 136 patients who underwent laparoscopic colectomy for TCC between April 2016 and December 2021. Patients were divided into an ESSQS-qualified surgeon group (surgery performed by an ESSQS-qualified surgeon, n = 52) and a non ESSQS-qualified surgeon (surgery performed by a non ESSQS-unqualified surgeon, n = 84). Clinicopathological and surgical features were compared between groups. RESULTS: Postoperative complications occurred in 37 patients (27.2%). The proportion of patients who developed postoperative complications was lower in the ESSQS-qualified surgeon group (8.0%) than that in the non ESSQS-qualified surgeon group (34.5%; p < 0.017). Multivariate analysis revealed "Operation by ESSQS-qualified surgeon surgeon" (odds ratio (OR) 0.360, 95% confidence interval (CI) 0.140-0.924; p = 0.033), blood loss (OR 4.146, 95% CI 1.688-10.184; p = 0.002), and clinical N status (OR 4.563, 95% CI 1.814-11.474; p = 0.001) as factors independently associated with postoperative complications. CONCLUSION: The present multicenter study confirmed the feasibility and safety of laparoscopic colectomy for TCC and revealed that ESSQS-qualified surgeon achieved better surgical outcomes.
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Colectomía , Colon Transverso , Neoplasias del Colon , Laparoscopía , Humanos , Colectomía/efectos adversos , Colon Transverso/cirugía , Colon Transverso/patología , Neoplasias del Colon/cirugía , Neoplasias del Colon/patología , Laparoscopía/efectos adversos , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
PURPOSE: Properly selecting patients for aggressive curative resection for pulmonary metastases (PMs) from colorectal cancer (CRC) is desirable. We purposed to clarify prognostic factors and risk factors for early recurrence after metachronous PM resection. METHODS: Clinical data of 151 patients who underwent R0 resection for metachronous PMs from CRC at two institutions between 2008 and 2021 were reviewed. RESULTS: Seventy-six patients (50.3%) were male, and the median age was 71 (42-91) years. The numbers of colon/rectal cancers were 76/75, with pStage I/II/III/IV/unknown in 15/34/86/13/3. The duration from primary surgery to PM was 19.7 (1.0-106.4) months. The follow-up period was 41.9 (0.3-156.2) months. The 1-, 3-, and 5-year recurrence-free survival (RFS) rates were 75.1%, 53.7%, and 51.1%, and the 1-, 3-, and 5-year overall survival (OS) rates were 97.7%, 87.5%, and 68.2%. On multivariate analysis, lymph node metastasis of the primary lesion (HR 1.683, 95%CI 1.003-2.824, p = 0.049) was an independent predictor of poor RFS, and history of resection for extrapulmonary metastasis (e-PM) (HR 2.328, 95%CI 1.139-4.761, p = 0.021) was an independent predictor of poor OS. Patients who experienced early recurrence (< 6 months) after PM resection showed poorer OS than others (3-year OS 50.8% vs. 90.2%, p = 0.002). On multivariate analysis, e-PM was an independent predictor of early recurrence after PM resection (OR 3.989, 95%CI 1.002-15.885, p = 0.049). CONCLUSION: Since a history of e-PM was a predictor of early recurrence and poor OS after R0 resection for PM, surgical treatment of patients with a history of e-PM should be considered carefully.
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Neoplasias Colorrectales , Neoplasias Pulmonares , Metastasectomía , Humanos , Masculino , Anciano , Femenino , Resultado del Tratamiento , Neoplasias Colorrectales/patología , Neoplasias Pulmonares/cirugía , Neoplasias Pulmonares/secundario , Tasa de Supervivencia , Recurrencia Local de Neoplasia/cirugía , Enfermedad Crónica , Pronóstico , Estudios RetrospectivosRESUMEN
BACKGROUND: Slot-scan digital radiography (SSDR) is equipped with detachable scatter grids and a variable copper filter. In this study, this function was used to obtain parameters for low-dose imaging for whole-spine imaging. METHODS: With the scatter grid removed and the beam-hardening (BH) filters (0.0, 0.1, 0.2, or 0.3 mm) inserted, the tube voltage (80, 90, 100, 110, or 120 kV) and the exposure time were adjusted to 20 different parameters that produce equivalent image quality. Slot-scan radiographs of an acrylic phantom were acquired with the set parameters, and the optimal parameters (four types) for each filter were determined using the figure of merit. For the four types of parameters obtained in the previous section, SSDR was performed on whole-spine phantoms by varying the tube current, and the parameter with the lowest radiation dose was determined by visual evaluation. RESULTS: The parameters for each filter according to the FOM results were 90 kV, 400 mA, and 2.8 ms for 0.0 mm thickness; 100 kV, 400 mA, and 2.0 ms for 0.1 mm thickness; 100 kV, 400 mA, and 2.8 ms for 0.2 mm thickness; and 110 kV, 400 mA, and 2.2 ms for 0.3 mm thickness. Visual evaluation of the varying tube currents was performed using these four parameters when the BH filter thicknesses were 0.0, 0.1, 0.2, and 0.3 mm. The entrance surface dose was 59.44 µGy at 90 kV, 125 mA, and 2.8 ms; 57.39 µGy at 100 kV, 250 mA, and 2.0 ms; 46.89 µGy at 100 kV, 250 mA, and 2.8 ms; and 39.48 µGy at 110 kV, 250 mA, and 2.2 ms, indicating that the 0.3-mm BH filter was associated with the minimum dose. CONCLUSION: Whole-spine SSDR could reduce the dose by 79% while maintaining the image quality.
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Intensificación de Imagen Radiográfica , Humanos , Intensificación de Imagen Radiográfica/métodos , Dosis de Radiación , Fantasmas de Imagen , CintigrafíaRESUMEN
PURPOSE: For advanced left colon cancer, lymph node dissection at the root of the inferior mesenteric artery is recommended. Whether the left colic artery (LCA) should be preserved or resected remains contentious. METHODS: The 367 patients who underwent laparoscopic sigmoidectomy or anterior resection and who were pathologically node-positive were reviewed. Patients were divided into LCA-preserving group (LCA-P, n = 60) and LCA-non-preserving group (LCA-NP, n = 307). Propensity score matching was applied to minimize selection bias and 59 patients were matched. RESULTS: Before matching, the rates of poor performance status and cardiovascular disease were higher in the LCA-P group (p < 0.001). After matching, operation time was longer (276 vs. 240 min, p = 0.001), the frequency of splenic flexure mobilization (62.7% vs. 33.9%, p = 0.003) and lymphovascular invasion (84.7% vs. 55.9%, p = 0.001) was higher in the LCA-P group. Severe postoperative complications (CD ≥ 3) occurred only in the LCA-NP group (0% vs. 8.4%, p = 0.028). The median follow-up period was 38.5 months (range 2.0-70.0 months). The 5-year RFS rates (67.8% vs. 66.0%, p = 0.871) and OS rates (80.4% vs. 74.9%, p = 0.308) were comparable between the groups. CONCLUSIONS: Laparoscopic LCA-sparing surgery for left-sided colorectal cancer reduces the risk of severe complications and offers a favorable long-term prognosis.
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Neoplasias del Colon , Laparoscopía , Neoplasias del Recto , Humanos , Arteria Mesentérica Inferior/cirugía , Escisión del Ganglio Linfático , Colon Sigmoide/cirugía , Neoplasias del Recto/cirugía , Neoplasias del Recto/patología , Neoplasias del Colon/cirugía , Estudios RetrospectivosRESUMEN
Tauopathies are a subset of neurodegenerative diseases characterized by abnormal tau inclusions. Specifically, three-repeat tau and four-repeat tau in Alzheimer's disease, three-repeat tau in Pick's disease (PiD) and four-repeat tau in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) form amyloid-like fibrous structures that accumulate in neurons and/or glial cells. Amplification and cell-to-cell transmission of abnormal tau based on the prion hypothesis are believed to explain the onset and progression of tauopathies. Recent studies support not only the self-propagation of abnormal tau, but also the presence of conformationally distinct tau aggregates, namely tau strains. Cryogenic electron microscopy analyses of patient-derived tau filaments have revealed disease-specific ordered tau structures. However, it remains unclear whether the ultrastructural and biochemical properties of tau strains are inherited during the amplification of abnormal tau in the brain. In this study, we investigated template-dependent amplification of tau aggregates using a cellular model of seeded aggregation. Tau strains extracted from human tauopathies caused strain-dependent accumulation of insoluble filamentous tau in SH-SY5Y cells. The seeding activity towards full-length four-repeat tau substrate was highest in CBD-tau seeds, followed by PSP-tau and Alzheimer's disease (AD)-tau seeds, while AD-tau seeds showed higher seeding activity than PiD-tau seeds towards three-repeat tau substrate. Abnormal tau amplified in cells inherited the ultrastructural and biochemical properties of the original seeds. These results strongly suggest that the structural differences of patient-derived tau strains underlie the diversity of tauopathies, and that seeded aggregation and filament formation mimicking the pathogenesis of sporadic tauopathy can be reproduced in cultured cells. Our results indicate that the disease-specific conformation of tau aggregates determines the tau isoform substrate that is recruited for templated amplification, and also influences the prion-like seeding activity.
Asunto(s)
Encéfalo/metabolismo , Agregación Patológica de Proteínas/metabolismo , Tauopatías/metabolismo , Proteínas tau/metabolismo , Encéfalo/patología , Línea Celular Tumoral , Humanos , Ovillos Neurofibrilares/metabolismo , Ovillos Neurofibrilares/patología , Neuronas/metabolismo , Neuronas/patología , Agregación Patológica de Proteínas/patología , Tauopatías/patologíaRESUMEN
BACKGROUND: The recurrence rate after hepatectomy for colorectal cancer liver metastasis (CRLM) is high, and there is no consensus regarding the effect of adjuvant chemotherapy (AC) using oxaliplatin (doublet AC) in these patients. METHODS: The present study included 91 patients who underwent hepatectomy for complete resection at our hospitals between 2008 and 2018. Based on whether or not they had undergone doublet AC, patients were divided into AC (n = 35) and non-AC (n = 56) groups. The recurrent risk was evaluated by the Memorial Sloan Kettering Cancer Center clinical risk score (MSKCC-CRS). RESULTS: The number of females and median age were higher in the AC group (51.4% vs 25.0%, p = 0.010 and 67 vs 61 years, p = 0.012, respectively). The median follow-up period was 45 months (range, 6-101 months). Doublet AC was an independent prognostic factor for 5-year relapse-free survival (hazard ratio, 0.225; 95%CI, 0.097-0.522; p < 0.001) and for 5-year overall survival (hazard ratio, 0.165; 95%CI, 0.057-0.476; p < 0.001) in multivariate analysis. In patients with a high risk of recurrence (MSKCC-CRS 3-5), 5-year relapse-free survival and 5-year overall survival was higher in the doublet AC group than in the non-AC group (p < 0.01). In low-risk patients (MSKCC-CRS 0-2), 5-year relapse-free survival and 5-year overall survival were similar between the groups. CONCLUSIONS: Doublet AC could have a positive effect on prognosis after curative resection of CRLM, especially in high-risk patients. The selection of patients and AC regimen should take into consideration the risk of recurrence.
Asunto(s)
Neoplasias Colorrectales , Neoplasias Hepáticas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia Adyuvante , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Femenino , Fluorouracilo/uso terapéutico , Hepatectomía , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/cirugía , Persona de Mediana Edad , Recurrencia Local de Neoplasia/cirugía , Oxaliplatino/efectos adversos , Pronóstico , Estudios Retrospectivos , Factores de RiesgoRESUMEN
PURPOSE: Although adjuvant chemotherapy (AC) using fluoro-pyrimidine and oxaliplatin (FU + oxaliplatin) is recommended after curative resection for locally advanced colon cancer patients, several randomized controlled trials have shown no additional effect of oxaliplatin in patients aged ≥ 70 years. Here, we examined the effectiveness of FU + oxaliplatin on the long-term outcome of old patients with a high risk of recurrence. METHODS: This multicenter, retrospective study included 346 colon cancer patients diagnosed with pathological T4 and/or N2 disease from 2016 to 2020. They were divided into an old group (≥ 70 years, n = 197) and a young group (< 70 years, n = 167). Propensity score matching was used to minimize selection bias, and 126 patients per group were matched. RESULTS: Before matching, the rates of poor performance status (p < 0.001) and the presence of comorbidities (76.1% vs. 47.9%, p < 0.001) were higher in the old group. Although all baseline factors were similar between groups, after matching, the AC rate was lower in the old group (45.2% vs. 65.1%, p = 0.002). In the old group, relapse-free (82.2% vs. 55.6% and 69.6%, p < 0.05) and overall survival (83.1% vs. 80.0% and 44.4%, p < 0.05) rates were significantly higher in the AC patients with FU + oxaliplatin than in the AC patients with only FU and the non-AC patients. CONCLUSION: The selected old colon cancer patients with a high risk of recurrence gained an additional benefit with respect to prognosis from FU + oxaliplatin as AC.