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BACKGROUND: Ascites increases perioperative complications and risk of death, but is not an absolute contraindication for colectomy in patients with colon cancer. It remains unclear whether postoperative risks can be minimized using a laparoscopic versus open approach. METHODS: Data were retrospectively analyzed from 2152 patients with ascites who underwent laparoscopic or open partial colectomy with diagnosis of colon cancer from 2005 to 2013 using the American College of Surgeons National Surgical Quality Improvement Program database. Postoperative outcomes were analyzed using two-sample tests of proportions and two-sample T tests. Adjusted odds ratios (OR) or ß coefficients for postoperative complications, hospital length of stay, and 30-day mortality were calculated using multivariable logistic or linear regression. P values <0.05 two-tailed were considered statistically significant. RESULTS: 205 patients (9.53%) with ascites underwent laparoscopic colectomy (LC). There was no significant difference in operative time between laparoscopic versus open surgery (145 vs. 146 min, P = 0.69). LC was associated with decreased likelihood of overall complications (adjusted OR 0.7 95% CI 0.4-1.0, P = 0.046) and shorter hospital length of stay (9 days vs. 15 days, adjusted ß = -4.2, 95% CI -7.7 to -0.7, P = 0.018). There was no difference in 30-day mortality (adjusted OR 0.82, 95% CI 0.50-1.35, P = 0.429). CONCLUSIONS: Laparoscopic colectomy decreases postoperative complications and hospital length of stay in patients with colon cancer and ascites. Laparoscopic approach should be considered for patients in this high-risk population.
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Ascite/complicações , Colectomia/métodos , Neoplasias do Colo/cirurgia , Laparoscopia , Tempo de Internação/estatística & dados numéricos , Hepatopatias/complicações , Complicações Pós-Operatórias/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/complicações , Bases de Dados Factuais , Feminino , Humanos , Modelos Lineares , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Fatores de Risco , Resultado do TratamentoRESUMO
The ability to escape apoptosis is a hallmark of cancer-initiating cells and a key factor of resistance to oncolytic therapy. Here, we identify FAM96A as a ubiquitous, evolutionarily conserved apoptosome-activating protein and investigate its potential pro-apoptotic tumor suppressor function in gastrointestinal stromal tumors (GISTs). Interaction between FAM96A and apoptotic peptidase activating factor 1 (APAF1) was identified in yeast two-hybrid screen and further studied by deletion mutants, glutathione-S-transferase pull-down, co-immunoprecipitation and immunofluorescence. Effects of FAM96A overexpression and knock-down on apoptosis sensitivity were examined in cancer cells and zebrafish embryos. Expression of FAM96A in GISTs and histogenetically related cells including interstitial cells of Cajal (ICCs), "fibroblast-like cells" (FLCs) and ICC stem cells (ICC-SCs) was investigated by Northern blotting, reverse transcription-polymerase chain reaction, immunohistochemistry and Western immunoblotting. Tumorigenicity of GIST cells and transformed murine ICC-SCs stably transduced to re-express FAM96A was studied by xeno- and allografting into immunocompromised mice. FAM96A was found to bind APAF1 and to enhance the induction of mitochondrial apoptosis. FAM96A protein or mRNA was dramatically reduced or lost in 106 of 108 GIST samples representing three independent patient cohorts. Whereas ICCs, ICC-SCs and FLCs, the presumed normal counterparts of GIST, were found to robustly express FAM96A protein and mRNA, FAM96A expression was much reduced in tumorigenic ICC-SCs. Re-expression of FAM96A in GIST cells and transformed ICC-SCs increased apoptosis sensitivity and diminished tumorigenicity. Our data suggest FAM96A is a novel pro-apoptotic tumor suppressor that is lost during GIST tumorigenesis.
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Apoptose/genética , Proteínas de Transporte/genética , Tumores do Estroma Gastrointestinal/genética , Proteínas Supressoras de Tumor/genética , Animais , Fator Apoptótico 1 Ativador de Proteases/genética , Linhagem Celular , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Expressão Gênica/genética , Células HEK293 , Humanos , Células Intersticiais de Cajal/metabolismo , Metaloproteínas , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Mitocôndrias/genética , Peixe-Zebra/genéticaRESUMO
Context: Early prediction of hypothalamic-pituitary-adrenal (HPA) axis function following transsphenoidal surgery (TSS) can improve patient safety and reduce costs. Objective: Systematic measurement of ACTH and cortisol at extubation following anesthesia to predict remission from Cushing's disease (CD) and HPA axis preservation following non-CD surgery. Design: Retrospective analysis of clinical data between August 2015 and May 2022. Setting: Referral center. Patients: Consecutive patients (n = 129) undergoing TSS who had perioperative ACTH and cortisol measurements. Interventions: ACTH and cortisol measurement at extubation. Further serial 6-hourly measurements in CD patients. Main outcome measures: Prediction of future HPA axis status based on ACTH/cortisol at extubation. Results: ACTH and cortisol increased sharply in all patients at extubation. CD patients (n = 101) had lower ACTH values than non-CD patients (110.1 vs 293.1â pg/mL; P < 0.01). In non-CD patients, lower plasma ACTH at extubation predicted the need for eventual corticosteroid replacement (105.8 vs 449.1â pg/mL, P < 0.01). In CD patients, the peak post-extubation cortisol at 6â hours was a robust predictor for nonremission (60.7 vs 219.2â µg/dL, P = 0.03). However, normalized early postoperative value (NEPV; the post-extubation values minus the peak preoperative CRH or desmopressin test values) of cortisol reliably distinguished nonremission earlier, at the time of extubation (-6.1 vs 5.9, P = 0.01), and later. Conclusions: We found that at extubation following TSS, ACTH can predict the need for eventual steroid replacement in non-Cushing's patients. In patients with CD, we found a robust prediction of nonremission with NEPV cortisol at extubation and later.
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PURPOSE: Missense mutated von Hippel Lindau (VHL) protein (pVHL) maintains intrinsic function but undergoes proteasomal degradation and tumor initiation and/or progression in VHL disease. Vorinostat can rescue missense mutated pVHL and arrest tumor growth in preclinical models. We asked whether short-term oral vorinostat could rescue pVHL in central nervous system hemangioblastomas in patients with germline missense VHL. PATIENTS AND METHODS: We administered oral vorinostat to 7 subjects (ages 46.0 ± 14.5 years) and then removed symptomatic hemangioblastomas surgically (ClinicalTrials.gov identifier NCT02108002). RESULTS: Vorinostat was tolerated without serious adverse events by all patients. pVHL expression was elevated in neoplastic stromal cells compared with untreated hemangioblastomas from same patients. We found transcriptional suppression of downstream hypoxia-inducible factor (HIF) effectors. Mechanistically, vorinostat prevented Hsp90 recruitment to mutated pVHL in vitro. The effects of vorinostat on the Hsp90-pVHL interaction, pVHL rescue, and transcriptional repression of downstream HIF effectors was independent of the location of the missense mutation on the VHL locus. We confirmed a neoplastic stromal cell-specific effect in suppression of protumorigenic pathways with single-nucleus transcriptomic profiling. CONCLUSIONS: We found that oral vorinostat treatment in patients with germline missense VHL mutations has a potent biologic effect that warrants further clinical study. These results provide biologic evidence to support the use of proteostasis modulation for the treatment of syndromic solid tumors involving protein misfolding. Proteostasis modulation with vorinostat rescues missense mutated VHL protein. Further clinical trials are needed to demonstrate tumor growth arrest.
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Produtos Biológicos , Neoplasias do Sistema Nervoso Central , Hemangioblastoma , Doença de von Hippel-Lindau , Humanos , Doença de von Hippel-Lindau/genética , Vorinostat , Proteostase , Proteína Supressora de Tumor Von Hippel-Lindau/genéticaRESUMO
CONTEXT: Single ACTH measurements have limited ability to distinguish patients with Cushing's disease (CD) from those in remission or with other conditions. OBJECTIVE: To investigate the changes in ACTH levels before and after transsphenoidal surgery (TSS) to identify trends that could confirm remission from CD and help establish ACTH cutoffs for targeted clinical trials in CD. DESIGN: Retrospective analysis of CD patients who underwent TSS from 2005 to -2019. SETTING: Referral center. PATIENTS: CD patients (n = 253) with ACTH measurements before and after TSS. INTERVENTIONS: TSS for CD. MAIN OUTCOME MEASURES: Remission after TSS. RESULTS: Remission was observed in 223 patients after TSS. Those in remission had higher ACTH variability at AM (P = .02) and PM (P < .001) time points compared to nonremission. The nonremission group had a significantly narrower diurnal range compared to the remission group (P = <.0001). A decrease in plasma ACTH of ≥50% from mean preoperative levels predicted CD remission after TSS, especially when using PM values. The absolute plasma ACTH concentration and ratio of preoperative to postoperative values were significantly associated with nonremission after multivariable logistic regression (adj P < .001 and .001, respectively). CONCLUSIONS: Our findings suggest that ACTH variability is suppressed in CD, and remission from CD is associated with the restoration of this variability. Furthermore, a decrease in plasma ACTH by 50% or more may serve as a predictor of remission post-TSS. These insights could guide clinicians in developing rational outcome measures for interventions targeting CD adenomas.
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Adenoma , Hipersecreção Hipofisária de ACTH , Humanos , Hipersecreção Hipofisária de ACTH/diagnóstico , Hipersecreção Hipofisária de ACTH/cirurgia , Resultado do Tratamento , Estudos Retrospectivos , Adenoma/cirurgia , Hormônio AdrenocorticotrópicoRESUMO
OBJECTIVE: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common problem during the postoperative course after pituitary surgery. Although treatment of this condition is well characterized, prevention strategies are less studied and reported. The authors sought to characterize outcomes and predictive factors of SIADH after implementation of routine postoperative fluid restriction for patients undergoing endoscopic transsphenoidal surgery for pituitary adenoma. METHODS: In March 2018, routine postoperative fluid restriction to 1000 ml/day for 7 days was instituted for all patients who underwent surgery for pituitary adenoma. These patients were compared with patients who underwent surgery for pituitary adenoma between March 2016 and March 2018, prior to implementation of routine fluid restriction. Patients with preoperative history of diabetes insipidus (DI) or concern for postsurgical DI were excluded. Patients were followed by neuroendocrinologists and neurosurgeons, and sodium levels were checked between 7 and 10 days postoperatively. SIADH was defined by a serum sodium level less than 136 mmol/L, with or without symptoms within 10 days after surgery. Thirty-day readmission was recorded and reviewed to determine underlying reasons. RESULTS: In total, 82 patients in the fluid-unrestricted cohort and 135 patients in the fluid-restricted cohort were analyzed. The patients in the fluid-restricted cohort had a significantly lower rate of postoperative SIADH than patients in the fluid-unrestricted cohort (5% vs 15%, adjusted OR [95% CI] 0.1 [0.0-0.6], p = 0.01). Higher BMI was associated with lower rate of postoperative SIADH (adjusted OR [95%] 0.9 [0.9-1.0], p = 0.03), whereas female sex was associated with higher rate of SIADH (adjusted OR [95% CI] 3.1 [1.1-9.8], p = 0.03). There was no difference in the 30-day readmission rates between patients in the fluid-unrestricted and fluid-restricted cohorts (4% vs 7%, adjusted OR [95% CI] 0.5 [0-5.1], p = 0.56). Thirty-day readmission was more likely for patients with history of hypertension (adjusted OR [95% CI] 5.7 [1.3-26.3], p = 0.02) and less likely for White patients (adjusted OR [95% CI] 0.3 [0.1-0.9], p = 0.04). CONCLUSIONS: Routine fluid restriction reduced the rate of SIADH in patients who underwent surgery for pituitary adenoma but was not associated with reduction in 30-day readmission rate.
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Adenoma , Diabetes Insípido , Hiponatremia , Síndrome de Secreção Inadequada de HAD , Neoplasias Hipofisárias , Adenoma/cirurgia , Diabetes Insípido/etiologia , Diabetes Insípido/prevenção & controle , Feminino , Humanos , Síndrome de Secreção Inadequada de HAD/diagnóstico , Síndrome de Secreção Inadequada de HAD/etiologia , Síndrome de Secreção Inadequada de HAD/prevenção & controle , Neoplasias Hipofisárias/cirurgia , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controle , Estudos Retrospectivos , Sódio , VasopressinasRESUMO
Sporadic pituitary adenomas occur in over 10% of the population. Hormone-secreting adenomas, including those causing Cushing's disease (CD), cause severe morbidity and early mortality. Mechanistic studies of CD are hindered by a lack of in vitro models and control normal human pituitary glands. Here, we surgically annotate adenomas and adjacent normal glands in 25 of 34 patients. Using single-cell RNA sequencing (RNA-seq) analysis of 27594 cells, we identify CD adenoma transcriptomic signatures compared with adjacent normal cells, with validation by bulk RNA-seq, DNA methylation, qRT-PCR, and immunohistochemistry. CD adenoma cells include a subpopulation of proliferating, terminally differentiated corticotrophs. In CD adenomas, we find recurrent promoter hypomethylation and transcriptional upregulation of PMAIP1 (encoding pro-apoptotic BH3-only bcl-2 protein noxa) but paradoxical noxa downregulation. Using primary CD adenoma cell cultures and a corticotroph-enriched mouse cell line, we find that selective proteasomal inhibition with bortezomib stabilizes noxa and induces apoptosis, indicating its utility as an anti-tumor agent.
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Adenoma , Hipersecreção Hipofisária de ACTH , Neoplasias Hipofisárias , Adenoma/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Animais , Apoptose , Humanos , Camundongos , Hipersecreção Hipofisária de ACTH/genética , Hipersecreção Hipofisária de ACTH/patologia , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologiaRESUMO
OBJECTIVE: Degenerative cervical myelopathy (DCM) results in significant morbidity. The duration of symptoms prior to surgical intervention may be associated with postoperative surgical outcomes and functional recovery. The authors' objective was to investigate whether delayed surgical treatment for DCM is associated with worsened postoperative outcomes. METHODS: Data from 1036 patients across 14 surgical centers in the Quality Outcomes Database were analyzed. Baseline demographic characteristics and findings of preoperative and postoperative symptom evaluations, including duration of symptoms, were assessed. Postoperative functional outcomes were measured using the Neck Disability Index (NDI) and modified Japanese Orthopaedic Association (mJOA) scale. Symptom duration was classified as either less than 12 months or 12 months or greater. Univariable and multivariable regression were used to evaluate for the associations between symptom duration and postoperative outcomes. RESULTS: In this study, 513 patients (49.5%) presented with symptom duration < 12 months, and 523 (50.5%) had symptoms for 12 months or longer. Patients with longer symptom duration had higher BMI and higher prevalence of anxiety and diabetes (all p < 0.05). Symptom duration ≥ 12 months was associated with higher average baseline NDI score (41 vs 36, p < 0.01). However, improvements in NDI scores from baseline were not significantly different between groups at 3 months (p = 0.77) or 12 months (p = 0.51). Likewise, the authors found no significant differences between groups in changes in mJOA scores from baseline to 3 months or 12 months (both p > 0.05). CONCLUSIONS: Surgical intervention resulted in improved mJOA and NDI scores at 3 months, and this improvement was sustained in both patients with short and longer initial symptom duration. Patients with DCM can still undergo successful surgical management despite delayed presentation.
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Vértebras Cervicais , Doenças da Medula Espinal , Vértebras Cervicais/cirurgia , Descompressão Cirúrgica/métodos , Humanos , Período Pós-Operatório , Estudos Prospectivos , Doenças da Medula Espinal/diagnóstico , Resultado do TratamentoRESUMO
OBJECTIVE: Resection of meningiomas in direct contact with the anterior optic apparatus carries risk of injury to the visual pathway. Stereotactic radiosurgery (SRS) offers a minimally invasive alternative. However, its use is limited owing to the risk of radiation-induced optic neuropathy. Few SRS studies have specifically assessed the risks and benefits of treating meningiomas in direct contact with the optic nerve, chiasm, or optic tract. The authors hypothesized that SRS is safe for select patients with meningiomas in direct contact with the anterior optic apparatus. METHODS: The authors performed an international multicenter retrospective analysis of 328 patients across 11 institutions. All patients had meningiomas in direct contract with the optic apparatus. Patients were followed for a median duration of 56 months after SRS. Neurological examinations, including visual function evaluations, were performed at follow-up visits. Clinical and treatment variables were collected at each site according to protocol. Tumor volumes were assessed with serial MR imaging. Variables predictive of visual deficit were identified using univariable and multivariable logistic regression. RESULTS: SRS was the initial treatment modality for 64.6% of patients, and 93% of patients received SRS as a single fraction. Visual information was available for 302 patients. Of these patients, visual decline occurred in 29 patients (9.6%), of whom 12 (41.4%) had evidence of tumor progression. Visual decline in the remaining 17 patients (5.6%) was not associated with tumor progression. Pre-SRS Karnofsky Performance Status predicted visual decline in adjusted analysis (adjusted OR 0.9, 95% CI 0.9-1.0, p < 0.01). Follow-up imaging data were available for 322 patients. Of these patients, 294 patients (91.3%) had radiographic evidence of stability or tumor regression at last follow up. Symptom duration was associated with tumor progression in adjusted analysis (adjusted OR 1.01, adjusted 95% CI 1.0-1.02, adjusted p = 0.02). CONCLUSIONS: In this international multicenter study, the vast majority of patients exhibited tumor control and preservation of visual function when SRS was used to treat meningioma in direct contact with the anterior optic pathways. SRS is a relatively safe treatment modality for select patients with perioptic meningiomas in direct contact with the optic apparatus.
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Neoplasias Meníngeas , Meningioma , Radiocirurgia , Seguimentos , Humanos , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/radioterapia , Neoplasias Meníngeas/cirurgia , Meningioma/diagnóstico por imagem , Meningioma/radioterapia , Meningioma/cirurgia , Radiocirurgia/efeitos adversos , Radiocirurgia/métodos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND & AIMS: Gastrointestinal stromal tumors (GIST) are related to interstitial cells of Cajal (ICC) and often contain activating stem cell factor receptor (Kit) or platelet-derived growth factor receptor alpha (Pdgfra) mutations. Kit/Pdgfra inhibitors such as imatinib mesylate have increased progression-free survival in metastatic GIST but are not curative. In mouse models we investigated whether Kit(low) ICC progenitors could represent an inherently Kit/Pdgfra inhibitor-resistant reservoir for GIST. METHODS: Isolated Kit(low)Cd44(+)Cd34(+) cells were characterized after serial cloning. The tumorigenic potential of spontaneously transformed cells was investigated in nude mice. The Kit(low)Cd44(+)Cd34(+) cells' responsiveness to Kit activation and blockade was studied by enumerating them in Kit(K641E) mice (a GIST model), in mice with defective Kit signaling, and pharmacologically. RESULTS: Single isolated Kit(low)Cd44(+)Cd34(+) cells were clonogenic and capable of self-renewal and differentiation into ICC. In nude mice, spontaneously transformed cells formed malignant tumors expressing GIST markers. The Kit(low)Cd44(+)Cd34(+) cells were resistant to in vitro Kit blockade, including by imatinib, and occurred in normal numbers in mice with reduced Kit signaling. In Kit(K641E) mice, the mutant ICC stem cells were grossly hyperplastic but remained imatinib-resistant. In contrast, the cancer stem, cell-targeting drug salinomycin blocked the proliferation of Kit(low)Cd44(+)Cd34(+) cells and increased their sensitivity to imatinib. CONCLUSIONS: Kit(low)Cd44(+)Cd34(+) progenitors are true stem cells for normal and hyperplastic ICC and give rise to GIST. Resistance to Kit/Pdgfra inhibitors is inherent in GIST and is caused by the native ICC stem cells' lack of dependence on Kit for survival, which is maintained after the acquisition of oncogenic Kit mutation. Cancer stem cell drugs may target these cells.
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Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Tumores do Estroma Gastrointestinal/patologia , Células Intersticiais de Cajal/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Animais , Antígenos CD34/análise , Benzamidas , Biomarcadores Tumorais/metabolismo , Diferenciação Celular , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Células Clonais , Relação Dose-Resposta a Droga , Regulação para Baixo , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/metabolismo , Receptores de Hialuronatos/análise , Hiperplasia , Mesilato de Imatinib , Células Intersticiais de Cajal/imunologia , Células Intersticiais de Cajal/metabolismo , Células Intersticiais de Cajal/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Nus , Mutação , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Piranos/farmacologia , Pirimidinas/farmacologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Fatores de Tempo , Carga TumoralRESUMO
Robotic-navigated screw placement has potential for higher precision and accuracy. Robotic assistance is well-described in the lumbar spine, however only few studies have evaluated its use in the cervical spine. Surgical treatment for hangman's fractures after nonunion typically involves C2-3 anterior fusion or posterior occipito-cervical fusion. However, occipito-cervical fusion involves loss of mobility in the cervical spine with associated morbidity. We have previously described a minimally invasive approach using percutaneous screw fixation with X-ray navigation. Robotic assistance is ideally suited for cervical fusion given smaller bony anatomy and adjacent critical structures. We describe a young healthy patient who presented with a hangman's fracture initially managed conservatively with immobilization. She presented with nonunion and persistent symptoms. Surgical options considered included anterior cervical discectomy and fusion, or posterior cervical fusion with or without extension to the occiput. These options would have involved some loss of flexion/extension and rotational motion with associated morbidity. We performed percutaneous screw fixation of the hangman's fracture using MAZOR-X robotic navigation and achieved good radiographic fracture reduction with accurate screw placement. To our knowledge this is the first case of a robotic-assisted percutaneous screw fixation for a hangman's fracture. Robotic-navigated screw placement can be used safely and accurately for cervical spine fractures.
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BACKGROUND: Brainstem and spinal cord hemangioblastomas are a common manifestation of von Hippel-Lindau (VHL) disease. Cysts and associated syringes are the most common cause of significant morbidity in these patients. Surgical treatment of symptomatic hemangioblastomas are often complicated by the presence of multiple potential lesions, leading to cyst and syrinx formation. OBSERVATIONS: The authors present a case of a patient with multiple VHL-related hemangioblastomas who presented with syringobulbia and holocord syrinx. Resection of two cyst wall hemangioblastomas and one cervical hemangioblastoma only transiently improved syringobulbia. Eventual resolution of syringobulbia and collapse of the holocord syrinx only occurred following removal of a large lower thoracic hemangioblastoma. LESSONS: Surgical management of hemangioblastomas and associated cysts in patients with VHL should only target lesions most likely contributing to neurological deficits as excess surgical intervention risks treatment-related morbidity. The authors illustrate how anatomical and pathophysiological considerations as well as patient symptoms are key to identifying target lesions for resection and developing deliberate treatment plans.
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BACKGROUND: Giant pituitary macroadenomas with a diameter >4 cm are rare tumors, accounting for only about 5% of pituitary adenomas. They are more difficult to maximally resect safely owing to limited access as well as encasement of adjacent structures. Acidophil stem cell adenomas are rare immature neoplasms proposed to derive from common progenitor cells of somatotroph and lactotroph cells. These adenomas comprise about 4.3% of surgically removed pituitary adenomas. No previous reports have described acidophil stem cell adenomas that grow to the size of giant macroadenomas. This rare entity poses special challenges given the need for maximal safe resection in an immature neoplasm. OBSERVATIONS: The authors report a 21-year-old female who presented with 3 years of progressive visual decline and a giant macroadenoma. She underwent endoscopic transsphenoidal surgery for decompression. Given the tumor size and involvement of adjacent critical structures, gross-total resection was not achieved. The authors review the literature on giant pituitary adenomas and provide a discussion on clinical management for this rare entity. LESSONS: The authors present a very rare case of a giant pituitary adenoma of acidophil stem cell origin and discuss the technical and management challenges in this rare entity.
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Molecular mechanisms of malignant transformation in spinal cord gliomas are not well-understood. Our objective was to investigate genetic causes of malignant transformation in a primary spinal cord glioma. A 32-year-old female patient presented with bilateral lower extremity weakness and was diagnosed with a primary spinal cord glioma from T9 to T12, with a syrinx extending from the craniocervical junction to the conus. She underwent resection in 2006. Pathology showed an abundance of Rosenthal fibers, calcification and degenerative features consistent with a low-grade pilocytic astrocytoma. She presented in 2020 with tumor recurrence and underwent re-resection. Whole exome sequencing, DNA methylation profiling and immunohistochemistry were performed on her initial and recurrent tumor samples. Immunohistochemical profiling of her recurrent tumor showed pleomorphic cells with extensive necrosis consistent with a high-grade glioma. DNA methylation profiling showed that the initial tumor clustered with pilocytic astrocytomas, whereas the recurrent lesion clustered with anaplastic astrocytomas, confirming malignant transformation. Whole-exome sequencing showed interim acquisition of a rare fibroblast growth factor receptor-transforming acidic coiled-coil (FGFR1-TACC1) gene fusion. We report an FGFR1-TACC1 fusion associated with malignant transformation in a primary spinal cord glioma. Our study adds to growing reports of FGFR-TACC fusions, which are amenable to receptor tyrosine kinase inhibition.
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BACKGROUND & AIMS: Gastric dysfunction in the elderly may cause reduced food intake, frailty, and increased mortality. The pacemaker and neuromodulator cells interstitial cells of Cajal (ICC) decline with age in humans, and their loss contributes to gastric dysfunction in progeric klotho mice hypomorphic for the anti-aging Klotho protein. The mechanisms of ICC depletion remain unclear. Klotho attenuates Wnt (wingless-type MMTV integration site) signaling. Here, we examined whether unopposed Wnt signaling could underlie aging-associated ICC loss by up-regulating transformation related protein TRP53 in ICC stem cells (ICC-SC). METHODS: Mice aged 1-107 weeks, klotho mice, APCΔ468 mice with overactive Wnt signaling, mouse ICC-SC, and human gastric smooth muscles were studied by RNA sequencing, reverse transcription-polymerase chain reaction, immunoblots, immunofluorescence, histochemistry, flow cytometry, and methyltetrazolium, ethynyl/bromodeoxyuridine incorporation, and ex-vivo gastric compliance assays. Cells were manipulated pharmacologically and by gene overexpression and RNA interference. RESULTS: The klotho and aged mice showed similar ICC loss and impaired gastric compliance. ICC-SC decline preceded ICC depletion. Canonical Wnt signaling and TRP53 increased in gastric muscles of klotho and aged mice and middle-aged humans. Overstimulated canonical Wnt signaling increased DNA damage response and TRP53 and reduced ICC-SC self-renewal and gastric ICC. TRP53 induction persistently inhibited G1/S and G2/M cell cycle phase transitions without activating apoptosis, autophagy, cellular quiescence, or canonical markers/mediators of senescence. G1/S block reflected increased cyclin-dependent kinase inhibitor 1B and reduced cyclin D1 from reduced extracellular signal-regulated kinase activity. CONCLUSIONS: Increased Wnt signaling causes age-related ICC loss by up-regulating TRP53, which induces persistent ICC-SC cell cycle arrest without up-regulating canonical senescence markers.
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Envelhecimento/fisiologia , Senescência Celular/fisiologia , Células Intersticiais de Cajal/fisiologia , Estômago/fisiologia , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Pontos de Checagem do Ciclo Celular , Feminino , Humanos , Proteínas Klotho/genética , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Modelos Animais , Estômago/citologia , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima , Via de Sinalização Wnt , Adulto JovemRESUMO
Gastrointestinal functions decline with ageing leading to impaired quality of life, and increased morbidity and mortality. Neurodegeneration is believed to underlie ageing-associated dysmotilities but the mechanisms have not been fully elucidated. We used progeric mice deficient in the anti-ageing peptide Klotho to investigate the contribution of key cell types of the gastric musculature to ageing-associated changes in stomach function and the underlying mechanisms. Klotho expression, enteric neurons, interstitial cells of Cajal (ICC), smooth muscle cells and electrical activity were assessed by immunofluorescence, confocal microscopy, 3-dimensional reconstruction, flow cytometry, quantitative RT-PCR, Western immunoblotting and intracellular recordings. Gastric emptying of solids was analysed by the [13C]octanoic acid breath test. Circulating and tissue trophic factors were measured by enzyme immunoassays and quantitative RT-PCR. The role of oxidative stress was investigated in organotypic cultures. Klotho expression was detected in gastric glands, myenteric neurons and smooth muscle cells. Progeric Klotho-deficient mice had profound loss of ICC and ICC stem cells without a significant decrease in neuron counts, expression of neuronal nitric oxide synthase or smooth muscle myosin. Slow wave amplitude and nitrergic inhibitory junction potentials were reduced while solid emptying was unchanged. Klotho-deficient mice were marantic and had low insulin, insulin-like growth factor-I and membrane-bound stem cell factor. Klotho deficiency accentuated oxidative stress and ICC loss. We conclude that Klotho-deficient, progeric mice display a gastric phenotype resembling human ageing and involving profound ICC loss. Klotho protects ICC by preserving their precursors, limiting oxidative stress, and maintaining nutritional status and normal levels of trophic factors important for ICC differentiation.
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Esvaziamento Gástrico , Mucosa Gástrica/metabolismo , Estresse Oxidativo , Progéria/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Fator de Células-Tronco/metabolismo , Células-Tronco/metabolismo , Potenciais de Ação , Animais , Western Blotting , Diferenciação Celular , Modelos Animais de Doenças , Regulação para Baixo , Estimulação Elétrica , Sistema Nervoso Entérico/metabolismo , Citometria de Fluxo , Imunofluorescência , Regulação da Expressão Gênica , Genótipo , Glucuronidase/genética , Glucuronidase/metabolismo , Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Células Intersticiais de Cajal/metabolismo , Proteínas Klotho , Camundongos , Camundongos Mutantes , Microscopia Confocal , Mutação , Miócitos de Músculo Liso/metabolismo , Estado Nutricional , Fenótipo , Progéria/genética , Progéria/fisiopatologia , Proteínas Proto-Oncogênicas c-kit/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Células-Tronco/genética , Estômago/inervação , Estômago/fisiopatologia , Técnicas de Cultura de TecidosRESUMO
BACKGROUND: Reversible cerebral vasoconstriction syndrome (RCVS) is a rare complication after carotid endarterectomy (CEA). Only a limited number of prior cases of RCVS have been reported after CEA for asymptomatic carotid stenosis. CASE DESCRIPTION: In this report we present an unusual case of RCVS associated with multifocal intraparenchymal hemorrhage, subarachnoid hemorrhage, subdural hematoma, and ischemic stroke after CEA for asymptomatic carotid stenosis. We review preexisting studies and draw correlations with implications for understanding the mechanisms of RCVS. CONCLUSIONS: A high index of suspicion should be maintained in post-CEA patients presenting with headaches or focal neurologic deficits, and vigilance with serial vascular imaging may help minimize long-term complications.
Assuntos
Estenose das Carótidas/cirurgia , Endarterectomia das Carótidas/efeitos adversos , Vasoespasmo Intracraniano/etiologia , Vasoespasmo Intracraniano/patologia , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: The number of patients undergoing preoperative risk stratification in the United States is expected to increase as the population ages. A large percentage of patients undergo some form of preoperative testing, and society guidelines suggest that up to 50% of the testing in lower risk surgical subgroups is unnecessary. The Revised Cardiac Risk Index and the risk calculator of the American College of Surgeons National Surgical Quality Improvement Program are widely used tools as the first step of preoperative cardiac evaluation. The Revised Cardiac Risk Index was developed to fill a need for objective perioperative cardiac risk evaluation. Despite the ease of use of Revised Cardiac Risk Index, it is uncertain if the stratification is accurate for surgical patients because its accuracy in large surgical samples has not been tested. With the National Surgical Quality Improvement Program risk calculator having excellent accuracy in estimating cardiac complications (area under the receiver operating characteristic 0.895), a unique opportunity to test the predictive accuracy of postsurgical cardiac events became available. The purpose of this study is to determine the accuracy of the Revised Cardiac Risk Index for predicting cardiovascular complications after adhesiolysis for small bowel obstruction. METHODS: From 2005 to 2015, 34,032 cases of open or laparoscopic adhesiolysis (Current Procedural Terminology codes 44005 and 44180) for small bowel obstruction (International Classification of Diseases, 10th edition [ICD-10]) were analyzed using the National Surgical Quality Improvement Program dataset. Revised Cardiac Risk Index estimates were calculated for each case and compared to reported cardiovascular complications (myocardial infarction or cardiac arrest) using univariable logistic regression. Overall predictive accuracy was assessed by measuring model discrimination (area under the receiver operating characteristic) and model calibration (Hosmer-Lemeshow chi-squared statistics). RESULTS: Although the Revised Cardiac Risk Index predicted cardiovascular complications with an odds ratio of 2.3 and a 95% confidence interval of 1.9 to 2.8 (P < .001) and the Hosmer-Lemeshow chi-square was significant (0.22, Pâ¯=â¯0.64), the area under the receiver operating characteristic was poor (0.63, 95% confidence interval 0.59-0.67). CONCLUSION: Despite its relative simplicity, the Revised Cardiac Risk Index performed poorly as a predictor of cardiovascular complications after adhesiolysis for small bowel obstruction. These findings question the utility of the Revised Cardiac Risk Index in this patient population. Future studies should aim to develop models that are computationally simple while retaining predictive accuracy.
Assuntos
Doenças Cardiovasculares/epidemiologia , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Obstrução Intestinal/cirurgia , Complicações Pós-Operatórias/epidemiologia , Adulto , Idoso , Doenças Cardiovasculares/etiologia , Feminino , Humanos , Laparoscopia/efeitos adversos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Medição de Risco , Estados Unidos/epidemiologiaRESUMO
Stem cell factor (mouse: Kitl, human: KITLG) and insulin-like growth factor-1 (IGF1), acting via KIT and IGF1 receptor (IGF1R), respectively, are critical for the development and integrity of several tissues. Autocrine/paracrine KITLG-KIT and IGF1-IGF1R signaling are also activated in several cancers including gastrointestinal stromal tumors (GIST), the most common sarcoma. In murine gastric muscles, IGF1 promotes Kitl-dependent development of interstitial cells of Cajal (ICC), the non-neoplastic counterpart of GIST, suggesting cooperation between these pathways. Here, we report a novel mechanism linking IGF1-IGF1R and KITLG-KIT signaling in both normal and neoplastic cells. In murine gastric muscles, the microenvironment for ICC and GIST, human hepatic stellate cells (LX-2), a model for cancer niches, and GIST cells, IGF1 stimulated Kitl/KITLG protein and mRNA expression and promoter activity by activating several signaling pathways including AKT-mediated glycogen synthase kinase-3ß inhibition (GSK3i). GSK3i alone also stimulated Kitl/KITLG expression without activating mitogenic pathways. Both IGF1 and GSK3i induced chromatin-level changes favoring transcriptional activation at the Kitl promoter including increased histone H3/H4 acetylation and H3 lysine (K) 4 methylation, reduced H3K9 and H3K27 methylation and reduced occupancy by the H3K27 methyltransferase EZH2. By pharmacological or RNA interference-mediated inhibition of chromatin modifiers we demonstrated that these changes have the predicted impact on KITLG expression. KITLG knock-down and immunoneutralization inhibited the proliferation of GIST cells expressing wild-type KIT, signifying oncogenic autocrine/paracrine KITLG-KIT signaling. We conclude that membrane-to-nucleus signaling involving GSK3i establishes a previously unrecognized link between the IGF1-IGF1R and KITLG-KIT pathways, which is active in both physiologic and oncogenic contexts and can be exploited for therapeutic purposes.