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1.
Nature ; 622(7981): 48-52, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37619607

RESUMO

The formation of stars and planets is accompanied not only by the build-up of matter, namely accretion, but also by its expulsion in the form of highly supersonic jets that can stretch for several parsecs1,2. As accretion and jet activity are correlated and because young stars acquire most of their mass rapidly early on, the most powerful jets are associated with the youngest protostars3. This period, however, coincides with the time when the protostar and its surroundings are hidden behind many magnitudes of visual extinction. Millimetre interferometers can probe this stage but only for the coolest components3. No information is provided on the hottest (greater than 1,000 K) constituents of the jet, that is, the atomic, ionized and high-temperature molecular gases that are thought to make up the jet's backbone. Detecting such a spine relies on observing in the infrared that can penetrate through the shroud of dust. Here we report near-infrared observations of Herbig-Haro 211 from the James Webb Space Telescope, an outflow from an analogue of our Sun when it was, at most, a few times 104 years old. These observations reveal copious emission from hot molecules, explaining the origin of the 'green fuzzies'4-7 discovered nearly two decades ago by the Spitzer Space Telescope8. This outflow is found to be propagating slowly in comparison to its more evolved counterparts and, surprisingly, almost no trace of atomic or ionized emission is seen, suggesting its spine is almost purely molecular.

2.
Nature ; 620(7974): 516-520, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37488359

RESUMO

Terrestrial and sub-Neptune planets are expected to form in the inner (less than 10 AU) regions of protoplanetary disks1. Water plays a key role in their formation2-4, although it is yet unclear whether water molecules are formed in situ or transported from the outer disk5,6. So far Spitzer Space Telescope observations have only provided water luminosity upper limits for dust-depleted inner disks7, similar to PDS 70, the first system with direct confirmation of protoplanet presence8,9. Here we report JWST observations of PDS 70, a benchmark target to search for water in a disk hosting a large (approximately 54 AU) planet-carved gap separating an inner and outer disk10,11. Our findings show water in the inner disk of PDS 70. This implies that potential terrestrial planets forming therein have access to a water reservoir. The column densities of water vapour suggest in-situ formation via a reaction sequence involving O, H2 and/or OH, and survival through water self-shielding5. This is also supported by the presence of CO2 emission, another molecule sensitive to ultraviolet photodissociation. Dust shielding, and replenishment of both gas and small dust from the outer disk, may also play a role in sustaining the water reservoir12. Our observations also reveal a strong variability of the mid-infrared spectral energy distribution, pointing to a change of inner disk geometry.

3.
N Engl J Med ; 388(9): 813-823, 2023 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-36856617

RESUMO

BACKGROUND: Whether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown. METHODS: In a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated. RESULTS: At a median follow-up of 14.7 months, the neoadjuvant-adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P = 0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant-adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant-adjuvant group and 14% in the adjuvant-only group. CONCLUSIONS: Among patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified. (Funded by the National Cancer Institute and Merck Sharp and Dohme; S1801 ClinicalTrials.gov number, NCT03698019.).


Assuntos
Antineoplásicos Imunológicos , Melanoma , Terapia Neoadjuvante , Neoplasias Cutâneas , Humanos , Adjuvantes Imunológicos , Progressão da Doença , Melanoma/tratamento farmacológico , Melanoma/patologia , Melanoma/cirurgia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Quimioterapia Adjuvante
4.
Ann Surg Oncol ; 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38958807

RESUMO

BACKGROUND: For women at increased risk of breast cancer, the National Comprehensive Cancer Network (NCCN) guidelines recommend clinical encounters every 6-12 months. While screening mammography has corresponded with a relative risk reduction in breast cancer mortality of approximately 20%, evidence validating clinical breast examination (CBE) as an efficacious screening modality is deficient. Our study aimed to assess the conventional merit of regular CBE for breast cancer detection among individuals at increased risk of breast cancer development. METHODS: Women > 18 years with documented high-risk encounters at Corewell Health West from 1 January 2018 to 31 December 22 were retrospectively reviewed. High-risk criteria included genetic predisposition, 5-year (> 1.7%) or lifetime (> 20%) Tyrer-Cuzick and/or Gail Model risk estimations, thoracic radiotherapy before age 30 years, lobular carcinoma in-situ, or atypical hyperplasia. Patients with a history of breast cancer or bilateral prophylactic mastectomy prior to 2018 were excluded. RESULTS: Of the 9171 cumulative high-risk encounters among 2493 women, only one breast cancer was detected by CBE. CBE resulted in 1 (0.04%) cancer diagnosis compared with 30 (1.2%) detected on screening imaging and 10 (0.4%) self-reported. Of the 30 image-detected cancers, 28 (93.3%) had no detectable clinical findings at the time of preoperative consultation. Self-reported and CBE-detected cancers were more likely to be of higher clinical stage compared with imaging-detected malignancies. CONCLUSIONS: The role of routine CBE as a cancer detection modality in the high-risk patient population appears to be limited. Telemedicine can be offered to individuals who have completed screening imaging but are unable to commit and/or are inconvenienced by in-person high-risk breast cancer assessments.

5.
J Surg Oncol ; 129(4): 827-834, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38115237

RESUMO

BACKGROUND: Postoperative inpatients experience increased stress due to pain and poor restorative sleep than non-surgical inpatients. OBJECTIVES AND METHODS: A total of 101 patients, undergoing major oncologic surgery, were randomized to a postoperative sleep protocol (n = 50) or standard postoperative care (n = 51), between August 2020 and November 2021. The primary endpoint of the study was postoperative sleep time after major oncologic surgery. Sleep time and steps were measured using a Fitbit Charge 4®. RESULTS: There was no statistically significant difference found in postoperative sleep time between the sleep protocol and standard group (median sleep time of 427 min vs. 402 min; p = 0.852, respectively). Major complication rates were similar in both groups (7.4% vs. 8.9%). Multivariate analysis found sex and Charlson Comorbidity Index to be significant factors affecting postoperative sleep time and step count. Postoperative delirium was only observed in the standard group, although this did not reach statistical significance. There were no in hospital mortalities. CONCLUSION: The use of a sleep protocol was found to be safe in our study population. There was no statistical difference in postoperative sleep time or major complications. Institution of a more humane sleep protocol for postoperative inpatients should be considered.


Assuntos
Neoplasias , Sono , Humanos , Hospitais , Neoplasias/cirurgia , Complicações Pós-Operatórias/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto
7.
J Biol Chem ; 298(3): 101612, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35065969

RESUMO

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons progressively and rapidly degenerate, eventually leading to death. The first protein found to contain ALS-associated mutations was copper/zinc superoxide dismutase 1 (SOD1), which is conformationally stable when it contains its metal ligands and has formed its native intramolecular disulfide. Mutations in SOD1 reduce protein folding stability via disruption of metal binding and/or disulfide formation, resulting in misfolding, aggregation, and ultimately cellular toxicity. A great deal of effort has focused on preventing the misfolding and aggregation of SOD1 as a potential therapy for ALS; however, the results have been mixed. Here, we utilize a small-molecule polytherapy of diacetylbis(N(4)-methylthiosemicarbazonato)copper(II) (CuATSM) and ebselen to mimic the metal delivery and disulfide bond promoting activity of the cellular chaperone of SOD1, the "copper chaperone for SOD1." Using microscopy with automated image analysis, we find that polytherapy using CuATSM and ebselen is highly effective and acts in synergy to reduce inclusion formation in a cell model of SOD1 aggregation for multiple ALS-associated mutants. Polytherapy reduces mutant SOD1-associated cell death, as measured by live-cell microscopy. Measuring dismutase activity via zymography and immunoblotting for disulfide formation showed that polytherapy promoted more effective maturation of transfected SOD1 variants beyond either compound alone. Our data suggest that a polytherapy of CuATSM and ebselen may merit more study as an effective method of treating SOD1-associated ALS.


Assuntos
Esclerose Lateral Amiotrófica , Compostos de Cobre Orgânico , Superóxido Dismutase-1 , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Materiais Biomiméticos/farmacologia , Cobre/metabolismo , Dissulfetos/química , Humanos , Isoindóis/farmacologia , Chaperonas Moleculares/metabolismo , Mutação , Compostos de Cobre Orgânico/farmacologia , Compostos Organosselênicos/farmacologia , Dobramento de Proteína/efeitos dos fármacos , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo
8.
J Surg Res ; 285: 205-210, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36696707

RESUMO

INTRODUCTION: Access to patients' electronic medical records (EMRs) on personal communication devices (PCDs) is beneficial but can negatively impact surgeons. In a recent op-ed, Cohen et al. explored this technology "empowerment/enslavement paradox" and its potential effect on surgeon burnout. We examined if there is a relationship between accessing EMRs on PCDs and surgeon burnout. METHODS: This was a cohort study with retrospective and prospective arms. Trainees and attendings with a background in general surgery completed the Maslach Burnout Index for Medical Personnel, a validated survey scored on three areas of burnout (emotional exhaustion, depersonalization, and low personal accomplishment). Data on login frequency to EMRs on PCDs over the previous 6 mo were obtained. Pearson correlation coefficients were calculated to determine if burnout and login frequency were associated. RESULTS: There were 52 participants included. Residents were 61.5% (n = 32) of participants. The mean login frequency over 6 mo was 431.0 ± 323.9. The mean scores (out of 6) for emotional exhaustion, depersonalization, and personal accomplishment were 2.3 ± 1.1, 1.9 ± 1.2, and 4.9 ± 0.8, respectively. There was no correlation between burnout and logins. Residents had higher median depersonalization scores (2.3 versus 1.2, P = 0.03) and total logins (417.5 versus 210.0, P < 0.001) than attendings. Participants who overestimated logins had higher median emotional exhaustion and depersonalization scores than those who underestimated (2.6 versus 1.4, P = 0.03, and 2.4 versus 0.8, P = 0.003, respectively). CONCLUSIONS: Using EMRs on PCDs is common, but frequency of logins did not correlate with burnout scores in this study. However, perception of increased workload may contribute to experiencing burnout.


Assuntos
Esgotamento Profissional , Escravização , Cirurgiões , Humanos , Estudos Retrospectivos , Estudos de Coortes , Estudos Prospectivos , Satisfação no Emprego , Esgotamento Profissional/psicologia , Esgotamento Psicológico , Inquéritos e Questionários
9.
Ann Oncol ; 33(4): 384-394, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35093516

RESUMO

BACKGROUND: Primary analyses of the phase III BrighTNess trial showed addition of carboplatin with/without veliparib to neoadjuvant chemotherapy significantly improved pathological complete response (pCR) rates with manageable acute toxicity in patients with triple-negative breast cancer (TNBC). Here, we report 4.5-year follow-up data from the trial. PATIENTS AND METHODS: Women with untreated stage II-III TNBC were randomized (2 : 1 : 1) to paclitaxel (weekly for 12 doses) plus: (i) carboplatin (every 3 weeks for four cycles) plus veliparib (twice daily); (ii) carboplatin plus veliparib placebo; or (iii) carboplatin placebo plus veliparib placebo. All patients then received doxorubicin and cyclophosphamide every 2-3 weeks for four cycles. The primary endpoint was pCR. Secondary endpoints included event-free survival (EFS), overall survival (OS), and safety. Since the co-primary endpoint of increased pCR with carboplatin plus veliparib with paclitaxel versus carboplatin with paclitaxel was not met, secondary analyses are descriptive. RESULTS: Of 634 patients, 316 were randomized to carboplatin plus veliparib with paclitaxel, 160 to carboplatin with paclitaxel, and 158 to paclitaxel. With median follow-up of 4.5 years, the hazard ratio for EFS for carboplatin plus veliparib with paclitaxel versus paclitaxel was 0.63 [95% confidence interval (CI) 0.43-0.92, P = 0.02], but 1.12 (95% CI 0.72-1.72, P = 0.62) for carboplatin plus veliparib with paclitaxel versus carboplatin with paclitaxel. In post hoc analysis, the hazard ratio for EFS was 0.57 (95% CI 0.36-0.91, P = 0.02) for carboplatin with paclitaxel versus paclitaxel. OS did not differ significantly between treatment arms, nor did rates of myelodysplastic syndromes, acute myeloid leukemia, or other secondary malignancies. CONCLUSIONS: Improvement in pCR with the addition of carboplatin was associated with long-term EFS benefit with a manageable safety profile, and without increasing the risk of second malignancies, whereas adding veliparib did not impact EFS. These findings support the addition of carboplatin to weekly paclitaxel followed by doxorubicin and cyclophosphamide neoadjuvant chemotherapy for early-stage TNBC.


Assuntos
Terapia Neoadjuvante , Neoplasias de Mama Triplo Negativas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis , Carboplatina , Ciclofosfamida , Doxorrubicina , Feminino , Seguimentos , Humanos , Paclitaxel , Neoplasias de Mama Triplo Negativas/patologia
10.
Ann Surg Oncol ; 29(2): 791-801, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34648098

RESUMO

BACKGROUND: Talimogene laherparepvec (T-VEC) is an oncolytic virus approved for the treatment of unresectable, recurrent melanoma. The role of T-VEC after progression on systemic immunotherapy (IO) remains undefined. The goal of this study was to characterize the efficacy of T-VEC after failure of IO in patients with unresectable metastatic melanoma. METHODS: An international, multi-institutional review of AJCC version 8 stage IIIB-IV melanoma patients treated with T-VEC after failure of IO was performed at six centers from October 2015-December 2020. Primary outcome was in-field response; secondary outcomes included analyses of in-field and overall progression-free survival (PFS) and in-field and overall disease-free survival (DFS) after a complete response. Subset analysis of T-VEC initiation sequentially after or concurrently with IO was performed. RESULTS: Of 112 patients, median age at T-VEC initiation was 69 years (range 21-93); 65 (58%) were male. Before T-VEC, 57% patients received one IO regimen, 42% received two or more, with most patients (n = 74, 66%) receiving T-VEC sequential to IO. Most were stage 3C (n = 51, 46%) at T-VEC initiation, 29 (26%) received injections to nodal disease. Over median follow-up of 14 months, in-field response at final T-VEC injection was 37% complete (CR), 14% partial (PR). T-VEC initiation sequentially or concurrently did not significantly affect in-field response (p = 0.26). Median in-field PFS was 15 months (95% confidence interval 4.6-NE). Median overall DFS after CR was 32 months (95% confidence interval 17-NE). CONCLUSIONS: T-VEC after failure of IO is effective in unresectable, metastatic stage IIIB-IV melanoma. T-VEC initiation sequentially or concurrently did not significantly affect in-field response.


Assuntos
Melanoma , Terapia Viral Oncolítica , Neoplasias Cutâneas , Adulto , Idoso , Idoso de 80 Anos ou mais , Produtos Biológicos , Herpesvirus Humano 1 , Humanos , Imunoterapia , Masculino , Melanoma/terapia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/terapia , Neoplasias Cutâneas/terapia , Adulto Jovem
11.
Ann Surg Oncol ; 28(2): 914-919, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32661849

RESUMO

INTRODUCTION: Current recommendations for early-stage breast cancer are largely based on the NSABP B-06 trial demonstrating equivalent survival between mastectomy and lumpectomy. We sought to compare breast-conserving therapy (BCT) with mastectomy for treatment of early-stage breast cancer in a contemporary patient population. METHODS: A query of the NCDB PUF identified female breast cancer patients diagnosed from 2004 to 2015. Patients with stage I or II disease were included. BCT was defined as the receipt of lumpectomy plus radiation. Propensity scores were tabulated using race, age, Charlson/Deyo score, tumor site, laterality, histology, grade, size, number of nodes positive, lymph-vascular invasion, receptor status, receipt of chemotherapy, and endocrine therapy. Patients who received BCT versus mastectomy were matched using a 1:1 nearest neighbor technique. The primary outcome measured was overall survival. RESULTS: After exclusions and matching, two equal groups of 101,118 patients remained. Median follow-up was 42 months. The majority had invasive ductal histology (77%), and node-negative disease (84%). Receptor status included ER-positive (83%), PR-positive (73%), and HER2/Neu-positive (15%). Chemotherapy was received in 38% and endocrine therapy in 71%. Propensity score matching yielded equivalent groups across all target variables. The 5-year overall survival was superior for BCT compared with mastectomy (92.9% vs. 89.7%, p < 0.001; Fig. 1). This survival advantage persisted for both stage I (p < 0.001) and stage II (p < 0.001) disease on subgroup analysis. Fig. 1 Overall survival in female patients with early stage invasive breast cancer (stage I or II) undergoing breast conservation surgery with radiation compared with mastectomy. BCS breast conservation surgery CONCLUSIONS: BCT is associated with superior overall survival compared with mastectomy for early-stage breast cancer using well-matched, contemporary data.


Assuntos
Neoplasias da Mama , Mastectomia Segmentar , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Bases de Dados Factuais , Feminino , Humanos , Mastectomia , Estadiamento de Neoplasias , Pontuação de Propensão
12.
Osteoarthritis Cartilage ; 28(2): 231-238, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31682906

RESUMO

OBJECTIVE: To evaluate infrared (IR) spectroscopy of serum as a screening tool to differentiate dogs affected by naturally occurring osteoarthritis (OA) associated with cranial cruciate ligament rupture (CrCLR) and controls. METHOD: 104 adult dogs with CrCLR (affected group) and 50 adult control dogs were recruited for this prospective observational study. Serum samples were collected preoperatively from CrCLR dogs and from a subset of these dogs at 4-, and 12-week post-surgical intervention to stabilize the affected stifles. Serum was collected once from control dogs. Dry films were made from serum samples, and IR absorbance spectra acquired. Data preprocessing, principal component analysis and multivariate analysis of covariance were performed to separate samples from the two groups, and to evaluate temporal differences. Weighted logistic regression with L1 regularization method was used to develop a predictive model. Model performance based on an independent test set was evaluated. RESULTS: Spectral data analysis revealed significant separation between the sera of CrCLR and control dogs (P < 0.0001), but not amongst different time points in the OA group. The sensitivity, specificity, AUC and accuracy of the test set were 84.62%, 96.15%, 93.20% and 92.31% respectively. CONCLUSIONS: These findings confirm the potential of IR-spectroscopy of serum with chemometrics methods to differentiate controls from dogs with OA associated with CrCLR. This is the first step in development of an economic, and comparatively simple IR-based screening serum test for OA. Utility of this tool as a clinical screening and diagnostic test requires further investigation and validation.


Assuntos
Lesões do Ligamento Cruzado Anterior/veterinária , Doenças do Cão/sangue , Osteoartrite/veterinária , Animais , Ligamento Cruzado Anterior/cirurgia , Lesões do Ligamento Cruzado Anterior/sangue , Lesões do Ligamento Cruzado Anterior/diagnóstico , Lesões do Ligamento Cruzado Anterior/cirurgia , Estudos de Casos e Controles , Cães , Programas de Rastreamento , Osteoartrite/sangue , Osteoartrite/diagnóstico , Osteoartrite/cirurgia , Espectroscopia de Infravermelho com Transformada de Fourier , Joelho de Quadrúpedes/lesões , Joelho de Quadrúpedes/cirurgia
17.
Pharmacogenomics J ; 18(1): 187-195, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-27779249

RESUMO

Differences in response to medications have a strong genetic component. By leveraging publically available data, the spectrum of such genomic variation can be investigated extensively. Pharmacogenomic variation was extracted from the 1000 Genomes Project Phase 3 data (2504 individuals, 26 global populations). A total of 12 084 genetic variants were found in 120 pharmacogenes, with the majority (90.0%) classified as rare variants (global minor allele frequency <0.5%), with 52.9% being singletons. Common variation clustered individuals into continental super-populations and 23 pharmacogenes contained highly differentiated variants (FST>0.5) for one or more super-population comparison. A median of three clinical variants (PharmGKB level 1A/B) was found per individual, and 55.4% of individuals carried loss-of-function variants, varying by super-population (East Asian 60.9%>African 60.1%>South Asian 60.3%>European 49.3%>Admixed 39.2%). Genome sequencing can therefore identify clinical pharmacogenomic variation, and future studies need to consider rare variation to understand the spectrum of genetic diversity contributing to drug response.


Assuntos
Variação Genética/genética , Proteínas/genética , Alelos , Etnicidade/genética , Frequência do Gene/genética , Genética Populacional/métodos , Humanos , Farmacogenética/métodos
19.
Ann Surg Oncol ; 25(1): 83-90, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29063296

RESUMO

BACKGROUND: Multifocal intrahepatic cholangiocarcinoma (ICC) has traditionally been treated with surgical resection when amenable. Intra-arterial therapy (IAT) for multifocal ICC has not been directly compared with surgical resection. METHODS: A single-center, retrospective review of consecutive patients treated for multifocal ICC was conducted. Patients with distant metastases or treatment with systemic chemotherapy alone were excluded. Patients were divided into two groups: surgical resection versus IAT; IAT included transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and hepatic arterial infusion (HAI) pump therapy. Subjects were also analyzed by surgical resection, TACE, and HAI pump therapy. RESULTS: Overall, 116 patients with multifocal ICC were studied, 57 in the surgical resection group and 59 in the IAT group (TACE = 41, HAI pump = 16, TARE = 2). The IAT group was characterized by a higher incidence of bilobar disease (88.1% vs. 47.4%, p < 0.001), larger tumors (median 10.6 vs. 7.5 cm, p = 0.004), higher incidence of macrovascular invasion (44.1% vs. 24.6%, p = 0.027), and higher rate of nodal metastases (57.6% vs. 28.6%, p = 0.002). Median overall survival for surgical resection was 20 months versus 16 months for IAT (p = 0.627). Multivariate analysis found that macrovascular invasion [hazard ratio (HR) 2.52, 95% confidence interval (CI) 1.56-4.09] and non-receipt of systemic chemotherapy (HR 3.81, 95% CI 2.23-6.52) were independent poor prognostic risk factors. Surgical resection was not associated with a survival advantage over IAT on multivariate analysis (p = 0.242). CONCLUSION: Despite selection bias for use of surgical resection compared with IAT, no survival advantage was conferred in the treatment of multifocal ICC.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/terapia , Colangiocarcinoma/secundário , Colangiocarcinoma/terapia , Hepatectomia , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/terapia , Ablação por Radiofrequência , Idoso , Antineoplásicos/administração & dosagem , Vasos Sanguíneos/patologia , Quimioembolização Terapêutica , Feminino , Artéria Hepática , Humanos , Infusões Intra-Arteriais , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Radioterapia/métodos , Estudos Retrospectivos , Taxa de Sobrevida , Carga Tumoral
20.
BMC Pulm Med ; 18(1): 170, 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30453935

RESUMO

BACKGROUND: Non-Tuberculous Mycobacterial-pulmonary disease (NTM-PD) is increasing in incidence and prevalence. Mycobacterium abscessus (M.abscessus) is a rapid growing multi-resistant NTM associated with severe NTM-PD requiring prolonged antibiotic therapy. Complications of therapy are common but reports on direct complications of active NTM-PD are rare. Vasculitis has been described as a rare complication of NTM-PD, most often in individuals with inherited immune defects. This case is the first to describe an ANCA positive vasculitide (Microscopic Polyangiitis) secondary to M.abscessus pulmonary disease. CASE PRESENTATION: A 70 year old female with bronchiectasis underwent a clinical decline associated with the growth of M.abscessus and was diagnosed with NTM-PD. Before treatment could be initiated she developed small joint arthralgia and a glove and stocking axonal loss sensorimotor neuropathy. Positive Perinuclear Anti-Neutrophil Cytoplasmic Antibodies (P-ANCA) and Myeloperoxidase-ANCA (MPO-ANCA) titres led to a diagnosis of microscopic polyangiitis. Further investigation revealed reduced interferon-gamma production but no other significant immune dysfunction. Dual treatment with immunosuppressive therapy (Corticosteroids/Cyclophosphamide) for vasculitis and antimicrobial therapy for M.abscessus NTM-PD was initiated. Clinical stability was difficult to achieve with reductions in immunosuppression triggering vasculitic flares. One flare led to retinal vein occlusion with impending visual loss requiring escalation in immunosuppression to Rituximab infusions. An increase in immunosuppression led to a deterioration in NTM-PD necessitating alterations to antibiotic regimes. Adverse effects including alopecia and Achilles tendonitis have further limited antibiotic choices resulting in a strategy of pulsed intra-venous therapy to stabilise NTM-PD. CONCLUSIONS: This is the first reported case of an ANCA positive vasculitis secondary to M.abscessus pulmonary disease. This rare but important complication had a significant impact on the patient adding to the complexity of an already significant disease and treatment burden. The potential role of reduced interferon-gamma production in this case highlights the importance of investigating immune function in those with mycobacterial infection and the intricate relationship between mycobacterial infection and immune dysfunction. Immune dysfunction caused by genetic defects or immunosuppressive therapy is a known risk factor for NTM-PD. Balancing immunosuppressive therapy with prolonged antimicrobial treatment is challenging and likely to become more common as the number of individuals being treated with biologics and immunosuppressive agents increases.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos/sangue , Bronquiectasia/complicações , Poliangiite Microscópica/diagnóstico , Infecções por Mycobacterium não Tuberculosas/complicações , Mycobacterium abscessus/isolamento & purificação , Idoso , Antibacterianos/uso terapêutico , Feminino , Humanos , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico
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