RESUMO
BACKGROUND: RET mutations occur in 70% of medullary thyroid cancers, and RET fusions occur rarely in other thyroid cancers. In patients with RET-altered thyroid cancers, the efficacy and safety of selective RET inhibition are unknown. METHODS: We enrolled patients with RET-mutant medullary thyroid cancer with or without previous vandetanib or cabozantinib treatment, as well as those with previously treated RET fusion-positive thyroid cancer, in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response), as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety. RESULTS: In the first 55 consecutively enrolled patients with RET-mutant medullary thyroid cancer who had previously received vandetanib, cabozantinib, or both, the percentage who had a response was 69% (95% confidence interval [CI], 55 to 81), and 1-year progression-free survival was 82% (95% CI, 69 to 90). In 88 patients with RET-mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the percentage who had a response was 73% (95% CI, 62 to 82), and 1-year progression-free survival was 92% (95% CI, 82 to 97). In 19 patients with previously treated RET fusion-positive thyroid cancer, the percentage who had a response was 79% (95% CI, 54 to 94), and 1-year progression-free survival was 64% (95% CI, 37 to 82). The most common adverse events of grade 3 or higher were hypertension (in 21% of the patients), increased alanine aminotransferase level (in 11%), increased aspartate aminotransferase level (in 9%), hyponatremia (in 8%), and diarrhea (in 6%). Of all 531 patients treated, 12 (2%) discontinued selpercatinib owing to drug-related adverse events. CONCLUSIONS: In this phase 1-2 trial, selpercatinib showed durable efficacy with mainly low-grade toxic effects in patients with medullary thyroid cancer with and without previous vandetanib or cabozantinib treatment. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).
Assuntos
Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Pirazóis/administração & dosagem , Piridinas/administração & dosagem , Neoplasias da Glândula Tireoide/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Hipertensão/induzido quimicamente , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-ret/análise , Proteínas Proto-Oncogênicas c-ret/genética , Pirazóis/efeitos adversos , Piridinas/efeitos adversos , Transaminases/sangue , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: RET fusions are oncogenic drivers in 1 to 2% of non-small-cell lung cancers (NSCLCs). In patients with RET fusion-positive NSCLC, the efficacy and safety of selective RET inhibition are unknown. METHODS: We enrolled patients with advanced RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated separately in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response) as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety. RESULTS: In the first 105 consecutively enrolled patients with RET fusion-positive NSCLC who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54 to 73). The median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59 to 100). The most common adverse events of grade 3 or higher were hypertension (in 14% of the patients), an increased alanine aminotransferase level (in 12%), an increased aspartate aminotransferase level (in 10%), hyponatremia (in 6%), and lymphopenia (in 6%). A total of 12 of 531 patients (2%) discontinued selpercatinib because of a drug-related adverse event. CONCLUSIONS: Selpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Pirazóis/administração & dosagem , Piridinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Hipertensão/induzido quimicamente , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Mutação , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-ret/análise , Proteínas Proto-Oncogênicas c-ret/genética , Pirazóis/efeitos adversos , Piridinas/efeitos adversos , Transaminases/sangue , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: The smartphone-based 6-min walking test (6WT) is an established digital outcome measure in patients undergoing surgery for degenerative lumbar disorders (DLD). In addition to the 6WTs primary outcome measure, the 6-min walking distance (6WD), the patient's distance to first symptoms (DTFS) and time to first symptoms (TTFS) can be recorded. This is the first study to analyse the psychometric properties of the DTFS and TTFS. METHODS: Forty-nine consecutive patients (55 ± 15.8 years) completed the 6WT pre- and 6 weeks (W6) postoperative. DTFS and TTFS were assessed for reliability and content validity using disease-specific patient-reported outcome measures. The Zurich Claudication Questionnaire patient satisfaction subscale was used as external criterion for treatment success. Internal and external responsiveness for both measures at W6 was evaluated. RESULTS: There was a significant improvement in DTFS and TTFS from baseline to W6 (p < 0.001). Both measures demonstrated a good test-retest reliability (ß = 0.86, 95% CI 0.81-0.90 and ß = 0.83, 95% CI 0.76-0.87, both p < 0.001). The DTFS exceeded the 6WD capability to differentiate between satisfied (82%) and unsatisfied patients (18%) with an AUC of 0.75 (95% CI 0.53-0.98) vs. 0.70 (95% CI 0.52-0.90). The TTFS did not demonstrate meaningful discriminative abilities. CONCLUSION: Change in DTFS can differentiate between satisfied and unsatisfied patients after spine surgery. Digital outcome measures on the 6WT metric provide spine surgeons and researchers with a mean to assess their patient's functional disability and response to surgical treatment in DLD.
Assuntos
Vértebras Lombares , Medidas de Resultados Relatados pelo Paciente , Humanos , Vértebras Lombares/cirurgia , Reprodutibilidade dos Testes , Resultado do Tratamento , CaminhadaRESUMO
BACKGROUND: The worldwide spread of smartphone usage enables new possibilities for longitudinal monitoring of objective functional impairment (OFI) in patients undergoing surgery for lumbar degenerative disc disease (DDD). METHODS: Three patients, undergoing elective surgery for lumbar DDD, self-assessed OFI using a recently validated 6-min walking test (6WT) smartphone application. Results are presented as raw 6-min walking distance (6WD) as well as in reference to age- and sex-specific healthy population reference values using standardized z-scores (number of standard deviations). In parallel, patient-reported outcome measures (PROMs), including numeric rating scale (NRS) leg-pain and Core Outcome Measures Index (COMI) were obtained before (pre) and 6 weeks (6 W) as well as 3 months (3 M) after surgery. Descriptive analyses were used to compare PROMs with repeated 6WT measurements over time. The feasibility and benefits of the longitudinal OFI measurements using the 6WT app are discussed. RESULTS: One patient presented a favorable outcome, reflected by a clinically meaningful improvement in PROMs. Correspondingly, the 6WT distance gradually improved above the normal population values ((pre 399 m (z-score - 1.96) vs. 6 W 494 m (- 0.85) vs. 3 M 557 m (- 0.1)). One patient experienced initial improvement at 6 W, followed by a decline in 6WD at 3 M which promoted further interventions with subsequent recovery ((358 m (z-score - 3.29) vs 440 m (- 2.2) vs 431 m (- 2.32) vs 471 m (- 1.78)). The last patient showed a lack of improvement in PROMs as well as in OFI (360 m (z-score 0.0) vs 401 m (0.30) vs 345 m (- 0.11)) resulting in secondary surgery. CONCLUSION: The longitudinal assessment of OFI using the 6WT app was feasible and provided the physician with a detailed history of patients' postoperative walking capacity complementing commonly used PROMs.
Assuntos
Autoavaliação Diagnóstica , Degeneração do Disco Intervertebral/cirurgia , Complicações Pós-Operatórias/diagnóstico , Smartphone , Telemedicina/métodos , Caminhada , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Telemedicina/instrumentaçãoRESUMO
PURPOSE OF REVIEW: We describe recent developments in the rapidly evolving field of anaplastic lymphoma kinase-targeting agents. RECENT FINDINGS: Five targeted drugs are currently available in the clinic via regular approval or named patient programs, including crizotinib, ceritinib, alectinib, brigatinib and lorlatinib. Further drugs are tested in clinical trials. This review summarizes published data, together with drug-specific information on dosing and toxicity. Moreover, we discuss different clinical scenarios and potential treatment options in patients with tumor progression, based on current literature and our own experience. SUMMARY: Patients with metastatic, anaplastic lymphoma kinase-rearranged nonsmall cell lung cancer should be managed by interdisciplinary expert teams. New drugs with enhanced brain activity are available, and some patients may benefit from local therapies.
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Quinase do Linfoma Anaplásico/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Quinase do Linfoma Anaplásico/metabolismo , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Ensaios Clínicos Fase III como Assunto , Humanos , Neoplasias Pulmonares/enzimologia , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
AIMS: Anterior lumbar interbody fusion procedures (ALIF) and total disc replacement (TDR) with anterior exposure of the lumbar spine entail a risk of a vascular injury and dysfunction of the sympathetic and parasympathetic nerves due to disturbance of the inferior and superior hypogastric plexus. While retrograde ejaculation is a known complication of the anterior spinal approach in males, post-operative sexual as well as urinary function in females has not yet been thoroughly investigated and was hence the aim of this study. METHODS: Fifteen female patients documented their sexual and urinary function preoperatively, 3 months and 6 months postoperatively, using the validated questionnaires FSFI (Female Sexual Function Index) and ICIQ (International Consultation of Incontinence Questionnaire). Randomization tests were used to statistically analyze expectation values over time (two-sided, P < 0.05). RESULTS: While no statistically significant change in the total FSFI score occurred over time, a significant increase in FSFI desire score was noted between preoperative (2.95 ± 0.8) and 6 months follow-up (3.51 ± 0.6, P = 0.02). Urinary continence remained unchanged over time. CONCLUSION: In summary, ALIF and lumbar TDR do not seem to negatively influence sexual and urinary function in females. In contrast, increased sexual desire was noted, likely secondary to post-surgical pain relief.
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Vértebras Lombares/cirurgia , Fusão Vertebral/efeitos adversos , Substituição Total de Disco/efeitos adversos , Micção/fisiologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Comportamento Sexual , Inquéritos e Questionários , Resultado do TratamentoRESUMO
OBJECTIVE: Although several studies have suggested that the incidence of intracranial aneurysms (IAs) is higher in smokers, the higher prevalence of subarachnoid hemorrhage (SAH) in smokers remains uncertain. It is unclear whether smoking additionally contributes to the formation of multiple aneurysms and the risk of rupture. The aim of this study was to determine whether smoking is associated with IA formation, multiplicity, or rupture. METHODS: Patients from the prospective multicenter @neurIST database (n = 1410; 985 females [69.9%]) were reviewed for the presence of SAH, multiple aneurysms, and smoking status. The prevalence of smokers in the population of patients diagnosed with at least one IA was compared with that of smokers in the general population. RESULTS: The proportion of smokers was higher in patients with IAs (56.2%) than in the reference population (51.4%; p < 0.001). A significant association of smoking with the presence of an IA was found throughout group comparisons (p = 0.01). The presence of multiple IAs was also significantly associated with smoking (p = 0.003). A trend was found between duration of smoking and the presence of multiple IAs (p = 0.057). However, the proportion of smokers among patients suffering SAH was similar to that of smokers among patients diagnosed with unruptured IAs (p = 0.48). CONCLUSIONS: Smoking is strongly associated with IA formation. Once an IA is present, however, smoking does not appear to increase the risk of rupture compared with IAs in the nonsmoking population. The trend toward an association between duration of smoking and the presence of multiple IAs stresses the need for counseling patients with IAs regarding lifestyle modification.
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Aneurisma Intracraniano/epidemiologia , Aneurisma Intracraniano/etiologia , Tabagismo/complicações , Tabagismo/epidemiologia , Adulto , Idoso , Aneurisma Roto/epidemiologia , Progressão da Doença , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Hemorragia Subaracnóidea/epidemiologia , Hemorragia Subaracnóidea/etiologiaRESUMO
OBJECTIVEPatient-reported outcome measures (PROMs) are standard of care for the assessment of functional impairment. Subjective outcome measures are increasingly complemented by objective ones, such as the "Timed Up and Go" (TUG) test. Currently, only a few studies report pre- and postoperative TUG test assessments in patients with lumbar spinal stenosis (LSS).METHODSA prospective two-center database was reviewed to identify patients with LSS who underwent lumbar decompression with or without fusion. The subjective functional status was estimated using PROMs for pain (visual analog scale [VAS]), disability (Roland-Morris Disability Index [RMDI] and Oswestry Disability Index [ODI]), and health-related quality of life (HRQoL; 12-Item Short-Form Physical Component Summary [SF-12 PCS] and the EQ-5D) preoperatively, as well as on postoperative day 3 (D3) and week 6 (W6). Objective functional impairment (OFI) was measured using age- and sex-standardized TUG test results.RESULTSSixty-four patients (n = 32 [50%] male, mean age 66.8 ± 11.7 years) were included. Preoperatively, they reported a mean VAS back pain score of 4.1 ± 2.7, VAS leg pain score of 5.4 ± 2.7, RMDI of 10.4 ± 5.3, ODI of 41.9 ± 16.2, SF-12 PCS score of 32.7 ± 8.3, and an EQ-5D index of 0.517 ± 0.226. The preoperative rates of severe, moderate, and mild OFI were 4.7% (n = 3), 12.5% (n = 8), and 7.8% (n = 5), respectively, and the mean OFI T-score was 116.3 ± 23.7. At W6, 60 (93.8%) of 64 patients had a TUG test result within the normal population range (no OFI); 3 patients (4.7%) had mild and 1 patient (1.6%) severe OFI. The mean W6 OFI T-score was significantly decreased (103.1 ± 13.6; p < 0.001). Correspondingly, the PROMs showed a decrease in subjective VAS back pain (1.6 ± 1.7, p < 0.001) and leg pain (1.0 ± 1.8, p < 0.001) scores, disability (RMDI 5.3 ± 4.7, p < 0.001; ODI 21.3 ± 16.1, p < 0.001), and increase in HRQoL (SF-12 PCS 40.1 ± 8.3, p < 0.001; EQ-5D 0.737 ± 0.192, p < 0.001) at W6. The W6 responder status (clinically meaningful improvement) ranged between 81.3% (VAS leg pain) and 29.7% (EQ-5D index) of patients.CONCLUSIONSThe TUG test is a quick and easily applicable tool that reliably measures OFI in patients with LSS. Objective tests incorporating longer walking time should be considered if OFI is suspected but fails to be proven by the TUG test, taking into account that neurogenic claudication may not clinically manifest during the brief TUG examination. Objective tests do not replace the subjective PROM-based assessment, but add valuable information to a comprehensive patient evaluation.
Assuntos
Vértebras Lombares , Atividade Motora/fisiologia , Estenose Espinal/fisiopatologia , Estenose Espinal/cirurgia , Idoso , Idoso de 80 Anos ou mais , Descompressão Cirúrgica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Medição da Dor , Recuperação de Função Fisiológica/fisiologia , Reprodutibilidade dos Testes , Estenose Espinal/complicaçõesRESUMO
INTRODUCTION: Several imaging modalities are under investigation to unravel the pathophysiological mystery of delayed performance deficits in patients after mild traumatic brain injury (mTBI). Although both imaging and neuropsychological studies have been conducted, only few data on longitudinal correlations of diffusion tensor imaging (DTI), susceptibility weighted imaging (SWI) and extensive neuropsychological testing exist. METHODS: MRI with T1- and T2-weighted, SWI and DTI sequences at baseline and 12 months of 30 mTBI patients were compared with 20 healthy controls. Multiparametric assessment included neuropsychological testing of cognitive performance and post-concussion syndrome (PCS) at baseline, 3 and 12 months post-injury. Data analysis encompassed assessment of cerebral microbleeds (Mb) in SWI, tract-based spatial statistics (TBSS) and voxel-based morphometry (VBM) of DTI (VBM-DTI). Imaging markers were correlated with neuropsychological testing to evaluate sensitivity to cognitive performance and post-concussive symptoms. RESULTS: Patients with Mb in SWI in the acute phase showed worse performance in several cognitive tests at baseline and in the follow-ups during the chronic phase and higher symptom severity in the post concussion symptom scale (PCSS) at twelve months post-injury. In the acute phase there was no statistical difference in structural integrity as measured with DTI between mTBI patients and healthy controls. At twelve months post-injury, loss of structural integrity in mTBI patients was found in nearly all DTI indices compared to healthy controls. CONCLUSIONS: Presence of Mb detected by SWI was associated with worse cognitive outcome and persistent PCS in mTBI patients, while DTI did not prove to predict neuropsychological outcome in the acute phase.
Assuntos
Concussão Encefálica , Hemorragia Cerebral , Hemorragia Cerebral/diagnóstico por imagem , Imagem de Tensor de Difusão , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Testes NeuropsicológicosRESUMO
BACKGROUND: Ceritinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor, which has shown robust anti-tumour efficacy, along with intracranial activity, in patients with ALK-rearranged non-small-cell lung cancer. In phase 1 and 2 studies, ceritinib has been shown to be highly active in both ALK inhibitor-naive and ALK inhibitor-pretreated patients who had progressed after chemotherapy (mostly multiple lines). In this study, we compared the efficacy and safety of ceritinib versus single-agent chemotherapy in patients with advanced ALK-rearranged non-small-cell lung cancer who had previously progressed following crizotinib and platinum-based doublet chemotherapy. METHODS: In this randomised, controlled, open-label, phase 3 trial, we recruited patients aged at least 18 years with ALK-rearranged stage IIIB or IV non-small-cell lung cancer (with at least one measurable lesion) who had received previous chemotherapy (one or two lines, including a platinum doublet) and crizotinib and had subsequent disease progression, from 99 centres across 20 countries. Other inclusion criteria were a WHO performance status of 0-2, adequate organ function and laboratory test results, a life expectancy of at least 12 weeks, and having recovered from previous anticancer treatment-related toxicities. We randomly allocated patients (1:1; with blocking [block size of four]; stratified by WHO performance status [0 vs 1-2] and presence or absence of brain metastases) to oral ceritinib 750 mg per day fasted (in 21 day treatment cycles) or chemotherapy (intravenous pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 [investigator choice], every 21 days). Patients who discontinued chemotherapy because of progressive disease could cross over to the ceritinib group. The primary endpoint was progression-free survival, assessed by a masked independent review committee using Response Evaluation Criteria in Solid Tumors 1.1 in the intention-to-treat population, assessed every 6 weeks until month 18 and every 9 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01828112, and is ongoing but no longer recruiting patients. FINDINGS: Between June 28, 2013, and Nov 2, 2015, we randomly allocated 231 patients; 115 (50%) to ceritinib and 116 (50%) to chemotherapy (40 [34%] to pemetrexed, 73 [63%] to docetaxel, and three [3%] discontinued before receiving treatment). Median follow-up was 16·5 months (IQR 11·5-21·4). Ceritinib showed a significant improvement in median progression-free survival compared with chemotherapy (5·4 months [95% CI 4·1-6·9] for ceritinib vs 1·6 months [1·4-2·8] for chemotherapy; hazard ratio 0·49 [0·36-0·67]; p<0·0001). Serious adverse events were reported in 49 (43%) of 115 patients in the ceritinib group and 36 (32%) of 113 in the chemotherapy group. Treatment-related serious adverse events were similar between groups (13 [11%] in the ceritinib group vs 12 [11%] in the chemotherapy group). The most frequent grade 3-4 adverse events in the ceritinib group were increased alanine aminotransferase concentration (24 [21%] of 115 vs two [2%] of 113 in the chemotherapy group), increased γ glutamyltransferase concentration (24 [21%] vs one [1%]), and increased aspartate aminotransferase concentration (16 [14%] vs one [1%] in the chemotherapy group). Six (5%) of 115 patients in the ceritinib group discontinued because of adverse events compared with eight (7%) of 116 in the chemotherapy group. 15 (13%) of 115 patients in the ceritinib group and five (4%) of 113 in the chemotherapy group died during the treatment period (from the day of the first dose of study treatment to 30 days after the final dose). 13 (87%) of the 15 patients who died in the ceritinib group died because of disease progression and two (13%) died because of an adverse event (one [7%] cerebrovascular accident and one [7%] respiratory failure); neither of these deaths were considered by the investigator to be treatment related. The five (4%) deaths in the chemotherapy group were all due to disease progression. INTERPRETATION: These findings show that patients derive significant clinical benefit from a more potent ALK inhibitor after failure of crizotinib, and establish ceritinib as a more efficacious treatment option compared with chemotherapy in this patient population. FUNDING: Novartis Pharmaceuticals Corporation.
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Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Pemetrexede/uso terapêutico , Pirimidinas/uso terapêutico , Receptores Proteína Tirosina Quinases/genética , Sulfonas/uso terapêutico , Taxoides/uso terapêutico , Adulto , Alanina Transaminase/sangue , Quinase do Linfoma Anaplásico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aspartato Aminotransferases/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/secundário , Crizotinibe , Progressão da Doença , Intervalo Livre de Doença , Docetaxel , Feminino , Rearranjo Gênico , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos de Platina/administração & dosagem , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas/efeitos adversos , Critérios de Avaliação de Resposta em Tumores Sólidos , Retratamento , Sulfonas/efeitos adversos , gama-Glutamiltransferase/sangueRESUMO
Immunotherapy is becoming a standard of care for many cancers. Immune-checkpoint inhibitors (ICI) can generate immune-related adverse events. Interstitial lung disease (ILD) has been identified as a rare but potentially severe event.Between December 2015 and April 2016, we conducted a retrospective study in centres experienced in ICI use. We report the main features of ICI-ILD with a focus on clinical presentation, radiological patterns and therapeutic strategies.We identified 64 (3.5%) out of 1826 cancer patients with ICI-ILD. Patients mainly received programmed cell death-1 inhibitors. ILD usually occurred in males, and former or current smokers, with a median age of 59â years. We observed 65.6% grade 2/3 severity, 9.4% grade 4 severity and 9.4% fatal ILD. The median (range) time from initiation of immunotherapy to ILD was 2.3 (0.2-27.4) months. Onset tended to occur earlier in lung cancer versus melanoma: median 2.1 and 5.2â months, respectively (p=0.02). Ground-glass opacities (81.3%) were the predominant lesions, followed by consolidations (53.1%). Organising pneumonia (23.4%) and hypersensitivity pneumonitis (15.6%) were the most common patterns. Overall survival at 6â months was 58.1% (95% CI 37.7-73.8%).ICI-ILD often occurs early and displays suggestive radiological features. As there is no clearly identified risk factor, oncologists need to diagnose and adequately treat this adverse event.
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Imunoterapia/efeitos adversos , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/mortalidade , Pulmão/diagnóstico por imagem , Neoplasias/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , França , Humanos , Estimativa de Kaplan-Meier , Pulmão/fisiopatologia , Doenças Pulmonares Intersticiais/etiologia , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Suíça , Tomografia Computadorizada por Raios X , Adulto JovemRESUMO
BACKGROUND: Accurate lymph node staging is essential for adequate prognostication and therapy planning in patients with non-small cell lung cancer (NSCLC). FDG-PET/CT is a sensitive tool for the detection of metastases, including non-palpable supraclavicular lymph node (SCLN) metastases. Histological proof of metastatic spread and mutation analysis is crucial for optimal staging and therapy. The aim of this study was to investigate the value of ultrasound-guided fine needle aspiration cytology (FNAC) and core biopsy (CB) of FDG active, non-palpable SCLN's in patients with suspicion for lung cancer. METHODS: Twelve consecutive patients with suspected lung cancer and FDG-positive SCLN underwent FNAC (n = 11) and/or CB (n = 10) and were included and evaluated retrospectively in this study. Cytologic and/or histologic evaluation was performed to confirm initially suspected diagnosis (lung cancer), to confirm N3 stage, and to screen for driver mutations in lung adenocarcinoma. RESULTS: FNAC alone showed diagnostic success in 11/11 cases (100%), CB alone in 9/10 patients (90%), and the combination of both procedures was successful in 12/12 cases (100%). Lymph node metastases from NSCLC (7 adenocarcinoma, 2 squamous cell carcinoma) could be confirmed in 9 patients. Other diagnoses were small cell lung cancer (SCLC), breast cancer and sarcoidosis. There was enough material for immunhistochemistry in all patients. For molecular testing, material from this lymph node biopsies and lung biopsy was used. In two patients with adenocarcinoma of the lung driver mutations were detected (EGFR Exon 19 deletion and ALK rearrangement) out of the lymph node metastasis. CONCLUSIONS: US-guided combined FNAC and CB of FDG positive supraclavicular lymph nodes in patients with suspected lung cancer is a safe and effective procedure to confirm N3-stage and to obtain representative material for molecular testing.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Neoplasias Pulmonares/diagnóstico , Linfonodos/patologia , Idoso , Quinase do Linfoma Anaplásico , Biópsia com Agulha de Grande Calibre , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Clavícula , Receptores ErbB/genética , Feminino , Fluordesoxiglucose F18/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Receptores Proteína Tirosina Quinases/genética , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
PURPOSE: The goal of this study is to determine the relationship of radiological grading scales of lumbar degenerative disc disease (DDD) with postoperative pain intensity, functional impairment, and health-related quality of life (HRQoL). METHODS: Response to surgical treatment at 6 weeks (W6) on the visual analogue scale (VAS) for back and leg pain, Oswestry-Disability (ODI) and Roland-Morris Disability Index (RMDI), Timed Up and Go (TUG) test, EuroQol (EQ) 5D, and Short-Form Health-Survey (SF-12) physical component summary (PCS) was compared between patients with different Modic (MOD) and Pfirrmann (PFI) grades. Longitudinal outcomes at day 3 (D3), W6, 6 months (M6), and 1 year (Y1) were compared. RESULTS: The study included 338 patients (mean age, 58.6 years), of which n = 202 (59.8%) had MOD 1-3 and n = 217 (64.2%) PFI 4-5 changes. Patients with MOD 1-3 were as likely as patients without MOD changes to be treatment-responders at W6 in terms of VAS leg pain, ODI, RMDI, TUG, EQ5D, and SF-12 PCS. Similarly, patients with PFI 4-5 were as likely as patients with PFI 1-3 changes to be treatment-responders at W6. Longitudinal outcomes were similar at D3, W6, M6, and Y1 between patients with and without MOD changes. Patients with PFI 4-5 fared similar to those with PFI 1-3 except for inferior HRQoL on the SF-12 PCS metric at Y1. CONCLUSIONS: There was no distinct relationship between commonly used radiological grading scales of lumbar DDD with clinical outcome. Therefore, no prognosis should be made on the grounds of preoperative PFI and MOD classifications for patients undergoing spine surgery for lumbar DDD.
Assuntos
Degeneração do Disco Intervertebral/diagnóstico por imagem , Degeneração do Disco Intervertebral/cirurgia , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/cirurgia , Angiografia por Ressonância Magnética/métodos , Avaliação de Resultados em Cuidados de Saúde/métodos , Qualidade de Vida , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Although most patients with a mild traumatic brain injury (mTBI) recover within days to weeks, some experience persistent physical, cognitive and emotional symptoms, often described as post-concussion syndrome (PCS). The optimal recovery time including return-to-work (RTW) after mTBI is unclear. In this single-centre parallel-group trial, patients assigned three days (3D-group) or seven days (7D-group) sick leave were compared with a comprehensive neuropsychological test battery including the Post-Concussion Symptom Scale (PCSS) within one week, after three and 12 months post-injury. The influence of the effective time until RTW on post-concussional symptoms and cognitive performance was analysed. The 3D-group rated significantly higher mean scores in some PCSS symptoms, tended to fulfil diagnosis criteria of PCS more often and showed better cognitive performance in several neuropsychological test scores than the 7D-group at all three time-points of follow-up. Overall, patients returned to work 11.35 d post-injury, thus distinctly above both recommended sick leaves. There was a trend for longer sick leave in patients randomized into the 3D-group. Further analyses revealed that the group with an absolute RTW within one week showed lower symptom severity in fatigue at 3 and 12 months, less PCS and faster performance in fine motor speed at 12 months than the group with an absolute RTW after one week. Our data underline the heterogeneity of mTBI and show that acute and sub-acute symptoms are not prognostic factors for neuropsychological outcome at one year. Later, ability to work seems to be prognostic for long-term occurrence of PCS.
Assuntos
Concussão Encefálica/psicologia , Cognição/fisiologia , Síndrome Pós-Concussão/psicologia , Adulto , Concussão Encefálica/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Síndrome Pós-Concussão/diagnóstico , Retorno ao Trabalho , Licença Médica , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: One of the standard options in the treatment of stage IIIA/N2 non-small-cell lung cancer is neoadjuvant chemotherapy and surgery. We did a randomised trial to investigate whether the addition of neoadjuvant radiotherapy improves outcomes. METHODS: We enrolled patients in 23 centres in Switzerland, Germany and Serbia. Eligible patients had pathologically proven, stage IIIA/N2 non-small-cell lung cancer and were randomly assigned to treatment groups in a 1:1 ratio. Those in the chemoradiotherapy group received three cycles of neoadjuvant chemotherapy (100 mg/m(2) cisplatin and 85 mg/m(2) docetaxel) followed by radiotherapy with 44 Gy in 22 fractions over 3 weeks, and those in the control group received neoadjuvant chemotherapy alone. All patients were scheduled to undergo surgery. Randomisation was stratified by centre, mediastinal bulk (less than 5 cm vs 5 cm or more), and weight loss (5% or more vs less than 5% in the previous 6 months). The primary endpoint was event-free survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00030771. FINDINGS: From 2001 to 2012, 232 patients were enrolled, of whom 117 were allocated to the chemoradiotherapy group and 115 to the chemotherapy group. Median event-free survival was similar in the two groups at 12·8 months (95% CI 9·7-22·9) in the chemoradiotherapy group and 11·6 months (8·4-15·2) in the chemotherapy group (p=0·67). Median overall survival was 37·1 months (95% CI 22·6-50·0) with radiotherapy, compared with 26·2 months (19·9-52·1) in the control group. Chemotherapy-related toxic effects were reported in most patients, but 91% of patients completed three cycles of chemotherapy. Radiotherapy-induced grade 3 dysphagia was seen in seven (7%) patients. Three patients died in the control group within 30 days after surgery. INTERPRETATION: Radiotherapy did not add any benefit to induction chemotherapy followed by surgery. We suggest that one definitive local treatment modality combined with neoadjuvant chemotherapy is adequate to treat resectable stage IIIA/N2 non-small-cell lung cancer. FUNDING: Swiss State Secretariat for Education, Research and Innovation (SERI), Swiss Cancer League, and Sanofi.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiorradioterapia Adjuvante/métodos , Neoplasias Pulmonares/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/secundário , Quimiorradioterapia Adjuvante/efeitos adversos , Feminino , Humanos , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/métodos , Estadiamento de Neoplasias , Pneumonectomia/métodos , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: The management of small unruptured incidentally discovered intracranial aneurysms (SUIAs) is still controversial. The aim of this study is to assess the safety of a management protocol of SUIAs, where selected cases with SUIAs are observed and secured only if signs of instability (growth) are documented. METHODS: A prospective consecutive cohort of 292 patients (2006-2014) and 368 SUIAs (anterior circulation aneurysms (ACs) smaller than 7â mm and posterior circulation aneurysms smaller than 4â mm without previous subarachnoid haemorrhage) was observed (mean follow-up time of 3.2â years and 1177.6 aneurysm years). Factors associated with aneurysm growth were systematically reviewed from the literature. RESULTS: The aneurysm growth probability was 2.6±0.1% per year. The rate of unexpected aneurysm rupture before treatment was 0.24% per year (95% CI 0.17% to 2.40%). The calculated rate of aneurysm rupture after growth was 6.3% per aneurysm-year (95% CI 1% to 22%). Aneurysms located in the posterior circulation and aneurysms with lobulation were more likely to grow. Females or patients suffering hypertension were more likely to have an aneurysm growing. The probability of aneurysms growth increased with the size of the dome and was proportional to the number of aneurysms diagnosed in a patient. CONCLUSIONS: It is safe to observe patients diagnosed with SUIAs using periodic imaging. Intervention to secure the aneurysm should be performed after growth is observed.
Assuntos
Aneurisma Intracraniano/terapia , Conduta Expectante , Adulto , Idoso , Aneurisma Roto/diagnóstico por imagem , Aneurisma Roto/terapia , Estudos de Coortes , Feminino , Humanos , Achados Incidentais , Aneurisma Intracraniano/diagnóstico por imagem , Estimativa de Kaplan-Meier , Estudos Longitudinais , Angiografia por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Seleção de Pacientes , Medição de RiscoRESUMO
BACKGROUND: The Timed Up and Go (TUG) test is a reliable tool for evaluating objective functional impairment (OFI) in patients with degenerative disc disease before a surgical intervention. The aim of this study is to assess the validity of the TUG test to measure change in function postoperatively. METHODS: In a prospective two-center study, OFI was assessed by the TUG test in patients scheduled for lumbar spine surgery, as well as 3 days (D3) and 6 weeks (W6) postoperatively. At each time point, the TUG test results were correlated with established subjective measures of pain intensity (visual analogue scale (VAS) for back and leg pain), functional impairment (Oswestry Disability Index (ODI)) and health-related quality of life (HRQoL; Short Form-12 (SF12)). RESULTS: The patient cohort comprised 136 patients with a mean age of 57.7 years; 76 were males, 54 had a microdiscectomy for lumbar disc herniation, 58 a decompression for a lumbar spinal stenosis, 24 had a surgical fusion procedure. The mean OFI t-score was 125.1 before surgery, and as patients improved on the subjective measures in the postoperative interval, the OFI t-score likewise decreased to 118.8 (D3) and 103.4 (W6). The Pearson correlation coefficient (PCC) between the OFI t-score and VAS leg pain was 0.187 preoperatively (p = 0.029) and 0.252 at W6 (p = 0.003). The PCC between OFI t-score and the ODI was 0.324 preoperatively (p < 0.001) and 0.413 at W6 (p < 0.001). The PCC between OFI t-score and physical HRQoL (SF12) was -0.091 preoperatively (p = 0.293) and -0.330 at W6 (p < 0.001). CONCLUSIONS: The TUG test is sensitive to change, and reflects the postoperative functional outcome even more exact than preoperatively, as indicated by better correlation coefficients of the OFI t-score with subjective measures of pain intensity, functional impairment and HRQoL.
Assuntos
Descompressão Cirúrgica/efeitos adversos , Discotomia/efeitos adversos , Degeneração do Disco Intervertebral/cirurgia , Medidas de Resultados Relatados pelo Paciente , Complicações Pós-Operatórias/diagnóstico , Estenose Espinal/cirurgia , Adulto , Idoso , Feminino , Humanos , Vértebras Lombares/cirurgia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Estudos Prospectivos , Qualidade de VidaRESUMO
INTRODUCTION: The introduction of the European Working Time directive 2003/88/EC has led to a reduction of the working hours with distinct impact on the clinical and surgical activity of neurosurgical residents in training. METHODS: A survey was performed among European neurosurgical residents between 06/2014 and 03/2015. Multiple logistic regression was used to assess the relationship between responder-specific variables (e.g., age, gender, country, postgraduate year (PGY)) and outcome (e.g., working time). RESULTS: A total of 652 responses were collected, of which n = 532 responses were taken into consideration. In total, 17.5, 22.1, 29.5, 19.5, 5.9, and 5.5 % of European residents indicated to work <40, 40-50, 51-60, 61-70, 71-80, or >80 h/week, respectively. Residents from France and Turkey (OR 4.72, 95 % CI 1.29-17.17, p = 0.019) and Germany (OR 2.06, 95 % CI 1.15-3.67, p = 0.014) were more likely to work >60 h/week than residents from other European countries. In total, 29 % of European residents were satisfied with their current working time, 11.3 % indicated to prefer reduced working time. More than half (55 %) would prefer to work more hours/week if this would improve their clinical education. Residents that rated their operative exposure as insufficient were 2.3 times as likely as others to be willing to work more hours (OR 2.32, 95 % CI 1.47-3.70, p < 0.001). Less than every fifth European resident spends >50 % of his/her working time in the operating room. By contrast, 77.4 % indicate to devote >25 % of their daily working time to administrative work. For every advanced PGY, the likelihood to spend >50 % of the working time in the OR increases by 19 % (OR 1.19, 95 % CI 1.02-1.40, p = 0.024) and the likelihood to spend >50 % of the working time with administrative work decreases by 18 % (OR 0.84, 95 % CI 0.76-0.94, p = 0.002). CONCLUSIONS: The results of this survey on >500 European neurosurgical residents clearly prove that less than 40 % conform with the 48-h week as claimed by the WTD2003/88/EC. Still, more than half of them would chose to work even more hours/week if their clinical education were to improve; probably due to subjective impression of insufficient training.
Assuntos
Internato e Residência/estatística & dados numéricos , Neurocirurgia/educação , Neurocirurgia/estatística & dados numéricos , Carga de Trabalho/estatística & dados numéricos , Adulto , Fatores Etários , Certificação , Europa (Continente) , Docentes , Feminino , Humanos , Satisfação no Emprego , Masculino , Pessoa de Meia-Idade , Salas Cirúrgicas/organização & administração , Fatores Sexuais , Cirurgiões/estatística & dados numéricos , Inquéritos e Questionários , Recursos HumanosRESUMO
INTRODUCTION: Neurosurgical training aims at educating future generations of specialist neurosurgeons and at providing the highest-quality medical services to patients. Attaining and maintaining these highest standards constitutes a major responsibility of academic or other training medical centers. METHODS: An electronic survey was sent to European neurosurgical residents between 06/2014 and 03/2015. Multiple logistic regression analysis was used to assess the effect size of the relationship between responder-specific variables (e.g., age, gender, postgraduate year (PGY), country) and the outcomes (e.g., satisfaction). RESULTS: A total of 652 responses were collected, of which n = 532 were taken into consideration. Eighty-five percent were 26-35 years old, 76 % male, 62 % PGY 4 or higher, and 73.5 % working at a university clinic. Satisfaction rates with theoretical education such as clinical lectures (overall: 50.2 %), anatomical lectures (31.2 %), amongst others, differed largely between the EANS member countries. Likewise, satisfaction rates with practical aspects of training such as hands-on surgical experience (overall: 73.9 %), microsurgical training (52.5 %), simulator training (13.4 %), amongst others, were highly country-dependant. In general, 89.1 % of European residents carried out the first surgical procedure under supervision within the first year of training. Supervised lumbar-/cervical spine surgeries were performed by 78.2 and 17.9 % of European residents within 12 and 24 months of training, respectively, and 54.6 % of European residents operate a cranial case within the first 36 months of training. Logistic regression analysis identified countries where residents were much more or much less likely to operate as primary surgeons compared to the European average. The caseload of craniotomies per trainee (overall: 30.6 % ≥10 craniotomies/month) and spinal procedures (overall: 29.7 % ≥10 spinal surgeries/month) varied throughout the countries and was significantly associated with more advanced residency (craniotomy: OR 1.35, 95 % CI 1.18-1.53, p < 0.001; spinal surgery: OR 1.37, 95 % CI 1.20-1.57, p < 0.001). CONCLUSIONS: Theoretical and practical aspects of neurosurgical training are highly variable throughout European countries, despite some efforts within the last two decades to harmonize this. Some countries are rated significantly above (and others significantly below) the current European average for several analyzed parameters. It is hoped that the results of this survey should provide the incentive as well as the opportunity for a critical analysis of the local conditions for all training centers, but especially those in countries scoring significantly below the European average.
Assuntos
Internato e Residência/estatística & dados numéricos , Neurocirurgia/educação , Adulto , Fatores Etários , Certificação , Estudos de Coortes , Avaliação Educacional , Europa (Continente) , Docentes/normas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Inquéritos e QuestionáriosRESUMO
INTRODUCTION: Substantial country differences in neurosurgical training throughout Europe have recently been described, ranging from subjective rating of training quality to objective working hours per week. The aim of this study was to analyse whether these differences translate into the results of the written and oral part of the European Board Examination in Neurological Surgery (EBE-NS). METHODS: Country-specific composite scores for satisfaction with quality of theoretical and practical training, as well as working hours per week, were obtained from an electronic survey distributed among European neurosurgical residents between June 2014 and March 2015. These were related to anonymous country-specific results of the EBE-NS between 2009 and 2016, using uni- and multivariate linear regression analysis. RESULTS: A total of n = 1025 written and n = 63 oral examination results were included. There was a significant linear relationship between the country-specific EBE-NS result in the written part and the country-specific composite score for satisfaction with quality of theoretical training [adjusted regression coefficient (RC) -3.80, 95 % confidence interval (CI) -5.43-7 -2.17, p < 0.001], but not with practical training or working time. For the oral part, there was a linear relationship between the country-specific EBE-NS result and the country-specific composite score for satisfaction with quality of practical training (RC 9.47, 95 % CI 1.47-17.47, p = 0.021), however neither with satisfaction with quality of theoretical training nor with working time. CONCLUSION: With every one-step improvement on the country-specific satisfaction score for theoretical training, the score in the EBE-NS Part 1 increased by 3.8 %. With every one-step improvement on the country-specific satisfaction score for practical training, the score in the EBE-NS Part 2 increased by 9.47 %. Improving training conditions is likely to have a direct positive influence on the knowledge level of trainees, as measured by the EBE-NS. The effect of the actual working time on the theoretical and practical knowledge of neurosurgical trainees appears to be insignificant.