Estudo randomizado, aberto, utilizando protetor cutâneo em spray à base de terpolímero acrílico versus hidratante padrão na prevenção de radiodermatite aguda em pacientes com câncer de canal anal e reto / An open randomized study using a skin protector spray made of acrylic terpolymers versus and standardized moisturizer in preventing acute radiodermatitis in patients with anal and rectal cancer

Pacientes com câncer de canal anal e reto em tratamento por radioterapia apresentam alta prevalência de radiodermatite com descamação úmida, desfecho que causa impactos clínicos, econômicos e sociais. Estudos sobre a efetividade de produtos na prevenção das radiodermatites representam uma lacuna de conhecimento na área oncológica, podendo o seu desenvolvimento contribuir para a diminuição dos impactos negativos desse evento, do tempo ocioso do equipamento pela interrupção do tratamento e da possibilidade de falha local da doença. Objetivou-se analisar a efetividade do protetor cutâneo em spray à base de terpolímero acrílico na prevenção da radiodermatite com descamação úmida nos pacientes com câncer de canal anal e reto em comparação com um hidratante padronizado na instituição à base de Calendula officinalis L. e Aloe barbadensis. Ensaio clínico randomizado, aberto, em instituição única, referência nacional no tratamento de doenças oncológicas, com amostra 63 pacientes que foram randomizados nos grupos: experimental, com uso do protetor cutâneo em spray, e controle, usando o hidratante Dnativ Revita Derm. Os pacientes foram acompanhados na consulta de enfermagem, com cegamento do avaliador da pele quanto ao uso da intervenção. A escala de avaliação de pele utilizada foi a da Radiation Therapy Oncology Group. A coleta de dados ocorreu por meio dos formulários de avaliação inicial e subsequente, sendo o desfecho principal medido a ocorrência de radiodermatite com descamação úmida, e os secundários a ocorrência de interrupção temporária da radioterapia por radiodermatite, de eventos adversos aos produtos e de severidade da radiodermatite. As análises se deram por Intenção de Tratar e Protocolo, sendo utilizadas as estatísticas descritiva, analítica e inferenciais no tratamento dos dados, com nível de significância de ≤ 0,10. Pesquisa aprovada pelo Comitê de Ética sob parecer nº 5.322.985 e registrado no Clinical Trials sob número: NCT04067310T. A regressão logística binária mostrou que os participantes expostos ao protetor cutâneo em spray tiveram menor chance de apresentar a radiodermatite com descamação úmida quando comparados ao grupo controle. A redução absoluta do risco de radiodermatite foi de 18% no grupo experimental. A incidência geral de radiodermatite foi de 100%, sendo 36,5% graus mais severos. A incidência de radiodermatite Grau 1 foi maior no grupo experimental, enquanto os graus mais severos (Graus 3 e 4) tiveram maior incidência no grupo controle; 17,5% dos participantes tiveram interrupção da radioterapia por radiodermatite, variando de 3 a 15 dias, com média de seis dias interrompidos. Apesar de relevantes clinicamente, esses resultados sobre a interrupção temporária do tratamento e a severidade da radiodermatite não tiveram significância estatística. Foram considerados fatores de risco para a descamação úmida: sexo feminino, diagnóstico C.21 e C.21.8, altas doses de radioterapia (5400-6000cGy), tipo histológico carcinoma espinocelular, umidade antes e durante a radioterapia e uso de proteção íntima. Concluiu-se que o protetor cutâneo em spray é um produto efetivo na prevenção da radiodermatite com descamação úmida nos pacientes com câncer de canal anal e reto, afirmação que sustenta a tese defendida. Nesse sentido, os resultados podem orientar a revisão dos protocolos assistenciais de prevenção da radiodermatite utilizados pelo enfermeiro no âmbito da consulta de enfermagem em radioterapia, com vistas a reduzir os impactos no seguimento terapêutico e na qualidade de vida dos pacientes com câncer de canal anal e reto.

Patients' ongoing anal and rectal cancer radiotherapy exhibit a high prevalence of radiodermatitis with moist desquamation, impairing clinical, economic, and social outcomes. Clinical trials targeting product efficacy in preventing radiodermatitis are lacking in the current literature. These products could contribute to diminishing adverse effects, reducing equipment idle time by therapy interruption, and increasing the cure rate. Our goal is to evaluate the effectiveness of cutaneous spray based on acrylic terpolymers in preventing radiodermatitis with moist desquamation in patients with rectal or anal cancer. Spray effectiveness was defied against a standardized moisturizer in the institution made of Calendula officinalis L. and Aloe barbadensis extracts. An open, single-blind, randomized clinical study was conducted in a single institution, reference in national treatment in oncological diseases, with a sample size (n) of 63 patients. Patients were randomized into two groups: (i) experimental, using cutaneous protector spray; and (ii) control, using moisturizer Dnativ Revita Derm. RTOC's scale was used for evaluating skin condition. Data was collected in forms, which considered: (i) the primary outcome of radiodermatitis with moist desquamation occurrence; and (ii) the secondary outcome of radiotherapy interruption caused by radiodermatitis occurrence and severity, and product adverse effects. Analyses were performed by intention to treat and per protocol, using descriptive, analytical, and inferential statistics, with a significance level of ≤ 0.10 (α). Research was approved by the Ethics committee under approval nº 5.322.985 and registered in Clinical Trials under number NCT04067310T. Binary logistic regression demonstrated that patients exposed to cutaneous spray protector were less prone to develop radiodermatitis with moist desquamation compared to the control group. Absolute reduction in radiodermatitis risk was 18% in the experimental group. The radiodermatitis overall incidence was 100%, with 36.5% of higher severity. The incidence of grade 1 radiodermatitis was higher in the experimental group, while the more severe grades (3 and 4) had a higher incidence in the control group; 17.5% of the participants had an interruption of radiotherapy due to radiodermatitis, ranging from 3 to 15 days, with an average of six interrupted days. Despite being clinically relevant, these results regarding the temporary interruption of treatment and the severity of radiodermatitis were not statistically significant. Risk factors for moist desquamation were considered: female gender, diagnosis of C.21 and C.21.8, high radiation doses (5400 to 6000 cGy), histological type squamous cell carcinoma, humidity before and during radiotherapy, and use of intimate protection. In conclusion, the skin protector spray is an effective product in the prevention of radiodermatitis with moist desquamation in patients with anal and rectal cancer. In this sense, the results can guide the review of care protocols for the prevention of radiodermatitis used by nurses in the context of nursing consultations in radiotherapy to reduce the impacts on therapeutic follow-up and the quality of life of patients with cancer of the anal canal and straight.

Los pacientes con cáncer de canal anal y recto en tratamiento con radioterapia tienen una alta prevalencia de radiodermatitis con descamación húmeda, desenlace que genera impactos clínicos, económicos y sociales. Los estudios sobre la efectividad de los productos en la prevención de la radiodermatitis representan un vacío de conocimiento en el área de oncología y pueden contribuir para la reducción de los impactos negativos, el tiempo de inactividad de los equipos por interrupción del tratamiento y la posibilidad de falla local de la enfermedad. El objetivo de este estudio fue analizar la eficacia de un protector cutáneo en spray a base de terpolímero acrílico en la prevención de la radiodermatitis con descamación húmeda en pacientes con cáncer anal y rectal frente a una crema hidratante estandarizada de la institución a base de Calendula officinalis L. y Aloe barbadensis. Ensayo clínico aleatorizado, abierto, en una sola institución, referente nacional en el tratamiento de enfermedades oncológicas, con una muestra de 63 pacientes que fueron aleatorizados en grupos: experimental, utilizando spray protector para la piel, y control, utilizando Dnativ Revita Derm hidratante. Los pacientes fueron seguidos en la consulta de enfermería, cegándose el evaluador de piel en cuanto al uso de la intervención. La escala de valoración de la piel utilizada fue la del RTOC. Los datos se recopilaron mediante formularios de evaluación inicial y posterior, siendo el resultado principal medido la aparición de radiodermatitis con descamación húmeda y los resultados secundarios la interrupción temporal de la radioterapia debido a la radiodermatitis, los eventos adversos de los productos y la gravedad de la radiodermatitis. Los análisis fueron realizados por Intención de Tratar y Protocolo, utilizando estadística descriptiva, analítica e inferencial en el procesamiento de datos, con nivel de significación ≤ 0,10. Investigación aprobada por el Comité de Ética con dictamen nº 5.322.985 y registrada en Ensayos Clínicos con el número: NCT04067310T. La regresión logística binaria mostró que los participantes expuestos al protector de piel en aerosol tenían menos probabilidades de tener radiodermatitis con descamación húmeda en comparación con el grupo de control. La reducción absoluta del riesgo de radiodermatitis fue del 18 % en el grupo experimental. La incidencia global de radiodermatitis fue del 100%, siendo el 36,5% grados más graves. La incidencia de radiodermatitis Grado 1 fue mayor en el grupo experimental, mientras que los grados más severos (3 y 4) tuvieron mayor incidencia en el grupo control; El 17,5% de los participantes tuvo interrupción de la radioterapia por radiodermatitis, variando de 3 a 15 días, con un promedio de seis días de interrupción. A pesar de ser clínicamente relevantes, estos resultados en cuanto a la interrupción temporal del tratamiento y la gravedad de la radiodermatitis no fueron estadísticamente significativos. Se consideraron factores de riesgo para descamación húmeda: sexo femenino, diagnóstico C.21 y C.21.8, dosis altas (5400-6000cGy), carcinoma epidermoide de tipo histológico, humedad antes y durante la radioterapia y uso de protección íntima. Se concluyó que el spray protector de piel es un producto eficaz en la prevención de la radiodermatitis con descamación húmeda en pacientes con cáncer anal y rectal, afirmación que sustenta la tesis defendida. En ese sentido, los resultados pueden orientar la revisión de los protocolos de atención para la prevención de la radiodermitis utilizados por los enfermeros en el contexto de las consultas de enfermería en radioterapia, con el objetivo de reducir los impactos en el seguimiento terapéutico y en la calidad de vida de los pacientes con cáncer del canal anal y recto.

Early discontinuation of adjuvant chemotherapy in patients with early-stage pancreatic cancer correlates with inferior survival: A multicenter population-based cohort study.

BACKGROUND: The current study aimed to determine the association between timing and completion of adjuvant chemotherapy and outcomes in real-world patients with early-stage pancreatic cancer. METHODS: In this multi-center cohort study patients with early-stage pancreatic cancer who were diagnosed from 2007-2017 and underwent complete resection in the province of Saskatchewan were examined. Cox proportional multivariate analyses were performed for correlation with recurrence and survival. RESULTS: Of 168 patients, 71 eligible patients with median age of 69 years and M:F of 37:34 were identified. Median time to the start of adjuvant therapy from surgery was 73 days. Of all patients, 49 (69%) patients completed adjuvant chemotherapy and 22 (31%) required early treatment discontinuation. Median recurrence-free survival of patients who completed treatment was 22 months (95%CI:15.8-28.2) vs. 9 months (3.3-14.7) if treatment was discontinued early (P<0.001). Median overall survival of those who completed treatment was 33 (17.5-48.5) vs. 16 months (17.5-48.5) with early treatment discontinuation (P<0.001). In the multivariate analysis, treatment discontinuation was significantly correlated with recurrent disease, hazard ratio (HR), 2.57 (1.41-4.68), P = 0.002 and inferior survival, HR, 2.55 (1.39-4.68), P = 0.003. No correlation between treatment timing and survival was noted. CONCLUSIONS: Early discontinuation but not the timing of adjuvant chemotherapy correlates with inferior outcomes.

Life-prolonging treatment restrictions and outcomes in patients with cancer and COVID-19: an update from the Dutch Oncology COVID-19 Consortium.

AIM OF THE STUDY: The coronavirus disease 2019 (COVID-19) pandemic significantly impacted cancer care. In this study, clinical patient characteristics related to COVID-19 outcomes and advanced care planning, in terms of non-oncological treatment restrictions (e.g. do-not-resuscitate codes), were studied in patients with cancer and COVID-19. METHODS: The Dutch Oncology COVID-19 Consortium registry was launched in March 2020 in 45 hospitals in the Netherlands, primarily to identify risk factors of a severe COVID-19 outcome in patients with cancer. Here, an updated analysis of the registry was performed, and treatment restrictions (e.g. do-not-intubate codes) were studied in relation to COVID-19 outcomes in patients with cancer. Oncological treatment restrictions were not taken into account. RESULTS: Between 27th March 2020 and 4th February 2021, 1360 patients with cancer and COVID-19 were registered. Follow-up data of 830 patients could be validated for this analysis. Overall, 230 of 830 (27.7%) patients died of COVID-19, and 60% of the remaining 600 patients with resolved COVID-19 were admitted to the hospital. Patients with haematological malignancies or lung cancer had a higher risk of a fatal outcome than other solid tumours. No correlation between anticancer therapies and the risk of a fatal COVID-19 outcome was found. In terms of end-of-life communication, 50% of all patients had restrictions regarding life-prolonging treatment (e.g. do-not-intubate codes). Most identified patients with treatment restrictions had risk factors associated with fatal COVID-19 outcome. CONCLUSION: There was no evidence of a negative impact of anticancer therapies on COVID-19 outcomes. Timely end-of-life communication as part of advanced care planning could save patients from prolonged suffering and decrease burden in intensive care units. Early discussion of treatment restrictions should therefore be part of routine oncological care, especially during the COVID-19 pandemic.

Using a Simple Prescription Gap to Determine Warfarin Discontinuation Can Lead to Substantial Misclassification.

BACKGROUND: Warfarin remains widely used and a key comparator in studies of other direct oral anticoagulants. As longer-than-needed warfarin prescriptions are often provided to allow for dosing adjustments according to international normalized ratios (INRs), the common practice of using a short allowable gap between dispensings to define warfarin discontinuation may lead to substantial misclassification of warfarin exposure. We aimed to quantify such misclassification and determine the optimal algorithm to define warfarin discontinuation. METHODS: We linked Medicare claims data from 2007 to 2014 with a multicenter electronic health records system. The study cohort comprised patients ≥65 years with atrial fibrillation and venous thromboembolism initiating warfarin. We compared results when defining warfarin discontinuation by (1) different gaps (3, 7, 14, 30, and 60 days) between dispensings and (2) having a gap ≤60 days or bridging larger gaps if there was INR ordering at least every 42 days (60_INR). Discontinuation was considered misclassified if there was an INR ≥2 within 7 days after the discontinuation date. RESULTS: Among 3,229 patients, a shorter gap resulted in a shorter mean follow-up time (82, 95, 117, 159, 196, and 259 days for gaps of 3, 7, 14, 30, 60, and 60_INR, respectively; p < 0.001). Incorporating INR (60_INR) can reduce misclassification of warfarin discontinuation from 68 to 4% (p < 0.001). The on-treatment risk estimation of clinical endpoints varied significantly by discontinuation definitions. CONCLUSION: Using a short gap between warfarin dispensings to define discontinuation may lead to substantial misclassification, which can be improved by incorporating intervening INR codes.

Catch-up Growth and Discontinuation of Fludrocortisone Treatment in Aldosterone Synthase Deficiency.

BACKGROUND: Aldosterone synthase deficiency (ASD) caused by mutations in the CYP11B2 gene is characterized by isolated mineralocorticoid deficiency. Data are scarce regarding clinical and biochemical outcomes of the disease in the follow-up. OBJECTIVE: Assessment of the growth and steroid profiles of patients with ASD at the time of diagnosis and after discontinuation of treatment. DESIGN AND METHOD: Children with clinical diagnosis of ASD were included in a multicenter study. Growth and treatment characteristics were recorded. Plasma adrenal steroids were measured using liquid chromatography-mass spectrometry. Genetic diagnosis was confirmed by CYP11B2 gene sequencing and in silico analyses. RESULTS: Sixteen patients from 12 families were included (8 females; median age at presentation: 3.1 months, range: 0.4 to 8.1). The most common symptom was poor weight gain (56.3%). Median age of onset of fludrocortisone treatment was 3.6 months (range: 0.9 to 8.3). Catch-up growth was achieved at median 2 months (range: 0.5 to 14.5) after treatment. Fludrocortisone could be stopped in 5 patients at a median age of 6.0 years (range: 2.2 to 7.6). Plasma steroid profiles revealed reduced aldosterone synthase activity both at diagnosis and after discontinuation of treatment compared to age-matched controls. We identified 6 novel (p.Y195H, c.1200 + 1G > A, p.F130L, p.E198del, c.1122-18G > A, p.I339_E343del) and 4 previously described CYP11B2 variants. The most common variant (40%) was p.T185I. CONCLUSIONS: Fludrocortisone treatment is associated with a rapid catch-up growth and control of electrolyte imbalances in ASD. Decreased mineralocorticoid requirement over time can be explained by the development of physiological adaptation mechanisms rather than improved aldosterone synthase activity. As complete biochemical remission cannot be achieved, a long-term surveillance of these patients is required.

Adverse Events of Thiopurine Therapy in Pediatric Inflammatory Bowel Disease and Correlations with Metabolites: A Cohort Study.

BACKGROUND: In the recent era of growing availability of biological agents, the role of thiopurines needs to be reassessed with the focus on toxicity. AIMS: We assessed the incidence and predictive factors of thiopurine-induced adverse events (AE) resulting in therapy cessation in pediatric inflammatory bowel disease (IBD), related to thiopurine metabolites and biochemical abnormalities, and determined overall drug survival. METHODS: We performed a retrospective, single-center study of children diagnosed with IBD between 2000 and 2019 and treated with thiopurine therapy. The incidence of AE and overall drug survival of thiopurines were evaluated using the Kaplan-Meier method. Correlations between thiopurine metabolites and biochemical tests were computed using Spearman's correlation coefficient. RESULTS: Of 391 patients with IBD, 233 patients (162 Crohn's disease, 62 ulcerative colitis, and 9 IBD-unclassified) were prescribed thiopurines (230 azathioprine and 3 mercaptopurine), of whom 50 patients (22%) discontinued treatment, at least temporary, due to thiopurine-induced AE (median follow-up 20.7 months). Twenty-six patients (52%) were rechallenged and 18 of them (70%) tolerated this. Sixteen patients (6%) switched to a second thiopurine agent after azathioprine intolerance and 10 of them (63%) tolerated this. No predictive factors for development of AE could be identified. Concentrations of 6-thioguanine nucleotides (6-TGN) were significantly correlated with white blood cell and neutrophil count, 6-methylmercaptopurine (6-MMP) concentrations with alanine aminotransferase and gamma-glutamyltranspeptidase. CONCLUSIONS: Approximately 20% of pediatric patients with IBD discontinued thiopurine treatment due to AE. A rechallenge or switch to mercaptopurine is an effective strategy after development of AE. Concentrations of 6-TGN and 6-MMP are associated with biochemical abnormalities.

Treatment patterns and intensification within 5 year of follow-up of the first-line anti-TNFα used for the treatment of IBD: Results from the VERNE study.

BACKGROUND: Anti-TNFα represent one of the main treatment approaches for the management of inflammatory bowel diseases (IBD). Therefore,the evaluation of their treatment patterns over time provides valuable insights about the clinical value of therapies and associated costs. AIMS: To assess the treatment patterns with the first anti-TNFα in IBD. METHODS: Retrospective, observational study. RESULTS: 310 IBD patients were analyzed along a 5-year follow-up period. 56.2% of Crohn's disease (CD) patients started with adalimumab (ADA), while 43.8% started with infliximab (IFX). 12.9% of ulcerative colitis (UC) patients initiated with ADA, while 87.1% initiated with IFX. Treatment intensification was required in 28.9% of CD and 37.1% of UC patients. Median time to treatment intensification was shorter in UC than in CD (5.3 vs. 14.3 months; p = 0.028). Treatment discontinuation due to reasons other than remission were observed in 40.7% of CD and 40.5% of UC patients, although, in UC patients there was a trend to lower discontinuation rates with IFX (36.6%) than with ADA (66.7%). Loss of response accounted for approximately one-third of discontinuations, in both CD and UC. CONCLUSIONS: Around one-third of IBD biologic-naive patients treated with an anti-TNFα required treatment intensification (earlier in UC) and around 40% discontinued the anti-TNFα due to inappropriate disease control.

Predictors of early withdrawal from follow-up visits after laparoscopic sleeve gastrectomy in a Japanese institution.

PURPOSE: Postoperative weight loss is related to postoperative adherence to follow-up after bariatric/metabolic surgery, but many patients stop attending follow-up visits early. The aim of this study was to clarify predictors of early withdrawal from follow-up after laparoscopic sleeve gastrectomy (LSG) in a Japanese institution. METHODS: One hundred and fifty-three patients who underwent LSG were retrospectively included in this study. Multivariate analysis was performed to evaluate independent predictors of withdrawal from follow-up visits within 12 months after LSG among significant or nearly significant factors in the univariate analyses. The discrimination power of significant factors was estimated using area under the receiver operating characteristic curve (AUC). RESULTS: Within 12 months after LSG, 25 of the 153 patients withdrew from follow-up visits. The multivariate analysis showed that age was the only significant predictor of withdrawal. The AUC for age was 0.685, and the cut-off value was < 40 years. The younger patients (< 40 years old) had a significantly higher rate of withdrawal compared with the older patients (≥ 40 years) (27.0% vs. 8.9%). CONCLUSION: Older Japanese patients (≥ 40 years old) may be better candidates for LSG. We consider it significant to continue to emphasize the importance of follow-up visits in younger patients after LSG.

Discontinuation of anti-PD-1 monotherapy in advanced melanoma-Outcomes of daily clinical practice.

There is no consensus on the optimal treatment duration of anti-PD-1 for advanced melanoma. The aim of our study was to gain insight into the outcomes of anti-PD-1 discontinuation, the association of treatment duration with progression and anti-PD-1 re-treatment in relapsing patients. Analyses were performed on advanced melanoma patients in the Netherlands who discontinued first-line anti-PD-1 monotherapy in the absence of progressive disease (n = 324). Survival was estimated after anti-PD-1 discontinuation and with a Cox model the association of treatment duration with progression was assessed. At the time of anti-PD-1 discontinuation, 90 (28%) patients had a complete response (CR), 190 (59%) a partial response (PR) and 44 (14%) stable disease (SD). Median treatment duration for patients with CR, PR and SD was 11.2, 11.5 and 7.2 months, respectively. The 24-month progression-free survival and overall survival probabilities for patients with a CR, PR and SD were, respectively, 64% and 88%, 53% and 82%, 31% and 64%. Survival outcomes of patients with a PR and CR were similar when anti-PD-1 discontinuation was not due to adverse events. Having a PR at anti-PD-1 discontinuation and longer time to first response were associated with progression [hazard ratio (HR) = 1.81 (95% confidence interval, CI = 1.11-2.97) and HR = 1.10 (95% CI = 1.02-1.19; per month increase)]. In 17 of the 27 anti-PD-1 re-treated patients (63%), a response was observed. Advanced melanoma patients can have durable remissions after (elective) anti-PD-1 discontinuation.

Late Awakening Is Common in Settings Without Withdrawal of Life-Sustaining Therapy in Out-of-Hospital Cardiac Arrest Survivors Who Undergo Targeted Temperature Management.

OBJECTIVES: We investigated awakening time and characteristics of awakening compared nonawakening and factors contributing to poor neurologic outcomes in out-of-hospital cardiac arrest survivors in no withdrawal of life-sustaining therapy settings. DESIGN: Retrospective analysis of the Korean Hypothermia Network Pro registry. SETTING: Multicenter ICU. PATIENTS: Adult (≥ 18 yr) comatose out-of-hospital cardiac arrest survivors who underwent targeted temperature management at 33-36°C between October 2015 and December 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We measured the time from the end of rewarming to awakening, defined as a total Glasgow Coma Scale score greater than or equal to 9 or Glasgow Coma Scale motor score equals to 6. The primary outcome was awakening time. The secondary outcome was 6-month neurologic outcomes (poor outcome: Cerebral Performance Category 3-5). Among 1,145 out-of-hospital cardiac arrest survivors, 477 patients (41.7%) regained consciousness 30 hours (6-71 hr) later, and 116 patients (24.3%) awakened late (72 hr after the end of rewarming). Young age, witnessed arrest, shockable rhythm, cardiac etiology, shorter time to return of spontaneous circulation, lower serum lactate level, absence of seizures, and multisedative requirement were associated with awakening. Of the 477 who woke up, 74 (15.5%) had poor neurologic outcomes. Older age, liver cirrhosis, nonshockable rhythm, noncardiac etiology, a higher Sequential Organ Failure Assessment score, and higher serum lactate levels were associated with poor neurologic outcomes. Late awakeners were more common in the poor than in the good neurologic outcome group (38/74 [51.4%] vs 78/403 [19.4%]; p < 0.001). The awakening time (odds ratio, 1.005; 95% CIs, 1.003-1.008) and late awakening (odds ratio, 3.194; 95% CIs, 1.776-5.746) were independently associated with poor neurologic outcomes. CONCLUSIONS: Late awakening after out-of-hospital cardiac arrest was common in no withdrawal of life-sustaining therapy settings and the probability of awakening decreased over time.

Early factors for predicting discontinuation to subcutaneous Apomorphine infusion in Parkinson's disease: A prospective analysis of the Thai Apomorphine Registry.

INTRODUCTION: Although continuous subcutaneous apomorphine infusion (CSAI) is an effective therapy for Parkinson's disease (PD) with motor fluctuations, data from Asian cohorts is limited. The therapy is often discontinued due to the complexity of its delivery. METHODS: Fifty-one PD patients undergoing CSAI as an add-on therapy were enrolled in the Thai Apomorphine Registry, an electronic database that recorded clinical characteristics and parameters during the 14-consecutive-day titration and long-term follow-up. Factors at the time of titration were documented in order to identify predictors of long-term discontinuation. RESULTS: Following initiation, PD patients were administered a mean CSAI dose of 5.89 mg/h (SD 1.36) over a mean time of 12.28 h (SD 1.90) each day. The mean follow-up period was 626.2 days (SD 619.17). Significant reductions in UPDRS-I, II, III, and IV scores, total NMSQ score, PDQ-8 score, daily off and dyskinesia hours, Timed Up and Go test, walking step test, levodopa-equivalent daily dose, number of times a day the levodopa was taken versus pre-CSAI values were observed (p < 0.05, each). Thirty-five (68.6%) patients discontinued during the follow-up period. Relative risks of variables recorded at the time of titration that determined discontinuation of CSAI therapy were an absence of full-time caregivers, achieving a daily off hours reduction <3.5 h, and NMSQ scores at the time of CSAI titration ≥9.5 points. CONCLUSION: Identifying factors that predict discontinuation of CSAI at the time of its initiation may help physicians to better understand the patient's drug response and how to manage them long-term.

Continued Discontinuation of TKI Treatment in Medullary Thyroid Carcinoma - Lessons From Individual Cases With Long-Term Follow-Up.

Background: The tyrosine kinase inhibitors (TKI) vandetanib and cabozantinib are approved as targeted therapies in advanced medullary thyroid carcinoma (MTC) with symptoms or high tumour burden. Only recently, toxicity in long-time TKI usage was analysed. However, little is known about the impact of TKI discontinuation on MTC disease course after longer-term therapy. Here, we report our experience in a series of 7 MTC patients with vandetanib treatment of up to 87 months followed by discontinuation for concerns of toxicity or due to side-effects. The discontinuation of TKI therapy is a relevant clinical scenario. To our knowledge we present the largest single center series on an important aspect of TKI management. Methods: Retrospective analysis of MTC patients with continued discontinuation of vandetanib treatment in a tertiary referral endocrine tumour centre. Analysis included a review of patients' records for TKI indication, and treatment response as well indications for continued TKI discontinuation and follow-up by clinical assessment, calcitonin and CEA doubling times as well as imaging (ultrasound, CT). Results: Seven MTC patients [6 sporadic MTC, 1 Multiple Endocrine Neplasie Type 2a (MEN2a)] with previous vandetanib treatment (median: 41 months; range 7-87 months) and continued TKI discontinuation were identified out of 161 analysed MTC files. TKI treatment was initiated due to high tumour burden and symptoms or RECIST (Response Evaluation Criteria In Solid Tumors) progression in all patients. Two patients (29%) remained stable after discontinuation of vandetanib until now (follow-up of 47 and 61 months). Both patients had been on TKI therapy for 73 and 58 months. Five patients (71%) developed progressive disease after TKI discontinuation. In 2 patients, vandetanib was restarted after 45 and 52 months resulting again in disease control. One patient was enrolled in a new RET kinase inhibitor trial after 45 months of vandetanib discontinuation. Two patients declined restart of treatment due to mental health issues leading to discontinuation of vandetanib in the first place (after 7 and 38 months of treatment) and both patients died of rapidly progressive disease. At time points of tumour progression, calcitonin-doubling time (CDT) was < 2 years in all patients. Conclusion: This case series suggests that discontinuation of long-term vandetanib treatment with documented stable disease does not automatically result in rapid disease progression but may be followed by prolonged "TKI free" stable disease in individual patients. Analysis of calcitonin and CDT during discontinuation is indicated as it will unmask tumour progression earlier than imaging. Restart with the same TKI is possible in case of progression.

Attitudes of patients with a rheumatic disease on drug use in the COVID-19 pandemic.

BACKGROUND: Anti-rheumatic drugs can increase the predisposition to infection, and patients may be unaware of continuing their treatment during the COVID-19 pandemic. OBJECTIVE: This study aimed to assess whether patients maintain their treatment for rheumatic conditions during the pandemic period and determine the factors responsible for discontinuation. METHODS: Patients were randomly selected from the prospectively collected database of our tertiary referral center. The patients were interviewed by telephone through a standardized closed-ended questionnaire, which is targeting the continuity of the treatment plan and the considerations related to the individual choice. The patients were asked whether they hesitated to visit the hospital for follow-up or intravenous drug administration. RESULTS: A total of 278 patients completed the questionnaire. While 62 of the patients (22.3%) had reduced or interrupted the treatment, only 11 patients (3.9%) stopped the treatment completely. A significant difference was observed between the duration of illness and the discontinuation of treatment. (p = 0.023) There was a significant difference in disease activity between the group that stopped treatment and continued treatment. (p = 0.001) There was no statistically significant difference in other demographic characteristics. One hundred thirty-five patients (48.6%) made the treatment decision by themselves, and 80% continued the treatment. Reasons for stopping the treatment were anxiety (48.4%), not being able to go to the hospital for intravenous treatment (45.1%), and not being able to find the drug (6.5%). CONCLUSION: Since patients with long-term illnesses were found to be significantly more likely to stop their treatment, this group of patients should be monitored.

Late-onset hypophysitis after discontinuation of nivolumab treatment for advanced skin melanoma: a case report.

BACKGROUND: Nivolumab is an anti-programmed cell death protein 1 antibody, typically used as cancer immunotherapy agent. Despite multiple clinical benefits it might cause autoimmune-related side-effects, often involving the endocrine system. To our knowledge, this is the first case of nivolumab-induced hypophysitis manifesting several months after treatment discontinuation. CASE PRESENTATION: We, herein, report a 53-year-old patient with hypophysitis and isolated adrenocorticotropic hormone deficiency, who presented with recurring syncopal episodes and persistent mild hyponatremia. The performed challenged tests were consistent with secondary adrenal insufficiency, while responses of other anterior pituitary hormones were preserved. Magnetic resonance imaging revealed thickened pituitary stalk, consistent with hypophysitis. The patient's condition gradually improved after administration of hydrocortisone, with normalization of sodium and glucose-levels. The related literature is discussed. CONCLUSIONS: We conclude that even after discontinuation of nivolumab, isolated adrenal insufficiency can occur. Therefore, in case of administration of such agents, clinical assessment, and routine monitoring of blood pressure, sodium-, glucose-levels, pituitary hormones as well as magnetic resonance imaging are needed to identify such conditions and prevent an adrenal crisis.

Impact of COVID-19 on medical treatment patterns in gynecologic oncology: a MITO group survey.

OBJECTIVE: COVID-19 is a global public health emergency. The increasing spread of COVID-19 presents challenges for the clinical care of patients with gynecological tumors. The Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) performed a survey to evaluate the impact of the COVID-19 pandemic on medical treatment of gynecological cancer, with a focus on chemotherapy and oral treatment with poly(ADP)-ribose polymerase inhibitors (PARP-i). METHODS: The survey consisted of a self-administered online questionnaire, sent via email between November 2020 and January 2021 to all members of MITO group. RESULTS: Forty-nine centers completed the questionnaire. The majority of respondents (83%) use screening tests to determine COVID-19 status in patients who were to undergo chemotherapy or oral medications. All respondents to our survey continued cancer therapy in patients who tested negative for COVID-19 during the pandemic. Seventy-three percent of respondents declared they stopped treatment with chemotherapy or PARP-i only after a positive swab and resumed therapy when negative tests were confirmed. CONCLUSIONS: COVID-19 positivity impacted patterns of treatment in patients diagnosed with ovarian cancer within the MITO group. Further investigations are needed to evaluate whether these modifications influence oncological clinical outcomes.

The effect of total compression time and rate (slope) of compression on the incidence of symptomatic Eustachian tube dysfunction and middle ear barotrauma: a Phase II prospective study.

Eustachian tube dysfunction (ETD) and middle ear barotrauma (MEB) are common reported complications during hyperbaric oxygen treatment. Our Phase I study data was the first to demonstrate a statistically significant decrease in the occurrence of symptomatic ETD and MEB. The Phase I Trial suggested the total time interval and rate (slope) of compression (ROC) may be a determining factor in ETD and MEB. This Phase II study investigates an optimal rate of compression to reduce ETD and MEB when considering each multiplace treatment (with multiple patients) as the unit of observation as a group, rather than for each individual patient. Data were collected prospectively on 1,244 group patient-treatment exposures, collectively including 5,072 individual patient-treatment/exposures. We randomly assigned patient-treatment group exposures to four different time interval and rate (slope) of compression. These compression rates and slopes were identical to those used in the Phase I trial. All patients experiencing symptoms of MEB requiring compression stops were evaluated post treatment for the presence of ETD and MEB using the O'Neill Grading System (OGS) for ETD. Data were analyzed using the IBM-SPSS statistical software program. A statistically significant decrease in the number of compression holds was observed in the 15-minute compression schedule, correlating to the results observed in the Phase I trial. The 15-minute linear compression profile continues to demonstrate the decreased need for patient symptomatic compression stops (as in the Phase I trial) using a USN TT9 during elective hyperbaric oxygen treatments in a Class A multiplace hyperbaric chamber. Trial Registration: ClinicalTrials.gov Identifier: NCT04776967.

Differences in Antipsychotic Treatment Discontinuation Among Veterans With Schizophrenia in the U.S. Department of Veterans Affairs.

OBJECTIVE: Effectiveness of antipsychotic drugs is inferred from relatively small randomized clinical trials conducted with carefully selected and monitored participants. This evidence is not necessarily generalizable to individuals treated in daily clinical practice. The authors compared the clinical effectiveness between all oral and long-acting injectable (LAI) antipsychotic medications used in the treatment of schizophrenia in the U.S. Department of Veterans Affairs (VA) health care system. METHODS: This was an observational study utilizing VA pharmacy data from 37,368 outpatient veterans with schizophrenia. Outcome measures were all-cause antipsychotic discontinuation and psychiatric hospitalizations. Oral olanzapine was used as the reference group. RESULTS: In multivariable analysis, clozapine (hazard ratio=0.43), aripiprazole long-acting injectable (LAI) (hazard ratio=0.71), paliperidone LAI (hazard ratio=0.76), antipsychotic polypharmacy (hazard ratio=0.77), and risperidone LAI (hazard ratio=0.91) were associated with reduced hazard of discontinuation compared with oral olanzapine. Oral first-generation antipsychotics (hazard ratio=1.16), oral risperidone (hazard ratio=1.15), oral aripiprazole (hazard ratio=1.14), oral ziprasidone (hazard ratio=1.13), and oral quetiapine (hazard ratio=1.11) were significantly associated with an increased risk of discontinuation compared with oral olanzapine. No treatment showed reduced risk of psychiatric hospitalization compared with oral olanzapine; quetiapine was associated with a 36% worse outcome in terms of hospitalizations compared with olanzapine. CONCLUSIONS: In a national sample of veterans with schizophrenia, those treated with clozapine, two of the LAI second-generation antipsychotics, and antipsychotic polypharmacy continued the same antipsychotic therapy for a longer period of time compared with the reference drug. This may reflect greater overall acceptability of these medications in clinical practice.

Correlation Between Surrogate End Points and Overall Survival in a Multi-institutional Clinicogenomic Cohort of Patients With Non-Small Cell Lung or Colorectal Cancer.

Importance: Contemporary observational cancer research requires associating genomic biomarkers with reproducible end points; overall survival (OS) is a key end point, but interpretation can be challenging when multiple lines of therapy and prolonged survival are common. Progression-free survival (PFS), time to treatment discontinuation (TTD), and time to next treatment (TTNT) are alternative end points, but their utility as surrogates for OS in real-world clinicogenomic data sets has not been well characterized. Objective: To measure correlations between candidate surrogate end points and OS in a multi-institutional clinicogenomic data set. Design, Setting, and Participants: A retrospective cohort study was conducted of patients with non-small cell lung cancer (NSCLC) or colorectal cancer (CRC) whose tumors were genotyped at 4 academic centers from January 1, 2014, to December 31, 2017, and who initiated systemic therapy for advanced disease. Patients were followed up through August 31, 2020 (NSCLC), and October 31, 2020 (CRC). Statistical analyses were conducted on January 5, 2021. Exposures: Candidate surrogate end points included TTD; TTNT; PFS based on imaging reports only; PFS based on medical oncologist ascertainment only; PFS based on either imaging or medical oncologist ascertainment, whichever came first; and PFS defined by a requirement that both imaging and medical oncologist ascertainment have indicated progression. Main Outcomes and Measures: The primary outcome was the correlation between candidate surrogate end points and OS. Results: There were 1161 patients with NSCLC (648 women [55.8%]; mean [SD] age, 63 [11] years) and 1150 with CRC (647 men [56.3%]; mean [SD] age, 54 [12] years) identified for analysis. Progression-free survival based on both imaging and medical oncologist documentation was most correlated with OS (NSCLC: ρ = 0.76; 95% CI, 0.73-0.79; CRC: ρ = 0.73; 95% CI, 0.69-0.75). Time to treatment discontinuation was least associated with OS (NSCLC: ρ = 0.45; 95% CI, 0.40-0.50; CRC: ρ = 0.13; 95% CI, 0.06-0.19). Time to next treatment was modestly associated with OS (NSCLC: ρ = 0.60; 0.55-0.64; CRC: ρ = 0.39; 95% CI, 0.32-0.46). Conclusions and Relevance: This cohort study suggests that PFS based on both a radiologist and a treating oncologist determining that a progression event has occurred was the surrogate end point most highly correlated with OS for analysis of observational clinicogenomic data.

Ruxolitinib discontinuation in polycythemia vera: Patient characteristics, outcomes, and salvage strategies from a large multi-institutional database.

Ruxolitinib is approved for the treatment of patients with polycythemia vera (PV) who are intolerant or resistant to hydroxyurea. While ruxolitinib discontinuation in myelofibrosis is associated with dismal outcomes, the analogous experience in PV has not been reported. Using a large, multi-institutional database of PV patients, we identified 93 patients with PV who were treated with ruxolitinib, of whom 22 discontinued therapy. Adverse events were the primary reason for discontinuation. After a median follow-up of 18.2 months following ruxolitinib discontinuation, no patients experienced a thrombotic event. One patient died 20.8 months after discontinuation. As compared with the 71 patients who were still receiving treatment with ruxolitinib at last follow up, patients who discontinued ruxolitinib were older at time of treatment initiation (67.5 versus 64.8 years, p = 0.0058), but had similar patient and disease characteristics. After discontinuation, only 4 patients (18 %) received subsequent cytoreductive therapy, including hydroxyurea in one patient and pegylated interferon α-2a in three patients. In stark contrast to the experience in myelofibrosis, discontinuation of ruxolitinib in PV was associated with generally favorable outcomes. However, there is a lack of available salvage therapies, highlighting the need for further therapeutic development in PV.