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OBJECTIVE: To assess associations between social determinants of health (SDOH) needs and health-related quality of life (HRQOL) among surgical patients. BACKGROUND: Despite the profound impact of SDOH on health outcomes, studies examining the effect of SDOH needs on HRQOL among surgical patients are limited. METHODS: A retrospective study was conducted using responses from the SDOH needs assessment and the Patient-Reported Outcomes Measurement Information Systems Global Health instrument of adults seen in surgical clinics at a single institution. Patient characteristics including socioeconomic status (insurance type, education level, and employment status) were extracted. Stepwise multivariable logistic regression analyses were performed to identify independent predictors of global health scores. RESULTS: A total of 8512 surgical patients (mean age: 55.6±15.8 years) were included. 25.2% of patients reported one or more SDOH needs. The likelihood of reporting at least one SDOH need varied by patient characteristics and socioeconomic status variables. In fully adjusted regression models, food insecurity [odds ratio (OR), 1.53; 95% CI, 1.38-1.70 and OR, 1.49; 95% CI, 1.22-1.81, respectively], housing instability (OR, 1.27; 95% CI, 1.12-1.43 and OR, 1.39; 95% CI, 1.13-1.70, respectively) lack of transportation (OR, 1.46; 95% CI, 1.27-1.68 and OR, 1.25; 95% CI, 1.00-1.57, respectively), and unmet medication needs (OR, 1.31; 95% CI, 1.13-1.52 and OR, 1.61; 95% CI, 1.28-2.03, respectively) were independent predictors of poor physical and mental health. CONCLUSIONS: SDOH needs are independent predictors of poor patient-reported physical and mental health among surgical patients. Assessing and addressing SDOH needs should be prioritized in health care settings and by policymakers to improve HRQOL.
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Qualidade de Vida , Determinantes Sociais da Saúde , Adulto , Humanos , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Pacientes , Razão de ChancesRESUMO
BACKGROUND: Unmet social needs (SNs) often coexist in distinct patterns within specific population subgroups, yet these patterns are understudied. OBJECTIVE: To identify patterns of social needs (PSNs) and characterize their associations with health-related quality-of-life (HRQoL) and healthcare utilization (HCU). DESIGN: Observational study using data on SNs screening, HRQoL (i.e., low mental and physical health), and 90-day HCU (i.e., emergency visits and hospital admission). Among patients with any SNs, latent class analysis was conducted to identify unique PSNs. For all patients and by race and age subgroups, compared with no SNs, we calculated the risks of poor HRQoL and time to first HCU following SNs screening for each PSN. PATIENTS: Adult patients undergoing SNs screening at the Mass General Brigham healthcare system in Massachusetts, United States, between March 2018 and January 2023. MAIN MEASURES: SNs included: education, employment, family care, food, housing, medication, transportation, and ability to pay for household utilities. HRQoL was assessed using the Patient-Reported Outcomes Measurement Information System Global-10. KEY RESULTS: Six unique PSNs were identified: "high number of social needs," "food and utility access," "employment needs," "interested in education," "housing instability," and "transportation barriers." In 14,230 patients with HRQoL data, PSNs increased the risks of poor mental health, with risk ratios ranging from 1.07(95%CI:1.01-1.13) to 1.80(95%CI:1.74-1.86). Analysis of poor physical health yielded similar findings, except that the "interested in education" showed a mild protective effect (0.97[95%CI:0.94-1.00]). In 105,110 patients, PSNs increased the risk of 90-day HCU, with hazard ratios ranging from 1.09(95%CI:0.99-1.21) to 1.70(95%CI:1.52-1.90). Findings were generally consistent in subgroup analyses by race and age. CONCLUSIONS: Certain SNs coexist in distinct patterns and result in poorer HRQoL and more HCU. Understanding PSNs allows policymakers, public health practitioners, and social workers to identify at-risk patients and implement integrated, system-wide, and community-based interventions.
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Aceitação pelo Paciente de Cuidados de Saúde , Qualidade de Vida , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Idoso , Massachusetts , Necessidades e Demandas de Serviços de SaúdeRESUMO
BACKGROUND: Collecting, monitoring, and responding to patient-generated health data (PGHD) are associated with improved quality of life and patient satisfaction, and possibly with improved patient survival in oncology. However, the current state of adoption, types of PGHD collected, and degree of integration into electronic health records (EHRs) is unknown. METHODS: The NCCN EHR Oncology Advisory Group formed a Patient-Reported Outcomes (PRO) Workgroup to perform an assessment and provide recommendations for cancer centers, researchers, and EHR vendors to advance the collection and use of PGHD in oncology. The issues were evaluated via a survey of NCCN Member Institutions. Questions were designed to assess the current state of PGHD collection, including how, what, and where PGHD are collected. Additionally, detailed questions about governance and data integration into EHRs were asked. RESULTS: Of 28 Member Institutions surveyed, 23 responded. The collection and use of PGHD is widespread among NCCN Members Institutions (96%). Most centers (90%) embed at least some PGHD into the EHR, although challenges remain, as evidenced by 88% of respondents reporting the use of instruments not integrated. Forty-seven percent of respondents are leveraging PGHD for process automation and adherence to best evidence. Content type and integration touchpoints vary among the members, as well as governance maturity. CONCLUSIONS: The reported variability regarding PGHD suggests that it may not yet have reached its full potential for oncology care delivery. As the adoption of PGHD in oncology continues to expand, opportunities exist to enhance their utility. Among the recommendations for cancer centers is establishment of a governance process that includes patients. Researchers should consider determining which PGHD instruments confer the highest value. It is recommended that EHR vendors collaborate with cancer centers to develop solutions for the collection, interpretation, visualization, and use of PGHD.
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Oncologia , Qualidade de Vida , Humanos , Atenção à Saúde , Registros Eletrônicos de Saúde , Inquéritos e QuestionáriosRESUMO
PURPOSE: Clinical trials in oncology evaluating the effects of patient-reported outcomes (PRO) collection have found that monitoring of symptoms with PROs is associated with improved clinical care through reduced acute care utilization and decreased patient symptom burden. This educational review will evaluate strategies for systematic PRO integration into everyday oncology clinical practice. METHODS: We outline key considerations for using PROs in clinical practice, highlighting evidence from published studies. We also discuss the benefits and challenges of PRO implementation in oncology. RESULTS: Implementing PRO collection in clinical practice can improve care delivery and facilitate patient-centered clinical research. Considerations for using PROs in clinical practice include choice of instrument, method of delivery, and frequency of query. Challenges with implementing systematic PRO collection include the costs and resources needed for implementation, impact on clinical workflow, and controlling/monitoring physician burnout. CONCLUSIONS: While challenges exist in terms of financial resources and staff participation/burnout, patient-reported outcomes in clinical practice provide a number of benefits, including symptom monitoring, clinical research, and potential real-time personalized clinical-decision support.
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Neoplasias/cirurgia , Participação do Paciente/estatística & dados numéricos , Medidas de Resultados Relatados pelo Paciente , Assistência Centrada no Paciente/normas , Guias de Prática Clínica como Assunto/normas , Qualidade da Assistência à Saúde/normas , Qualidade de Vida , Humanos , Neoplasias/psicologia , Resultado do TratamentoRESUMO
In a large survey (n = 809) conducted to understand how oncologists differ from nononcologists regarding routinely sharing visit notes with patients, oncologists were less likely to agree patient safety would improve (p = .03) or that patients would be offended after reading notes (p = .01); however, they agreed with nononcologists that sharing notes would lead to less candid documentation (69% vs. 73%; p = .39). Oncologists share a high level of worry about the impact of sharing notes on documentation practices, a concern that will need to be addressed as the practice of sharing visit notes expands to cancer care.
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Registros Eletrônicos de Saúde/normas , Oncologistas , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Percepção , Relações Médico-PacienteRESUMO
Importance: In observational studies, higher plasma 25-hydroxyvitamin D (25[OH]D) levels have been associated with improved survival in metastatic colorectal cancer (CRC). Objective: To determine if high-dose vitamin D3 added to standard chemotherapy improves outcomes in patients with metastatic CRC. Design, Setting, and Participants: Double-blind phase 2 randomized clinical trial of 139 patients with advanced or metastatic CRC conducted at 11 US academic and community cancer centers from March 2012 through November 2016 (database lock: September 2018). Interventions: mFOLFOX6 plus bevacizumab chemotherapy every 2 weeks and either high-dose vitamin D3 (n = 69) or standard-dose vitamin D3 (n = 70) daily until disease progression, intolerable toxicity, or withdrawal of consent. Main Outcomes and Measures: The primary end point was progression-free survival (PFS) assessed by the log-rank test and a supportive Cox proportional hazards model. Testing was 1-sided. Secondary end points included tumor objective response rate (ORR), overall survival (OS), and change in plasma 25(OH)D level. Results: Among 139 patients (mean age, 56 years; 60 [43%] women) who completed or discontinued chemotherapy and vitamin D3 (median follow-up, 22.9 months), the median PFS for high-dose vitamin D3 was 13.0 months (95% CI, 10.1 to 14.7; 49 PFS events) vs 11.0 months (95% CI, 9.5 to 14.0; 62 PFS events) for standard-dose vitamin D3 (log-rank P = .07); multivariable hazard ratio for PFS or death was 0.64 (1-sided 95% CI, 0 to 0.90; P = .02). There were no significant differences between high-dose and standard-dose vitamin D3 for tumor ORR (58% vs 63%, respectively; difference, -5% [95% CI, -20% to 100%], P = .27) or OS (median, 24.3 months vs 24.3 months; log-rank P = .43). The median 25(OH)D level at baseline for high-dose vitamin D3 was 16.1 ng/mL vs 18.7 ng/mL for standard-dose vitamin D3 (difference, -2.6 ng/mL [95% CI, -6.6 to 1.4], P = .30); at first restaging, 32.0 ng/mL vs 18.7 ng/mL (difference, 12.8 ng/mL [95% CI, 9.0 to 16.6], P < .001); at second restaging, 35.2 ng/mL vs 18.5 ng/mL (difference, 16.7 ng/mL [95% CI, 10.9 to 22.5], P < .001); and at treatment discontinuation, 34.8 ng/mL vs 18.7 ng/mL (difference, 16.2 ng/mL [95% CI, 9.9 to 22.4], P < .001). The most common grade 3 and higher adverse events for chemotherapy plus high-dose vs standard-dose vitamin D3 were neutropenia (n = 24 [35%] vs n = 21 [31%], respectively) and hypertension (n = 9 [13%] vs n = 11 [16%]). Conclusions and Relevance: Among patients with metastatic CRC, addition of high-dose vitamin D3, vs standard-dose vitamin D3, to standard chemotherapy resulted in a difference in median PFS that was not statistically significant, but with a significantly improved supportive hazard ratio. These findings warrant further evaluation in a larger multicenter randomized clinical trial. Trial Registration: ClinicalTrials.gov Identifier: NCT01516216.
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Adenocarcinoma/tratamento farmacológico , Colecalciferol/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Suplementos Nutricionais , Intervalo Livre de Progressão , Vitaminas/administração & dosagem , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Colecalciferol/efeitos adversos , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/secundário , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Vitamina D/análogos & derivados , Vitamina D/sangue , Vitaminas/efeitos adversosAssuntos
Adenocarcinoma/patologia , Neoplasias Primárias Desconhecidas/patologia , Adenocarcinoma/diagnóstico , Adenocarcinoma/tratamento farmacológico , Adolescente , Antineoplásicos/uso terapêutico , Humanos , Lapatinib/uso terapêutico , Masculino , Neoplasias Primárias Desconhecidas/diagnóstico , Neoplasias Primárias Desconhecidas/tratamento farmacológico , Medicina de PrecisãoRESUMO
BACKGROUND: Autophagy is a catabolic pathway that permits cells to recycle intracellular macromolecules, and its inhibition reduces pancreatic cancer growth in model systems. We evaluated hydoxychloroquine (HCQ), an inhibitor of autophagy, in patients with pancreatic cancer and analyzed pharmacodynamic markers in treated patients and mice. METHODS: Patients with previously treated metastatic pancreatic cancer were administered HCQ at 400 mg (n = 10) or 600 mg (n = 10) twice daily. The primary endpoint was 2-month progression-free survival (PFS). We analyzed peripheral lymphocytes from treated mice to identify pharmacodynamic markers of autophagy inhibition that were then assessed in peripheral lymphocytes from patients. RESULTS: Among 20 patients enrolled, 2 (10%) were without progressive disease at 2 months. Median PFS and overall survival were 46.5 and 69.0 days, respectively. Treatment-related grade 3/4 adverse events were lymphopenia (n = 1) and elevated alanine aminotransferase (n = 1). Tolerability and efficacy were similar at the two dose levels. Analysis of treated murine lymphocytes suggested that LC3-II expression by Western blot is a reliable marker for autophagy inhibition. Analysis of LC3-II in patient lymphocytes demonstrated inconsistent autophagy inhibition. CONCLUSION: Mouse studies identified LC3-II levels in peripheral lymphocytes as a potential pharmacodynamic marker of autophagy inhibition. In patients with previously treated metastatic pancreatic cancer, HCQ monotherapy achieved inconsistent autophagy inhibition and demonstrated negligible therapeutic efficacy.
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Adenocarcinoma/tratamento farmacológico , Autofagia/efeitos dos fármacos , Hidroxicloroquina/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/patologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica , Autofagia/genética , Intervalo Livre de Doença , Humanos , Hidroxicloroquina/farmacocinética , Linfócitos/efeitos dos fármacos , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Metástase Neoplásica , Neoplasias Pancreáticas/patologiaRESUMO
Innate inflammation promotes tumor development, although the role of innate inflammatory cytokines in established human tumors is unclear. Here we report clinical and translational results from a phase Ib trial testing whether IL-1ß blockade in human pancreatic cancer would alleviate myeloid immunosuppression and reveal antitumor T-cell responses to PD-1 blockade. Patients with treatment-naïve advanced pancreatic ductal adenocarcinoma (n=10) were treated with canakinumab, a high-affinity monoclonal human anti-interleukin-1ß (IL-1ß), the PD-1 blocking antibody spartalizumab, and gemcitabine/n(ab)paclitaxel. Analysis of paired peripheral blood from patients in the trial versus patients receiving multiagent chemotherapy showed a modest increase in HLA-DR+CD38+ activated CD8+ T cells and a decrease in circulating monocytic myeloid-derived suppressor cells (MDSCs) by flow cytometry for patients in the trial, but not in controls. Similarly, we used patient serum to differentiate monocytic MDSCs in vitro and showed that functional inhibition of T-cell proliferation was reduced when using on-treatment serum samples from patients in the trial but not when using serum from patients treated with chemotherapy alone. Within the tumor we observed few changes in suppressive myeloid-cell populations or activated T cells as assessed by single-cell transcriptional profiling or multiplex immunofluorescence, although increases in CD8+ T cells suggest that improvements in the tumor immune microenvironment might be revealed by a larger study. Overall, the data indicate that exposure to PD-1 and IL-1ß blockade induced a modest reactivation of peripheral CD8+ T cells and decreased circulating monocytic MDSCs; however, these changes did not lead to similarly uniform alterations in the tumor microenvironment.
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BACKGROUND: Recent trials suggest that programmed cell death 1 (PD-1)-directed immunotherapy may be beneficial for some patients with anal squamous cell carcinoma and biomarkers predictive of response are greatly needed. METHODS: This multicenter phase II clinical trial (NCT02919969) enrolled patients with metastatic or locally advanced incurable anal squamous cell carcinoma (n=32). Patients received pembrolizumab 200 mg every 3 weeks. The primary endpoint of the trial was objective response rate (ORR). Exploratory objectives included analysis of potential predictive biomarkers including assessment of tumor-associated immune cell populations with multichannel immunofluorescence and analysis of circulating tumor tissue modified viral-human papillomavirus DNA (TTMV-HPV DNA) using serially collected blood samples. To characterize the clinical features of long-term responders, we combined data from our prospective trial with a retrospective cohort of patients with anal cancer treated with anti-PD-1 immunotherapy (n=18). RESULTS: In the phase II study, the ORR to pembrolizumab monotherapy was 9.4% and the median progression-free survival was 2.2 months. Despite the high level of HPV positivity observed with circulating TTMV-HPV DNA testing, the majority of patients had low levels of tumor-associated CD8+PD-1+ T cells on pretreatment biopsy. Patients who benefited from pembrolizumab had decreasing TTMV-HPV DNA scores and a complete responder's TTMV-HPV DNA became undetectable. Long-term pembrolizumab responses were observed in one patient from the trial (5.3 years) and three patients (2.5, 6, and 8 years) from the retrospective cohort. Long-term responders had HPV-positive tumors, lacked liver metastases, and achieved a radiological complete response. CONCLUSIONS: Pembrolizumab has durable efficacy in a rare subset of anal cancers. However, despite persistence of HPV infection, indicated by circulating HPV DNA, most advanced anal cancers have low numbers of tumor-associated CD8+PD-1+ T cells and are resistant to pembrolizumab.
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Anticorpos Monoclonais Humanizados , Neoplasias do Ânus , Carcinoma de Células Escamosas , Infecções por Papillomavirus , Humanos , Estudos Retrospectivos , Estudos Prospectivos , Receptor de Morte Celular Programada 1 , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias do Ânus/tratamento farmacológico , DNARESUMO
BACKGROUND: The Cancer-Specific Geriatric Assessment (CSGA) is a primarily self-administered paper survey of validated measures. METHODS: We developed and tested the feasibility of a computer-based CSGA in patients ≥70 years of age who were receiving treatment for gastrointestinal malignancies at the Dana-Farber Cancer Institute. From December 2009 to June 2011, patients were invited to complete the CSGA at baseline (start of new treatment) and follow-up (at the first of 4 months later or within 4 weeks of completing treatment). Feasibility endpoints were proportion of eligible patients consented, proportion completing CSGA at baseline and follow-up, time to complete CSGA, and proportion of physicians reporting CSGA results that led to a change in clinical decision-making. RESULTS: Of the 49 eligible patients, 38 consented (76% were treatment naive). Median age was 77 years (range: 70-89 years), and 48% were diagnosed with colorectal cancer. Mean physician-rated Karnofsky Performance Status was 87.5 at baseline (SD 8.4) and 83.5 at follow-up (SD 8). At baseline, 92% used a touchscreen computer; 97% completed the CSGA (51% independently). At follow-up, all patients used a touchscreen computer; 71% completed the CSGA (41% independently). Mean time to completion was 23 minutes at baseline (SD 8.4) and 20 minutes at follow-up (SD 5.1). The CSGA added information to clinical assessment for 75% at baseline (n = 27) and 65% at follow-up (n = 17), but it did not alter immediate clinical decision-making. CONCLUSION: The computer-based CSGA feasibility endpoints were met, although approximately half of patients required assistance. The CSGA added information to clinical assessment but did not affect clinical decision-making, possibly due to limited alternate treatment options in this subset of patients.
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Coleta de Dados , Neoplasias Gastrointestinais/epidemiologia , Avaliação Geriátrica , Idoso , Idoso de 80 Anos ou mais , Tomada de Decisões , Feminino , Neoplasias Gastrointestinais/patologia , Neoplasias Gastrointestinais/terapia , Humanos , Avaliação de Estado de Karnofsky , MasculinoRESUMO
BACKGROUND: Treatments that target the vascular endothelial growth factor (VEGF) pathway have efficacy in colorectal cancer. We evaluated tolerability and efficacy of tivozanib (an oral VEGF receptor-1, -2, -3 inhibitor) plus everolimus (an oral mammalian target of rapamycin inhibitor). METHODS: The phase Ib study followed a 3 + 3 dose-escalation design with three dose levels. The primary objective in the follow-on phase II study was improvement in 2-month progression-free survival (PFS) from 30% (historical benchmark) to 50% in patients with refractory, metastatic colorectal cancer. RESULTS: Dose-limiting toxicities in the phase Ib study were grade 3 fatigue and dehydration. Oral tivozanib (1 mg daily for 3 of 4 weeks) and oral everolimus (10 mg daily continuously) were advanced to a 40-patient phase II study. The most common grade 3-4 adverse events were thrombocytopenia and hypophosphatemia. The 2-month PFS rate was 50%, with 20 of 40 patients having stable disease (SD). Seven (18%) patients were treated for ≥6 months. Median PFS and overall survival (OS) times were 3.0 months (95% confidence interval [CI]: 1.9-3.6 months) and 5.6 months (95% CI: 4.4-10.6 months), respectively. Patients who developed grade 1+ hypertension had increased SD rates (65.2% vs. 29.4%) and longer OS times (10.6 vs. 3.7 months). CONCLUSIONS: The oral combination of tivozanib and everolimus was well tolerated, with stable disease achieved in 50% of patients with refractory, metastatic colorectal cancer.
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Neoplasias Colorretais/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Quinolinas/administração & dosagem , Sirolimo/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Everolimo , Humanos , Estadiamento de Neoplasias , Compostos de Fenilureia/efeitos adversos , Quinolinas/efeitos adversos , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Resultado do TratamentoRESUMO
PURPOSE: To examine the feasibility of integrating a symptom management platform into the electronic health record (EHR) using electronic patient-reported outcomes (ePROs) during oral cancer-directed therapy (OCDT) and explore the impact of prompting oncology nurse navigators (ONNs) to respond to severe symptomatic adverse events (SAEs). MATERIALS AND METHODS: Adults prescribed OCDT at Dana-Farber Cancer Institute were consecutively invited to participate. Participants received weekly messages to complete ePROs. The first half enrolled in a passive (P) group where ePROs responses could be viewed anytime, but outreach was not expected. The second half enrolled in an active (A) group where severe SAEs prompted emails to ONNs for outreach within 1 business day. Feasibility was the proportion of participants completing ≥2 ePROs during the first 30 days. Participants were followed for up to 90 days. RESULTS: From June 25, 2019, to August 18, 2021, 100 participants enrolled, and 96 remained enrolled for at least 30 days. Overall, average age was 59 years, 80% female, and 9% used the platform in Spanish. Twenty-two A (45%) and 27 P (57%) participants met the feasibility threshold (P = .26). ePROs returned at 30 days were similar (P = .50): 0 ePROs 17 A, 13 P; 1 ePRO 10 A, 7 P; 2 ePROs 3 A, 5 P; 3 ePROs 1 A, 4 P; 4 ePROs 7 A, 8 P; and 5 ePROs 11 A, 10 P. Documented telephone encounters at 30 days were similar (109 A, 101 P; P = .86). CONCLUSION: EHR-embedded ePROs administered weekly for people on OCDT was feasible, although many went incomplete. ePRO completion was not clearly affected by nursing calls for severe SAEs. Future efforts will investigate improving engagement and addressing symptoms proactively.
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Registros Eletrônicos de Saúde , Neoplasias Bucais , Adulto , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Estudos de Viabilidade , Medidas de Resultados Relatados pelo Paciente , Neoplasias Bucais/terapia , SoftwareRESUMO
BACKGROUND: Recombinant granulocyte colony-stimulating factor (G-CSF) is routinely administered for prophylaxis or treatment of chemotherapy-induced neutropenia. Chronic myelopoiesis and granulopoiesis in patients with cancer has been shown to induce immature monocytes and neutrophils that contribute to both systemic and local immunosuppression in the tumor microenvironment. The effect of recombinant G-CSF (pegfilgrastim or filgrastim) on the production of myeloid-derived suppressive cells is unknown. Here we examined patients with pancreatic cancer, a disease known to induce myeloid-derived suppressor cells (MDSCs), and for which pegfilgrastim is routinely administered concurrently with FOLFIRINOX but not with gemcitabine-based chemotherapy regimens. METHODS: Serial blood was collected from patients with pancreatic ductal adenocarcinoma newly starting on FOLFIRINOX or gemcitabine/n(ab)paclitaxel combination chemotherapy regimens. Neutrophil and monocyte frequencies were determined by flow cytometry from whole blood and peripheral blood mononuclear cell fractions. Serum cytokines were evaluated pretreatment and on-treatment. Patient serum was used in vitro to differentiate healthy donor monocytes to MDSCs as measured by downregulation of major histocompatibility complex II (HLA-DR) and the ability to suppress T-cell proliferation in vitro. C57BL/6 female mice with pancreatic tumors were treated with FOLFIRINOX with or without recombinant G-CSF to directly assess the role of G-CSF on induction of immunosuppressive neutrophils. RESULTS: Patients receiving FOLFIRINOX with pegfilgrastim had increased serum G-CSF that correlated with an induction of granulocytic MDSCs. This increase was not observed in patients receiving gemcitabine/n(ab)paclitaxel without pegfilgrastim. Interleukin-18 also significantly increased in serum on FOLFIRINOX treatment. Patient serum could induce MDSCs as determined by in vitro functional assays, and this suppressive effect increased with on-treatment serum. Induction of MDSCs in vitro could be recapitulated by addition of recombinant G-CSF to healthy serum, indicating that G-CSF is sufficient for MDSC differentiation. In mice, neutrophils isolated from spleen of G-CSF-treated mice were significantly more capable of suppressing T-cell proliferation. CONCLUSIONS: Pegfilgrastim use contributes to immune suppression in both humans and mice with pancreatic cancer. These results suggest that use of recombinant G-CSF as supportive care, while critically important for mitigating neutropenia, may complicate efforts to induce antitumor immunity.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neutropenia , Neoplasias Pancreáticas , Animais , Feminino , Humanos , Camundongos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Gencitabina , Fator Estimulador de Colônias de Granulócitos/farmacologia , Terapia de Imunossupressão , Leucócitos Mononucleares , Camundongos Endogâmicos C57BL , Neutropenia/induzido quimicamente , Neutropenia/tratamento farmacológico , Neutropenia/prevenção & controle , Paclitaxel/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Proteínas Recombinantes , Microambiente TumoralRESUMO
While BRAF inhibitor combinations with EGFR and/or MEK inhibitors have improved clinical efficacy in BRAFV600E colorectal cancer (CRC), response rates remain low and lack durability. Preclinical data suggest that BRAF/MAPK pathway inhibition may augment the tumor immune response. We performed a proof-of-concept single-arm phase 2 clinical trial of combined PD-1, BRAF and MEK inhibition with sparatlizumab (PDR001), dabrafenib and trametinib in 37 patients with BRAFV600E CRC. The primary end point was overall response rate, and the secondary end points were progression-free survival, disease control rate, duration of response and overall survival. The study met its primary end point with a confirmed response rate (24.3% in all patients; 25% in microsatellite stable patients) and durability that were favorable relative to historical controls of BRAF-targeted combinations alone. Single-cell RNA sequencing of 23 paired pretreatment and day 15 on-treatment tumor biopsies revealed greater induction of tumor cell-intrinsic immune programs and more complete MAPK inhibition in patients with better clinical outcome. Immune program induction in matched patient-derived organoids correlated with the degree of MAPK inhibition. These data suggest a potential tumor cell-intrinsic mechanism of cooperativity between MAPK inhibition and immune response, warranting further clinical evaluation of optimized targeted and immune combinations in CRC. ClinicalTrials.gov registration: NCT03668431.
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Neoplasias Colorretais , Melanoma , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Receptor de Morte Celular Programada 1/genética , Melanoma/patologia , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Neoplasias Colorretais/genética , Mutação , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Inibidores de Proteínas Quinases/farmacologiaRESUMO
PURPOSE: With the growing number of available targeted therapeutics and molecular biomarkers, the optimal care of patients with cancer now depends on a comprehensive understanding of the rapidly evolving landscape of precision oncology, which can be challenging for oncologists to navigate alone. METHODS: We developed and implemented a precision oncology decision support system, GI TARGET, (Gastrointestinal Treatment Assistance Regarding Genomic Evaluation of Tumors) within the Gastrointestinal Cancer Center at the Dana-Farber Cancer Institute. With a multidisciplinary team, we systematically reviewed tumor molecular profiling for GI tumors and provided molecularly informed clinical recommendations, which included identifying appropriate clinical trials aided by the computational matching platform MatchMiner, suggesting targeted therapy options on or off the US Food and Drug Administration-approved label, and consideration of additional or orthogonal molecular testing. RESULTS: We reviewed genomic data and provided clinical recommendations for 506 patients with GI cancer who underwent tumor molecular profiling between January and June 2019 and determined follow-up using the electronic health record. Summary reports were provided to 19 medical oncologists for patients with colorectal (n = 198, 39%), pancreatic (n = 124, 24%), esophagogastric (n = 67, 13%), biliary (n = 40, 8%), and other GI cancers. We recommended ≥ 1 precision medicine clinical trial for 80% (406 of 506) of patients, leading to 24 enrollments. We recommended on-label and off-label targeted therapies for 6% (28 of 506) and 25% (125 of 506) of patients, respectively. Recommendations for additional or orthogonal testing were made for 42% (211 of 506) of patients. CONCLUSION: The integration of precision medicine in routine cancer care through a dedicated multidisciplinary molecular tumor board is scalable and sustainable, and implementation of precision oncology recommendations has clinical utility for patients with cancer.
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Neoplasias Gastrointestinais , Medicina de Precisão , Humanos , Oncologia , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/terapia , Genômica , Técnicas de Diagnóstico MolecularRESUMO
IMPORTANCE: Patients 80 years and older with pancreatic ductal adenocarcinoma (PDAC) have not consistently received treatments that have established benefits in younger older adults (aged 60-79 years), yet patients 80 years and older are increasingly being offered surgery. Whether adjuvant chemotherapy (AC) provides additional benefit among patients 80 years and older with PDAC following surgery is not well understood. OBJECTIVE: To describe patterns of AC use in patients 80 years and older following surgical resection of PDAC and to compare overall survival between patients who received AC and those who did not. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study among patients 80 years or older diagnosed with PDAC (stage I-III) between 2004 to 2016 who underwent a pancreaticoduodenectomy at hospitals across the US reporting to the National Cancer Database. EXPOSURES: AC vs no AC 90 days following diagnosis of PDAC. MAIN OUTCOMES AND MEASURES: The proportion of patients who received AC was assessed over the study period. Overall survival was compared between patients who received AC and those who did not using Kaplan-Meier estimates and multivariable Cox proportional hazards regression. A landmark analysis was performed to address immortal time bias. A propensity score analysis was performed to address indication bias. Subgroup analyses were conducted in node-negative, margin-negative, clinically complex, node-positive, and margin-positive cohorts. RESULTS: Between 2004 and 2016, 2569 patients 80 years and older (median [IQR] age, 82 [81-84] years; 1427 were women [55.5%]) underwent surgery for PDAC. Of these patients, 1217 (47.4%) received AC. Findings showed an 18.6% (95% CI, 8.0%-29.0%; P = .001) absolute increase in the use of AC among older adults who underwent a pancreaticoduodenectomy comparing rates in 2004 vs 2016. Receipt of AC was associated with a longer median survival (17.2 months; 95% CI, 16.1-19.0) compared with those who did not receive AC (12.7 months; 95% CI, 11.8-13.6). This association was consistent in propensity and subgroup analyses. In multivariable analysis, receipt of AC (hazard ratio [HR], 0.72; 95% CI, 0.65-0.79; P < .001), female sex (HR, 0.88; 95% CI, 0.80-0.96; P < .001), and surgery in the more recent time period (≥2011) (HR, 0.90; 95% CI, 0.82-0.99; P = .02) were associated with a decreased hazard of death. An increased hazard of death was associated with higher pathologic stage (stage II: HR, 1.68; 95% CI, 1.43-1.97; P < .001; stage III: HR, 2.39; 95% CI, 1.88-3.04; P < .001), positive surgical margins (HR, 1.49; 95% CI, 1.34-1.65; P < .001), length of stay greater than median (10 days) (HR, 1.17; 95% CI, 1.07-1.28; P < .001), and receipt of oncologic care at a nonacademic facilities (Community Cancer Program: HR, 1.20; 95% CI, 1.07-1.35; P < .001; Integrated Network Cancer Program: HR, 1.25; 95% CI, 1.07-1.46; P < .001). CONCLUSIONS AND RELEVANCE: In this cohort study, the use of AC among patients who underwent resection for PDAC increased over the study period, yet it still was administered to fewer than 50% of patients. Receipt of AC was associated with a longer median survival.
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Adenocarcinoma , Neoplasias Pancreáticas , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/cirurgia , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/cirurgia , Estudos RetrospectivosRESUMO
Objective: As part of ongoing implementation of electronic patient-reported outcome tools at the Dana-Farber Cancer Institute, here we describe the development of the electronic New Patient Intake Questionnaire. Materials and Methods: The original New Patient Intake Questionnaire includes a review of symptoms, oncology history, family history, health behaviors, health and social status, health literacy and numeracy, which was modified for integration into the EHR using content determination, build and configuration, implementation, analytics, and interventions. The engagement of key stakeholders, including patients, clinical staff, and providers, throughout the development and deployment of the electronic Questionnaire was crucial to producing a successful tool. Continual modifications based on input of stakeholders (such as mode of tool deployment) were made to ensure the utility and usability of the tool for both patients and providers. Results: Implementation of the EHR-integrated electronic New Patient Intake Questionnaire improved collection of the PRD by increasing questionnaire accessibility for patients, while also providing all available data to clinicians and researchers. Careful consideration of the content and configuration of the questionnaire allowed for a successful, institute-wide implementation of the tool. Discussion: This effort demonstrates the feasibility of implementation of a system-wide electronic questionnaire, emphasizing the importance of iterative refinement to create a tool that is both patient-centric and usable for clinicians. Conclusions: The electronic New Patient Intake Questionnaire allows for systematic collection of the PRD, which should benefit cancer care outcomes through innovative care delivery and healthcare interventions.
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Importance: Often electronic tools are built with English proficient (EP) patients in mind. Cancer patients with limited English proficiency (LEP) experience gaps in care and are at risk for excess toxic effects if they are unable to effectively communicate with their care team. Objective: To evaluate whether electronic patient-reported outcome tools (ePROs) built to improve health outcomes for EP patients might also be acceptable for LEP patients in the context of oral cancer-directed therapies (OCDT). Design, Setting, and Participants: This qualitative study was conducted at a single National Cancer Institute-designated comprehensive cancer center. In 2019, English-speaking and Spanish-speaking LEP patients with cancer receiving oral chemotherapies were recruited to participate in a qualitative focus group examining patient attitudes toward ePROs and electronic tools that are used to manage adherence and symptoms related to oral therapies. Six focus groups were held for EP patients and 1 for Spanish-speaking LEP patients. LEP was defined as patients who self-identified as needing an interpreter to navigate the health care system. Data analysis was performed April through June of 2019. Exposures: Enrolled patients participated in a focus group lasting approximately 90 minutes. Main Outcomes and Measures: The perspectives of patients with cancer treated with oral chemotherapies on integrating ePROs into their care management. Results: Among the 46 participants included in the study, 46 (100%) were White, 10 (22%) were Latinx Spanish-speaking, 43 (93%) were female, and 37 (80%) were aged at least 50 years or older. Among the 6 focus groups with 6 to 8 EP patients (ranging from 6 to 8 participants) and 1 focus group with 10 Spanish-speaking LEP patients, this qualitative study found that EP and LEP patients had different levels of acceptability of using technology and ePRO tools to manage their OCDT. EP patients felt generally positive toward OCDT and were not generally interested in using electronic tools to manage their care. LEP patients generally disliked OCDT and welcomed the use of technology for health management, particularly when addressing gaps in symptom management by their oncology clinicians. Conclusions and Relevance: Although most electronic interventions target EP patients, these findings reveal the willingness of LEP patients to participate in technology-based interventions. Expanding ePROs to LEP patients may help to manage gaps in communication about treatment and potential adverse events because of the willingness of LEP patients to use ePRO tools to manage their health. This qualitative assessment is a strategic step in determining the resources needed to narrow the digital health gap and extend the value of PROs to the LEP oncology population.
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Proficiência Limitada em Inglês , Neoplasias , Barreiras de Comunicação , Eletrônica , Feminino , Hispânico ou Latino , Humanos , Masculino , Neoplasias/tratamento farmacológico , Medidas de Resultados Relatados pelo PacienteRESUMO
As part of ongoing efforts to meaningfully improve recruitment, enrollment, and accrual of older adults into cancer clinical trials, the National Cancer Institute (NCI) sponsored a workshop with experts across the country entitled Engaging Older Adults in the NCI Clinical Trials Network: Challenges and Opportunities. Three working groups, including Study Design, Infrastructure, and Stakeholders, were formed, who worked together to offer synergistic improvements in the system. Here, we summarize the workshop discussions of the Infrastructure Working Group, whose goal was to address infrastructural challenges, identify underlying resources, and offer solutions to facilitate accrual of older adults into cancer clinical trials. Based on preconference work and workshop discussions, four key recommendations to strengthen NCI infrastructure were proposed: 1) further centralize resources and expertise; 2) provide training for clinical research staff; (3) develop common data elements; and 4) evaluate what works and does not work. These recommendations provide a strategy to improve the infrastructure to enroll more older adults in cancer clinical trials.