RESUMO
BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDA) is a highly lethal disease characterized by a spatially heterogeneous tumor microenvironment. Within the PDA microenvironment, cells organize into communities where cell fate is influenced by neighboring cells of diverse ontogeny and function. However, it remains unclear how cell neighborhoods in the tumor microenvironment evolve with treatment and impact clinical outcomes. METHODS: Here, using automated chromogenic multiplex immunohistochemistry and unsupervised computational image analysis of human PDA tumors, we investigated cell neighborhoods in surgically resected tumors from patients with chemotherapy-naïve PDA (n = 59) and neoadjuvant chemotherapy-treated PDA (n = 57). Single cells were defined by lineage markers (CD3, CD8, Foxp3, CD68, CK19), proliferation (Ki67), and neighboring cells. RESULTS: Distinct intratumoral immune and tumor cell subsets were defined by neighboring cells. Higher content of stromal-associated macrophages was seen in chemotherapy-naïve tumors from long-term survivors (overall survival >3 years) compared with short-term survivors (overall survival <1 year), whereas immune-excluded tumor cells were higher in short-term survivors. Chemotherapy-treated vs -naïve tumors showed lower content of tumor-associated T cells and macrophages but similar densities of stromal-associated immune cells. However, proliferating tumor cell subsets with immune-rich neighborhoods were higher in chemotherapy-treated tumors. In a blinded analysis of tumors from patients treated with neoadjuvant chemotherapy, a composite index comprising lower quantities of immune-excluded tumor cells and higher spatially distinct immune cell subsets was associated with prolonged survival. CONCLUSIONS: Together, these data provide new insights into discrete cell communities in PDA and show their clinical relevance.
Assuntos
Carcinoma Ductal Pancreático , Terapia Neoadjuvante , Neoplasias Pancreáticas , Microambiente Tumoral , Humanos , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/cirurgia , Microambiente Tumoral/imunologia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/tratamento farmacológico , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/análise , Quimioterapia Adjuvante , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Resultado do Tratamento , Linfócitos do Interstício Tumoral/imunologia , Proliferação de Células , Imuno-HistoquímicaRESUMO
BACKGROUND: During the COVID-19 public health emergency, the FDA and NIH altered clinical trial requirements to protect participants and manage study conduct. Given their detailed knowledge of research protocols and regular contact with patients, clinicians, and sponsors, clinical research professionals offer important perspectives on these changes. METHODS: We developed and distributed an anonymous survey assessing COVID-19-related clinical trial adjustment experiences, perceptions, and recommendations to Clinical Research Office personnel at the Harold C. Simmons Comprehensive Cancer Center. Responses were compared using the Fisher exact test. RESULTS: A total of 94 of 109 contacted research personnel (87%) responded. Among these individuals, 58% had >5 years' professional experience in clinical research, and 56% had personal experience with a COVID-19-related change. Respondents perceived that these changes had a positive impact on patient safety; treatment efficacy; patient and staff experience; and communication with patients, investigators, and sponsors. More than 90% felt that positive changes should be continued after COVID-19. For remote consent, telehealth, therapy shipment, off-site diagnostics, and remote monitoring, individuals with personal experience with the specific change and individuals with >5 years' professional experience were numerically more likely to recommend continuing the adjustment, and these differences were significant for telehealth (P=.04) and therapy shipment (P=.02). CONCLUSIONS: Clinical research professionals perceive that COVID-19-related clinical trial adjustments positively impact multiple aspects of study conduct. Those with greatest experience-both specific to COVID-19-related changes and more generally-are more likely to recommend that these adjustments continue in the future.
Assuntos
Pesquisa Biomédica/normas , COVID-19/prevenção & controle , Atenção à Saúde/normas , Comunicação Interdisciplinar , Guias de Prática Clínica como Assunto/normas , SARS-CoV-2/isolamento & purificação , Telemedicina/métodos , COVID-19/virologia , Humanos , Inquéritos e QuestionáriosRESUMO
BACKGROUND: NAD(P)H:quinone oxidoreductase 1 (NQO1) is a two-electron oxidoreductase expressed in multiple tumour types. ARQ 761 is a ß-lapachone (ß-lap) analogue that exploits the unique elevation of NQO1 found in solid tumours to cause tumour-specific cell death. METHODS: We performed a 3+3 dose escalation study of 3 schedules (weekly, every other week, 2/3 weeks) of ARQ 761 in patients with refractory advanced solid tumours. Tumour tissue was analysed for NQO1 expression. After 20 patients were analysed, enrolment was restricted to patients with NQO1-high tumours (H-score ≥ 200). RESULTS: A total of 42 patients were treated. Median number of prior lines of therapy was 4. Maximum tolerated dose was 390 mg/m2 as a 2-h infusion every other week. Dose-limiting toxicity was anaemia. The most common treatment-related adverse events were anaemia (79%), fatigue (45%), hypoxia (33%), nausea (17%), and vomiting (17%). Transient grade 3 hypoxia, reflecting possible methemoglobinaemia, occurred in 26% of patients. Among 32 evaluable patients, best response was stable disease (n = 12); 6 patients had tumour shrinkage. There was a trend towards improved efficacy in NQO1-high tumours (P = 0.06). CONCLUSIONS: ARQ 761 has modest single-agent activity, which appears associated with tumour NQO1 expression. Principal toxicities include anaemia and possible methemoglobinaemia.
Assuntos
Apoptose/efeitos dos fármacos , NAD(P)H Desidrogenase (Quinona)/análise , NAD(P)H Desidrogenase (Quinona)/biossíntese , Naftoquinonas/uso terapêutico , Necrose/induzido quimicamente , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Naftoquinonas/química , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: Sarcopenic obesity and muscle attenuation have been associated with survival in patients with borderline resectable and advanced pancreatic ductal adenocarcinoma (PDA); however, these relationships are unknown for patients with resectable PDA. This study examined the associations between skeletal muscle and adipose tissue as measured on baseline computed tomography (CT) and the overall survival (OS) of participants with resectable PDA in a secondary analysis of the Southwest Oncology Group S1505 clinical trial (identifier: NCT02562716). METHODS: The S1505 phase II clinical trial enrolled patients with resectable PDA who were randomized to receive modified FOLFIRINOX or gemcitabine and nab-paclitaxel as perioperative chemotherapy, followed by surgical resection. Baseline axial CT images at the L3 level were analyzed with externally validated software, and measurements were recorded for skeletal muscle area and skeletal muscle density, visceral adipose tissue area (VATA) and density, and subcutaneous adipose tissue area and density. The relationships between CT metrics and OS were analyzed using Cox regression models, with adjustment for baseline participant characteristics. RESULTS: Of 98 eligible participants with available baseline abdominal CT, 8 were excluded because of imaging quality (eg, orthopedic hardware), resulting in 90 evaluable cases: 51 men (57.0%; mean age, 63.2 years [SD, 8.5]; mean body mass index [BMI], 29.3 kg/m2 [SD, 6.4]), 80 White (89.0%), 6 Black (7.0%), and 4 unknown race (4.0%). Sarcopenia was present in 32 participants (35.9%), and sarcopenic obesity was present in 10 participants (11.2%). Univariable analyses for the 6 variables of interest indicated that the standardized mean difference (hazard ratio [HR], 0.75; 95% CI, 0.57-0.98; P = .04) was statistically significantly associated with OS. In models adjusted for sex, race, age, BMI, performance score, contrast use, sarcopenia, and sarcopenic obesity, VATA was statistically significantly associated with OS (HR, 1.58; 95% CI, 1.00-2.51; P = .05). No difference was observed in OS between participants according to sarcopenic obesity or sarcopenia categories. The median OS estimates were 25.1 months for participants without sarcopenic obesity, 18.6 months for participants with sarcopenic obesity, 23.6 months for participants without sarcopenia, and 27.9 months for participants with sarcopenia. CONCLUSION: This was the first study to systematically evaluate body composition parameters in a prospective multicenter trial of patients with resectable PDA who received perioperative chemotherapy. Visceral adipose tissue was associated with survival; however, there was no association between OS and sarcopenia or sarcopenic obesity. Further studies should evaluate these findings in more detail.
Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Sarcopenia , Humanos , Masculino , Pessoa de Meia-Idade , Adenocarcinoma/complicações , Adenocarcinoma/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica , Composição Corporal , Obesidade/complicações , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/cirurgia , Estudos Prospectivos , Sarcopenia/complicações , Sarcopenia/diagnóstico por imagem , Feminino , IdosoRESUMO
Regular physical activity reduces the progression of several cancers and offers physical and mental health benefits for cancer survivors. However, many cancer survivors are not sufficiently active to achieve these health benefits. Possible biological mechanisms through which physical activity could affect cancer progression include reduced systemic inflammation and positive changes in metabolic markers. Chronic and acute hyperglycemia could have downstream effects on cell proliferation and tumorigenesis. One novel strategy to motivate cancer survivors to be more active is to provide personalized biological-based feedback that demonstrates the immediate positive impact of physical activity. Continuous glucose monitors (CGMs) have been used to demonstrate the acute beneficial effects of physical activity on insulin sensitivity and glucose metabolisms in controlled lab settings. Using personal data from CGMs to illustrate the immediate impact of physical activity on glucose patterns could be particularly relevant for cancer survivors because they are at a higher risk for developing type 2 diabetes (T2D). As a pilot project, this study aims to (1) test the preliminary effect of a remotely delivered physical activity intervention that incorporates personalized biological-based feedback on daily physical activity levels, and (2) explore the association between daily glucose patterns and cancer-related insulin pathway and inflammatory biomarkers in cancer survivors who are at high risk for T2D. We will recruit 50 insufficiently active, post-treatment cancer survivors who are at elevated risk for T2D. Participants will be randomly assigned into (1) a group that receives personalized biological feedback related to physical activity behaviors; and (2) a control group that receives standard educational material. The feasibility and preliminary efficacy of this wearable sensor-based, biofeedback-enhanced 12-week physical activity intervention will be evaluated. Data from this study will support the further refinement and enhancement of a more comprehensive remotely delivered physical activity intervention that targets cancer survivors. Trial registration: ClinicalTrials.gov Identifier: NCT05490641.
Assuntos
Sobreviventes de Câncer , Diabetes Mellitus Tipo 2 , Neoplasias , Dispositivos Eletrônicos Vestíveis , Exercício Físico/psicologia , Retroalimentação , Glucose , Humanos , Neoplasias/terapia , Projetos Piloto , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
PURPOSE: The COVID-19 pandemic has led to profound changes in clinical research, including remote consent, telehealth, off-site procedures, shipment of therapy, and remote study monitoring. We assessed longitudinal perceptions of these adjustments among clinical research professionals. METHODS: We distributed an anonymous survey assessing experiences, perceptions, and recommendations regarding COVID-19-related clinical research adjustments to cancer clinical research office personnel in May 2020 and again in November 2020. Responses were compared using Fisher's exact and Mann-Whitney U tests. RESULTS: A total of 90 of 102 invited research personnel (88%) responded. Fifty-three (59%) reported participating in both initial and follow-up surveys. The proportion of respondents reporting personal experience with COVID-19-related adjustments increased over time, particularly for remote initial consent (29% v 4%), remote reconsent (24% v 9%), and remote study monitoring (36% v 22%). Perceived impact of COVID-19-related adjustments on data quality (P = .02) and patient experience (P = .002) improved significantly. However, perceived effect on patient safety (P = .02) and respondent's experience (P = .09) became less favorable. Individuals with personal experience with the adjustment were more likely to recommend continuing remote consent (62% v 38%; P = .04), remote monitoring (69% v 45%; P = .05), and therapy shipment (67% v 35%; P = .01) after the COVID-19 pandemic, with nonsignificant trends for off-site diagnostics (44% v 24%; P = .13) and telehealth visits (66% v 45%; P = .08). CONCLUSION: More than 6 months into the global pandemic, perceptions of COVID-19-related clinical research changes remain favorable. Experienced individuals are more likely to recommend that these changes continue in the future.
Assuntos
COVID-19 , Telemedicina , Atitude , Humanos , Pandemias , SARS-CoV-2RESUMO
IMPORTANCE: As cancer treatment has become more individualized, oncologic clinical trials have become more complex. Increasingly numerous and stringent eligibility criteria frequently include tumor molecular or genomic characteristics that may not be readily identified in medical records, rendering it difficult to best match clinical trials with clinical sites and to identify potentially eligible patients once a clinical trial has been selected and activated. Partly because of these factors, enrollment rates for cancer clinical trials remain low, creating delays and increased costs for drug development. Information technology (IT) platforms have been applied to the implementation and conduct of clinical trials to improve efficiencies in several medical fields, and these platforms have recently been introduced to oncologic studies. OBSERVATIONS: This review summarizes cancer and noncancer studies that used IT platforms for assistance with clinical trial site selection, patient recruitment, and patient screening. The review does not address the use of IT in other aspects of clinical research, such as wearable physical activity monitors or telehealth visits. A large number of IT platforms (which may be patient facing, site or investigator facing, or sponsor facing) are now commercially available. These applications use artificial intelligence and/or natural language processing to identify and summarize protocol eligibility criteria, institutional patient populations, and individual electronic health records. Although there is an expanding body of literature examining the role of this technology, relatively few studies to date have been performed in oncologic settings. CONCLUSIONS AND RELEVANCE: This review found that an increasing number and variety of IT platforms were available to assist in the planning and conduct of clinical trials. Because oncologic clinical care and clinical trial protocols are particularly complex, nuanced, and individualized, published experience with this technology in other fields may not be fully applicable to cancer settings. The extent to which these services will overcome ongoing and increasing challenges in cancer clinical research remains unclear.
Assuntos
Tecnologia da Informação , Neoplasias , Inteligência Artificial , Humanos , Processamento de Linguagem Natural , Neoplasias/tratamento farmacológico , Seleção de PacientesRESUMO
Importance: Clinical outcomes after curative treatment of resectable pancreatic ductal adenocarcinoma (PDA) remain suboptimal. To assess the potential of early control of systemic disease with multiagent perioperative chemotherapy, we conducted a prospective trial. Objective: To determine 2-year overall survival (OS) using perioperative chemotherapy for resectable PDA. Design, Setting, and Participants: This was a randomized phase 2 trial of perioperative chemotherapy with a pick-the-winner design. It was conducted across the National Clinical Trials Network, including academic and community centers all across the US. Eligibility required patients with Zubrod Performance Score of 0 or 1, confirmed tissue diagnosis of PDA, and resectable disease per Intergroup criteria. Interventions: Perioperative (12 weeks preoperative, 12 weeks postoperative) chemotherapy with either fluorouracil, irinotecan, and oxaliplatin (mFOLFIRINOX, arm 1) or gemcitabine/nab-paclitaxel (arm 2). Main Outcomes and Measures: The primary outcome was 2-year overall survival (OS), using a pick-the-winner design; for 100 eligible patients, accrual up to 150 patients was planned to account for cases deemed ineligible at central radiology review. Results: From 2015 to 2018, 147 patients were enrolled; 43 patients (29%) had ineligible disease, beyond resectability criteria, at central radiology review. There were 102 eligible and evaluable patients, 55 in arm 1 and 47 in arm 2, of whom the median (range) age was 66 (44-76) and 64 (46-76) years, respectively; 36 patients (65%) in arm 1 and 24 (51%) in arm 2 were men. In arm 1, 34 (62%) had Zubrod Performance Score of 0, while in arm 2, 31 (66%) did; and 44 (80%) in arm 1 and 39 (83%) in arm 2 had head tumors. Of 102 patients, 84% and 85% completed preoperative chemotherapy, 73% and 70% underwent resection, and 49% and 40% completed all treatment. Adverse events were expected hematologic toxic effects, fatigue, and gastrointestinal toxicities. Two-year OS was 47% (95% CI, 31%-61%) for arm 1 and 48% (95% CI, 31%-63%) for arm 2; median OS was 23.2 months (95% CI, 17.6-45.9 months) and 23.6 months (95% CI, 17.8-31.7 months). Neither arm's 2-year OS estimate was significantly higher than the a priori threshold of 40%. Median disease-free survival after resection was 10.9 months in arm 1 and 14.2 months in arm 2. Conclusions and Relevance: This phase 2 randomized clinical trial did not demonstrate an improved OS with perioperative chemotherapy, compared with historical data from adjuvant trials in resectable pancreatic cancer. Two-year OS was 47% with mFOLFIRINOX and 48% with gemcitabine/nab-paclitaxel for all eligible patients starting treatment for resectable PDA. The trial also demonstrated adequate safety and high resectability rates with perioperative chemotherapy, and challenges in quality control for resectability criteria. Trial Registration: ClinicalTrials.gov Identifier: NCT02562716.
Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia Adjuvante , Fluoruracila/efeitos adversos , Humanos , Leucovorina/efeitos adversos , Masculino , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Estudos ProspectivosRESUMO
The purpose of this work was to develop and validate a rapid, sensitive and robust liquid chromatography tandem mass spectrometric method for the quantification of ß-lapachone in human plasma and to use that method to analyze human clinical samples. Sample preparation for the developed method involved liquid-liquid extraction using ethyl acetate for extraction of ß-lapachone and cryptotanshinone (internal standard) from human plasma. Chromatographic resolution was achieved on a Kinetex C18 column using a gradient elution and a chromatographic flow rate of 0.5â¯mL/min. The retention times of ß-lapachone and cryptotanshinone were 1.98 and 2.28â¯min, respectively, and the method had a total run time of 4â¯min. Bioanalytical method validation was conducted in accordance with the United States Food and Drug Administration regulatory guidelines. The method was validated over 2 calibration ranges in order to support high- and low-dose clinical studies. Calibration curve-1 covered the range of 0.25-50â¯ng/mL and calibration curve-2 covered the range of 50-2000â¯ng/mL. The method was determined to be accurate (percent relative errors between -1.07 to 5.36 %), precise (percent relative standard deviations less than 7.4), and sensitive (LLOQ 0.25â¯ng/mL). ß-lapachone was determined to be stable (% change from timeâ¯=â¯0 between -11.6 and 12.6 %) across the autosampler, benchtop, freeze/thaw and long-term (63 days) stability studies. The validated bioanalytical method was employed to determine ß-lapachone concentrations in human plasma samples from a clinical study.