RESUMO
INTRODUCTION: Adjuvant (A) multiagent chemotherapy (MC) is the standard of care for patients with pancreatic adenocarcinoma (PDAC). Tolerating MC following a morbid operation may be difficult, thus neoadjuvant (NA) treatment is preferable. This study examined how the timing of chemotherapy was related to the regimen given and ultimately the overall survival (OS). METHODS: The National Cancer Database was queried from 2006 to 2017 for nonmetastatic PDAC patients who underwent surgical resection and received MC or single-agent chemotherapy (SC) pre- or postresection. Predictors of receiving MC were determined using multivariable logistic regression. Five-year OS was evaluated using the Kaplan-Meier and Cox proportional hazards model. RESULTS: A total of 12,440 patients (NA SC, n = 663; NA MC, n = 2313; A SC, n = 6152; A MC, n = 3312) were included. MC utilization increased from 2006-2010 to 2011-2017 (33.1%-49.7%; odds ratio [OR]: 0.59; p < 0.001). Younger age, fewer comorbidities, higher clinical stage, and larger tumor size were all associated with receipt of MC (all p < 0.001), but NA treatment was the greatest predictor (OR 5.18; 95% confidence interval [CI]: 4.63-5.80; p < 0.001). MC was associated with increased median 5-year OS (26.0 vs. 23.9 months; hazard ratio [HR]: 0.92; 95% CI: 0.88-0.96) and NA MC was associated with the highest survival (28.2 months) compared to NA SC (23.3 months), A SC (24.0 months), and A MC (24.6 months; p < 0.001). CONCLUSION: Use and timing of MC contribute to OS in PDAC with an improved 5-year OS compared to SC. The greatest predictor of receiving MC was being given as NA therapy and the greatest survival benefit was the NA MC subgroup. Randomized studies evaluating the timing of effective MC in PDAC are needed.
Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/patologia , Adenocarcinoma/patologia , Quimioterapia Adjuvante , Terapia Neoadjuvante , Modelos de Riscos Proporcionais , Estudos RetrospectivosRESUMO
BACKGROUND: The benefit of adjuvant therapy (AT) remains unclear in pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant therapy (NAT) and surgical resection. METHODS: The 2019 National Cancer Database was queried for patients with non-metastatic PDAC who received NAT followed by pancreaticoduodenectomy. Only patients with data regarding receipt of AT were included. Patients were classified if they had nodal down-staging specifically, or any downstaging (Tumor, Nodal, or overall). Propensity score matching (PSM) adjusted for pretreatment covariate imbalance between groups. The weighted Kaplan-Meier method and log-rank test were used to estimate the cumulative survival. RESULTS: After exclusion criteria and PSM, a total of 2784 patients remained; 1689 (60.7%) received AT and 1095 (39.3%) did not receive AT. Among all, those with additional AT had a significantly improved overall survival (OS) (p < 0.001). Upon evaluation of patients without downstaging after NAT, those who received AT had improved OS (no nodal downstaging or any downstaging; p = 0.002; p = 0.001). When evaluating patients with downstaging after NAT, those receiving AT did not have improved OS (nodal downstaging or any downstaging: p = 0.352; p = 0.99). CONCLUSION: Response to NAT appears to correlate with the benefit of AT following pancreaticoduodenectomy; patients who have a favorable response to NAT may not benefit from AT.
Assuntos
Carcinoma Ductal Pancreático , Terapia Neoadjuvante , Neoplasias Pancreáticas , Pancreaticoduodenectomia , Humanos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/tratamento farmacológico , Masculino , Feminino , Terapia Neoadjuvante/mortalidade , Quimioterapia Adjuvante , Idoso , Pessoa de Meia-Idade , Taxa de Sobrevida , Carcinoma Ductal Pancreático/cirurgia , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Adenocarcinoma/mortalidade , Adenocarcinoma/cirurgia , Adenocarcinoma/tratamento farmacológico , Estudos Retrospectivos , Seguimentos , PrognósticoRESUMO
OBJECTIVE: This study investigated how self-reliance and denial influence the relationship between help-seeking attitudes and behaviour. METHOD: Australian university students (N = 406) completed an online survey and females with elevated eating disorder (ED) concerns and high impairment were included in the study (N = 137). Participants completed measures of help-seeking attitudes, perceived barriers, and actual help-seeking behaviour. Via moderated logistic regression, we examined self-reliance and denial as perceived barriers to help-seeking. RESULTS: Of the total sample, over 33.7% of university students reported substantial ED concerns and impairment of whom 65.0% believed they needed help. While a majority reported that help-seeking would be useful (85.4%), only a minority of participants had sought professional help for their concerns (38.7%). Self-reliance and denial were frequently endorsed barriers and moderated the relationship between help-seeking attitudes and behaviours. CONCLUSION: ED concerns are common among university students and perceived barriers play a moderating role between attitudes and help-seeking. Future prevention and early intervention programs should address students' denial, while the importance of reaching out for professional help (rather than relying on themselves) could be highlighted with peer support.
Assuntos
Transtornos da Alimentação e da Ingestão de Alimentos , Aceitação pelo Paciente de Cuidados de Saúde , Feminino , Humanos , Universidades , Austrália , EstudantesRESUMO
BACKGROUND: A randomized, double-blind, placebo-controlled phase 2b trial of the tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine was conducted in patients with resected stage III/IV melanoma. Dendritic cells (DCs) were harvested with and without granulocyte-colony stimulating factor (G-CSF). This analysis investigates differences in clinical outcomes and RNA gene expression between DC harvest methods. METHODS: The TLPLDC vaccine is created by loading autologous tumor lysate into yeast cell wall particles (YCWPs) and exposing them to phagocytosis by DCs. For DC harvest, patients had a direct blood draw or were pretreated with G-CSF before blood draw. Patients were randomized 2:1 to receive TLPLDC or placebo. Differences in disease-free survival (DFS) and overall survival (OS) were evaluated. RNA-seq analysis was performed on the total RNA of TLPLDC + G and TLPLDC vaccines to compare gene expression between groups. RESULTS: 144 patients were randomized: 103 TLPLDC (47 TLPLDC/56 TLPLDC + G) and 41 placebo (19 placebo/22 placebo + G). Median follow-up was 27.0 months. Both 36-month DFS (55.8% vs. 24.4% vs. 30.0%, p = 0.010) and OS (94.2% vs. 69.8% vs. 70.9%, p = 0.024) were improved in TLPLDC compared to TLPLDC + G or placebo, respectively. When compared to TLPLDC + G vaccine, RNA-seq from TLPLDC vaccine showed upregulation of genes associated with DC maturation and downregulation of genes associated with DC suppression or immaturity. CONCLUSIONS: Patients receiving TLPLDC vaccine without G-CSF had improved OS and DFS. Outcomes remained similar between patients receiving TLPLDC + G and placebo. Direct DC harvest without G-CSF had higher expression of genes linked to DC maturation, likely improving clinical efficacy.
Assuntos
Vacinas Anticâncer , Melanoma , Humanos , Células Dendríticas , Fator Estimulador de Colônias de Granulócitos , Melanoma Maligno CutâneoRESUMO
Rapamycin inhibits the mechanistic (formally mammalian) target of rapamycin (mTOR), an evolutionarily conserved intracellular kinase that influences activation of growth signaling pathways and immune responses to malignancy. Rapamycin has been found to have both immunosuppressant and immunostimulatory effects throughout the innate and adaptive responses based on the inhibition of mTOR signaling. While the immunosuppressant properties of rapamycin and mTOR inhibition explain rapamycin's success in the prevention of transplant rejection, the immunostimulatory characteristics are likely partially responsible for rapamycin's anti-neoplastic effects. The immunologic response to rapamycin is at least partially dependent on the dose and administration schedule, with lower doses inducing immunostimulation and intermittent dosing promoting immune function while limiting metabolic and immunosuppressant toxicities. In addition to its FDA-approved application in advanced malignancies, rapamycin may be effective as a chemopreventive agent, suspending progression of low-grade cancers, preventing invasive conversion of in situ malignancy, or delaying malignant transformation of established pre-malignant conditions.
Assuntos
Neoplasias , Sirolimo , Humanos , Quimioprevenção , Imunossupressores/farmacologia , Neoplasias/prevenção & controle , Neoplasias/tratamento farmacológico , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/metabolismoRESUMO
BACKGROUND: Neoadjuvant chemotherapy (NAC) or chemoradiation (NAC+XRT) is incorporated into the treatment of localized pancreatic adenocarcinoma (PDAC), often with the goal of downstaging before resection. However, the effect of downstaging on overall survival, particularly the differential effects of NAC and NAC+XRT, remains undefined. This study examined the impact of downstaging from NAC and NAC+XRT on overall survival. METHODS: The National Cancer Data Base (NCDB) was queried from 2006 to 2015 for patients with non-metastatic PDAC who received NAC or NAC+XRT. Rates of overall and nodal downstaging, and pathologic complete response (pCR) were assessed. Predictors of downstaging were evaluated using multivariable logistic regression. Overall survival (OS) was assessed with Kaplan-Meier and Cox proportional hazards modeling. RESULTS: The study enrolled 2475 patients (975 NAC and 1500 NAC+XRT patients). Compared with NAC, NAC+XRT was associated with higher rates of overall downstaging (38.3 % vs 23.6 %; p ≤ 0.001), nodal downstaging (16.0 % vs 7.8 %; p ≤ 0.001), and pCR (1.7 % vs 0.7 %; p = 0.041). Receipt of NAC+XRT was independently predictive of overall (odds ratio [OR] 2.28; p < 0.001) and nodal (OR 3.09; p < 0.001) downstaging. Downstaging by either method was associated with improved 5-year OS (30.5 vs 25.2 months; p ≤ 0.001). Downstaging with NAC was associated with an 8-month increase in median OS (33.7 vs 25.6 months; p = 0.005), and downstaging by NAC+XRT was associated with a 5-month increase in median OS (30.0 vs 25.0 months; p = 0.008). Cox regression showed an association of overall downstaging with an 18 % reduction in the risk of death (hazard ratio [HR] 0.82; 95 % confidence interval, 0.71-0.95; p = 0.01) CONCLUSION: Downstaging after neoadjuvant therapies improves survival. The addition of radiation therapy may increase the rate of downstaging without affecting overall oncologic outcomes.
Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Quimiorradioterapia , Quimioterapia Adjuvante , Humanos , Terapia Neoadjuvante , Estadiamento de Neoplasias , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias PancreáticasRESUMO
BACKGROUND: The implications of major venous injury to the lower extremity are not well established. We aimed to determine the significance of concomitant and isolated femoropopliteal venous injury and assess the impact of surgical management strategies on limb outcomes. METHODS: The Fasciotomy and Vascular Injury Outcomes database was queried for limbs sustaining femoropopliteal arterial, venous, or concomitant injuries in Iraq or Afghanistan between 2004 and 2012. Demographics, injury patterns and severity, interventions, and outcomes were compared between patients sustaining isolated arterial injuries (IAIs) and concomitant arteriovenous injuries (AVIs). In limbs with any venous injury, outcomes were compared between those undergoing venous repair and venous ligation. RESULTS: Three hundred thirty patients (133 IAIs, 135 AVIs, 62 isolated venous injuries [IVIs]) were included. AVI was associated with greater limb injury severity: median extremity Abbreviated Injury Scale (AVI 4 vs. IAI 3, P = 0.01), Mangled Extremity Severity Score >7 (25.9% vs. 13.5%, P = 0.01), and multilevel vascular injury (6.7% vs. 0.8%, P = 0.01) and with greater fasciotomy use (83.0% vs. 69.2%, P = 0.01). No differences were present in tourniquet use/time, shunting, or nature of arterial repair. No differences in vascular or limb complications (71.1% vs. 63.9%, P = 0.21) or amputation rate (25.9% vs. 18.8%, P = 0.16) were present, though the limb deep venous thrombosis rate was 12.6% in AVIs versus 7.5% in IAIs (P = 0.17). Limbs with IVI had a 12.9% amputation and a 74.2% complication rate. Repair (n = 103) versus ligation (n = 94) of venous injuries was not associated with a difference in amputation (18.4% vs. 25.5%, P = 0.23) or limb complication rates (71.8% vs. 72.3%, P = 0.94). CONCLUSIONS: Despite higher extremity injury severity and more frequent fasciotomies, concomitant venous injury was not associated with poorer limb salvage or complications. With nontrivial amputation and complication rates, IVI is indicative of severe limb trauma. Repair of femoropopliteal venous injuries does not appear to influence limb outcomes.
Assuntos
Traumatismos da Perna , Militares , Lesões do Sistema Vascular , Humanos , Lesões do Sistema Vascular/diagnóstico por imagem , Lesões do Sistema Vascular/cirurgia , Estudos Retrospectivos , Resultado do Tratamento , Índices de Gravidade do Trauma , Traumatismos da Perna/cirurgia , Salvamento de Membro , Amputação Cirúrgica , Extremidade Inferior/irrigação sanguínea , Artéria Femoral/cirurgiaRESUMO
INTRODUCTION: Lymphadenectomy (LND) is recommended following surgical resection of ≥ T1b gallbladder cancer (GBC). However, frequency and stage-specific survival benefits of LND remain unclear. PATIENTS AND METHODS: The National Cancer Database (NCDB; 2006-15) was queried for resected pathologic stage I-III GBC. LND performance, predictors of receiving LND, and LND association with overall survival (OS) were assessed. RESULTS: Of 2302 total patients, 1343 (58.3%) underwent LND. Patients who underwent LND were younger and more frequently had private health insurance, a negative surgical margin, higher pathologic T stage, and received adjuvant chemotherapy (all p < 0.001). LND rates were highest at academic centers (70.1%) relative to all other facility types (p < 0.001). LND was independently associated with improved OS [hazard ratio (HR) 0.52, 95% confidence interval (CI) 0.44-0.61]. LND was associated with improved OS for pT1b, pT2, and pT3 patients (all p < 0.05) on univariate analysis. LND was independently associated with improved OS in pT2 (HR 0.44, CI 0.35-0.56) and pT3 (HR 0.54, CI 0.43-0.69) patients. CONCLUSIONS: LND is associated with a 48% reduction in risk of death in patients with resectable non-metastatic GBC, with greatest impact in pT2-3 patients. Patients without LND have similar OS to patients with node-positive disease, highlighting the importance of LND. Underutilization of LND likely results in undertreatment of patients with undiagnosed nodal disease, which may contribute to unfavorable oncologic outcomes.
Assuntos
Carcinoma in Situ , Neoplasias da Vesícula Biliar , Quimioterapia Adjuvante , Neoplasias da Vesícula Biliar/patologia , Neoplasias da Vesícula Biliar/cirurgia , Humanos , Excisão de Linfonodo , Estadiamento de Neoplasias , Modelos de Riscos ProporcionaisRESUMO
OBJECTIVE: Difficulties with emotion regulation is considered an important maintaining factor of disordered eating. One of the most commonly used measures of this construct is the Difficulties in Emotion Regulation Scale (DERS). The aim of this study was to explore the factor structure of this measure in young females and to examine its reliability and validity with respect to disordered eating. METHOD: Females aged 17-25 years (M age = 19.6 years, N = 486) were examined in the analyses. Confirmatory factor analyses were conducted followed by regression analyses examining the DERS subscales as predictors of eating disorder severity and disordered eating behaviors. RESULTS: The original 6-factor 36-item model did not fit well and analyses indicated a 6-factor 30-item solution was a more suitable fit for our population. Validity and reliability of the 30-item solution were found to be acceptable. Regression analyses also indicated the 36- and 30-item models were able to adequately predict eating disorder severity and disordered eating behaviors with the "Awareness" and "Goals" subscales being predictors of the former, and the "Impulsivity" subscale being a significant predictor of the latter. DISCUSSION: The overall findings suggest that an abbreviated version of the DERS might be more appropriate than the original version with young females and that this measure exhibits stronger relationships with eating disorder severity and disordered eating behaviors than the longer version. Further examinations of the psychometric properties of the DERS with clinical populations are indicated.
Assuntos
Emoções , Transtornos da Alimentação e da Ingestão de Alimentos/psicologia , Autorrelato , Adolescente , Adulto , Sintomas Afetivos/diagnóstico , Análise Fatorial , Feminino , Humanos , Psicometria , Reprodutibilidade dos Testes , Autorrelato/normas , Adulto JovemRESUMO
Checkpoint inhibitors have invigorated cancer immunotherapy research, including cancer vaccination. Classic early phase trial design and endpoints used in developing chemotherapy are not suited for evaluating all forms of cancer treatment. Peripheral T cell response dynamics have demonstrated inconsistency in assessing the efficacy of cancer vaccination. Tumor infiltrating lymphocytes (TILs), reflect the local tumor microenvironment and may prove a superior endpoint in cancer vaccination trials. Cancer vaccines may also promote success in combination immunotherapy treatment of weakly immunogenic tumors. This review explores the impact of TILs as an endpoint for cancer vaccination in multiple malignancies, summarizes the current literature regarding TILs analysis, and discusses the challenges of providing validity and a standardized implementation of this approach.
Assuntos
Vacinas Anticâncer , Neoplasias , Humanos , Linfócitos do Interstício Tumoral , Vacinas Anticâncer/uso terapêutico , Neoplasias/terapia , Neoplasias/patologia , Imunoterapia , Microambiente TumoralRESUMO
NeuVax is a vaccine comprised of the HER2-derived MHC class I peptide E75 (nelipepimut-S, NPS) combined with GM-CSF. We completed a randomized trial of preoperative vaccination with NeuVax versus GM-CSF alone in patients with ductal carcinoma in situ (DCIS). The primary objective was to evaluate for NPS-specific cytotoxic T lymphocyte (CTL) responses. Patients with human leukocyte antigen (HLA)-A2-positive DCIS were enrolled and randomized 2:1 to NeuVax versus GM-CSF alone and received two inoculations prior to surgery. The number of NPS-specific CTL was measured pre-vaccination, at surgery, and 1 and 3 to 6 months post-operation by dextramer assay. Differences in CTL responses between groups and between pre-vaccination and 1-month post-operation were analyzed using a two-sample t test or Wilcoxon rank sum test. The incidence and severity of adverse events were compared between groups. Overall, 45 patients were registered; 20 patients were HLA-A2 negative, 7 declined participation, 1 withdrew, and 4 failed screening for other reasons. The remaining 13 were randomized to NeuVax (n = 9) or GM-CSF alone (n = 4). Vaccination was well-tolerated with similar treatment-related toxicity between groups with the majority (>89%) of adverse events being grade 1. The percentage of NPS-specific CTLs increased in both arms between baseline (pre-vaccination) and 1-month post-operation. The increase was numerically greater in the NPS+GM-CSF arm, but the difference was not statistically significant. NPS+GM-CSF is safe and well-tolerated when given preoperatively to patients with DCIS. In patients with HLA-A2-positive DCIS, two inoculations with NPS+GM-CSF can induce in vivo immunity and a continued antigen-specific T-cell response 1-month postsurgery. PREVENTION RELEVANCE: This trial showed that vaccination of patients with HLA-A2-positive DCIS with NeuVax in the preoperative setting can induce a sustained antigen-specific T-cell response. This provides proof of principle that vaccination in the preoperative or adjuvant setting may stimulate an adaptive immune response that could potentially prevent disease recurrence.
Assuntos
Vacinas Anticâncer , Carcinoma Intraductal não Infiltrante , Humanos , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Carcinoma Intraductal não Infiltrante/cirurgia , Antígeno HLA-A2 , Recidiva Local de Neoplasia/patologia , Fragmentos de Peptídeos , Vacinas de Subunidades Antigênicas/efeitos adversos , Vacinas Anticâncer/efeitos adversosRESUMO
BACKGROUND: The tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine is made by ex vivo priming matured autologous dendritic cells (DCs) with yeast cell wall particles (YCWPs) loaded with autologous tumor lysate (TL). The tumor lysate, particle only (TLPO) vaccine uses autologous TL-loaded YCWPs coated with silicate for in vivo DC loading. Here we report the 36-month prespecified analyses of this prospective, randomized, double-blind trial investigating the ability of the TLPO and TLPLDC (±granulocyte-colony stimulating factor (G-CSF)) vaccines to prevent melanoma recurrence in high-risk patients. METHODS: Patients with clinically disease-free stage III/IV melanoma were randomized 2:1 initially to TLPLDC versus placebo (n=124) and subsequently TLPO versus TLPLDC (n=63). All patients were randomized and blinded; however, the placebo control arm was replaced in the second randomization scheme with another novel vaccine; some analyses in this paper therefore reflect a combination of the two randomization schemes. Patients receiving the TLPLDC vaccine were further divided by their method of DC harvest (with or without G-CSF pretreatment); this was not randomized. The use of standard of care checkpoint inhibitors was not stratified between groups. Safety was assessed and Kaplan-Meier and log-rank analyses compared disease-free (DFS) and overall survival (OS). RESULTS: After combining the two randomization processes, a total of 187 patients were allocated between treatment arms: placebo (n=41), TLPLDC (n=103), or TLPO (n=43). The allocation among arms created by the addition of patients from the two separate randomization schemes does not reflect concurrent randomization among all treatment arms. TLPLDC was further divided by use of G-CSF in DC harvest: no G-CSF (TLPLDC) (n=47) and with G-CSF (TLPLDC+G) (n=56). Median follow-up was 35.8 months. Only two patients experienced a related adverse event ≥grade 3, one each in the TLPLDC+G and placebo arms. DFS was 27.2% (placebo), 55.4% (TLPLDC), 22.9% (TLPLDC+G), and 60.9% (TLPO) (p<0.001). OS was 62.5% (placebo), 93.6% (TLPLDC), 57.7% (TLPLDC+G), and 94.6% (TLPO) (p=0.002). CONCLUSIONS: The TLPO and TLPLDC (without G-CSF) vaccines were associated with improved DFS and OS in this clinical trial. Given production and manufacturing advantages, the efficacy of the TLPO vaccine will be confirmed in a phase 3 trial. TRIAL REGISTRATION NUMBER: NCT02301611.
Assuntos
Vacinas Anticâncer , Melanoma , Humanos , Estudos Prospectivos , Vacinas Anticâncer/uso terapêutico , Células Dendríticas , Fator Estimulador de Colônias de Granulócitos , Melanoma Maligno CutâneoRESUMO
BACKGROUND: Primary thymic adenocarcinoma represents an exceptionally rare malignancy, for which the cornerstone of therapy is margin-negative resection, with radiation and systemic therapy reserved for invasive and advanced disease. Thymic adenocarcinoma has not been previously reported in the setting of a concomitant malignancy, as reported herein. CASE PRESENTATION: We present a case of a 55-year-old previously healthy male diagnosed with acute myeloid leukemia, also found to have a mediastinal mass. Evaluation of the mediastinal mass with tumor markers, biopsies, and next-generation sequencing proved non-diagnostic, while he was simultaneously treated with induction chemotherapy to prevent leukemia-related blast crisis. After completing and recovering from induction chemotherapy, he underwent successful thymectomy during a chemotherapy holiday, with a margin-negative resection of thymic adenocarcinoma. He has subsequently recovered and undergone successful allogeneic hematopoietic stem cell transplant. CONCLUSIONS: We present a case of synchronous adult acute myeloid leukemia and primary thymic adenocarcinoma requiring a tailored approach for management of simultaneous malignancies.
Assuntos
Adenocarcinoma , Leucemia Mieloide Aguda , Timoma , Neoplasias do Timo , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Adulto , Biomarcadores Tumorais , Humanos , Masculino , Pessoa de Meia-Idade , Timectomia , Timoma/diagnóstico , Timoma/terapia , Neoplasias do Timo/diagnóstico , Neoplasias do Timo/patologia , Neoplasias do Timo/terapiaRESUMO
INTRODUCTION: HER2 is a prevalent growth factor in a variety of malignancies, most prominently breast cancer. Over-expression has been correlated with the poorest overall survival and has been the target of successful therapies such as trastuzumab. AE37 is a novel, HER2-directed vaccine based on the AE36 hybrid peptide (aa776-790), which is derived from the intracellular portion of the HER2 protein, and the core portion of the MHC Class II invariant chain (the Ii-Key peptide). This hybrid peptide is given with GM-CSF immunoadjuvant as the AE37 vaccine. AREAS COVERED: This article describes in detail the preclinical science leading to the creation of the AE37 vaccine and examines use of this agent in multiple clinical trials for breast and prostate cancer. The safety profile of AE37 is discussed and opinions on the potential of the vaccine in breast and prostate cancer patient subsets along with other malignancies, are offered. EXPERT OPINION: Future trials utilizing the AE37 vaccine to treat other HER2-expressing malignancies are likely to see similar success, and this will be enhanced by combination immunotherapy. Ii-Key modification of other peptides of interest across oncology and virology could yield impressive results over the longer term.
Assuntos
Neoplasias da Mama/prevenção & controle , Vacinas Anticâncer/administração & dosagem , Receptor ErbB-2/imunologia , Neoplasias da Mama/patologia , Vacinas Anticâncer/imunologia , Feminino , Humanos , Imunoterapia , Masculino , Recidiva Local de Neoplasia , Neoplasias da Próstata/prevenção & controleRESUMO
Pancreatic ductal adenocarcinoma (PDAC) remains deadly despite advances in systemic therapies and surgical techniques. While there is increasing utilization of immune therapies across diverse cancer types, PDAC remains generally resistant to these treatments. We report a case of locally advanced PDAC treated with preoperative radiation and anti-PD-1 immunotherapy guided by preoperative PD-L1 tumor analysis. After 4 months of preoperative therapy, the patient was submitted to resection, demonstrating a near-complete pathologic response on final tumor analysis. We will discuss the relevant literature and current state of immunotherapeutics for PDAC.
RESUMO
No approved medical therapies prevent progression of low-grade prostate cancer. Rapamycin inhibits cell proliferation and augments immune responses, producing an antitumor effect. Encapsulated rapamycin (eRapa) incorporates rapamycin into a pH-sensitive polymer, ensuring consistent dosing. Here, we present results from a phase I trial evaluating the safety and tolerability of eRapa in patients with prostate cancer. Patients with Gleason ≤7 (3+4) disease (low and intermediate risk) under active surveillance were enrolled in a 3+3 study with three eRapa dosing cohorts (cohort 1, 0.5 mg/week; cohort 2, 1 mg/week; and cohort 3, 0.5 mg/day). Patients were treated for 3 months and followed for an additional 3 months to assess safety, pharmacokinetics, quality of life (QoL), immune response, and disease progression. Fourteen patients (cohort 1, n = 3; cohort 2, n = 3; and cohort 3, n = 8) were enrolled. In cohort 3, one dose-limiting toxicity (DLT; neutropenia) and two non-DLT grade 1-2 adverse events (AE) occurred that resulted in patient withdrawal. All AEs in cohorts 1 and 2 were grade 1. Peak serum rapamycin concentration was 7.1 ng/mL after a 1 mg dose. Stable trough levels (â¼2 ng/mL) developed after 48-72 hours. Daily dosing mildly worsened QoL, although QoL recovered after treatment cessation in all categories, except fatigue. Weekly dosing increased naïve T-cell populations. Daily dosing increased central memory cell populations and exhaustion markers. No disease progression was observed. In conclusion, treatment with eRapa was safe and well-tolerated. Daily dosing produced higher frequencies of lower grade toxicities and transient worsening of QoL, while weekly dosing impacted immune response. Future studies will verify clinical benefit and long-term tolerability.Prevention Relevance: There is an unmet medical need for a well-tolerated treatment capable of delaying progression of newly diagnosed low-grade prostate cancer. This treatment would potentially obviate the need for future surgical intervention and improve the perception of active surveillance as a more acceptable option among this patient population.
Assuntos
Neoplasias da Próstata/terapia , Sirolimo/efeitos adversos , Conduta Expectante , Idoso , Progressão da Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias da Próstata/diagnóstico , Qualidade de Vida , Sirolimo/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND AND OBJECTIVES: Routine lymphadenectomy (LND) for resectable hepatocellular carcinoma (HCC) remains controversial. We evaluated national LND trends to identify pre-operative factors associated with node-positive disease to determine which patients might benefit from LND. METHODS: We identified HCC patients in the National Cancer Database (NCDB) treated with surgical resection between 2004 and 2015. Demographic, operative, pathologic, and survival data were compared. Multivariable regression was performed to determine preoperative predictors of pathologic nodal disease. RESULTS: Of 8095 total resected patients, 1442 (17.8%) underwent hepatectomy with LND. Patients who received LND had higher preoperative clinical T (T3-T4: 20.0% vs 12.1%, p < 0.001) and N (N1: 3.3% vs 0.6%, p < 0.001) stages. The strongest independent predictor of pathologic nodal disease was clinical N stage (OR 106.54, CI 44.10-257.42). Survival was highest in patients whose surgeons omitted LND or were found with LND to be node-negative on final pathology (p < 0.001). Clinical node positivity had high negative predictive value (97.9%) but moderate positive predictive value (56.3%) in estimating pathologic nodal status. CONCLUSIONS: Defining preoperative clinical nodal status is imperative in HCC patients. Clinical node positivity was the strongest predictor of pathologic nodal disease and its associated worse prognosis. LND can be considered selectively in clinically node-positive patients.
Assuntos
Carcinoma Hepatocelular/cirurgia , Hepatectomia/mortalidade , Neoplasias Hepáticas/cirurgia , Excisão de Linfonodo/mortalidade , Linfonodos/patologia , Padrões de Prática Médica/estatística & dados numéricos , Idoso , Carcinoma Hepatocelular/patologia , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Immunotherapy has revolutionized the treatment of melanoma, yet survival remains poor for patients with metastatic disease. The autologous tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine has been shown to be safe adjuvant therapy for patients with resected stage III/IV melanoma who complete the primary vaccine series. Here, we describe an open-label trial of patients with metastatic melanoma treated with TLPLDC vaccine in addition to standard of care (SoC) therapies. The TLPLDC vaccine is created by loading autologous tumor lysate into yeast cell wall particles, which are phagocytosed by autologous dendritic cells ex vivo. Patients who recurred while enrolled in a phase IIb trial of adjuvant TLPLDC vaccine (crossover cohort) and patients with measurable metastatic melanoma cohort were offered TLPLDC vaccine along with SoC therapies. Tumor response was measured by RECIST 1.1 criteria. Overall survival (OS) and progression-free survival (PFS) were estimated by intention-to-treat analysis. Fifty-four patients were enrolled (28 in crossover cohort; 26 in metastatic melanoma cohort). The vaccine was well-tolerated with no grade ≥3 adverse events when given with SoC therapies to include checkpoint inhibitors, BRAF/MEK inhibitors, tyrosine kinase inhibitors, intralesional therapy and/or radiation. In the crossover arm, OS was 76.5% and PFS was 57.1% (median follow-up of 13.9 months). In the metastatic melanoma arm, OS was 85.7% and PFS was 52.2% (median follow-up 8.5 months). The TLPLDC vaccine is well-tolerated and safe in combination with SoC therapies. Future trials will determine the efficacy of TLPLDC in combination with SoC therapies in metastatic melanoma.