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1.
J Surg Oncol ; 129(2): 244-253, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37800378

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 Retrospectivos
3.
J Immunother Cancer ; 11(8)2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37536936

RESUMO

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 Cutâneo
4.
Ann Surg Oncol ; 30(11): 6662-6670, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37330447

RESUMO

BACKGROUND: Achieving optimal surgical outcomes in pancreatic adenocarcinoma requires a combination of both curative-intent resection to oncologic standards and stage-specific neoadjuvant or adjuvant therapy. This investigation sought to examine factors associated with receipt of standard-adherent surgery (SAS) and guideline-recommended therapy (GRT) and determine the impact of compliance on patient survival. PATIENTS AND METHODS: From the 2006-2016 National Cancer Database, 21,304 patients underwent resection for nonmetastatic pancreatic adenocarcinoma. SAS was defined as pancreatic resection with negative margins and ≥ 15 lymph nodes examined. Stage-specific GRT was defined by current National Comprehensive Cancer Network guidelines. Multivariable models were used to determine predictors of adherence to SAS and GRT and prognostic impact on overall survival. RESULTS: Overall, SAS was achieved in 39% and GRT in 65% of patients, but only 30% received both SAS and GRT. Increasing age, minority race, uninsured status, and greater comorbidities were associated with a decreased odds of receiving both SAS and GRT (all p < 0.05). SAS (HR 0.79; CI 0.76-0.81; p < 0.001) and GRT (HR 0.67; CI 0.65-0.69; p < 0.001) were each independently associated with a survival advantage. Receipt of both SAS and GRT was associated with significant improvement in median OS compared with receiving neither (2.2 years vs 1.1 years; p < 0.001) which was independently associated with a 78% increased risk of death (HR 1.78; CI 1.70-1.86; p < 0.001). CONCLUSIONS: Despite survival benefits associated with adherence to operative standards and receipt of guideline-recommended therapy, compliance remains poor. Future efforts must be directed toward improved education and implementation efforts around both operative standards and therapy guidelines.


Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Humanos , Adenocarcinoma/cirurgia , Adenocarcinoma/tratamento farmacológico , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/tratamento farmacológico , Terapia Combinada , Prognóstico , Estudos Retrospectivos , Quimioterapia Adjuvante , Neoplasias Pancreáticas
5.
J Burn Care Res ; 44(6): 1273-1277, 2023 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-37279511

RESUMO

Inhalation injury is diagnosed in up to one-third of burn patients and is associated with increased morbidity and mortality. There are multiple scoring systems to grade inhalation injury, but no study has evaluated the ability of these scoring systems to predict outcomes of interest such as overall survival. We conducted a prospective, observational study of 99 intubated burn patients who underwent fiberoptic bronchoscopy within 24 hr of admission and graded inhalation injury using three scoring systems: abbreviated injury score (AIS), inhalation injury severity score (I-ISS), and mucosal score (MS). Agreement between scoring systems was assessed with Krippendorff's alpha (KA). Multivariable analyses were conducted to determine if variables were associated with overall survival. At admission, median AIS, I-ISS, and MS scores were 2 for all scoring systems. Patients who died had higher overall injury burden than those who survived and had similar median admission AIS and MS scores, but higher I-ISS scores. There was strong correlation between the inhalation injury grade at admission using the three scoring systems (KA = 0.85). On regression analysis, the only scoring system independently associated with overall survival was I-ISS (score 3 compared to scores 1-2: OR 13.16, 95% CI 1.65-105.07; P = .02). Progression of injury after initial assessment may contribute to the poor correlation between admission score and overall survival for injuries graded with AIS and MS. Repeated assessment may more accurately identify patients at increased risk for mortality.


Assuntos
Queimaduras , Humanos , Escala de Gravidade do Ferimento , Estudos Prospectivos , Hospitalização , Broncoscopia
8.
Cancer Immunol Immunother ; 72(3): 697-705, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36045304

RESUMO

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 Cutâneo
9.
Ann Surg Oncol ; 30(3): 1436-1448, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36460898

RESUMO

BACKGROUND: High-volume centers (HVC), academic centers (AC), and longer travel distances (TD) have been associated with improved outcomes for patients undergoing surgery for pancreatic adenocarcinoma (PAC). Effects of mediating variables on these associations remain undefined. The purpose of this study is to examine the direct effects of hospital volume, facility type, and travel distance on overall survival (OS) in patients undergoing surgery for PAC and characterize the indirect effects of patient-, disease-, and treatment-related mediating variables. PATIENTS AND METHODS: Using the National Cancer Database, patients with non-metastatic PAC who underwent resection were stratified by annual hospital volume (< 11, 11-19, and ≥ 20 cases/year), facility type (AC versus non-AC), and TD (≥ 40 versus < 40 miles). Associations with survival were evaluated using multiple regression models. Effects of mediating variables were assessed using mediation analysis. RESULTS: In total, 19,636 patients were included. Treatment at HVC or AC was associated with lower risk of death [hazard ratio (HR) 0.90, confidence interval (CI) 0.88-0.92; HR 0.89, CI 0.86-0.91, respectively]. TD did not impact OS. Patient-, disease-, and treatment-related variables explained 25.5% and 41.8% of the survival benefit attained from treatment at HVC and AC, reducing the survival benefit directly attributable to each variable to 4.9% and 6.4%, respectively. CONCLUSIONS: Treatment of PAC at HVC and AC was associated with improved OS, but the magnitude of this benefit was less when mediating variables were considered. From a healthcare utilization and cost-resource perspective, further research is needed to identify patients who would benefit most from selective referral to HVC or AC.


Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/cirurgia , Adenocarcinoma/cirurgia , Fatores de Confusão Epidemiológicos , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Neoplasias Pancreáticas
10.
Clin Immunol ; 245: 109095, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35973640

RESUMO

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/metabolismo
11.
J Surg Res ; 279: 374-382, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35820319

RESUMO

INTRODUCTION: Pancreatectomy is associated with high morbidity and mortality. Therefore, patient selection and risk prediction is paramount. In this study, three validated perioperative risk scoring systems were compared among patients undergoing pancreatectomy to identify the most clinically useful model. MATERIALS AND METHODS: The 2014-2017 American College of Surgeons National Surgical Quality Improvement Program database was queried for pancreatectomy patients. Three models were evaluated: National Surgical Quality Improvement Program Universal Risk Calculator (URC), Model for End-Stage Liver Disease (MELD), and Modified Frailty Index-5 Factor (mFI-5). Outcomes were 30-d mortality and complications. Predictive performance of the models was compared using area under the receiver operating characteristic curve (AUC) and Brier scores. RESULTS: Twenty two thousand one hundred twenty three pancreatectomy patients were identified. The 30-d mortality rate was 1.4% (n = 319). Complications occurred in 6020 cases (27.2%). AUC (95% CI) for 30-d mortality were 0.70 (0.67-0.73), 0.63 (0.60-0.67), and 0.60 (0.57-0.63) for URC, MELD, and mFI-5, respectively, with Brier score of 0.014 for all three models. AUC (95% confidence interval) for any complication was 0.59 (0.58-0.59) for URC, 0.53 (0.52-0.54) for MELD, and 0.53 (0.52-0.54) for mFI-5, with Brier scores 0.193 (URC), 0.200 (MELD), and 0.197 (mFI-5). For individual complications, URC was more predictive than MELD or mFI-5. CONCLUSIONS: Of the validated preoperative risk scoring systems, URC was most predictive of both complications and 30-d mortality. None of the models performed better than fair to good. The lack of predictive accuracy of currently existing models highlights the need for development of improved perioperative risk models.


Assuntos
Doença Hepática Terminal , Doença Hepática Terminal/complicações , Humanos , Pancreatectomia/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Curva ROC , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença
12.
Ann Surg Oncol ; 29(9): 6015-6028, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35583691

RESUMO

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 Pancreáticas
13.
J Gastrointest Surg ; 26(2): 352-359, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35064457

RESUMO

BACKGROUND: Planned pancreatoduodenectomy (PD) for pancreatic adenocarcinoma (PDAC) can be aborted due to intraoperative findings. There is little guidance regarding the need for prophylactic bypass following an aborted PD to prevent symptomatic biliary obstruction or gastric outlet obstruction (GOO) postoperatively. The aim of this study was to characterize postoperative interventions and postsurgical survival in patients following aborted PD. METHODS: Patients with PDAC treated with neoadjuvant therapy and staging laparoscopy prior to planned PD between 2010 and 2015 were reviewed for aborted PDs. Data on postoperative biliary obstruction, GOO, procedural intervention, and postsurgical survival were analyzed. RESULTS: Of 271 planned PDs, 47 (17.3%) were aborted. Thirty-six patients had ≥ 2 months of follow-up data and were included. Six patients underwent hepaticojejunostomy and nine patients underwent gastrojejunostomy at the time of the aborted PD. Sixteen of 30 patients (53%) without a surgical biliary bypass required endoscopic intervention, but none required palliative surgery. Ten of 27 patients (37%) without an operative gastrojejunostomy required intervention, but none required palliative surgery. Endoscopic or percutaneous therapy was required to treat 13/16 (81%) patients who presented with postoperative biliary obstructions and 6/10 (60%) of GOOs. Median survival following aborted PD was 13.3 months (CI 8.9-17.7). There were no differences in survival when comparing patients who developed a biliary obstruction (p = 0.92) or GOO (p = 0.90) to asymptomatic patients. CONCLUSIONS: Following aborted PD, patients commonly develop obstructive symptoms. However, these symptoms can generally be managed without surgical intervention. In asymptomatic patients, preemptive surgical bypasses are not required at the time of aborted PD.


Assuntos
Adenocarcinoma , Derivação Gástrica , Obstrução da Saída Gástrica , Neoplasias Pancreáticas , Adenocarcinoma/cirurgia , Derivação Gástrica/efeitos adversos , Obstrução da Saída Gástrica/etiologia , Humanos , Terapia Neoadjuvante , Cuidados Paliativos , Neoplasias Pancreáticas/patologia , Pancreaticoduodenectomia/efeitos adversos
14.
J Surg Res ; 272: 117-124, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34968784

RESUMO

BACKGROUND: Traumatic brain injury (TBI) is one of the most prevalent diagnoses among trauma populations and places significant strain on valuable rural hospital resources. Limited studies show safety and efficacy of implementation of a Brain Injury Guideline (BIG) protocol at a Department of Defense (DoD) Level 1 trauma center. MATERIALS AND METHODS: Data from patients diagnosed with traumatic brain injury during the study period were collected from our institutional trauma database. A retrospective review was performed on patients identified in the database to collect demographic and injury related data. All primary and secondary outcome data were analyzed using two-tailed Fischer's exact tests, Pearson Chi-square tests, and non-parametric Mann Whitney U tests. RESULTS: A total of 354 patients were included in the study, 189 pre-implementation and 165 post-implementation. Demographics, head injury severity, initial HCT findings, and BIG classification distributions were well-matched. There was a significant reduction in neurosurgical consultations (NSC) (98.4% pre- to 77.0% post-implementation, P<0.001) and ICU admissions (84.1% pre-, 74.5% post-implementation, P=0.025) following protocol implementation. There were no differences between groups in ICU LOS (P=0.239), incidence of worsening findings on RHCT (P=0.894), or in-hospital mortality (P=0.814). There was a slight reduction in hospital LOS from 4.0d pre-implementation to 3.0d post-implementation (P=0.043). CONCLUSIONS: Implementation of a BIG protocol at our Level 1 trauma center suggested at a relationship with fewer NSCs and ICU admissions. Management of mild and moderate TBI by acute care and trauma surgeons without direct neurosurgical oversight is safe and implies a reduction in utilization of hospital resources.


Assuntos
Lesões Encefálicas Traumáticas , Lesões Encefálicas , Lesões Encefálicas Traumáticas/diagnóstico , Lesões Encefálicas Traumáticas/epidemiologia , Lesões Encefálicas Traumáticas/terapia , Mortalidade Hospitalar , Humanos , Estudos Retrospectivos , Centros de Traumatologia
15.
Int Wound J ; 19(2): 370-379, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34240793

RESUMO

Optimal treatment of full-thickness skin injuries requires dermal and epidermal replacement. To spare donor dermis, dermal substitutes can be used ahead of split-thickness skin graft (STSG) application. However, this two-stage procedure requires an additional general anaesthetic, often prolongs hospitalisation, and increases outpatient services. Although a few case series have described successful single-stage reconstructions, with application of both STSG and dermal substitute at the index operation, we have little understanding of how the physical characteristics of dermal substitutes affects the success of a single-stage procedure. Here, we evaluated several dermal substitutes to optimise single-stage skin replacement in a preclinical porcine model. A porcine full-thickness excisional wound model was used to evaluate the following dermal substitutes: autologous dermal graft (ADG; thicknesses 0.15-0.60 mm), Integra (0.4-0.8 mm), Alloderm (0.9-1.6 mm), and chitosan-based hydrogel (0.1-0.2 mm). After excision, each wound was treated with either a dermal substitute followed by STSG or STSG alone (control). Endpoints included graft take at postoperative days (PODs) 7 and 14, wound closure at POD 28, and wound contracture from POD 28-120. Graft take was highest in the STSG alone and hydrogel groups at POD 14 (86.9% ± 19.5% and 81.3% ± 12.3%, respectively; P < .001). There were no differences in graft take at POD 7 or in wound closure at POD 28, though highest rates of wound closure were seen in the STSG alone and hydrogel groups (93.6% ± 9.1% and 99.8% ± 0.5%, respectively). ADG-treated wounds demonstrated the least amount of wound contracture at each time point. Increase dermal substitute thickness was associated with worse percent graft take at PODs 14 and 28 (Spearman ρ of -0.50 and -0.45, respectively; P < .001). In this preclinical single-stage skin reconstruction model, thinner ADG and hydrogel dermal substitutes outperformed thicker dermal substitutes. Both substitute thickness and composition affect treatment success. Further preclinical and clinical studies to optimise this treatment modality are warranted.


Assuntos
Transplante de Pele , Pele Artificial , Animais , Sobrevivência de Enxerto , Pele , Suínos , Cicatrização
16.
J Surg Res ; 268: 650-659, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34474214

RESUMO

BACKGROUND: Surgical management of hepatic metastases in patients with stage IV breast cancer remains controversial. The purpose of this study was to examine the impact of hepatic metastasectomy on long-term outcomes. METHODS: The 2004-2015 National Cancer Database was queried for all patients diagnosed with stage IV breast cancer with metastases isolated to the liver. Patient demographics, disease-, treatment- and outcome-related data were analyzed. RESULTS: Of 2,895 patients, only 90 (3.1%) underwent hepatic resection. Compared to patients who did not undergo metastasectomy, patients treated with metastasectomy tended to be younger (52 ± 12.7 versus 59.2 ± 14.6; P < 0.001) and have private insurance (74.4% versus 45.3%; P < 0.001). Independent predictors of metastasectomy included younger age (OR 0.98; CI 0.96-0.99; P = 0.01), lobular carcinoma (OR 2.26; CI 1.06-4.82; P = 0.03), and prior surgery of the primary site (partial mastectomy (OR 6.96; CI 3.47-13.95; P < 0.001) or total mastectomy (OR 5.74; CI 3.06-10.76; P < 0.001)). Compared to no metastasectomy, hepatic metastasectomy was independently associated with a 37% reduction in the risk of death (HR 0.63; CI 0.44-0.91; P = 0.01). CONCLUSIONS: Stage IV breast cancer with metastases to the liver is rare and few patients undergo hepatic resection. However, in this select patient population, hepatic metastasectomy was associated with a significant survival advantage when included in the multimodal treatment of synchronous stage IV breast cancer.


Assuntos
Neoplasias da Mama , Neoplasias Colorretais , Neoplasias Hepáticas , Neoplasias Pulmonares , Metastasectomia , Neoplasias da Mama/patologia , Neoplasias Colorretais/patologia , Terapia Combinada , Feminino , Humanos , Fígado/patologia , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/cirurgia , Mastectomia , Estudos Retrospectivos , Taxa de Sobrevida
17.
Melanoma Res ; 31(4): 378-388, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34193804

RESUMO

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.


Assuntos
Vacinas Anticâncer/uso terapêutico , Células Dendríticas/transplante , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasias Cutâneas/patologia
18.
J Trauma Acute Care Surg ; 91(2S Suppl 2): S162-S168, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34039931

RESUMO

BACKGROUND: Military experience has shown low-titer O whole blood (LTOWB) to be safe and beneficial in the resuscitation of hemorrhaging trauma patients. However, few civilian centers use LTOWB for trauma resuscitation. We evaluated the early experience and safety of a LTOWB program at a level 1 civilian trauma center. METHODS: We retrospectively reviewed our trauma registry from January 2018 to June 2020 for patients admitted in shock (defined as ≥1 of the following: heart rate, >120 beats per minute; systolic blood pressure, <90 mm Hg; or shock index, >0.9) who received blood products within 24 hours. Patients were grouped by resuscitation provided: LTOWB (group 1), component therapy (CT; group 2), and LTOWB-CT (group 3). Safety, outcomes, and variables associated with LTOWB transfusion and mortality were analyzed. RESULTS: 216 patients were included: 34 in Group 1, 95 in Group 2, and 87 in Group 3. Patientsreceiving LTOWB were more commonly male (p<0.001) and had a penetrating injury (p=0.005). Groups 1 and 3 had higher median ISS scores compared to Group 2 (19 and 20 vs 17; p=0.01). Group 3 received more median units of blood product in the first 4h (p<0.001) and in the first 24h (p<0.001). There was no difference between groups in 24h mortality or transfusion-related complications (all p>0.05). Arrival ED SBP was associated with LTOWB transfusion (odds ratio [OR] 0.98, 95% confidence interval [CI] 0.95-1.00, p=0.03). ED lactate was independently associated with 24h mortality. (OR 1.27, CI 1.02-1.58, p=0.03). LTOWB transfusion was not associated with mortality (p=0.49). Abstract. CONCLUSION: Severely injured patients received LTOWB-CT and more overall product units but had similar 24 h mortality when compared with the LTOWB or CT groups. No increase in transfusion-related complications was seen after LTOWB transfusion. Low-titer O whole blood should be strongly considered in the resuscitation of trauma patients at civilian centers. LEVEL OF EVIDENCE: Retrospective, therapeutic, level IV.


Assuntos
Transfusão Total , Ressuscitação/métodos , Choque Hemorrágico/terapia , Centros de Traumatologia , Ferimentos e Lesões/terapia , Adulto , Transfusão Total/efeitos adversos , Transfusão Total/métodos , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Ressuscitação/efeitos adversos , Estudos Retrospectivos , Choque Hemorrágico/mortalidade , Resultado do Tratamento , Ferimentos e Lesões/mortalidade , Adulto Jovem
19.
Cancer Med ; 10(13): 4302-4311, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33982452

RESUMO

BACKGROUND: Checkpoint inhibitors (CPI) in combination with cell-based vaccines may produce synergistic antitumor immunity. The primary analysis of the randomized and blinded phase IIb trial in resected stage III/IV melanoma demonstrated TLPLDC is safe and improved 24-month disease-free survival (DFS) in the per treatment (PT) analysis. Here, we examine efficacy within pre-specified and exploratory subgroups. METHODS: Stage III/IV patients rendered disease-free by surgery were randomized 2:1 to TLPLDC vaccine versus placebo. The pre-specified PT analysis included only patients completing the primary vaccine/placebo series at 6 months. Kaplan-Meier analysis was used to compare 24-month DFS among subgroups. RESULTS: There were no clinicopathologic differences between subgroups except stage IV patients were more likely to receive CPI. In stage IV patients, 24-month DFS was 43% for vaccine versus 0% for placebo (p = 0.098) in the ITT analysis and 73% versus 0% (p = 0.002) in the PT analysis. There was no significant difference in 24-month DFS when stratified by use of immunotherapy or CPI. For patients with resected recurrent disease, 24-month DFS was 88.9% versus 33.3% (p = 0.013) in the PT analysis. All benefit from vaccination was in the PT analysis; no benefit was found in patients receiving up to three doses. CONCLUSION: The TLPLDC vaccine improved DFS in patients completing the primary vaccine series, particularly in the resected stage IV patients. The efficacy of the TLPLDC vaccine will be confirmed in a phase III study evaluating adjuvant TLPLDC + CPI versus Placebo + CPI in resected stage IV melanoma patients.


Assuntos
Vacinas Anticâncer/uso terapêutico , Células Dendríticas/imunologia , Melanoma/terapia , Recidiva Local de Neoplasia/prevenção & controle , Medicina de Precisão , Neoplasias Cutâneas/terapia , Idoso , Intervalo Livre de Doença , Método Duplo-Cego , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia Adotiva/métodos , Melanoma/mortalidade , Melanoma/patologia , Melanoma/cirurgia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Estadiamento de Neoplasias , Placebos/uso terapêutico , Estudos Prospectivos , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia
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