RESUMO
BACKGROUND: Stage IV melanoma has high mortality, largely unaffected by traditional therapies. Immunotherapy including cytokine therapies and checkpoint inhibitors improves outcomes, but has significant toxicities. In this phase I/IIa trial, we investigated safety and efficacy of a dendritoma vaccine, an active, specific immunotherapy, in stage IV melanoma patients. METHODS: Autologous tumor lysate and dendritic cells were fused creating dendritoma vaccines for each patient. Phase I patients were vaccinated every 3 months with IL-2 given for 5 days after initial inoculation. Phase IIa patients were vaccinated every 6 weeks with IL-2 given on days 1, 3 and 5 after initial inoculation. Toxicity and clinical outcomes were assessed. RESULTS: Twenty-five patients were enrolled and inoculated. All dendritoma and IL-2 toxicities were Assuntos
Vacinas Anticâncer/imunologia
, Células Dendríticas/imunologia
, Interleucina-2/imunologia
, Melanoma/imunologia
, Melanoma/terapia
, Idoso
, Artralgia/induzido quimicamente
, Vacinas Anticâncer/efeitos adversos
, Vacinas Anticâncer/uso terapêutico
, Calafrios/induzido quimicamente
, Terapia Combinada
, Células Dendríticas/metabolismo
, Relação Dose-Resposta a Droga
, Esquema de Medicação
, Eritema/induzido quimicamente
, Feminino
, Humanos
, Interleucina-2/efeitos adversos
, Interleucina-2/uso terapêutico
, Estimativa de Kaplan-Meier
, Masculino
, Pessoa de Meia-Idade
, Náusea/induzido quimicamente
, Recidiva Local de Neoplasia
, Estadiamento de Neoplasias
, Resultado do Tratamento
RESUMO
BACKGROUND: Intraoperative laser fluorescence angiography is a relatively new tool that can be used by colorectal surgeons to ensure adequate perfusion to bowel that remains after resection. It has been used mostly to determine an appropriate point of transection of the proximal bowel, as well as to ensure perfusion after the anastomosis has been constructed. We propose a different use of the technology in complex cases to ensure the ability to safely transect a major vascular pedicle and to ensure that perfusion will remain adequate. OBJECTIVE: The purpose of this article is to describe a new use for fluorescence angiography technology. DESIGN: This is a technical note. SETTINGS: The work was conducted at a tertiary care military medical center. PATIENTS: Patients included individuals requiring oncologic colorectal resection where the status of 1 major vascular pedicle was unknown or impaired. MAIN OUTCOME MEASURES: We assessed perfusion after occlusion of a major vascular pedicle for the short term in hospital outcomes. RESULTS: Adequate studies were obtained, and perfusion was maintained in both patients. Oncologic resections were performed, and short-term outcomes were comparable with any individual undergoing these procedures. LIMITATIONS: This study was limited because it is early experience that was not performed in the setting of a scientific investigation. CONCLUSIONS: Application of intraoperative fluorescence angiography in this setting appears to be safe and may assist the surgeon in estimating reliable vascular perfusion in patients such as these who require oncologic colorectal resection.
RESUMO
BACKGROUND: Recent evidence suggests trauma involving total body tissue damage increases the acute coagulopathy of trauma (ACOT) by various mechanisms, especially in massive transfusion (MT). Our hypothesis was that MT patients injured by explosion will have a higher international normalization ratio (INR) at admission than MT patients injured by gunshot wound (GSW). METHODS: A retrospective review was performed on US military injured in Operation Iraqi Freedom/Operation Enduring Freedom from March 2003 to September 2008, who received MT (≥ 10 red blood cells in 24 hours) and had an INR on admission. Two cohorts were created based on mechanism. Admission vital signs, labs, transfusion, and mortality data were compared. RESULTS: Seven hundred fifty-one MT patients were identified. Four hundred fifty patients had admission INR and were injured by either GSW or explosion. Patients demonstrated similar injury severity scale and Glasgow Coma Scale. Patients injured by explosion presented with higher INR, greater base deficit, and more tachycardic than patients injured by GSW. Transfusion of blood products was similar between both groups. CONCLUSIONS: The primary finding of this study is that patients injured by explosion presented with a higher INR than those injured by GSW, even with similar injury severity scale. In addition, patients injured by explosion presented more tachycardic and with a greater base deficit. These findings support the theory that ACOT is affected by the amount of tissue injured. Further research is needed into the pathophysiology of ACOT because this may impact care of patients with total body tissue damage/hypoxia and improve the treatment of their coagulopathy while minimizing the attendant complications.
Assuntos
Transtornos da Coagulação Sanguínea/etiologia , Ferimentos e Lesões/sangue , Doença Aguda , Adulto , Campanha Afegã de 2001- , Coagulação Sanguínea , Transtornos da Coagulação Sanguínea/sangue , Transfusão de Sangue , Feminino , Humanos , Escala de Gravidade do Ferimento , Coeficiente Internacional Normatizado , Guerra do Iraque 2003-2011 , Masculino , Estudos Retrospectivos , Ferimentos e Lesões/etiologia , Adulto JovemRESUMO
BACKGROUND: Fenoldopam mesylate is a highly selective dopamine-1 receptor agonist approved for the treatment of hypertensive emergencies that may have a role at low doses in preserving renal function in those at high risk for or with acute kidney injury (AKI). There is no data on low-dose fenoldopam in the burn population. The purpose of our study was to describe our use of low-dose fenoldopam (0.03-0.09 mug/kg/min) infusion in critically ill burn patients with AKI. METHODS: We performed a retrospective analysis of consecutive patients admitted to our burn intensive care unit (BICU) with severe burns from November 2005 through September 2008 who received low-dose fenoldopam. Data obtained included systolic blood pressure, serum creatinine, vasoactive medication use, urine output, and intravenous fluid. Patients on concomitant continuous renal replacement therapy were excluded. Modified inotrope score and vasopressor dependency index were calculated. One-way analysis of variance with repeated measures, Wilcoxson signed rank, and chi-square tests were used. Differences were deemed significant at p < 0.05. RESULTS: Seventy-seven patients were treated with low-dose fenoldopam out of 758 BICU admissions (10%). Twenty (26%) were AKI network (AKIN) stage 1, 14 (18%) were AKIN stage 2, 42 (55%) were AKIN stage 3, and 1 (1%) was AKIN stage 0. Serum creatinine improved over the first 24 hours and continued to improve through 48 hours (p < 0.05). There was an increase in systolic blood pressure in the first 24 hours that was sustained through 48 hours after initiation of fenoldopam (p < 0.05). Urine output increased after initiation of fenoldopam without an increase in intravenous fluid requirement (p < 0.05; p = NS). Modified inotrope score and vasopressor dependency index both decreased over 48 hours (p < 0.0001; p = 0.0012). CONCLUSIONS: These findings suggest that renal function was preserved and that urine output improved without a decrease in systolic blood pressure, increase in vasoactive medication use, or an increase in resuscitation requirement in patients treated with low-dose fenoldopam. A randomized controlled trial is required to establish the efficacy of low-dose fenoldopam in critically ill burn patients with AKI.
RESUMO
INTRODUCTION: Tumor vaccines use various strategies to generate immune responses, commonly targeting generic tumor-associated antigens. The tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine is produced from DC loaded with autologous tumor antigens, creating a patient-specific vaccine. Here, we describe initial phase I/IIa trial results. METHODS: This trial includes patients with any stage solid tumors, ECOG ≤1, and >4â¯months life-expectancy. A personalized vaccine is created using 1â¯mg of tumor and 120â¯ml blood (to isolate DC). Primary vaccination series (PVS) is four monthly inoculations. Patients are followed per standard of care (SOC). Endpoints include safety and tumor response (RECIST v1.1). RESULTS: 44 patients were enrolled and vaccinated consisting of 31 late stage patients with residual/measurable disease, and 13 disease-free patients after SOC therapies. While 4 patients progressed before completing the PVS, 12/31 (39%) demonstrated clinical benefit (2 complete responses, 4 partial responses, 6 stable disease). In the adjuvant setting, 46% of late stage patients remain disease free at a median of 22.5â¯months. CONCLUSIONS: The TLPLDC vaccine is scalable, generates a personalized DC vaccine, and requires little autologous tumor tissue and few DC. The vaccine is safe, with primarily grade 0-2 toxicities, and nearly 40% clinical benefit rate in varied tumors, warranting further study. TRIAL REGISTRATION: ISRCTN81339386, Registered 2/17/2016.
Assuntos
Vacinas Anticâncer/uso terapêutico , Células Dendríticas/imunologia , Imunoterapia/métodos , Neoplasias/terapia , Adulto , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Medicina de Precisão/métodos , Resultado do TratamentoRESUMO
AIM: We developed a novel approach to efficiently deliver autologous tumor antigens to the cytoplasm of dendritic cells (DC) using yeast cell wall particles (YCWP). MATERIALS AND METHODS: Loading of YCWP, leakage of protein from loaded YCWP and cytoplasmic delivery of YCWP content was assessed using fluorescent-tagged experiments. Spectrophotometric analysis compared the epitope-specific T-cell responses following antigen presentation via YCWP versus exogenous loading. The in vivo effectiveness of tumor lysate (TL) particle loaded DC (TLPLDC) vaccine was assessed using murine melanoma models. RESULTS: In fluorescence-tagged experiments, YCWP efficiently delivered antigen to the cytoplasm of DC. TLPLDC loading was more effective than conventional exogenous loading of DC. Finally, in murine melanoma models, TLPLDC outperformed an analogous dendritoma vaccine. CONCLUSION: The TLPLDC vaccine is commercially scalable and holds the potential of producing personalized vaccines.
Assuntos
Vacinas Anticâncer/uso terapêutico , Células Dendríticas/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Melanoma Experimental/patologia , Animais , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Modelos Animais de Doenças , Feminino , Imunoterapia/métodos , Neoplasias Pulmonares/imunologia , Melanoma Experimental/imunologia , Camundongos , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Folate binding protein(FBP) is an immunogenic protein over-expressed in endometrial(EC) and ovarian cancer(OC). We are conducting a phase I/IIa trial of E39 (GALE 301)+GM-CSF, an HLA-A2-restricted, FBP-derived peptide vaccine to prevent recurrences in disease-free EC and OC patients. This interim analysis summarizes toxicity, immunologic responses, and clinical outcomes to date. METHODS: HLA-A2+ patients were vaccinated(VG), and HLA-A2- or -A2+ patients were followed as controls(CG). Six monthly intradermal inoculations of E39+250mcg GM-CSF were administered to VG. Demographic, safety, immunologic, and recurrence rate(RR) data were collected and evaluated. RESULTS: This trial enrolled 51 patients; 29 in the VG and 22 in the CG. Fifteen patients received 1000mcg E39, and 14 received <1000mcg. There were no clinicopathologic differences between groups(all p ≥ 0.1). E39 was well-tolerated regardless of dose. DTH increased pre- to post-vaccination (5.7±1.5 mm vs 10.3±3.0 mm, p = 0.06) in the VG, and increased more in the 1000mcg group (3.8±2.0 mm vs 9.5±3.5 mm, p = 0.03). With 12 months median follow-up, the RR was 41% (VG) vs 55% (CG), p = 0.41. Among the 1000mcg patients, the RR was 13.3% vs 55% CG, p = 0.01. Estimated 2-year DFS was 85.7% in the 1000mcg group vs 33.6% in the CG (p = 0.021). CONCLUSIONS: This phase I/IIa trial reveals that E39+GM-CSF is well-tolerated and elicits a strong, dose-dependent in vivo immune response. Early efficacy results are promising in the 1000 mcg dose cohort. This study proves the safety and establishes the dose of E39 for a larger prospective, randomized, controlled trial in HLA-A2+ EC and OC patients to prevent recurrence.
Assuntos
Proteínas de Transporte/genética , Neoplasias do Endométrio/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Imunoterapia/métodos , Neoplasias Ovarianas/genética , Idoso , Feminino , Ácido Fólico , Humanos , Pessoa de Meia-IdadeRESUMO
STUDY DESIGN: A retrospective review of 930 combat casualties from March 2003 to September 2009 who received a massive transfusion. Mechanism was categorized as explosion (EXPL) (712), gunshot wound (GSW) (190), and blunt trauma (28). Cohorts were also categorized by fresh frozen plasma (FFP) to red blood cell (RBC) ratio: low, ≤1:1.5 and high, >1:1.5. Patient characteristics and in-hospital mortality rates were compared among groups. Propensity matching was used to control for confounding variables. RESULTS: Cohorts were similar in demographics, admission vital signs, and laboratory values. Median injury severity score was higher in EXPL compared to GSW. High FFP:RBC ratio was associated with improved survival compared to low ratio in the EXPL group (p < 0.01). The GSW group had similar survival in the high and low FFP:RBC ratio groups (p = 0.06). After propensity matching, a high FFP:RBC ratio was associated with improved survival compared to low ratio in both the EXPL (p < 0.01) and GSW groups (p = 0.05). CONCLUSIONS: High FFP:RBC ratios are associated with improved survival in combat casualties regardless of injury mechanism.
Assuntos
Traumatismos por Explosões/sangue , Transfusão de Sangue/métodos , Militares , Ferimentos por Arma de Fogo/sangue , Ferimentos não Penetrantes/sangue , Adulto , Campanha Afegã de 2001- , Traumatismos por Explosões/terapia , Eritrócitos , Feminino , Mortalidade Hospitalar , Humanos , Guerra do Iraque 2003-2011 , Masculino , Plasma , Estudos Retrospectivos , Taxa de Sobrevida , Índices de Gravidade do Trauma , Estados Unidos , Ferimentos por Arma de Fogo/terapia , Ferimentos não Penetrantes/terapia , Adulto JovemRESUMO
INTRODUCTION: Historically, mucormycosis infections have been associated with high mortality. The purpose of this study was to determine the incidence, associated mortality, and management strategies of mucormycosis in a major burn center. METHODS: A retrospective review was performed via obtaining all patients with mucormycosis admitted from January 2003 to November 2009 at our adult burn center was performed obtaining demographic data relevant to fungal burn wound infection or colonization. RESULTS: The incidence of mucormycosis at our facility was 4.9 per 1000 admissions; specifically, 11 military casualties and one civilian were diagnosed with mucormycosis. The median percentage Total Body Surface Area (TBSA) burned, 11 patients, or open wound, one patient, was 60 (IQR, 54.1-80.0), and the incidence of documented inhalation injury was 66.7% (8 of 12). Ten patients had surgical amputations. A median of eight days (IQR, 3.5-74.5) elapsed from diagnosis of mucormycosis until death in the 11 patients who expired. The overall mortality was 92%; however, autopsy attributed mucormycosis mortality was 54.5% (6 of 11) with all six patients having invasive mucormycosis. CONCLUSION: Aggressive surgical intervention should be undertaken for invasive mucormycosis; additionally, implementation of standardized protocols for patients with large soft tissue injuries may mitigate mucormycosis superimposition.
Assuntos
Antifúngicos/uso terapêutico , Traumatismos por Explosões/terapia , Queimaduras/terapia , Desbridamento , Militares/estatística & dados numéricos , Mucormicose/mortalidade , Infecção dos Ferimentos/mortalidade , Adulto , Amputação Cirúrgica , Traumatismos por Explosões/complicações , Superfície Corporal , Unidades de Queimados , Queimaduras/complicações , Queimaduras por Inalação/complicações , Queimaduras por Inalação/terapia , Humanos , Mucormicose/etiologia , Mucormicose/terapia , Estudos Retrospectivos , Índices de Gravidade do Trauma , Infecção dos Ferimentos/etiologia , Infecção dos Ferimentos/terapia , Adulto JovemRESUMO
OBJECTIVE: Adult burn patients who experience in-hospital cardiac arrest (CA) and undergo cardiopulmonary resuscitation (CPR) represent a unique patient population. We believe that they tend to be younger and have the added burden of the burn injury compared to other populations. Our objective was to determine the incidence, causes and outcomes following cardiac arrest (CA) and cardio-pulmonary resuscitation (CPR) within this population. METHODS: We conducted a retrospective review at the US Army Institute of Surgical Research (ISR) burn intensive care unit (BICU). Charts from 1st January 2000 through 31st August 2009 were reviewed for study. Data were collected all on adult burn patients who experienced in-hospital CA and CPR either in the BICU or associated burn operating room. Patients undergoing CPR elsewhere in our burn unit were excluded because we could not validate the time of CA since they are not routinely monitored with real-time rhythm strips. The study population included civilian burn patients from the local catchment area and burn casualties from the conflicts in Iraq and Afghanistan, but patients with do-not-resuscitate (DNR) orders were excluded. RESULTS: We found 57 burn patients who had in-hospital CA and CPR yielding an incidence of one or more in-hospital CA of 34 per 1000 admissions (0.34%). Fourteen of these patients (25%) survived to discharge while 43 (75%) died. The most common initial cardiac rhythm was pulseless electrical activity (50.9%). The most common etiology of CA among burn patients was respiratory failure (49.1%). The most significant variable affecting survival to discharge was duration of CPR (P < 0.01) with no patient surviving more than 7 min of CPR. CONCLUSIONS: CPR in burn patients is sometimes effective, and those patients who survive are likely to have good neurological outcomes. However, prolonged CPR times are unlikely to result in return of spontaneous circulation and may be considered futile. Further, those who experience multiple CA are unlikely to survive to discharge.
Assuntos
Queimaduras/complicações , Parada Cardíaca/epidemiologia , Adulto , Unidades de Queimados/estatística & dados numéricos , Queimaduras/mortalidade , Reanimação Cardiopulmonar/estatística & dados numéricos , Feminino , Parada Cardíaca/mortalidade , Parada Cardíaca/terapia , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Estados Unidos/epidemiologia , Adulto JovemRESUMO
BACKGROUND: In 2008, we showed that incomplete or delayed extremity fasciotomies were associated with mortality and muscle necrosis in war casualties with limb injury. Subsequently, we developed an education program focused on surgeon knowledge gaps regarding the diagnosis of compartment syndrome and prophylactic fasciotomy. The program included educational alerts, classroom training, video instruction, and a research publication. We compared casualty data before and after the program implementation to determine whether the education altered outcomes. METHODS: Similar to the previous study, a case series was made from combat casualty medical records. Casualties were US military servicemen with fasciotomies performed in Iraq, Afghanistan, or Germany between two periods (periods 1 and 2). RESULTS: In both periods, casualty demographics were similar. Most fasciotomies were performed to the lower leg and forearm. Period 1 had 336 casualties with 643 fasciotomies, whereas Period 2 had 268 casualties with 1,221 fasciotomies (1.9 vs. 4.6 fasciotomies per casualty, respectively; p < 0.0001). The mortality rate decreased in Period 2 (3%, 8 of 268 casualties) from Period 1 (8%, 26 of 336 casualties; p = 0.0125). Muscle excision and major amputation rates were similar in both periods (p > 0.05). Rates of casualties with revision fasciotomy decreased to 8% in Period 2, (22 of 268 casualties) versus 15% in Period 1 (51 of 336 casualties; p = 0.009). CONCLUSION: Combat casualty care following implementation of a fasciotomy education program was associated with improved survival, higher fasciotomy rates, and fewer revisions. Because delayed fasciotomy rates were unchanged, further effort to educate providers may be indicated. LEVEL OF EVIDENCE: Therapeutic study, level IV.
Assuntos
Síndromes Compartimentais/prevenção & controle , Extremidades/lesões , Fasciotomia , Adolescente , Campanha Afegã de 2001- , Síndromes Compartimentais/etiologia , Síndromes Compartimentais/mortalidade , Síndromes Compartimentais/cirurgia , Extremidades/cirurgia , Humanos , Guerra do Iraque 2003-2011 , Melhoria de Qualidade , Reoperação , Taxa de Sobrevida , Estados Unidos , Adulto JovemRESUMO
Few descriptions of temporary abdominal closure for planned relaparotomy have been reported in burned patients. The purpose of this study is to describe our experience and outcomes in the management of burned patients with an open abdomen. The authors performed a retrospective review of all admissions to our burn center from March 2003 to June 2008, identifying patients treated by laparotomy with temporary abdominal closure. The authors collected data on patient demographics, indication for laparotomy, methods of temporary and definitive abdominal closure, and outcomes. Of 2,104 patients admitted, 38 underwent a laparotomy with temporary abdominal closure. Their median TBSA was 55%, and the incidence of inhalation injury was 58%. Abdominal compartment syndrome was the most common indication for laparotomy (82%) followed by abdominal trauma (16%). The in-hospital mortality associated with an open abdomen was 68%. Temporary abdominal closure was performed most commonly using negative pressure wound therapy (90%). Fascial closure was performed in 21 patients but was associated with a 38% rate of failure requiring reexploration. Of 12 survivors, fascial closure was achieved in seven patients and five were managed with a planned ventral hernia. Burned patients who necessitate an open abdomen management strategy have a high morbidity and mortality. Fascial closure was associated with a high rate of failure but was successful in a select group of patients. Definitive abdominal closure with a planned ventral hernia was associated with no increased mortality and remains an option when "tension-free" fascial closure cannot be achieved.