A phase I/IIa clinical trial in stage IV melanoma of an autologous tumor-dendritic cell fusion (dendritoma) vaccine with low dose interleukin-2.

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

Fluorescence Angiography in Colorectal Resection.

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.

Mechanism of injury affects acute coagulopathy of trauma in combat casualties.

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.

Died of wounds on the battlefield: causation and implications for improving combat casualty care.

BACKGROUND: Understanding the epidemiology of death after battlefield injury is vital to combat casualty care performance improvement. The current analysis was undertaken to develop a comprehensive perspective of deaths that occurred after casualties reached a medical treatment facility. METHODS: Battle injury died of wounds (DOW) deaths that occurred after casualties reached a medical treatment facility from October 2001 to June 2009 were evaluated by reviewing autopsy and other postmortem records at the Office of the Armed Forces Medical Examiners (OAFME). A panel of military trauma experts classified the injuries as nonsurvivable (NS) or potentially survivable (PS), in consultation with an OAFME forensic pathologist. Data including demographics, mechanism of injury, physiologic and laboratory variables, and cause of death were obtained from the Joint Theater Trauma Registry and the OAFME Mortality Trauma Registry. RESULTS: DOW casualties (n = 558) accounted for 4.56% of the nonreturn to duty battle injuries over the study period. DOW casualties were classified as NS in 271 (48.6%) cases and PS in 287 (51.4%) cases. Traumatic brain injury was the predominant injury leading to death in 225 of 271 (83%) NS cases, whereas hemorrhage from major trauma was the predominant mechanism of death in 230 of 287 (80%) PS cases. In the hemorrhage mechanism PS cases, the major body region bleeding focus accounting for mortality were torso (48%), extremity (31%), and junctional (neck, axilla, and groin) (21%). Fifty-one percent of DOW casualties presented in extremis with cardiopulmonary resuscitation upon presentation. CONCLUSIONS: Hemorrhage is a major mechanism of death in PS combat injuries, underscoring the necessity for initiatives to mitigate bleeding, particularly in the prehospital environment.

Fenoldopam use in a burn intensive care unit: a retrospective study.

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.

Laparoscopic versus open repair of perforated peptic ulcer: Improving outcomes utilizing a standardized technique.

BACKGROUND/OBJECTIVE: The objective of this study was to compare the outcomes of patients who underwent laparoscopic and open repair of perforated peptic ulcers (PPUs) at our institution. METHODS: This is a retrospective review of a prospectively collected database of patients who underwent emergency laparoscopic or open repair for PPU between December 2010 and February 2014. RESULTS: A total of 131 patients underwent emergency repair for PPU (laparoscopic repair, n=63, 48.1% vs. open repair, n=68, 51.9%). There were no significant differences in baseline characteristics between both groups in terms of age (p=0.434), gender (p=0.305), body mass index (p=0.180), and presence of comorbidities (p=0.214). Both groups were also comparable in their American Society of Anesthesiologists (ASA) scores (p=0.769), Boey scores 0/1 (p=0.311), Mannheim Peritonitis Index > 27 (p=0.528), shock on admission (p<0.99), and the duration of symptoms > 24 hours (p=0.857). There was no significant difference in the operating time between the two groups (p=0.618). Overall, the laparoscopic group had fewer complications compared with the open group (14.3% vs. 36.8%, p=0.005). When reviewing specific complications, only the incidence of surgical site infection was statistically significant (laparoscopic 0.0% vs. open 13.2%, p=0.003). The other parameters were not statistically significant. The laparoscopic group did have a significantly shorter mean postoperative stay (p=0.008) and lower pain scores in the immediate postoperative period (p<0.05). Mortality was similar in both groups (open, 1.6% vs. laparoscopic, 2.9%, p < 0.99). CONCLUSION: Laparoscopic repair resulted in reduced wound infection rates, shorter hospitalization, and reduced postoperative pain. Our single institution series and standardized technique demonstrated lower morbidity rates in the laparoscopic group.

Tumor lysate particle loaded dendritic cell vaccine: preclinical testing of a novel personalized cancer vaccine.

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.

Initial phase I/IIa trial results of an autologous tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine in patients with solid tumors.

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 >4 months life-expectancy. A personalized vaccine is created using 1 mg of tumor and 120 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 22.5 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.

Transcervical diverticulectomy for Killian-Jamieson diverticulum.

Surgery for Killian-Jamieson diverticulum of the esophagus is scarcely reported in the literature owing to the rarity of this entity. This is a case report of such a diverticulum and a description of the transcervical diverticulectomy that we performed on a 49-year-old lady. The patient was investigated for symptoms of gastroesophageal reflux disease and was diagnosed with a left-sided Killian-Jamieson diverticulum.

The true impact of breast magnetic resonance imaging on the management of in situ disease: more is not better.

BACKGROUND: The optimal role of breast magnetic resonance imaging (MRI) in the management of ductal carcinoma in situ (DCIS) remains controversial. We sought to better define the impact of breast MRIs when utilized during the workup of DCIS. METHODS: Patients with biopsy-proven DCIS without any additional invasive disease were prospectively enrolled in the multidisciplinary breast cancer pathway and comprised the study group. Patients who met any additional criteria for MRI screening were excluded. RESULTS: From 2008 to 2014, 93 women met the inclusion criteria. 81 patients underwent MRI as part of their workup. One patient benefited from MRI via identification of occult malignancy not previously identified. 35 MRIs identified no additional information whereas 46 had additional findings. These findings led to 23 procedures and 16 negative biopsies; recommendations for 16 radiographic studies that were normal; and influenced nodal sampling in 7 women with 1 positive metastatic focus. CONCLUSIONS: The routine use of breast MRI for women diagnosed with DCIS has limited benefit. Often, it leads to multiple procedures and studies that are clinically insignificant and delays surgical treatment.

Interim analysis of a phase I/IIa trial assessing E39+GM-CSF, a folate binding protein vaccine, to prevent recurrence in ovarian and endometrial cancer patients.

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.

Successful laparoscopic management of combined traumatic diaphragmatic rupture and abdominal wall hernia: a case report.

BACKGROUND: Traumatic diaphragmatic rupture and traumatic abdominal wall hernia are two well-described but rare clinical entities associated with blunt thoracoabdominal injuries. To the best of our knowledge, the combination of these two clinical entities as a result of a motor vehicle accident has not been previously reported. CASE PRESENTATION: A 32-year-old Indian man was brought to our emergency department after being involved in a road traffic accident. He described a temporary loss of consciousness and had multiple tender bruises at his right upper anterior abdominal wall and left lumbar region. An initial examination revealed blood pressure of 99/63 mmHg, heart rate of 107 beats/minute, and oxygen saturation of 93 % on room air. His clinical parameters stabilized after initial resuscitation. A computed tomographic scan revealed a rupture of the left diaphragm as well as extensive disruptions of the left upper anterior abdominal wall. We performed exploratory laparoscopic surgery with the intention of primary repair. The diaphragmatic and abdominal wall defect was primarily closed, followed by reinforcement with PROLENE onlay mesh. The patient's postoperative recovery was complicated by infected hematomas over both flanks that were managed with ultrasound-guided percutaneous drainage. He was discharged well despite a prolonged hospital stay. CONCLUSIONS: We present a complex form of injuries managed successfully via a laparoscopic approach. Meticulous attention to potential complications in both the acute and convalescent phases is important for achieving a successful outcome following surgery.

Organization and operation of the marine ornamental fish and invertebrate export fishery in Puerto Rico.

This fishery was examined utilizing public records, stakeholder interviews, and operational site visits to describe the fishery for the Puerto Rico Coral Reef Advisory Committee as a first step toward development of policies for the effective management of these natural resources. The fishery is not large, including fewer than 20 licensed fishers operating primarily on the west end of the island. Only three operators export product, with the remaining fishers providing specimens to the exporters based upon customer orders. Most collection of coral reef species occurs over hard rubble zones mixed with relic reef structures and rock, or on the sides and frontal areas of active reefs. Other species are collected from among mangrove prop root zones, tidal flats, and seagrass beds. Collections are made using simple barrier and dip nets for fish and motile invertebrates such as shrimp. Invertebrates such as crabs, starfish, and sea cucumbers are commonly collected by overturning small rocks, gathering the specimens, and then replacing the rocks in their original positions. Specimens are carried to the boat and transferred to individual cup holders to maximize survival. Although statements concerning former use of chemicals to assist capture were noted, no evidence of current chemical use was observed. Specimens are held in re-circulating seawater systems onshore until collections are aggregated and shipped. The fishery strives to operate with mortality of<1%, as mortalities of>3% are described as unacceptable to customers. More than 100 fish species are collected in this fishery, but the top ten species account for >70% of the total numbers and >60% of the total value of the fishery, with a single species, Gramma loreto (Royal Gramma), comprising >40% of the numbers. More than 100 species of invertebrates are collected, but this fishery is also dominated by a handful of species, including anemones, hermit crabs, turbo snails, serpent starfish, and feather duster polychaetes.

Laparoscopic management of symptomatic urachal remnants in adulthood.

BACKGROUND: The traditional surgical approach to the excision of persistent urachal remnants is a lower midline laparotomy or semicircular infraumbilical incision. The aim of this study is to report our experience with laparoscopic urachus excision as a minimally invasive diagnostic and surgical technique. METHODS: This study was a prospective study involving patients who were diagnosed with persistent urachus and underwent laparoscopic excision. The morbidity, recovery, and outcomes of surgery were reviewed. RESULTS: Fourteen patients (8 men) with a mean age of 22.8 ± 6.42 years underwent laparoscopic excision. All patients presented with discharge from the umbilicus. Although four patients had no sonographic evidence of a patent urachus, a diagnostic laparoscopy detected a patent urachus that was excised laparoscopically. One patient required laparoscopic reoperation for persistent discharge, and one patient presented with bladder injury, which was repaired via a small Pfannenstiel incision without any morbidity. The mean operative time was 71.1 ± 0.28 minutes, and the mean duration of hospital stay was 1.3 ± 1.38 days. Pathological examination confirmed a benign urachal remnant in all cases. CONCLUSION: Laparoscopy is a useful alternative for the management of persistent or infected urachus, especially when its presence is clinically suspected despite the lack of sonographic evidence. The procedure is associated with low morbidity, although a small risk of bladder injury exists, particularly in cases of severe active inflammation. Recurrence is uncommon and was caused by inadequate excision of inflammatory tissue in our series that was easily managed laparoscopically.

Evaluation of predatory mite (Acari: Phytoseiidae) releases to suppress spruce spider mites, Oligonychus ununguis (Acari: Tetranychidae), on juniper.

A laboratory trial evaluated four phytoseiid species for their potential as biological control agents of spruce spider mite, Oligonychus ununguis (Jacobi) (Acari: Tetranychidae). An augmentative biological control approach, using the predatory mites Neoseiulus fallacis Garman and Galendromus occidentalis Nesbitt (Acari: Phytoseiidae), was evaluated for reducing pest mite densities and injury, and economic costs on Juniperus chinensis 'Sargentii' A. Henry (Cupressaceae) in an outdoor nursery. Sequential releases of predator species, individually and in combination, were tested and compared with two commonly used miticides, a low-toxicity miticide, horticultural oil, and a conventional miticide, hexythiazox. Timing of treatments was based on grower-determined need, and predator release rates were based on guidelines in literature received from producers of beneficial organisms. Predator releases were more expensive and provided less effective suppression of spruce spider mites, resulting in greater spider mite injury to plants, compared with conventional pesticides. However, spider mite damage to plants did not differ in an economically meaningful way between treatments. Unsatisfactory levels of control seem related to under estimations of actual spider mite abundance based on grower perceptions and the beat sampling technique used to estimate predator release rates. These data suggest that when initial populations of spruce spider mite are high, it is unlikely that sequential releases of predator species, individually or in combination, will suppress spider mite populations. In this trial, augmentative biological control control was 2.5-7 times more expensive than chemical controls.

Beat sampling accuracy in estimating spruce spider mite (Acari: Tetranychidae) populations and injury on juniper.

The use of a standardized beat sampling method for estimating spruce spider mite, Oligonychus ununguis (Jacobi) (Acari: Tetranychidae), densities on a widely used evergreen ornamental plant species, Juniperus chinensis variety 'Sargentii' A. Henry (Cupressaceae), was examined. There was a significant positive relationship between total spruce spider mite densities and spider mite densities from beat sampling on juniper. The slope and intercept of the relationship may be used by pest managers to predict total spider mite densities on plants from beat sample counts. Beat sampling dramatically underestimates the total number of spider mites on a foliage sample. The relationships between spruce spider mite feeding injury and spider mite density estimates from beat sampling juniper foliage and total spider mite counts on foliage were also examined. There was a significant positive relationship between spruce spider mite density as estimated from beat sampling and injury to the plants. There was a similar positive relationship between the total number of spruce spider mites and injury to the plants, suggesting that a pest manager could use beat sampling counts to estimate plant injury and related thresholds. These findings have important implications to decision-making for spruce spider mite control, especially as it relates to threshold levels and determining rates of predator releases. Further assessment of the effectiveness of beat and other sampling methods across multiple spider mite- host plant associations needs to be examined to enable pest managers to select sampling plans that are feasible and reliable.

Plasma-to-red cell ratio and mechanism of injury in massively transfused combat casualties.

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.