Feeding jejunostomy tube placement during resection of gastric cancers.

BACKGROUND: Feeding tube placement is common among patients undergoing gastrectomy, and national guidelines currently recommend consideration of a feeding jejunostomy tube (FJT) for all patients undergoing resection for gastric cancer. However, data are limited regarding the safety of FJT placement at the time of gastrectomy for gastric cancer. METHODS: The 2005-2011 American College of Surgeons National Surgical Quality Improvement Program Participant User Files were queried to identify patients who underwent gastrectomy for gastric cancer. Subjects were classified by the concomitant placement of an FJT. Groups were then propensity matched using a 1:1 nearest neighbor algorithm, and outcomes were compared between groups. The primary outcomes of interest were overall 30-d overall complications and mortality. Secondary end points included major complications, surgical site infection, and early reoperation. RESULTS: In total, 2980 subjects underwent gastrectomy for gastric cancer, among whom 715 (24%) also had an FJT placed. Patients who had an FJT placed were more likely to be male (61.6% versus 56.6%, P = 0.02), have recent weight loss (21.0% versus 14.8%, P < 0.01), and have undergone recent chemotherapy (7.9% versus 4.2%, P < 0.01) and radiation therapy (4.2% versus 1.3%, P < 0.01). They were also more likely to have undergone total (compared with partial) gastrectomy (66.6% versus 28.6%, P < 0.01) and have concomitant resection of an adjacent organ (40.4 versus 24.1%, P < 0.01). After adjustment with propensity matching, however, all baseline characteristics and treatment variables were highly similar. Between groups, there were no statistically significant differences in 30-d overall complications (38.8% versus 36.1%, P = 0.32) or mortality (5.8 versus 3.7%, P = 0.08). There were also no differences in major complications, surgical site infection, or early reoperation. Operative time was slightly longer among patients with feeding tubes placed (median, 248 versus 233 min, P = 0.01), but otherwise there were no significant differences in any outcomes between groups. CONCLUSIONS: Concomitant placement of FJT at the time of gastrectomy may result in slightly increased operative times but does not appear to lead to increased perioperative morbidity or mortality. Further investigation is needed to identify the patients most likely to benefit from FJT placement.

Nanoparticle delivered vascular disrupting agents (VDAs): use of TNF-alpha conjugated gold nanoparticles for multimodal cancer therapy.

Surgery, radiation and chemotherapy remain the mainstay of current cancer therapy. However, treatment failure persists due to the inability to achieve complete local control of the tumor and curtail metastatic spread. Vascular disrupting agents (VDAs) are a class of promising systemic agents that are known to synergistically enhance radiation, chemotherapy or thermal treatments of solid tumors. Unfortunately, there is still an unmet need for VDAs with more favorable safety profiles and fewer side effects. Recent work has demonstrated that conjugating VDAs to other molecules (polyethylene glycol, CNGRCG peptide) or nanoparticles (liposomes, gold) can reduce toxicity of one prominent VDA (tumor necrosis factor alpha, TNF-α). In this report, we show the potential of a gold conjugated TNF-α nanoparticle (NP-TNF) to improve multimodal cancer therapies with VDAs. In a dorsal skin fold and hindlimb murine xenograft model of prostate cancer, we found that NP-TNF disrupts endothelial barrier function and induces a significant increase in vascular permeability within the first 1-2 h followed by a dramatic 80% drop in perfusion 2-6 h after systemic administration. We also demonstrate that the tumor response to the nanoparticle can be verified using dynamic contrast-enhanced magnetic resonance imaging (MRI), a technique in clinical use. Additionally, multimodal treatment with thermal therapies at the perfusion nadir in the sub- and supraphysiological temperature regimes increases tumor volumetric destruction by over 60% and leads to significant tumor growth delays compared to thermal therapy alone. Lastly, NP-TNF was found to enhance thermal therapy in the absence of neutrophil recruitment, suggesting that immune/inflammatory regulation is not central to its power as part of a multimodal approach. Our data demonstrate the potential of nanoparticle-conjugated VDAs to significantly improve cancer therapy by preconditioning tumor vasculature to a secondary insult in a targeted manner. We anticipate our work to direct investigations into more potent tumor vasculature specific combinations of VDAs and nanoparticles with the goal of transitioning optimal regimens into clinical trials.

Concentration and volume effects in thermochemical ablation in vivo: results in a porcine model.

PURPOSE: To explore the effects of volume and concentration in thermochemical ablation using an in vivo porcine model. METHODS: Twelve swine 60-75 kg were used in this institutionally approved study. A needle design prototype coaxial device for reagent injections and a thermocouple were inserted into surgically exposed liver. Simultaneously, an acid and base (acetic acid and NaOH) were injected at 4 mL/min based on a 3 × 3 matrix with concentration (5, 10, and 15 mol/L) and volume on the axes (total volumes of 1, 2, and 4 mL). Three animals (centre grid position) strengthened the statistical analysis. Each animal received four identical injections (total 48). Temperatures and heart rate were recorded. Livers were formalin-fixed after sacrifice. After sectioning, coagulation zones were analysed by two observers. Area and slice thickness were used to calculate the volume, surface area, and sphericity for each treatment. RESULTS: Coagulation volumes ranged from 2.95 ± 0.29 to 14.72 ± 1.42 mL with a maximum of 18.3 mL. Highest peak temperature was 105°C with temperatures ranging 43.5 ± 2.6°C to 91.0 ± 6.5°C. There was no association between conditions and sphericity or heart rate. CONCLUSIONS: The method can be used successfully to ablate tissue in vivo. By neutralising acid in situ and releasing heat and a salt, this technique improves considerably upon the use of acetic acid used alone. Peak temperatures exceeded accepted coagulation thresholds even if the only mechanism operating was hyperthermia. Reagent concentrations and volumes increased the amount of the coagulum but not in a linear fashion.

In vivo comparison of simultaneous versus sequential injection technique for thermochemical ablation in a porcine model.

PURPOSE: To investigate simultaneous and sequential injection thermochemical ablation in a porcine model, and compare them to sham and acid-only ablation. MATERIALS AND METHODS: This IACUC-approved study involved 11 pigs in an acute setting. Ultrasound was used to guide placement of a thermocouple probe and coaxial device designed for thermochemical ablation. Solutions of 10 M acetic acid and NaOH were used in the study. Four injections per pig were performed in identical order at a total rate of 4 mL/min: saline sham, simultaneous, sequential, and acid only. Volume and sphericity of zones of coagulation were measured. Fixed specimens were examined by H&E stain. RESULTS: Average coagulation volumes were 11.2 mL (simultaneous), 19.0 mL (sequential) and 4.4 mL (acid). The highest temperature, 81.3°C, was obtained with simultaneous injection. Average temperatures were 61.1°C (simultaneous), 47.7°C (sequential) and 39.5°C (acid only). Sphericity coefficients (0.83-0.89) had no statistically significant difference among conditions. CONCLUSIONS: Thermochemical ablation produced substantial volumes of coagulated tissues relative to the amounts of reagents injected, considerably greater than acid alone in either technique employed. The largest volumes were obtained with sequential injection, yet this came at a price in one case of cardiac arrest. Simultaneous injection yielded the highest recorded temperatures and may be tolerated as well as or better than acid injection alone. Although this pilot study did not show a clear advantage for either sequential or simultaneous methods, the results indicate that thermochemical ablation is attractive for further investigation with regard to both safety and efficacy.

Resected irradiated rectal cancers: Are twelve lymph nodes really necessary in the era of neoadjuvant therapy?

BACKGROUND: Our study aims to identify the minimum number of lymph nodes (LN) associated with improved survival in patients who underwent NRT for stage II-III rectal cancer. METHODS: Adults with clinical stage II and III rectal adenocarcinoma in the National Cancer Data Base were stratified by NRT. Multivariable Cox regression modeling with restricted cubic splines was used to determine the minimum number of LNs associated with improved survival. RESULTS: Of 38,363 patients, 76% received NRT. After adjustment, a LNY≥12 was associated with improved survival among patients receiving NRT (HR 0.79, p < 0.0001) and those without NRT (HR 0.88, p = 0.04). Among patients receiving NRT, factors independently associated with LNY≥12 were younger age, private insurance, low comorbidity score, a recent year of diagnosis, higher T stage and grade, APR resection, and academic institution. CONCLUSIONS: A minimum LNY of 12 confers a survival benefit for rectal cancer patients regardless of receiving neoadjuvant radiation therapy.

Nanoparticle preconditioning for enhanced thermal therapies in cancer.

Nanoparticles show tremendous promise in the safe and effective delivery of molecular adjuvants to enhance local cancer therapy. One important form of local cancer treatment that suffers from local recurrence and distant metastases is thermal therapy. In this article, we review a new concept involving the use of nanoparticle-delivered adjuvants to 'precondition' or alter the vascular and immunological biology of the tumor to enhance its susceptibility to thermal therapy. To this end, a number of opportunities to combine nanoparticles with vascular and immunologically active agents are reviewed. One specific example of preconditioning involves a gold nanoparticle tagged with a vascular targeting agent (i.e., TNF-α). This nanoparticle embodiment demonstrates preconditioning through a dramatic reduction in tumor blood flow and induction of vascular damage, which recruits a strong and sustained inflammatory infiltrate in the tumor. The ability of this nanoparticle preconditioning to enhance subsequent heat or cold thermal therapy in a variety of tumor models is reviewed. Finally, the potential for future clinical imaging to judge the extent of preconditioning and thus the optimal timing and extent of combinatorial thermal therapy is discussed.

Freeze-thaw induced biomechanical changes in arteries: role of collagen matrix and smooth muscle cells.

Applications involving freeze-thaw, such as cryoplasty or cryopreservation can significantly alter artery biomechanics including an increase in physiological elastic modulus. Since artery biomechanics plays a significant role in hemodynamics, it is important to understand the mechanisms underlying these changes to be able to help control the biomechanical outcome post-treatments. Understanding of these mechanisms requires investigation of the freeze-thaw effect on arterial components (collagen, smooth muscle cells or SMCs), as well as the components' contribution to the overall artery biomechanics. To do this, isolated fresh swine arteries were subjected to thermal (freeze-thaw to -20 degrees C for 2 min or hyperthermia to 43 degrees C for 2 h) and osmotic (0.1-0.2 M mannitol) treatments; these treatments preferentially altered either the collagen matrix (hydration/stability) or smooth muscle cells (SMCs), respectively. Tissue dehydration, thermal stability and SMC functional changes were assessed from bulk weight measurements, analyses of the thermal denaturation profiles using Fourier transform infrared (FTIR) spectroscopy and in vitro arterial contraction/relaxation responses to norepinephrine (NE) and acetylcholine (AC), respectively. Additionally, Second Harmonic Generation (SHG) microscopy was performed on fresh and frozen-thawed arteries to directly visualize the changes in collagen matrix following freeze-thaw. Finally, the overall artery biomechanics was studied by assessing responses to uniaxial tensile testing. Freeze-thaw of arteries caused: (a) tissue dehydration (15% weight reduction), (b) increase in thermal stability (approximately 6.4 degrees C increase in denaturation onset temperature), (c) altered matrix arrangement observed using SHG and d) complete SMC destruction. While hyperthermia treatment also caused complete SMC destruction, no tissue dehydration was observed. On the other hand, while 0.2 M mannitol treatment significantly increased the thermal stability (approximately 4.8 degrees C increase in denaturation onset), 0.1 M mannitol treatment did not result in any significant change. Both 0.1 and 0.2 M treatments caused no change in SMC function. Finally, freeze-thaw (506+/-159 kPa), hyperthermia (268+/-132 kPa) and 0.2 M mannitol (304+/-125 kPa) treatments all caused significant increase in the physiological elastic modulus (Eartery) compared to control (185+/-92 kPa) with the freeze-thaw resulting in the highest modulus. These studies suggest that changes in collagen matrix arrangement due to dehydration as well as SMC destruction occurring during freeze-thaw are important mechanisms of freeze-thaw induced biomechanical changes.

Nanoparticle enhanced thermal therapies.

Thermal therapies such as hyperthermia, radiofrequency ablation, cryoablation, etc. have shown great potential and are gaining increasing clinical acceptance in the treatment of solid tumors. However, these treatment modalities are limited by the size of tumor that can be treated, incomplete tumor kill, and damage to adjacent normal tissues. To address these limitations, the concept of adjuvant-assisted thermal therapies has been proposed and tested to enhance the tumor destructive effects of thermal therapies. CYT-6091, a pegylated colloidal gold nanoparticle containing TNF-alpha bound to its surface, has been extensively investigated in our lab as an adjuvant to enhance thermal therapies. This paper describes our investigations of nanoparticle enhanced thermal therapies in various preclinical and translational models of solid tumors.