Quality of life outcomes after isolated limb infusion.

BACKGROUND: Isolated limb infusion (ILI) for the treatment of in-transit melanoma was originally described more than 10 years ago. Response rates of 45-53% have been reported in U.S. series. Long-term quality of life outcomes after this procedure have not been described. We hypothesized that ILI is rarely associated with long-term limb morbidity. METHODS: ILIs performed at our institution between July 2005 and June 2009 were reviewed. Patients were contacted cross-sectionally at 2 time points. During these interviews, response to treatment and postoperative limb function were assessed. RESULTS: Thirty-two ILIs were performed during the time period. Twenty-seven patients were treated for in-transit melanoma; 5 were treated for recurrent Merkel cell carcinoma. The 30-day mortality was 0%. Three patients (9%) required fasciotomy. Durable complete responses were achieved in 41% of patients, with mean follow-up time of 19.4 ± 9.6 months after infusion; after this period, 53% reported progression of disease. The most common postprocedure symptoms were edema (88%), numbness (59%), and pain (59%). By 3 months and at the time of last follow-up, the most common symptoms were edema (82%), numbness (65%), and stiffness (35%). No patients reported impaired limb function at the time of last follow-up compared to baseline. Median survival was 19.2 ± 4.2 months after infusion. CONCLUSIONS: ILI for melanoma and Merkel cell carcinoma is associated with postprocedure symptoms in most patients, most commonly edema, color change, and numbness. At last follow-up, no ILI patients had residual functional impairment in the treated limb.

Estrogen receptor alpha deletion enhances the metastatic phenotype of Ron overexpressing mammary tumors in mice.

BACKGROUND: The receptor tyrosine kinase family includes many transmembrane proteins with diverse physiological and pathophysiological functions. The involvement of tyrosine kinase signaling in promoting a more aggressive tumor phenotype within the context of chemotherapeutic evasion is gaining recognition. The Ron receptor is a tyrosine kinase receptor that has been implicated in the progression of breast cancer and evasion of tamoxifen therapy. RESULTS: Here, we report that Ron expression is correlated with in situ, estrogen receptor alpha (ERα)-positive tumors, and is higher in breast tumors following neoadjuvant tamoxifen therapy. We also demonstrate that the majority of mammary tumors isolated from transgenic mice with mammary specific-Ron overexpression (MMTV-Ron mice), exhibit appreciable ER expression. Moreover, genetic-ablation of ERα, in the context of Ron overexpression, leads to delayed mammary tumor initiation and growth, but also results in an increased metastasis. CONCLUSIONS: Ron receptor overexpression is associated with ERα-positive human and murine breast tumors. In addition, loss of ERα on a Ron overexpressing background in mice leads to the development of breast tumors which grow slower but which exhibit more metastasis and suggests that targeting of ERα, as in the case of tamoxifen therapy, may reduce the growth of Ron overexpressing breast cancers but may cause these tumors to be more metastatic.

Factors associated with recidivism following pancreaticoduodenectomy.

OBJECTIVES: Factors related to readmission after pancreaticoduodenectomy (PD) may include postoperative morbidity and the functional status of the patient. This study aimed to retrospectively review our institution's experience of readmission of patients who had undergone Whipple procedure PD. METHODS: Recidivism was defined as readmission to the primary or a secondary hospital within, respectively, 30 days, 30-90 days or 90 days postoperatively. Associations between recidivism, perioperative factors and patient characteristics were evaluated. RESULTS: During the past 5 years, 30-day, 30-90-day and 90-day recidivism rates were 14.5%, 18.5% and 27.4%, respectively. The most common reasons for readmission included dehydration and/or malnutrition (37.5% of readmissions) and pain (12.5%). Patients who underwent PD for chronic pancreatitis were more likely to be readmitted within 90 days of surgery than patients who underwent PD for malignancy (P < 0.01). Intraoperative transfusion was also associated with 30-90-day and 90-day recidivism (P < 0.01). Preoperative comorbidities, including Charlson Comorbidity Index score, number of pre-discharge complications, type of Whipple reconstruction, preoperative biliary stenting, need for vascular reconstruction and patient body mass index were not associated with recidivism. CONCLUSIONS: Our data confirm previous reports indicating high rates of readmission after PD. To our knowledge, this report is the first to demonstrate chronic pancreatitis as an independent risk factor for readmission.

Use of a mild traumatic brain injury guideline to reduce inpatient hospital imaging and charges.

PURPOSE: In children, mild traumatic brain injuries (TBI) account for 70% to 90% of head injuries. Without clear guidelines, many of these children may be exposed to excess radiation owing to unnecessary imaging. The purpose of this study was to evaluate the impact of a mild TBI guideline in reducing hospital charges and repeated imaging of pediatric patients. METHODS: Charts of all children who had at least one head computed tomography and were admitted to our level 1 trauma center with a blunt TBI and Glasgow Coma Scale of 13 to 15 were retrospectively reviewed. Patients were divided into 2 groups relative to the implementation of a TBI management guideline. RESULTS: A total of 742 patients were included, 389 preguideline and 353 postguideline. Implementation of the guideline was associated with reductions in the average number of head computed tomographies performed (1.6 vs 1.3, P = .006), length of stay (2.3 vs 1.7 days, P < .0001), and overall hospital charges ($21,760 vs $13,980, P = .006). No children were readmitted for missed injuries. CONCLUSIONS: Implementation of a simple guideline for the care of children with mild TBI can have significant impact on charges and length of stay while simultaneously reducing radiation exposure. Widespread implementation of such guidelines will improve efficiency without sacrificing quality of care in the management of mild TBI in the pediatric population.

Ron receptor tyrosine kinase activation confers resistance to tamoxifen in breast cancer cell lines.

Although tamoxifen treatment is associated with improved survival in patients with estrogen receptor (ER)-positive breast tumors, resistance remains an important clinical obstacle. Signaling through growth factor signaling pathways, in particular through receptor tyrosine kinases, has been demonstrated to confer tamoxifen resistance in an estradiol-independent manner. The Ron receptor tyrosine kinase, a member of the c-Met family of receptors, is expressed in a number of human epithelial tumors, and elevated expression of Ron is associated with poor prognosis in women with breast cancer. In this report, we evaluated the role of Ron receptor activation in conferring resistance to tamoxifen in human and murine breast cancer cell lines. Activation of Ron by its ligand, hepatocyte growth factor-like protein (HGFL) was associated with partial rescue from tamoxifen-induced growth inhibition in Ron-expressing cell lines. Western analysis revealed that treatment of the T47D human breast cancer cell line with tamoxifen and HGFL was associated with increased phosphorylation of mitogen-activated protein kinase (MAPK) 1/2 and phosphorylation of serine residue 118 of ER. Expression of ER-dependent genes was increased in cells treated with tamoxifen and HGFL by quantitative reverse transcription-polymerase chain reaction. All of these effects were inhibited by treatment with either a Ron-neutralizing antibody or a MEK1 inhibitor, suggesting the specificity of the effect to Ron, and the involvement of the MAPK 1/2 signaling pathway. In summary, these results illustrate a novel connection between the Ron receptor tyrosine kinase and an important mechanism of tamoxifen resistance in breast cancer.

Neoadjuvant therapy may lead to successful surgical resection and improved survival in patients with borderline resectable pancreatic cancer.

BACKGROUND: Borderline resectable pancreatic cancers are technically amenable to surgical resection, but are associated with increased risk of locoregional recurrence. Patients with these tumours may be treated with neoadjuvant therapy in an attempt to improve margin-negative resection rates. METHODS: The University of Cincinnati Pancreatic Cancer Database was retrospectively reviewed. Borderline resectable disease was defined by the following radiographic criteria: (i) short segment occlusion of the superior mesenteric vein (SMV), portal vein (PV) or SMV/PV confluence; (ii) short segment hepatic artery encasement, or (iii) superior mesenteric artery/coeliac artery abutment of <180 degrees. Patients with resectable disease who had questionable metastatic disease or poor performance status were also included. RESULTS: Twenty-nine patients met the criteria. Of these, 26 underwent a full course of neoadjuvant therapy. Twelve (46%) underwent surgical resection and 14 had tumour progression or were deemed unresectable at laparotomy. The most common neoadjuvant therapy regimen was gemcitabine-based chemotherapy alone (58%). Of those undergoing surgery, 67% had margin-negative (R0) resections and 42% required venous resection. Median survival was 15.5 months for unresected patients and 23.3 months for resected patients. DISCUSSION: Borderline resectable pancreatic tumours can be treated neoadjuvantly, resulting in margin-negative resection and survival rates similar to those in initially resectable disease.

Meta-analysis of trials evaluating parenteral antimicrobial therapy for skin and soft tissue infections.

BACKGROUND: Many trials have been carried out to determine the effectiveness of antimicrobial agents in treating skin and soft tissue infections. The results of these studies are often utilized to make determinations about the use of these antimicrobials against other types of infections. Despite the importance of these trials in determining clinical care, we hypothesized that many of these studies failed to include a variety of infections of significant enough severity to effectively draw objective conclusions about antimicrobial efficacy. METHODS: We conducted a modified PubMed search to identify studies of antimicrobial agents in treating soft tissue infections that were published from 1998 through 2008. We then evaluated these trials for specific recommended study criteria, which were based on published US Food and Drug Administration guidelines for the conduct of trials of antimicrobials for soft tissue infection. RESULTS: Seventeen studies were identified for inclusion in the trial. Upon review, only 30% of trials required both local and systemic signs of infection for inclusion in the trial. One trial stratified results on the basis of operative intervention, less than half reported patient comorbidities, and only 53% provided a specific definition for "cure." CONCLUSIONS: Our meta-analysis of current trials evaluating antimicrobial therapy for skin and soft tissue infections revealed substantial shortcomings in the design of most of these trials. These data provide evidence for the importance of designing specialist panels to objectively evaluate studies and photographs of included infections to ensure that conclusions drawn from these trials concerning clinical practice are justified.

A comparison of pancreaticoduodenectomy and duodenum-preserving head resection for the treatment of chronic pancreatitis.

BACKGROUND: For chronic pancreatitis, European prospective trials have concluded that duodenum-preserving head resections (DPHR) are associated with less morbidity and similar pain relief and quality of life (QoL) outcomes compared with pancreaticoduodenectomy (PD). However, DPHR procedures are seldom performed in North America. METHODS: Patients undergoing PD or DPHR for unremitting pain secondary to chronic pancreatitis were retrospectively identified. Quality of life was assessed cross-sectionally using the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire (QLQ-C30) and pancreatic cancer-specific supplemental module (QLQ-PAN26). RESULTS: Eighty-one patients underwent either a Whipple PD (n= 59) or a DPHR (Bern, Beger or Frey procedure, n= 22) for the treatment of pain caused by chronic pancreatitis over a 5-year period. The characteristics of patients undergoing DPHR and PD procedures were similar. Duration of procedure (360 min vs. 245 min), duration of hospital stay (12.0 days vs. 9.5 days) and estimated blood loss (535 ml vs. 214 ml) were all significantly less for DPHR patients (P < 0.05). Thirty-day morbidity and mortality, postoperative pain relief and QoL scores did not differ significantly between groups. CONCLUSIONS: Duodenum-preserving head resection is equally as effective as PD in relieving pain and improving QoL in chronic pancreatitis patients, and involves a shorter hospital stay and less blood loss.

Inclusion of a nitric oxide congener in the insufflation gas repletes S-nitrosohemoglobin and stabilizes physiologic status during prolonged carbon dioxide pneumoperitoneum.

A method to maintain organ blood flow during laparoscopic surgery has not been developed. Here we determined if ethyl nitrite, an S-nitrosylating agent that would maintain nitric oxide bioactivity (the major regulator of tissue perfusion), might be an effective intervention to preserve physiologic status during prolonged pneumoperitoneum. The study was conducted on appropriately anesthetized adult swine; the period of pneumoperitoneum was 240 minutes. Cohorts consisted of an anesthesia control group and groups insufflated with CO2 alone or CO2 containing fixed amounts of ethyl nitrite (1-300 ppm). Insufflation with CO2 alone produced declines in splanchnic organ blood flows and it reduced circulating levels of S-nitrosohemoglobin (i.e., nitric oxide bioactivity); these reductions were obviated by ethyl nitrite. In a specific example, preservation of kidney blood flow with ethyl nitrite kept serum creatinine and blood urea nitrogen concentrations constant whereas in the CO2 alone group both increased as kidney blood flow declined. The data indicate ethyl nitrite can effectively attenuate insufflation-induced decreases in organ blood flow and nitric oxide bioactivity leading to reductions in markers of acute tissue injury. This simple intervention provides a method for controlling a major source of laparoscopic-related morbidity and mortality: tissue ischemia and altered postoperative organ function.

A description of the preterm fetal sheep systemic and central responses to maternal general anesthesia.

BACKGROUND: The second trimester is recommended as the optimal time to conduct a surgical procedure on pregnant patients, even though the fetal responses to anesthesia at this age are not known. Here we assessed the responses of preterm fetal sheep to a standard anesthetic regimen of midazolam, thiopental, and isoflurane. METHODS: Variables were monitored in previously instrumented preterm pregnant sheep before, during, and after 4 h of general anesthesia. Isoflurane produced moderate fetal hypotension and bradycardia, whereas extubation was accompanied by increases in fetal heart rate and mean arterial blood pressure. RESULTS: We observed an initial increase in fetal Sao2 followed by a gradual decline to baseline. Within the fetal brain, oxygenated hemoglobin changed by <10% (nonsignificant) and deoxygenated hemoglobin and total hemoglobin varied by <5%. Overall, although O2 levels within the preterm fetal brain were not independently enhanced by isoflurane (as occurs in the older fetus and in the adult), they did remain constant even as fetal mean arterial pressure decreased by more than 20%. By extension, we failed to identify changes in cerebral oxygenation that could be construed as injurious. CONCLUSION: Any adverse preterm fetal response to maternal surgery should not be attributed solely to the actions of general anesthesia upon the fetus.

General anesthesia improves fetal cerebral oxygenation without evidence of subsequent neuronal injury.

Anesthetic exposure during pregnancy is viewed as a relatively routine medical practice. However, recent rodent studies have suggested that common anesthetic agents can damage the developing brain. Here we assessed this claim in a higher order species by exposing previously instrumented near-term pregnant sheep at gestational day 122 (+/-1) to a combination of midazolam, sodium thiopental, and isoflurane at clinically relevant doses and means of anesthetic delivery (i.e., active ventilation). Four hours of maternal general anesthesia produced an initial increase in fetal systemic oxygenation and a sustained increase in fetal cerebral oxygenation, as determined by in utero near-infrared spectroscopy. Postexposure monitoring failed to identify changes in physiologic status that could be injurious to the fetal brain. Finally, through the histologic assessment of noninstrumented sheep at the same gestational time point, we found no evidence for a direct fetal neuro-toxic effect of our triple-drug regimen. Collectively, these results appear to corroborate the presumed safety of inhalational anesthetic use during pregnancy.

Maternal insufflation during the second trimester equivalent produces hypercapnia, acidosis, and prolonged hypoxia in fetal sheep.

BACKGROUND: Anecdotal reports suggest that the second trimester is the safest time to conduct a laparoscopic procedure on a pregnant patient, but this supposition has not been tested empirically. METHODS: Previously instrumented preterm sheep (total n = 8) at gestational day 90 (term, 145 days) were anesthetized and then insufflated with carbon dioxide for 60 min at a pressure of 15 mmHg. Cardiovascular parameters were continuously recorded while blood gas status was determined before and at 15-min intervals during and up to 2 h after insufflation. RESULTS: Insufflation produced minimal maternal blood gas or cardiovascular changes except for a significant reduction in uterine blood flow. The decrease in perfusion increased fetal arterial blood partial pressure of carbon dioxide and decreased fetal pH, oxygen saturation, and oxygen content; there was also progressive fetal hypotension and bradycardia. After manually deflating the ewe, uterine blood flow returned to normal, and the fetal partial pressure of carbon dioxide and pH changes resolved within 1 h. However, fetal oxygen saturation and content remained depressed, and fetal cardiovascular status continued to decline during the 2-h postinsufflation monitoring period. CONCLUSION: Previous studies with near-term sheep determined that carbon dioxide pneumoperitoneum produces respiratory acidosis but does not decrease fetal oxygenation. In contrast, the current findings indicate that in the preterm fetus, insufflation-induced hypercapnia and acidosis are accompanied by prolonged fetal hypoxia and cardiovascular depression. This result suggests that additional work should be conducted to confirm the presumed safety of conducting minimally invasive procedures during the second trimester.