Joseph M. Galante

Saline versus Plasma-Lyte A in initial resuscitation of trauma patients: a randomized trial.

Objective:We sought to compare resuscitation with 0.9% NaCl versus Plasma-Lyte A, a calcium-free balanced crystalloid solution, hypothesizing that Plasma-Lyte A would better correct the base deficit 24 hours after injury. Background:Sodium chloride (0.9%) (0.9% NaCl), though often used for resuscitation of trauma patients, may exacerbate the metabolic acidosis that occurs with injury, and this acidosis may have detrimental clinical effects. Methods:We conducted a randomized, double-blind, parallel-group trial (NCT01270854) of adult trauma patients requiring blood transfusion, intubation, or operation within 60 minutes of arrival at the University of California Davis Medical Center. Based on a computer-generated, blocked sequence, subjects received either 0.9% NaCl or Plasma-Lyte A for resuscitation during the first 24 hours after injury. The primary outcome was mean change in base excess from 0 to 24 hours. Secondary outcomes included 24-hour arterial pH, serum electrolytes, fluid balance, resource utilization, and in-hospital mortality. Results:Of 46 evaluable subjects (among 65 randomized), 43% had penetrating injuries, injury severity score was 23 ± 16, 20% had admission systolic blood pressure less than 90 mm Hg, and 78% required an operation within 60 minutes of arrival. The baseline pH was 7.27 ± 0.11 and base excess −5.9 ± 5.0 mmol/L. The mean improvement in base excess from 0 to 24 hours was significantly greater with Plasma-Lyte A than with 0.9% NaCl {7.5 ± 4.7 vs 4.4 ± 3.9 mmol/L; difference: 3.1 [95% confidence interval (CI): 0.5–5.6]}. At 24 hours, arterial pH was greater [7.41 ± 0.06 vs 7.37 ± 0.07; difference: 0.05 (95% CI: 0.01–0.09)] and serum chloride was lower [104 ± 4 vs 111 ± 8 mEq/L; difference: −7 (95% CI: −10 to −3)] with Plasma-Lyte A than with 0.9% NaCl. Volumes of study fluid administered, 24-hour urine output, measures of resource utilization, and mortality did not significantly differ between the 2 arms. Conclusions:Compared with 0.9% NaCl, resuscitation of trauma patients with Plasma-Lyte A resulted in improved acid-base status and less hyperchloremia at 24 hours postinjury. Further studies are warranted to evaluate whether resuscitation with Plasma-Lyte A improves clinical outcomes. Randomized controlled trial, level I. (ClinicalTrials.gov Record UCDIRB-200917793.)

Pancreatic cancer cell lines deficient in argininosuccinate synthetase are sensitive to arginine deprivation by arginine deiminase

Eukaryotic cells can synthesize the non‐essential amino acid arginine from aspartate and citrulline using the enzyme argininosuccinate synthetase (ASS). It has been observed that ASS is underexpressed in various types of cancers ASS, for which arginine become auxotrophic. Arginine deiminase (ADI) is a prokaryotic enzyme that metabolizes arginine to citrulline and has been found to inhibit melanoma and hepatoma cancer cells deficient of ASS. We tested the hypothesis that pancreatic cancers have low ASS expression and therefore arginine deprivation by ADI will inhibit cell growth. ASS expression was examined in 47 malignant and 20 non‐neoplastic pancreatic tissues as well as a panel of human pancreatic cancer cell lines. Arginine deprivation was achieved by treatment with a recombinant form of ADI formulated with polyethylene glycol (PEG‐ADI). Effects on caspase activation, cell growth and cell death were examined. Furthermore, the effect of PEG‐ADI on the in vivo growth of pancreatic xenografts was examined. Eighty‐seven percent of the tumors lacked ASS expression; 5 of 7 cell lines similarly lacked ASS expression. PEG‐ADI specifically inhibited growth of those cell lines lacking ASS. PEG‐ADI treatment induced caspase activation and induction of apoptosis. PEG‐ADI was well tolerated in mice despite complete elimination of plasma arginine; tumor growth was inhibited by ∼50%. Reduced expression of ASS occurs in pancreatic cancer and predicts sensitivity to arginine deprivation achieved by PEG‐ADI treatment. Therefore, these findings suggest that arginine deprivation by ADI could provide a beneficial strategy for the treatment of pancreatic cancer, a malignancy in which new therapy is desperately needed.

Dermatofibrosarcoma protuberans: reappraisal of wide local excision and impact of inadequate initial treatment.

Background: The extent of local invasion in dermatofibrosarcoma protuberans (DFSP) is often clinically difficult to appreciate, and this leads to inadequate resections. We examined the effect of inadequate initial treatment and the efficacy of wide resection.Methods: We performed a retrospective analysis of the records of 35 patients with DFSP treated at our institution (1985 and 2001). Data were analyzed with Wilcoxon’s ranked sum test and Fisher’s exact test.Results: Of the 24 patients eligible for analysis, 11 had definitive wide resection after diagnostic excisions elsewhere (primary group), and 13 had recurrent tumors after previous surgical treatment elsewhere (recurrent group). Twenty-three patients were treated with wide resection only, and adjuvant radiation was administered to one patient who had a fibrosarcoma. At a median follow-up of 54 months, patients definitively treated at our institution had a 100% local recurrence–free survival. In comparison to the primary group, recurrent DFSPs were significantly larger and deeper and occurred in the head and neck region. Five cases had bone involvement, and of these, 80% occurred in the recurrent group.Conclusions: Inadequate initial treatment results in larger, deeper recurrent lesions, but these can be managed by appropriate wide excision. Wide resection of DFSP (whether recurrent or primary) with negative histological margins predicts a superior local recurrence–free survival.

Factors Associated With General Surgery Residents’ Desire to Leave Residency Programs: A Multi-institutional Study

IMPORTANCE General surgical residency continues to experience attrition. To date, work hour amendments have not changed the annual rate of attrition. OBJECTIVE To determine how often categorical general surgery residents seriously consider leaving residency. DESIGN, SETTING, AND PARTICIPANTS At 13 residency programs, an anonymous survey of 371 categorical general surgery residents and 10-year attrition rates for each program. Responses from those who seriously considered leaving surgical residency were compared with those who did not. MAIN OUTCOMES AND MEASURES Factors associated with the desire to leave residency. RESULTS The survey response rate was 77.6%. Overall, 58.0% seriously considered leaving training. The most frequent reasons for wanting to leave were sleep deprivation on a specific rotation (50.0%), an undesirable future lifestyle (47.0%), and excessive work hours on a specific rotation (41.4%). Factors most often cited that kept residents from leaving were support from family or significant others (65.0%), support from other residents (63.5%), and perception of being better rested (58.9%). On univariate analysis, older age, female sex, postgraduate year, training in a university program, the presence of a faculty mentor, and lack of Alpha Omega Alpha status were associated with serious thoughts of leaving surgical residency. On multivariate analysis, only female sex was significantly associated with serious thoughts of leaving residency (odds ratio, 1.2; 95% CI, 1.1-1.3; P = .003). Eighty-six respondents were from historically high-attrition programs, and 202 respondents were from historically low-attrition programs (27.8% vs 8.4% 10-year attrition rate, P = .04). Residents from high-attrition programs were more likely to seriously consider leaving residency (odds ratio, 1.8; 95% CI, 1.0-3.0; P = .03). CONCLUSIONS AND RELEVANCE A majority of categorical general surgery residents seriously consider leaving residency. Female residents are more likely to consider leaving. Thoughts of leaving seem to be associated with work conditions on specific rotations rather than with overall work hours and are more prevalent among programs with historically high attrition rates.

ERK/BCL-2 pathway in the resistance of pancreatic cancer to anoikis.

BACKGROUND Anoikis is a special type of programmed cell death after loss of cell-cell and cell-extracellular matrix interactions. Resistance to anoikis is likely involved in the process of metastasis, specifically during the tumor cell migration through lymph or vascular channels. We have previously shown that BCL-2 confers resistance to other forms of programmed cell death (i.e., apoptosis); furthermore, the extracellular signaling-regulated kinase (ERK) signaling pathway regulates BCL-2 expression. We therefore tested the hypothesis that pancreatic cancer cell lines are resistant to anoikis and this resistance is due to activation of ERK1/2 and subsequent overexpression of BCL-2. MATERIALS AND METHODS Pancreatic cancer cell lines (MIA-PaCa-2 and BxPC-3) were examined for cell death following loss of adherence to extracellular matrix. Subclones of the MIA-PaCa-2 cell line (either selected in vivo for increased metastatic potential [MIA-LM2] or overexpressing BCL-2 [MIA-BCL2]) were also examined for induction of anoikis following loss of extracellular matrix adherence. Finally, the effect of the ERK inhibitor (PD98059) on BCL-2 expression and induction of anoikis was examined. RESULTS Under conditions of loss of cell-extracellular matrix interaction, pancreatic cancer cells undergo varying amounts of anoikis. Basal levels of activated ERK and BCL-2 paralleled the sensitivity to induction of anoikis. The highly metastatic cell line, MIA-LM2, was more resistant to anoikis than the parental cell line. Inhibition of ERK down-regulated BCL-2 and was associated with restoration of sensitivity to anoikis. CONCLUSIONS Activation of a signaling pathway from ERK to overexpression of BCL-2 may confer resistance to anoikis, a critical step in the development of metastasis. Targeting the ERK/BCL-2 pathway may lead to sensitization of pancreatic cancer to anoikis, thereby decreasing the ability of these cells to metastasize.

Safety of Early Mobilization of Patients With Blunt Solid Organ Injuries

BACKGROUND Many surgeons believe that early mobilization of patients with blunt solid organ injuries increases the risk of delayed hemorrhage. OBJECTIVE To determine whether there is an association between the day of mobilization and rates of delayed hemorrhage from blunt solid organ injuries. DESIGN Retrospective cohort study. Univariate and multivariate analyses were performed to determine the association of mobilization with delayed hemorrhage of a solid organ requiring laparotomy. SETTING Level I trauma center. PATIENTS Adults with blunt renal, hepatic, or splenic injuries were identified from a trauma registry. MAIN OUTCOME MEASURES Medical records were used to determine the day of mobilization and to identify patients with delayed hemorrhage requiring laparotomy. RESULTS Four hundred fifty-four patients with blunt solid organ injuries were admitted to the hospital for nonoperative management. Failure rates of nonoperative management were 4.0%, 1.0%, and 7.1% for renal, hepatic, and splenic injuries, respectively. No patients with renal or hepatic injuries failed secondary to delayed hemorrhage. Ten patients (5.5%) with splenic injuries failed secondary to delayed hemorrhage. Eighty-four percent of patients with renal injuries, 80% with hepatic injuries, and 77% with splenic injuries were mobilized within 72 hours of admission. Day of mobilization was not associated with delayed splenic rupture in multivariate analysis (odds ratio, 0.97; 95% confidence interval, 0.90-1.05). CONCLUSIONS The timing of mobilization of patients with blunt solid organ injuries does not seem to contribute to delayed hemorrhage requiring laparotomy. Protocols incorporating periods of strict bed rest are unnecessary.

Extending the golden hour: Partial resuscitative endovascular balloon occlusion of the aorta in a highly lethal swine liver injury model.

BACKGROUND Combat-injured patients may require rapid and sustained support during transport; however, the prolonged aortic occlusion produced by conventional resuscitative endovascular balloon occlusion of the aorta (REBOA) may lead to substantial morbidity. Partial REBOA (P-REBOA) may permit longer periods of occlusion by allowing some degree of distal perfusion. However, the ability of this procedure to limit exsanguination is unclear. We evaluated the impact of P-REBOA on immediate survival and ongoing hemorrhage in a highly lethal swine liver injury model. METHODS Fifteen Yorkshire-cross swine were anesthetized, instrumented, splenectomized, and subjected to rapid 10% total blood loss followed by 30% liver amputation. Coagulopathy was created through colloid hemodilution. Randomized swine received no intervention (control), P-REBOA, or complete REBOA (C-REBOA). Central mean arterial pressure (cMAP), carotid blood flow, and blood loss were recorded. Balloons remained inflated in the P-REBOA and C-REBOA groups for 90 minutes followed by graded deflation. The study ended at 180 minutes from onset of hemorrhage or death of the animal. Survival analysis was performed, and data were analyzed using repeated-measures analysis of variance with post hoc pairwise comparisons. RESULTS Mean survival times in the control, P-REBOA, and C-REBOA groups were, 25 ± 21, 86 ± 40, and 163 ± 20 minutes, respectively (p < 0.001). Blood loss was greater in the P-REBOA group than the C-REBOA or control groups, but this difference was not significant (4,722 ± 224, 3,834 ± 319, 3,818 ± 37 mL, respectively, p = 0.10). P-REBOA resulted in maintenance of near-baseline carotid blood flow and cMAP, while C-REBOA generated extreme cMAP and prolonged supraphysiologic carotid blood flow. Both experimental groups experienced profound decreases in cMAP following balloon deflation. CONCLUSION In the setting of severe ongoing hemorrhage, P-REBOA increased survival time beyond the golden hour while maintaining cMAP and carotid flow at physiologic levels.

Effect of the 16-hour work limit on general surgery intern operative case volume: a multi-institutional study.

IMPORTANCE The 80-hour work-week limit for all residents was instituted in 2003 and studies looking at its effect have been mixed. Since the advent of the 16-hour mandate for postgraduate year 1 residents in July 2011, no data have been published regarding the effect of this additional work-hour restriction. OBJECTIVE To determine whether the 16-hour intern work limit, implemented in July 2011, has adversely affected operative experience. DESIGN, SETTING, AND PARTICIPANTS A retrospective review of categorical postgraduate year 1 Accreditation Council for Graduate Medical Education case logs from the intern class (N = 52) (with 16-hour work limit) compared with the 4 preceding years (2007-2010; N = 197) (without 16-hour work limit). A total of 249 categorical general surgery interns from 10 general surgery residency programs in the western United States were included. MAIN OUTCOMES AND MEASURES Total, major, first-assistant, and defined-category case totals. RESULTS As compared with the preceding 4 years, the 2011-2012 interns recorded a 25.8% decrease in total operative cases (65.9 vs 88.8, P = .005), a 31.8% decrease in major cases (54.9 vs 80.5, P < .001), and a 46.3% decrease in first-assistant cases (11.1 vs 20.7, P = .008). There were statistically significant decreases in cases within the defined categories of abdomen, endocrine, head and neck, basic laparoscopy, complex laparoscopy, pediatrics, thoracic, and soft tissue/breast surgery in the 16-hour shift intern era, whereas there was no decrease in trauma, vascular, alimentary, endoscopy, liver, and pancreas cases. CONCLUSIONS AND RELEVANCE The 16-hour work limit for interns, implemented in July 2011, is associated with a significant decrease in categorical intern operative experience. If the 16-hour shift were to be extended to all postgraduate year levels, one can anticipate that additional years of training will be needed to maintain the same operative volume.

Text Messaging Among Residents and Faculty in a University General Surgery Residency Program: Prevalence, Purpose, and Patient Care

BACKGROUND There is little information about the use of text messaging (texting) devices among resident and faculty physicians for patient-related care (PRC). OBJECTIVE To determine the prevalence, frequency, purpose, and concerns regarding texting among resident and attending surgeons and to identify factors associated with PRC texting. DESIGN E-mail survey. SETTING University medical center and its affiliated hospitals. PARTICIPANTS Surgery resident and attending staff. OUTCOME MEASURES Prevalence, frequency, purpose, and concerns regarding patient-related care text messaging. RESULTS Overall, 73 (65%) surveyed physicians responded, including 45 resident (66%) and 28 attending surgeons (62%). All respondents owned a texting device. Majority of surgery residents (88%) and attendings (71%) texted residents, whereas only 59% of residents and 65% of attendings texted other faculty. Most resident to resident text occurred at a frequency of 3-5 times/d (43%) compared with most attending to resident texts, which occurred 1-2 times/d (33%). Most resident to attending (25%) and attending to attending (30%) texts occurred 1-2 times/d. Among those that texted, PRC was the most frequently reported purpose for resident to resident (46%), resident to attending (64%), attending to resident (82%), and attending to other attending staff (60%) texting. Texting was the most preferred method to communicate about routine PRC (47% of residents vs 44% of attendings). Age (OR: 0.86, 95% CI: 0.79-0.95; p = 0.003), but not sex, specialty/clinical rotation, academic rank, or postgraduate year (PGY) level predicted PRC texting. CONCLUSIONS Most resident and attending staff surveyed utilize texting, mostly for PRC. Texting was preferred for communicating routine PRC information. Our data may facilitate the development of guidelines for the appropriate use of PRC texting.

Characteristics of Highly Ranked Applicants to General Surgery Residency Programs

IMPORTANCE With duty hour debates, specialization, and sex distribution changes in the applicant pool, the relative competitiveness for general surgery residency (GSR) is undefined. OBJECTIVE To determine the modern attributes of top-ranked applicants to GSR. DESIGN Validation cohort, survey. SETTING National sample of university and community-based GSR programs. PARTICIPANTS Data were abstracted from Electronic Residency Application Service files of the top 20-ranked applicants to 22 GSR programs. We ranked program competitiveness and blinded review of personal statements. MAIN OUTCOMES AND MEASURES Characteristics associated with applicant ranking by the GSR program (top 5 vs 6-20) and ranking by highly competitive programs were identified using t and χ2 tests and modified Poisson regression. RESULTS There were 333 unique applicants among the 440 Electronic Residency Application Service files. Most applicants had research experience (93.0%) and publications (76.8%), and 28.4% had Alpha Omega Alpha membership. Nearly half were women (45.2%), with wide variation by program (20.0%-75.0%) and a trend toward fewer women at programs in the South and West (38.0% and 37.5%, respectively). Men had higher United States Medical Licensing Examination Step 1 scores (238.0 vs 230.1; P < .001) but similar Step 2 scores (245.3 vs 244.5; P = .54). Using bivariate analysis, highly competitive programs were more likely to rank applicants with publications, research experience, Alpha Omega Alpha membership, higher Step 1 scores, and excellent personal statements and those who were male or Asian. However, the only significant predictors were Step 1 scores (relative risk [RR], 1.36 for every 10-U increase), publications (RR, 2.20), personal statements (RR, 1.62), and Asian race (RR, 1.70 vs white). Alpha Omega Alpha membership (RR, 1.62) and Step 1 scores (RR, 1.01) were the only variables predictive of ranking in the top 5. CONCLUSIONS AND RELEVANCE This national sample shows GSR is a highly competitive, sex-neutral discipline in which academic performance is the most important factor for ranking, especially in the most competitive programs. This study will inform applicants and program directors about applicants to the GSR program.