Research Spotlight

Kevelam, S. H., M. E. Steenweg, S. Srivastava, G. Helman, S. Naidu, R. Schiffmann, S. Blaser, A. Vanderver, N. I. Wolf and M. S. van der Knaap (2016). “Update on leukodystrophies: A historical perspective and adapted definition.” Neuropediatrics 47(6): 349-354.

Full text of this article.

Leukodystrophies were defined in the 1980s as progressive genetic disorders primarily affecting myelin of the central nervous system. At that time, a limited number of such disorders and no associated gene defects were known. The majority of the leukodystrophy patients remained without a specific diagnosis. In the following two decades, magnetic resonance imaging pattern recognition revolutionized the field, allowing the definition of numerous novel leukodystrophies. Their genetic defects were usually identified through genetic linkage studies. This process required substantial numbers of cases and many rare disorders remained unclarified. As recently as 2010, 50% of the leukodystrophy patients remained unclassified. Since 2011, whole-exome sequencing has resulted in an exponential increase in numbers of known, distinct, genetically determined, ultrarare leukodystrophies. We performed a retrospective study concerning three historical cohorts of unclassified leukodystrophy patients and found that currently at least 80% of the patients can be molecularly classified. Based on the original definition of the leukodystrophies, numerous defects in proteins important in myelin structure, maintenance, and function were expected. By contrast, a high percentage of the newly identified gene defects affect the housekeeping process of mRNA translation, shedding new light on white matter pathobiology and requiring adaptation of the leukodystrophy definition.

Ogola, G. O., A. Haider and S. Shafi (2016). “Hospitals with higher volumes of emergency general surgery patients achieve lower mortality rates: A case for establishing designated centers for emergency general surgery.” J Trauma Acute Care Surg: 2016 Dec [Epub ahead of print].

Full text of this article.

BACKGROUND: Higher volume has been associated with lower mortality for several surgical diseases. It is not known if this relationship exists in the management of Emergency General Surgery (EGS). Our hypothesis was that EGS patients treated at hospitals with higher EGS volume experienced lower mortality rates than those treated at low-volume hospitals. METHODS: This was a retrospective analysis of 2010 National Inpatient Sample data, maintained by the Agency for Healthcare Quality and Research as a representative national sample of inpatients. Patients with EGS diseases were identified using American Association for the Surgery of Trauma definitions using ICD-9 codes (2,640,725 patients from 943 hospitals). Multivariable hierarchical logistic regression model was used to estimate risk-standardized mortality rates (RSMR) for each hospital, adjusted for patient (age, sex, race, ethnicity, insurance type, socioeconomic status, comorbidities) and hospital characteristics (region, location, bed size, teaching status, and ownership). A cubic spline regression model with 4-knots was used to identify the volume associated with low mortality rates. RESULTS: The volume of EGS patients treated was inversely associated with hospital mortality rate. RSMR in hospitals in the highest quintile of volume (median, 7424 patients) was 1.62% (95% CI: 1.61-1.64%); at hospitals in the lowest quintile of volume (median, 68 patients), it was 6.1% (95% CI: 6.0-6.2%) (p <0.0001). Mortality rate stabilized at an annual volume of 688 (95% CI: 554-753) patients. The mortality rate in hospitals that treated fewer than 688 patients was 5.0% (95% CI: 4.8-5.1%), compared to 1.99% (95% CI: 1.96-2.01%) at those that treated 688 or more patients (p<0.0001). CONCLUSION: EGS patients treated at hospitals with a higher volume of EGS patients experienced lower mortality rates, with a possible threshold of 688 patients per year. A regionalized system of EGS care where complex patients are treated at large volume centers may improve patient outcomes.

Puhalla, S., S. Wilks, A. M. Brufsky, J. O’Shaughnessy, L. S. Schwartzberg, E. Berrak, J. Song and L. Vahdat (2016). “Clinical effects of prior trastuzumab on combination eribulin mesylate plus trastuzumab as first-line treatment for human epidermal growth factor receptor 2 positive locally recurrent or metastatic breast cancer: Results from a phase ii, single-arm, multicenter study.” Breast Cancer (Dove Med Press) 8: 231-239.

Full text of this article.

Eribulin mesylate, a novel nontaxane microtubule dynamics inhibitor in the halichondrin class of antineoplastic drugs, is indicated for the treatment of patients with metastatic breast cancer who previously received >/=2 chemotherapy regimens in the metastatic setting. Primary data from a Phase II trial for the first-line combination of eribulin plus trastuzumab in human epidermal growth factor receptor 2 positive patients showed a 71% objective response rate and tolerability consistent with the known profile of these agents. Here, we present prespecified analyses of efficacy of this combination based on prior trastuzumab use. Patients received eribulin mesylate 1.4 mg/m2 (equivalent to 1.23 mg/m2 eribulin [expressed as free base]) intravenously on days 1 and 8 plus trastuzumab (8 mg/kg intravenously/cycle 1, then 6 mg/kg) on day 1 of each 21-day cycle. Objective response rates, progression-free survival, and tolerability were assessed in patients who had and had not received prior adjuvant or neoadjuvant (neo/adjuvant) trastuzumab treatment. Fifty-two patients (median age: 59.5 years) received eribulin/trastuzumab for a median treatment duration of ~31 weeks; 40.4% (n=21) had been previously treated with neo/adjuvant trastuzumab prior to treatment with eribulin plus trastuzumab for metastatic disease (median time between neo/adjuvant and study treatment: 23 months). In trastuzumab-naive patients (n=31) compared with those who had received prior trastuzumab, objective response rate was 77.4% versus 61.9%, respectively; duration of response was 11.8 versus 9.5 months, respectively; clinical benefit rate was 87.1% versus 81.0%, respectively; and median progression-free survival was 12.2 versus 11.5 months, respectively. The most common grade 3/4 treatment-emergent adverse events (occuring in >/=5% of patients) in patients who received prior trastuzumab versus trastuzumab naive patients, respectively, were neutropenia (47.6% vs 32.3%), peripheral neuropathy (14.3% vs 25.8%), febrile neutropenia (14.3% vs 3.2%), fatigue (9.5% vs 6.5%), nausea (9.5% vs 0%), vomiting (9.5% vs 3.2%), and leukopenia (9.5% vs 3.2%). In patients with human epidermal growth factor receptor 2 positive metastatic breast cancer, first-line eribulin/trastuzumab treatment demonstrated substantial antitumor activity and was well tolerated, regardless of prior neo/adjuvant trastuzumab treatment.

Park, B. J., J. M. Snider, N. R. Bates, S. D. Cassivi, G. K. Jett, J. R. Sonett and E. M. Toloza (2016). “Prospective evaluation of biodegradable polymeric sealant for intraoperative air leaks.” J Cardiothorac Surg 11(1): 168.

Full text of this article.

BACKGROUND: A biodegradable polymeric sealant has been previously shown to reduce postoperative air leaks after open pulmonary resection. The aim of this study was to evaluate safety and efficacy during minimally invasive pulmonary resection. METHODS: In a multicenter prospective single-arm trial, 112 patients with a median age of 69 years (range 34-87 years) were treated with sealant for at least one intraoperative air leak after standard methods of repair (sutures, staples or cautery) following minimally invasive pulmonary resection (Video-Assisted Thoracic Surgery (VATS) or Robotic-Assisted). Patients were followed in hospital and 1 month after surgery for procedure-related and device-related complications and presence of air leak. RESULTS: Forty patients had VATS and 72 patients had Robotic-Assisted procedures with the majority (80/112, 71%) undergoing anatomic resection (61 lobectomy, 13 segmentectomy, 6 bilobectomy). There were no device-related adverse events. The overall morbidity rate was 41% (46/112), with major complications occurring in 16.1% (18/112). In-hospital mortality and 30-day mortality were 1.9% (2/103). The majority of intraoperative air leaks (107/133, 81%) were sealed after sealant application, and an additional 16% (21/133) were considered reduced. Forty-nine percent of patients (55/112) were free of air leak throughout the entire postoperative study period. Median chest tube duration was 2 days (range 1 – 46 days), and median length of hospitalization was 3 days (range 1 – 20 days). CONCLUSIONS: This study demonstrated that use of a biodegradable polymer for closure of intraoperative air leaks as an adjunct to standard methods is safe and effective following minimally invasive pulmonary resection.

Scherrer, J. F., J. Salas, F. D. Schneider, K. K. Bucholz, M. D. Sullivan, L. A. Copeland, B. K. Ahmedani, T. Burroughs and P. J. Lustman (2016). “Characteristics of new depression diagnoses in patients with and without prior chronic opioid use.” J Affect Disord 210: 125-129.

Full text of this article.

Chronic use (>90 Days) of opioid analgesics significantly increases the risk of development of new depression episodes (NDE). It is unclear whether depression that develops in this manner is similar to or different from NDE in persons not exposed to opioid analgesic use (OAU). METHODS: VA patients were classified into two groups, those who did not receive an opioid and developed depression (non-OAU+NDE, n=4314) and those that had >90 days OAU and developed NDE (OAU+NDE, n=444). OAU+NDE patients were compared to non-OAU+NDE in terms of depression severity (PHQ-9 scores), incidence of PTSD, other anxiety disorders and substance use disorders after NDE, receipt of acute phase antidepressant treatment, dual antidepressant treatment, mood stabilizers and atypical antipsychotics. Prior to computing bivariate analysis, the prevalence of pain conditions and average maximum pain scores were equalized between the two groups using propensity scores and inverse probability of treatment weighting. RESULTS: Controlling for pain, OAU+NDE patients had more depression symptoms (p=.012), more incident PTSD (p=.04) and opioid abuse/dependence and were more likely to receive 12 weeks of antidepressant treatment (p<.0001). Last, non-OAU+NDE were more likely to have incident diagnoses for any other anxiety disorder (p=.014). CONCLUSIONS: Within the limitations of electronic medical record data, results indicate OAU+NDE patients have more depression symptoms, greater treatment adherence and different comorbid psychiatric conditions compared to non-OAU+NDE, independent of pain. Overall OAU related depression is as severe as non-OAU related depression and repeated depression screening in chronic opioid therapy may be warranted for pain patients, regardless of pain severity.