Effect of the experience of surgical chairpersons on departmental National Institutes of Health funding.

BACKGROUND: Experience and application of recruitment packages can be critical in leadership efforts of surgical chairpersons in promoting research, although attrition of these efforts can happen over time due to lack of new resources. We aimed to examine the impact of experience of surgical chairpersons on departmental National Institutes of Health (NIH) funding. METHODS: Experience as a chairperson defined as the number of years spent as an interim or permanent chair was abstracted from the department Web site (US medical schools only). The NIH funding (US dollars) of the departments were obtained from the Blue Ridge Medical Institute (www.brimr.org). The change in NIH funding from the immediate previous financial year (2010-2009 and 2011-2010) was used to classify chairpersons into four groups: group 1 (-/-), group 2 (-/+), group 3 (+/+), and group 4 (+/-) for analysis. RESULTS: Median NIH funding were $1.9 (0.7-6) million, $1.8 (0.6-5) million, and $1.7 (0.7-5) million for 2009, 2010, and 2011, respectively, and the median experience as a surgical chairperson was 6 y (3-10). Recent chairpersons (<1 y) inherited departments that usually lost NIH funding (62%) and were frequently unable to develop a positive trend for growth over the next fiscal year ([-/-] n = 4 and [+/-] n = 2, 75%). Chairpersons who held their positions for 4-6 y were most likely to be associated with trends of positive funding growth, whereas chairpersons >10 y were most likely to have lost funding (66%, P = 0.07). CONCLUSIONS: Provision of new development dollars later in their tenure and retention of chairpersons might lead to more positive trends in increase in NIH funding.

Systematic review of outcomes of patients undergoing resection for colorectal liver metastases in the setting of extra hepatic disease.

BACKGROUND: Surgical resection for patients with colorectal liver metastases (CRLM) can offer patients a significant survival benefit. We hypothesised that patients with CRLM and extra hepatic disease (EHD) undergoing metastasectomy had comparable survival and describe outcomes based on the distribution of metastatic disease. METHODS: A systematic search using a predefined registered protocol was undertaken between January 2003 and June 2012. Primary exposure was hepatic resection for CRLM and primary outcome measure was overall survival. Meta-regression techniques were used to analyse differences between patients with and without extra hepatic disease. FINDINGS: From a pool of 4996 articles, 50 were retained for data extraction (3481 CRLM patients with EHD). The median survival (MS) was 30.5 (range, 9-98) months which was achieved with an operative mortality rate of 0-4.2%. The 3-year and 5-year overall survival (OS) were 42.4% (range, 20.6-77%) and 28% (range, 0-61%) respectively. Patients with EHD of the lungs had a MS of 45 (range, 39-98) months versus lymph nodes (portal and para-aortic) 26 (range, 21-48) months versus peritoneum 29 (range, 18-32) months. The MS also varied by the amount of liver disease - 42.2months (

Consequences of irradiation on bone and marrow phenotypes, and its relation to disruption of hematopoietic precursors.

The rising levels of radiation exposure, specifically for medical treatments and accidental exposures, have added great concern for the long term risks of bone fractures. Both the bone marrow and bone architecture are devastated following radiation exposure. Even sub-lethal doses cause a deficit to the bone marrow microenvironment, including a decline in hematopoietic cells, and this deficit occurs in a dose dependent fashion. Certain cell phenotypes though are more susceptible to radiation damage, with mesenchymal stem cells being more resilient than the hematopoietic stem cells. The decline in total bone marrow hematopoietic cells is accompanied with elevated adipocytes into the marrow cavity, thereby inhibiting hematopoiesis and recovery of the bone marrow microenvironment. Poor bone marrow is also associated with a decline in bone architectural quality. Therefore, the ability to maintain the bone marrow microenvironment would hinder much of the trabecular bone loss caused by radiation exposure, ultimately decreasing some comorbidities in patients exposed to radiation.

High fat diet rapidly suppresses B lymphopoiesis by disrupting the supportive capacity of the bone marrow niche.

The bone marrow (BM) niche is the primary site of hematopoiesis, and cues from this microenvironment are critical to maintain hematopoiesis. Obesity increases lifetime susceptibility to a host of chronic diseases, and has been linked to defective leukogenesis. The pressures obesity exerts on hematopoietic tissues led us to study the effects of a high fat diet (HFD: 60% Kcal from fat) on B cell development in BM. Seven week old male C57Bl/6J mice were fed either a high fat (HFD) or regular chow (RD) diet for periods of 2 days, 1 week and 6 weeks. B-cell populations (B220+) were not altered after 2 d of HFD, within 1 w B-cell proportions were reduced by -10%, and by 6 w by -25% as compared to RD (p<0.05). BM RNA was extracted to track the expression of B-cell development markers Il-7, Ebf-1 and Pax-5. At 2 d, the expression of Il-7 and Ebf-1 were reduced by -20% (p = 0.08) and -11% (p = 0.06) whereas Pax-5 was not significantly impacted. At one week, however, the expressions of Il-7, Ebf-1, and Pax-5 in HFD mice fell by -19%, -20% and -16%, and by six weeks were further reduced to -23%, -29% and -34% as compared to RD (p<0.05 for all), a suppression paralleled by a +363% increase in adipose encroachment within the marrow space (p<0.01). Il-7 is a critical factor in the early B-cell lineage which is secreted by supportive cells in the BM niche, and is necessary for B-cell commitment. These data indicate that BM Il-7 expression, and by extension B-cell differentiation, are rapidly impaired by HFD. The trend towards suppressed expression of Il-7 following only 2 d of HFD demonstrates how susceptible the BM niche, and the cells which rely on it, are to diet, which ultimately could contribute to disease susceptibility in metabolic disorders such as obesity.

Immunohistochemistry - microarray analysis of patients with peritoneal metastases of appendiceal or colorectal origin.

BACKGROUND: The value of immunohistochemistry (IHC)-microarray analysis of pathological specimens in the management of patients is controversial, although preliminary data suggest potential benefit. We describe the characteristics of patients undergoing a commercially available IHC-microarray method in patients with peritoneal metastases (PM) and the feasibility of this technique in this population. METHODS: We retrospectively analyzed consecutive patients with pathologically confirmed PM from appendiceal or colorectal primary who underwent Caris Molecular Intelligence(™) testing. IHC, microarray, FISH, and mutational analysis were included and stratified by Peritoneal Carcinomatosis Index (PCI) score, histology, and treatment characteristics. Statistical analysis was performed using non-parametric tests. RESULTS: Our study included 5 patients with appendiceal and 11 with colorectal PM. The median age of patients was 51 (IQR 39-65) years, with 11 (68%) female. The median PCI score of the patients was 17 (IQR 10-25). Hyperthermic intra-peritoneal chemoperfusion was performed in 4 (80%) patients with appendiceal primary tumors and 4 (36%) with colorectal primary. KRAS mutations were encountered in 40% of appendiceal vs. 30% colorectal tumors, while BRAF mutations were seen in 40% of colorectal PM and none of the patients with appendiceal PM (p = 0.06). IHC biomarker expression was not significantly different between the two primaries. Sufficient tumor for microarray analysis was found in 44% (n = 7) patients, which was not associated with previous use of chemotherapy (p > 0.20 for 5-FU/LV, Irinotecan and Oxaliplatin). CONCLUSION: In a small sample of patients with PM, the feasibility and results of IHC-microarray staining based on a commercially available test is reported. The apparent high incidence of the BRAF mutation in patients with PM may potentially offer opportunities for novel therapeutics and suggest that IHC-microarray is a method that can be used in this population.

Attributes of a surgical chairperson associated with extramural funding of a department of surgery.

BACKGROUND: Chairpersons of surgery departments are key stakeholders and role models and leaders of research in academic medical institutions. However, the characteristics of surgical chairpersons are understudied. This study aimed to investigate the association between the personal academic achievement of a surgical chairperson and the National Institutes of Health (NIH) funding of the department. METHODS: We calculated the Hirsch index (H-index), a measure of research productivity, for chairpersons of surgery of the top 90 research medical schools that were ranked by U.S. News & World Report. Specialty training, y as chairperson, location, and NIH institutional and department funding were analyzed. Nonparametric tests and linear regression methods were used to compare the different groups. RESULTS: Of the 90 chairpersons, 20 positions for chairs (22%) are either recent (<1 y) or unfilled (n = 6). Only 3% of all chairpersons are women, and the median H-index for the chairpersons is 20 (Interquartile range 14-27) with a median 101 publications with 14 cites per publication. Median surgery-specific NIH funding in 2011 was $1.7 million (Interquartile range $721,042-5,085,305). The chairperson's H-index was exponentially associated with department funding in multivariate models adjusting for institution rank, except when the H-index was extreme (<4 or >49) (coefficient 0.32, P = 0.02). CONCLUSIONS: The research productivity of a chairperson is the only personal attribute of those studied that is associated with the departmental NIH funding. This suggests the important role an academically productive surgical leader may play as a champion for the academic success of the department.

Altered composition of bone as triggered by irradiation facilitates the rapid erosion of the matrix by both cellular and physicochemical processes.

Radiation rapidly undermines trabecular architecture, a destructive process which proceeds despite a devastated cell population. In addition to the 'biologically orchestrated' resorption of the matrix by osteoclasts, physicochemical processes enabled by a damaged matrix may contribute to the rapid erosion of bone quality. 8w male C57BL/6 mice exposed to 5 Gy of Cs(137) γ-irradiation were compared to age-matched control at 2d, 10d, or 8w following exposure. By 10d, irradiation had led to significant loss of trabecular bone volume fraction. Assessed by reflection-based Fourier transform infrared imaging (FTIRI), chemical composition of the irradiated matrix indicated that mineralization had diminished at 2d by -4.3±4.8%, and at 10d by -5.8±3.2%. These data suggest that irradiation facilitates the dissolution of the matrix through a change in the material itself, a conclusion supported by a 13.7±4.5% increase in the elastic modulus as measured by nanoindentation. The decline in viable cells within the marrow of irradiated mice at 2d implies that the immediate collapse of bone quality and inherent increased risk of fracture is not solely a result of an overly-active biologic process, but one fostered by alterations in the material matrix that predisposes the material to erosion.

Bone structure and B-cell populations, crippled by obesity, are partially rescued by brief daily exposure to low-magnitude mechanical signals.

Deterioration of the immune and skeletal systems, each of which parallel obesity, reflects a fragile interrelationship between adiposity and osteoimmunology. Using a murine model of diet-induced obesity, this study investigated the ability of mechanical signals to protect the skeletal-immune systems at the tissue, cellular, and molecular level. A long-term (7 mo) high-fat diet increased total adiposity (+62%), accelerated age-related loss of trabecular bone (-61%), and markedly reduced B-cell number in the marrow (-52%) and blood (-36%) compared to mice fed a regular diet. In the final 4 mo of the protocol, the application of low-magnitude mechanical signals (0.2 g at 90 Hz, 15 min/d, 5 d/wk) restored both bone structure and B cells to those levels measured in control mice fed a regular diet. These phenotypic outcomes were achieved, in part, by reductions in osteoclastic activity and a biasing of hematopoietic stem cell differentiation toward the lymphoid B-cell lineage and away from a myeloid fate. These results emphasize that obesity undermines both the skeletal and immune systems, yet brief exposure to mechanical signals, perhaps as a surrogate to the salutary influence of exercise, diminishes the consequences of diabetes and obesity, restoring bone structure and normalizing B-cell populations by biasing of the fate of stem cells through mechanosensitive pathways.

Low magnitude mechanical signals mitigate osteopenia without compromising longevity in an aged murine model of spontaneous granulosa cell ovarian cancer.

Cancer progression is often paralleled by a decline in bone mass, raising risk of fracture. Concerns persist regarding anabolic interventions for skeletal protection, as these may inadvertently exacerbate neoplastic tissue expansion. Given bone's inherent mechanosensitivity, low intensity vibration (LIV), a mechanical signal that encourages osteoblastogenesis, could possibly slow cancer-associated bone loss, but this goal must be achieved without fostering disease progression. Seventy 12w female F1-SWRxSWXJ-9 mice, a strain prone to developing granulosa cell tumors, were randomized into baseline control (BC: n=10), age-matched control (AC: n=30), and LIV (n=30), which received mechanical signals (90Hz @ 0.3g) for 15m/day, 5 day/w over the course of 1 year. Survival curves for AC (10 died) and LIV (8 died) followed similar trends (p=0.62), indicating longevity was unperturbed by LIV. At 1 year, bone volume of proximal tibiae in LIV mice was 25% greater than AC (p<0.02), while bone volume of L5 vertebrae was 16% higher in LIV over AC (p<0.02). Primary lesions and peripheral metastases were apparent in both LIV and AC; however, overall tumor incidence was approximately 30% less in LIV (p=0.27) and, when disease was evident, involved fewer organ systems (p=0.09). Marrow-derived mesenchymal stem cells (MSC) were 52% lower (p<0.01) in LIV, and 31% lower (p=0.08) in mice lacking pathology, suggesting higher MSC levels in this model of cancer susceptibility may have contributed to tumor progression. These experiments indicate that LIV helps protect bone mass in mice inherently susceptible to cancer without compromising life expectancy, perhaps through mechanical control of stem cell fate. Further, these data reflect the numerous system-level benefits of exercise in general, and mechanical signals in particular, in the preservation of bone density and the suppression of cancer progression.

Devastation of adult stem cell pools by irradiation precedes collapse of trabecular bone quality and quantity.

Stem cell depletion and compromised bone marrow resulting from radiation exposure fosters long-term deterioration of numerous physiologic systems, with the degradation of the skeletal system ultimately increasing the risk of fractures. To study the interrelationship of damaged bone marrow cell populations with trabecular microarchitecture, 8- and 16-week-old C57BL/6 male mice were sublethally irradiated with 5 Gy of (137)Cs γ-rays, and adult stem cells residing in the bone marrow, as well as bone quantity and quality, were evaluated in the proximal tibia after 2 days, 10 days, and 8 weeks compared with age-matched controls. Total extracted bone marrow cells in the irradiated 8-week, young adult mice, including the hematopoietic cell niches, collapsed by 65% ± 11% after 2 days, remaining at those levels through 10 days, only recovering to age-matched control levels by 8 weeks. As early as 10 days, double-labeled surface was undetectable in the irradiated group, paralleled by a 41% ± 12% and 33% ± 4% decline in bone volume fraction (BV/TV) and trabecular number (Tb.N), respectively, and a 50% ± 10% increase in trabecular separation (Tb.Sp) compared with the age-matched controls, a compromised structure that persisted to 8 weeks postirradiation. Although the overall collapse of the bone marrow population and devastation of bone quality was similar between the "young adult" and "mature" mice, the impact of irradiation--and the speed of recovery--on specific hematopoietic subpopulations was dependent on age, with the older animals slower to restore key progenitor populations. These data indicate that, independent of animal age, complications arising from irradiation extend beyond the collapse of the stem cell population and extend toward damage to key organ systems. It is reasonable to presume that accelerating the recovery of these stem cell pools will enable the prompt repair of the skeletal system and ultimately reduce the susceptibility to fractures.

The effect of nanoparticle-enhanced photoacoustic stimulation on multipotent marrow stromal cells.

In this article, we report a novel nanoparticle-enhanced biophysical technique that differentiates multipotent marrow stromal cells (MSCs) toward osteoblasts. We show that a brief (10 min) daily nanoparticle-facilitated exposure of MSCs to nanosecond pulse laser-induced photoacoustic (PA) stimulation enhances their differentiation toward osteoblasts. To observe osteodifferentiation under PA stimulation, tissue culture plates were seeded with MSCs without the osteogenic culture supplements (OS, 0.01 M beta-glycerophosphate, 50 mg/L ascorbic acid, 10(-8) M dexamethasone) in the presence and absence of single-walled carbon nanotubes (SWNTs) and gold nanoparticles (GNPs). The alkaline phosphatase activity, calcium content, and osteopontin secretion were monitored as indicators of MSCs' differentiation toward osteoblasts. The PA stimulated groups show up to 612% increase in calcium content compared to the controls cultured with osteogenic supplements (without PA stimulation) after 16 days. Among the PA stimulated groups, at day 16, MSCs incubated with SWNTs at 10 microg/mL concentrations showed up to 97% greater calcium content than those that did not contain SWNTs. The results demonstrated that PA stimulation not only promotes osteogenesis but also is synergistically enhanced by the presence of nanoparticles and, thus, has major implications for bone regeneration applications.