Neuropeptide Y is analgesic in rats after plantar incision

Previous work has demonstrated that neuropeptide tyrosine (NPY), Y₁ receptor and Y₂ receptor are critical in modulation of pain after nerve injury. We hypothesized that NPY was important for nociception after surgical incision. As a model of postoperative pain, rats underwent a plantar incision in one hindpaw. Western blots were used to quantify changes in protein expression of NPY, Y₁ receptor and Y₂ receptor after incision in skin, muscle, and dorsal root ganglion (DRG). Pain-related behaviors were tested after incision in rats treated with intrathecal NPY, Y₁ receptor antagonist (BIBO3304 – Chemical Name: N-[(1R)-1-[[[[4-[[(Aminocarbonyl)amino]methyl]phenyl]methyl]amino]carbonyl]-4-[(aminoiminomethyl)amino]butyl]-α-phenyl-benzeneacetamide ditrifluoroacetate), Y₂ receptor antagonist (BIIE0246 – Chemical Name: N-[(1S)-4-[(Aminoiminomethyl)amino]-1-[[[2-(3,5-dioxo-1,2-diphenyl-1,2,4-triazolidin-4-yl)ethyl]amino]carbonyl]butyl]-1-[2-[4-(6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-yl)-1-piperazinyl]-2-oxoethyl]-cyclopentaneacetamide), combined NPY+antagonists, morphine, or vehicle. Pain behaviors were tested after incision in rats treated with locally applied intraplantar injections of NPY, Y₁ receptor and Y₂ receptor antagonists or vehicle. NPY protein expression was significantly downregulated in muscle for two days after incision. In contrast, Y₁ receptor and Y₂ receptor protein expression was upregulated in both skin and muscle. A single intrathecal injection of NPY reduced cumulative guarding pain scores, as did morphine. The intrathecal administration of Y₂ receptor antagonist also reduced pain scores; findings that were not observed when drugs were administered locally. Intrathecal Y₂ receptor antagonists and NPY improved mechanical threshold and heat withdrawal latency 2 h after incision. Intrathecal administration of NPY and/or central blockade of Y₂ receptor attenuated pain behaviors early after incision (postoperative day (POD) 1–2). Y₁ receptor antagonist administration blocked the anti-hyperalgesic effect of NPY. Together these data suggest a role for spinal NPY in postoperative pain.     

PTH improves titanium implant fixation more than pamidronate or renutrition in osteopenic rats chronically fed a low protein diet

Summary   

We evaluated the effects of parathyroid hormone (PTH), pamidronate, or renutrition on osseointegration of titanium implants in the proximal tibia of rats subject to prolonged low-protein diets. PTH improved mechanical fixation, microarchitecture, and increased pull-out strength. Pamidronate or renutrition had lesser effects. PTH can thus improve implant osseointegration in protein-malnourished rats.     

Laparoscopic Adrenalectomy for Isolated Adrenal Metastasis

Background Use of laparoscopy for isolated adrenal metastases is controversial. The aims of this study were to characterize patients with isolated adrenal metastases; compare operative characteristics of the laparoscopic adrenalectomy (LA) versus open adrenalectomy (OA) approach; and compare long-term oncological and surgical outcomes. Methods Our adrenal resection database (1995–2006) identified 63 OA and 31 LA cases done for isolated adrenal metastases. Subset analysis was performed for all patients from isolated lung metastases (n = 39) and for all tumors smaller than 4.5 cm (n = 49). Results Overall, local recurrence was 17%, median survival 30 months and 5-year estimated survival 31%. The only independent predictor of survival for all (n = 94) was adrenal tumor size less than 4.5 cm (P = 0.01). When comparing LA with OA, no differences in local recurrence, margin status, disease-free interval or overall survival were observed for the entire group, or for patients with metastases only from lung cancer (n = 39) or for those with tumors smaller than 4.5 cm (n = 49). LA provided significantly shorter operative time (175 vs 208 min, P = 0.04), lower estimated blood loss (EBL) (106 vs 749 cc, P < 0.0001), shorter length of hospital stay (2.8 vs 8.0 days, P < 0.0001) and fewer total complications (P < 0.0001). Conclusions LA is equivalent to OA in terms of margin status, local recurrence, disease-free interval and overall survival. LA for metastatic adrenal lesions is safe, with equivalent long-term oncological outcomes providing the additional benefits of a minimally invasive technique. LA can be recommended as an appropriate initial approach for isolated adrenal metastases.     

Erbium filtration: a cost-effective, dose-reducing filter which maintains abdominal image quality

The current study investigated the effect of erbium filtration on an anteroposterior abdominal image. The radiation dose reductions achieveable and the costeffectiveness of this filter were also evaluated. An assessment of the radiation dose delivered employing either the standard total filtration (3 mm Al equivalent) or 0.1 mm of erbium filtration added to the standard filtration was undertaken on 21 patients. Image quality was assessed using the Commission of European Communities (CEC) criteria. Significant reductions of 64.6 % in entrance surface (p = 0.0001) and 23.4 % in effective dose (p = 0.0099) were recorded with erbium filtration. Image quality was maintained and the cost per manSievert saved was ￡ 128. More widespread use of this dose reducing filter is advocated. Received: 7 August 1998; Revised: 19 February 1999; Accepted: 19 April 1999     

Results of hepatic resection for sarcoma metastatic to liver

OBJECTIVE: To evaluate the outcome of patients with liver metastases from sarcoma who underwent hepatic resection at a single institution and were followed up prospectively. SUMMARY BACKGROUND DATA: The value of hepatic resection for metastatic sarcoma is unknown. METHODS: There were 331 patients with liver metastases from sarcoma who were admitted to Memorial Hospital from 1982 to 2000, and 56 of them underwent resection of all gross hepatic disease. Patient, tumor, and treatment variables were analyzed to assess outcome. RESULTS: Of the 56 patients who underwent complete resection, 34 (61%) had gastrointestinal stromal tumors or gastrointestinal leiomyosarcomas. Half of the patients required an hepatic lobectomy or extended lobectomy. There were no perioperative deaths in the completely resected group, although 3 of the 75 patients who underwent exploration (4%) died. The postoperative 1-, 3-, and 5-year actuarial survival rates were 88%, 50%, and 30%, respectively, with a median of 39 months. In contrast, the 5-year survival rate of patients who did not undergo complete resection was 4%. On multivariate analysis, a time interval from the primary tumor to the development of liver metastasis greater than 2 years was a significant predictor of survival after hepatectomy. CONCLUSIONS: Complete resection of liver metastases from sarcoma in selected patients is associated with prolonged survival. Hepatectomy should be considered when complete gross resection is possible, especially when the time to the development of liver metastasis exceeds 2 years.     

Amputation for Recurrent Soft Tissue Sarcoma of the Extremity: Indications and Outcome

Background: Limb salvage after primary site failure of extremity soft tissue sarcoma is a challenging problem. Amputation may be the most effective treatment option in selected patients with local recurrence. We compared the outcome of patients treated with amputation versus limb-sparing surgery (LSS) for locally recurrent extremity sarcoma.Methods: From 1982 to 2000, 1178 patients with localized primary extremity sarcoma underwent LSS. Of these, 204 (17%) developed local recurrence. Eighteen (9%) required major amputation and the remainder underwent LSS, of which 34 were selected for matched-pair analysis according to established prognostic variables. Rates of recurrence or death were estimated by the Kaplan-Meier method. Following adjustment for prognostic variables, a Mantel-Haenszel test was used to compare the outcome between the two treatment groups.Results: Patients in each group were well matched. All patients had high-grade tumors deep to the fascia. Median time to local recurrence was similar for both groups. Median follow-up was 95 months. Amputation was associated with a significant improvement in local control of disease (94% vs. 74%; P = .04). We observed no difference in disease-free (P = .48), disease-specific (P = .74), or overall survival (P = .93) between the two groups. Median postrecurrence survival was 20 months and 5-year OS was 36% for the entire study group.Conclusions: Limb-sparing treatment achieves local control in the majority of recurrent extremity sarcomas for which amputation is infrequently indicated. Amputation improves local disease control but not survival under these circumstances.     

Soft tissue tumors of the abdominal wall: analysis of disease patterns and treatment

HYPOTHESIS: Abdominal wall tumors, though clinically similar, have varying degrees of biological behavior. DESIGN: Retrospective review of prospective databases. SETTING: Memorial Sloan-Kettering Cancer Center. PATIENTS: Eighty-five patients with abdominal wall soft tissue tumors. MAIN OUTCOME MEASURES: Primary endpoints included time to first local recurrence, distant metastases, and disease-related mortality. Survival analysis was performed by Kaplan-Meier method, and comparisons were made by log-rank analysis. RESULTS: Thirty-nine desmoids, 32 soft tissue sarcomas (STS), and 14 dermatofibrosarcoma protuberans (DFSP) underwent surgery directed at achieving margin-negative resection. Unlike DFSP, most STS (77%) and desmoids(87%) were deep lesions requiring full-thickness abdominal wall resection and mesh reconstruction. Median follow-up time was 53 months, 101 months, and 31 months, with 5-year local recurrence-free survival rates of 97%, 100%, and 75%, for desmoids, DFSP, and STS, respectively. Desmoid tumors resected with positive microscopic margins had higher local failure rates (68% [positive margin] vs 100% [negative margin] 5-yr local recurrence-free survival, P<.05). For STS, high grade, deep location, and size at or above 5 cm were adverse prognostic factors for disease-specific and distant recurrence-free survival (P<.05); patients experiencing local recurrence was associated with decreased 5-year relapse-free survival rates (87% [primary] vs 50% [local recurrence], P<.05). Characteristically, no DFSP or desmoid developed distant metastases. Soft tissue sarcomas had significantly lower relapse-free survival rates than DFSP or desmoids (P<.05). CONCLUSION: Abdominal wall tumors demonstrate a broad spectrum of biological behavior. Desmoids and DFSP are a local problem. High grade, size at or above 5 cm, and deep location predict distant failure and tumor-related mortality for patients with STS. Complete surgical resection is the recommended treatment approach to achieve local control. Stratification by prognostic factors will facilitate selection of patients with STS for adjuvant systemic therapies.     

Diabetic complications associated with new-onset diabetes mellitus in renal transplant recipients

BACKGROUND: Data are scarce regarding the incidence and risk factors for complications of new-onset diabetes mellitus (NODM) in renal transplant patients. METHODS: United States Renal Data System (USRDS) data from primary renal transplant recipients during 1995-2001 who developed NODM was used to examine diabetic complications over the first three years posttransplant. Prognostic models were used to evaluate patient characteristics and treatment choices associated with risk of each class of complications. Propensity scores for choice of calcineurin inhibitor were included in multivariate analyses. RESULTS: The analysis included 21,489 patients, of whom 4,105 developed NODM by 3 years posttransplant. One or more NODM complications developed in 2,393 patients (58.3% of all patients with NODM), comprising ketoacidosis (334, 8.1%), hyperosmolarity (131, 3.2%), renal complications (1,286, 31.3%), ophthalmic complications (340, 8.3%), neurological complications (665, 16.2%), peripheral circulatory disorders (170, 4.1%) and hypoglycemia/shock (301, 7.3%). Complications developed within a mean of 500 to 600 days from diagnosis of NODM. Multivariate analysis showed that increased recipient age, higher body mass index, African-American race, hepatitis C infection, hypertension as cause of end-stage renal disease, cold ischemia >or=30 hours, and use of tacrolimus each increased risk of complications. CONCLUSION: NODM is associated with similar complications to those seen in the general population, but these appear to develop at an accelerated rate. Obesity and use of tacrolimus are the only modifiable factors that appear to affect risk of NODM or its complications.     

FRAX provides robust fracture prediction regardless of socioeconomic status

Summary

We investigated the fracture risk assessment tool (FRAX) Canada calibration and discrimination according to income quintile in 51,327 Canadian women, with and without a competing mortality framework. Our data show that, under a competing mortality framework, FRAX provides robust fracture prediction and calibration regardless of socioeconomic status (SES).

Introduction

FRAX® predicts 10-year fracture risk. Social factors may independently affect fracture risk. We investigated FRAX calibration and discrimination according to SES.

Methods

Women aged ≥50 years with baseline femoral neck bone mineral density (BMD) were identified from the Manitoba Bone Density Program, Canada (n?=?51,327), 1996–2011. Mean household income, extracted from 2006 census files, was categorized into quintiles. Ten-year fracture probabilities were calculated using FRAX Canada. Incident non-traumatic fractures were studied in relation to income quintile in adjusted Cox proportional hazards models. We compared observed versus predicted fractures with and without a competing mortality framework.

Results

During mean 6.2?±?3.7 years of follow up, there were 6,392 deaths, 3,723 women with ≥1 major osteoporotic fracture (MOF), and 1,027 with hip fractures. Lower income was associated with higher risk for death, MOF, and hip fracture in adjusted models (all p?<?0.005). More women in income quintile 1 (lowest) versus quintile 5 experienced death (19 vs. 8 %), MOF (10 vs. 6 %), or hip fracture (3.0 vs. 1.3 %) (all p?≤?0.001). Adjustment for competing mortality mitigated the effect of SES on FRAX calibration, and good calibration was observed. FRAX provided good fracture discrimination for MOF and hip fracture within each income quintile (all p?<?0.001). Area under the curve was slightly lower for income quintiles 1 versus 5 for FRAX with BMD to predict MOF (0.68, 95 % CI 0.66–0.70 vs. 0.71, 95 % CI 0.69–0.74) and hip fracture (0.79, 95 % CI 0.76–0.81 vs. 0.87, 95 % CI 0.84–0.89).

Conclusion

Increased fracture risk in individuals of lower income is offset by increased mortality. Under a competing mortality framework, FRAX provides robust fracture prediction and calibration regardless of SES.     

WNT pathway signaling is associated with microvascular injury and predicts kidney transplant failure

Microvascular injury is associated with accelerated kidney transplant dysfunction and allograft failure. Molecular pathology can identify new mechanisms of microvascular injury while improving on the diagnostic and prognostic capabilities of traditional histology. We conducted a case‐control study of archived kidney biopsy specimens stored up to 10 years with microvascular injury (n = 50) compared with biopsy specimens without histologic injury (n = 45) from patients of similar age, race, and sex. We measured WNT gene expression with a multiplex quantification platform by using digital barcoding, given the importance of WNT reactivation to the response to wounding in the kidney microvasculature and other compartments. Of 210 genes from a commercial WNT panel, 71 were associated with microvascular injury and 79 were associated with allograft failure, with considerable overlap of genes between each set. Molecular pathology identified 46 biopsy specimens with molecular evidence of microvascular injury; 18 (39%) were either C4d negative, donor‐specific antibody negative, or had no microvascular injury by histology. The majority of cases with molecular evidence of microvascular injury had poor long‐term outcomes. We identified novel WNT pathway genes associated with microvascular injury and allograft failure in residual clinical biopsy specimens obtained up to 10 years earlier. Further mechanistic studies may identify the WNT pathway as a new diagnostic and therapeutic target.