John A. Abraham

MicroRNA-21 is overexpressed in human cholangiocarcinoma and regulates programmed cell death 4 and tissue inhibitor of metalloproteinase 3†

Cholangiocarcinomas (CCAs) are aggressive cancers, with high mortality and poor survival rates. Only radical surgery offers patients some hope of cure; however, most patients are not surgical candidates because of late diagnosis secondary to relatively poor accuracy of diagnostic means. MicroRNAs (miRs) are involved in every cancer examined, but they have not been evaluated in primary CCA. In this study, miR arrays were performed on five primary CCAs and five normal bile duct specimens (NBDs). Several miRs were dysregulated and miR‐21 was overexpressed in CCAs. miR‐21 differential expression in these 10 specimens was verified by quantitative reverse transcriptase polymerase chain reaction (qRT‐PCR). To validate these findings, qRT‐PCR for miR‐21 was then performed on 18 additional primary CCAs and 12 normal liver specimens. MiR‐21 was 95% sensitive and 100% specific in distinguishing between CCA and normal tissues, with an area under the receiver operating characteristic curve of 0.995. Inhibitors of miR‐21 increased protein levels of programmed cell death 4 (PDCD4) and tissue inhibitor of metalloproteinases 3 (TIMP3). Notably, messenger RNA levels of TIMP3 were significantly lower in CCAs than in normals. Conclusions: MiR‐21 is overexpressed in human CCAs. Furthermore, miR‐21 may be oncogenic, at least in part, by inhibiting PDCD4 and TIMP3. Finally, these data suggest that TIMP3 is a candidate tumor suppressor gene in the biliary tree. (HEPATOLOGY 2009.)

Treatment and Outcome of 82 Patients with Angiosarcoma

BackgroundAngiosarcomas are an uncommon type of malignancy that are generally thought to behave usually in a locally aggressive fashion; they often metastasize to distant sites.MethodsPatients with a diagnosis of angiosarcoma treated at our institution between 1980 and 2006 were analyzed for patient demographics, tumor characteristics, multimodality treatment, and outcomes.ResultsA total of 82 patients were divided into those with primary and advanced disease. Overall, the median age was 65 (range, 22–91) years, and 44% of patients were women. Median size of tumors was 3.8 cm, and 76% of tumors were intermediate or high grade. Tumors were located throughout the body: 32 cutaneous, 22 deep soft tissues or organs, 10 radiation or lymphedema field, 8 bone, and 7 nonirradiated breast. Of 46 patients with primary disease, all patients underwent surgical resection, 67% received radiotherapy, and 27% received chemotherapy. Five-year disease-specific survival was 60%, and negative prognostic factors included intermediate or high grade, and tumors arising in a radiated or lymphedema field. Of 36 patients with advanced disease, 36% underwent a palliative operation, 78% received radiation, and 58% received chemotherapy. Median survival was just 7.3 months, and cutaneous tumors predicted a better prognosis compared with other sites.ConclusionsPrimary angiosarcomas treated with aggressive surgical resection and the addition of radiation for close margins or worrisome pathologic features can result in long-term survival in most patients. The role of adjuvant chemotherapy is unclear. Patients with advanced disease have a poor prognosis, but there can be dramatic responses to chemotherapy in a minority of patients.

Hybrid Myxoinflammatory Fibroblastic Sarcoma/ Hemosiderotic Fibrolipomatous Tumor: Report of a Case Providing Further Evidence for a Pathogenetic Link

Myxoinflammatory fibroblastic sarcoma and hemosiderotic fibrolipomatous tumor are rare, slow-growing soft tissue tumors of the distal extremities with recurrent potential. Recent cytogenetic studies have shown a t(1;10)(p22;q24) or der(10)t(1;10) in combination with aberrations of chromosome 3 in a limited number of cases of both entities. Here we report a case of a 42-year-old female with a soft tissue tumor of the ankle showing hybrid morphologic features of myxoinflammatory fibroblastic sarcoma and hemosiderotic fibrolipomatous tumor, a der(10)t(1;10), and abnormalities of chromosome 3. This hybrid lesion provides further evidence for a close relationship between these 2 tumor types.

Methods for developing country level estimates of the incidence of deaths and non-fatal injuries from road traffic crashes

The estimates of the incidence of deaths and non-fatal injuries from road traffic crashes are essential inputs for prioritising national health and transport policies. This article sketches a methodology for assembling such estimates at the country level by piecing together data from a wide array of sources that include death registers, hospital records, funeral records, health surveys and police reports. Using examples of the types of data sources available in four developing countries (Iran, Mexico, Ghana and India), methods are proposed for making these consistent and extrapolating to estimates of injury incidence at the country level. This requires filling information gaps, mapping from varying case definitions, deriving population-based incidence estimates from sources that may not track denominator populations, and appropriately reapportioning cases assigned to poorly specified causes. The principles proposed here will form the methodological basis for a series of country reports to be published in the future.

Outcomes and Prognostic Factors for a Consecutive Case Series of 115 Patients with Somatic Leiomyosarcoma

BACKGROUND Leiomyosarcoma is an uncommon tumor that affects 500 to 1000 patients in the United States annually. The purpose of our study was to further define survival rates as well as to identify multivariable predictors of disease-specific mortality, local recurrence, and development of distant metastasis following surgical resection. METHODS We studied a consecutive series of patients treated for leiomyosarcoma at our institution (a tertiary-care referral center) over a ten-year period. Only patients with leiomyosarcoma of soft tissues, vasculature, or bone were included. Those with uterine, gastrointestinal, or cutaneous forms of the disease were excluded. This yielded a cohort of 115 patients with complete follow-up data on which statistical analysis was performed. RESULTS One-year, five-year, and ten-year disease-specific survival rates were 87%, 57%, and 19%, respectively. Tumor depth (p < 0.01), histological grade (p < 0.01), and metastasis at presentation (p = 0.03) were found to be multivariable predictors of mortality. Both retroperitoneal location (p = 0.01) and mitotic rate (p < 0.001) were predictive of distant metastasis. Resection margin was the only multivariable significant predictor of local recurrence in the group treated with surgical resection (p < 0.001). CONCLUSIONS Leiomyosarcoma is an aggressive disease, with a generally poor prognosis. Depth of tumor and high histological grade are indicators of a poor prognosis. Retroperitoneal tumors have a particularly high potential to metastasize.

Estimating the incidence of road traffic fatalities and injuries in Sri Lanka using multiple data sources

We used data from multiple sources to estimate the incidence of fatal and non-fatal road traffic injuries in Sri Lanka in 2005. We validated the accuracy of the data from the national traffic police by comparing with estimates based on national death registration. For estimating the incidence and patterns of non-fatal injuries, we used a nationally represented health survey (World Health Survey), and data on hospital admissions from a rural setting (Galle district). We estimate that in the year 2005, approximately 2300 people died in Sri Lanka due to road traffic crashes, approximately 300,000 were injured in non-fatal crashes and approximately 140,000 received care for their injuries at hospitals. While the road traffic death rate in Sri Lanka is low compared with other low-income countries, it has been steadily rising for several years. Although young adults are at high risk in non-fatal crashes, the elderly have the highest death rate. Pedestrians and bicyclists account for more than half of all road traffic deaths and riders of motorised two-wheelers accounted for an additional 13%. The government of Sri Lanka should act immediately to stop the needless loss of life by implementing the recommendations of the 2004 World Report on Road Traffic Injury Prevention.

Incidence of road injuries in Mexico: country report

We used data from various sources to triangulate to a national snapshot of the incidence of fatal and non-fatal road traffic injuries in Mexico in 2005. Data sources used include national death registration data, national hospital discharge data and a nationally representative health survey. We estimate that in 2005, 19,389 people died due to injuries and nearly one million were injured in road traffic crashes. While deaths in high-income countries are declining, this is not the case in Mexico. Young adult males are the demographic at the highest risk in non-fatal crashes, but the elderly have the highest road death rates primarily due to pedestrian crashes. Pedestrians alone comprise nearly half (48%) of all deaths. Cars pose a substantial threat to occupants (38% of deaths and 39% of hospital admissions) and to other road users.

Thromboembolism After Intramedullary Nailing for Metastatic Bone Lesions

BACKGROUND The risk of venous thromboembolism (VTE) in patients undergoing intramedullary nailing for skeletal metastatic disease is currently undefined. The purpose of our study was to determine the risk of thromboembolic events, to define the risk factors for VTE, and to define the rate of wound complications in this population. METHODS A retrospective review of surgical databases at three National Cancer Institute (NCI)-designated cancer centers identified 287 patients with a total of 336 impending or pathologic long-bone fractures that were stabilized with intramedullary nailing between February 2001 and April 2013. Statistical analysis was performed utilizing multivariable logistic regression and Fisher exact tests. RESULTS The overall rate of VTE was twenty-four (7.1%) of the 336; thirteen (3.9%) were pulmonary embolism (PE), and eleven (3.3%), deep venous thrombosis (DVT). In two patients, adequate anticoagulation data were not available. We found no significant relationship between the type of anticoagulant used and VTE. There was a significant positive correlation found between lung-cancer histology and the development of VTE (p < 0.001) or PE (p < 0.001). The absence of radiation therapy approached significance (p = 0.06) with respect to decreased overall VTE risk. Wound complications were documented for 11 (3.3%) of the operations. CONCLUSIONS There is a high rate of VTE among those with skeletal metastatic disease who undergo intramedullary nailing, even while receiving postoperative thromboembolic prophylaxis. Current anticoagulation protocols may be inadequate. Wound-complication risk with anticoagulant use in this population is low and should not be a deterrent to adequate anticoagulant use for this population.

Total joint arthroplasty in cancer patients

Increasing numbers of total joint arthroplasty (TJA) patients have a history, or an active diagnosis, of cancer. We aimed to evaluate the risk of early postoperative complications in these patients. In our series, a history of malignancy was associated with an elevated risk of ischemic cardiac events and postoperative deep vein thrombosis (DVT), while active malignancy was associated with increased respiratory and renal complications, hematoma/seroma formation and early postoperative mortality. Both groups presented increased rates of overall in-hospital complications. Patients with bone metastasis to the hip demonstrated increased DVT and 90-day mortality rates. Cancer patients have increased morbidity and mortality after TJA and should undergo comprehensive medical optimization and adapted thromboprophylaxis.

Recent advances in navigation-assisted musculoskeletal tumor resection

The techniques of surgical navigation to assist with various orthopaedic operations have been improving and are becoming more frequently described. The applications of this technology in orthopaedic oncology are currently being investigated, and case reports are seen in the literature with increasing frequency, making this a technology with which orthopaedic oncologists should become familiar. Although there are a number of potential applications for navigation systems in orthopaedic oncology, currently there are a number of limitations as well. Benefits that can be envisioned include but are not limited to improving the precision of a planned resection or precisely matching a reconstruction to a resection defect. Current limitations include the lack of a software system that incorporates all the functionality that an orthopaedic oncologist could use and a mechanism to define accuracy of a resection. Future directions include the potential development of navigation systems that work together with implant design systems, or with robotic systems that automate specific osteotomies during a resection procedure, further increasing the precision. Given the significant potential for benefit in orthopaedic oncology, it is expected that development and optimization of these systems for application in musculoskeletal tumor resection will continue over the coming years.