Dimethylamino Parthenolide Enhances the Inhibitory Effects of Gemcitabine in Human Pancreatic Cancer Cells

Introduction

Gemcitabine is standard treatment for pancreatic cancer but has limited clinical benefit due to chemoresistance. Nuclear factor-kappaB (NF-??B) can promote chemoresistance and is therefore an attractive therapeutic target. We hypothesize that NF-??B suppression with the novel, orally bioavailable inhibitor dimethylamino parthenolide (DMAPT) will sensitize pancreatic cancer cells to gemcitabine.

Methods

BxPC-3, PANC-1, and MIA PaCa-2 human pancreatic cancer cell lines were treated with gemcitabine and/or DMAPT. Effects on the NF-??B pathway were determined by electrophoretic mobility shift assay, ELISA, or Western blot. Proliferation and apoptosis were measured by cell counts and ELISA, respectively. The effect of gemcitabine in vivo was determined using a MIA PaCa-2 heterotopic xenograft model.

Results

Gemcitabine induced NF-??B activity in BxPC-3, PANC-1, and MIA PaCa-2 cells and decreased the level of the NF-??B inhibitor I??B?? in BxPC-3 and PANC-1 cells. DMAPT prevented the gemcitabine-induced activation of NF-??B. The combination of DMAPT/gemcitabine inhibited pancreatic cancer cell growth more than either agent alone. Gemcitabine also induced intratumoral NF-??B activity in vivo.

Conclusions

DMAPT enhanced the anti-proliferative effects of gemcitabine in association with NF-??B suppression in pancreatic cancer cells in vitro. Furthermore, gemcitabine induced NF-??B activity in vivo, thus supporting the evaluation of NF-??B-targeted agents to complement gemcitabine-based therapies.     

Intracranial hypotension producing reversible coma: a systematic review, including three new cases

Intracranial hypotension is a disorder of CSF hypovolemia due to iatrogenic or spontaneous spinal CSF leakage. Rarely, positional headaches may progress to coma, with frequent misdiagnosis. The authors review reported cases of verified intracranial hypotension-associated coma, including 3 previously unpublished cases, totaling 29. Most patients presented with headache prior to neurological deterioration, with positional symptoms elicited in almost half. Eight patients had recently undergone a spinal procedure such as lumbar drainage. Diagnostic workup almost always began with a head CT scan. Subdural collections were present in 86%; however, intracranial hypotension was frequently unrecognized as the underlying cause. Twelve patients underwent one or more procedures to evacuate the collections, sometimes with transiently improved mental status. However, no patient experienced lasting neurological improvement after subdural fluid evacuation alone, and some deteriorated further. Intracranial hypotension was diagnosed in most patients via MRI studies, which were often obtained due to failure to improve after subdural hematoma (SDH) evacuation. Once the diagnosis of intracranial hypotension was made, placement of epidural blood patches was curative in 85% of patients. Twenty-seven patients (93%) experienced favorable outcomes after diagnosis and treatment; 1 patient died, and 1 patient had a morbid outcome secondary to duret hemorrhages. The literature review revealed that numerous additional patients with clinical histories consistent with intracranial hypotension but no radiological confirmation developed SDH following a spinal procedure. Several such patients experienced poor outcomes, and there were multiple deaths. To facilitate recognition of this treatable but potentially life-threatening condition, the authors propose criteria that should prompt intracranial hypotension workup in the comatose patient and present a stepwise management algorithm to guide the appropriate diagnosis and treatment of these patients.     

The Role of Donor Bone Marrow Infusions in Withdrawal of Immunosuppression in Adult Liver Allotransplantation

We investigated the role of donor bone marrow cell (DBMC) infusions in immunosuppression withdrawal in adult liver transplantation. Patients enrolled were at least 3 years post-transplantation, with stable graft function. Forty-five (study group: G1) received DBMC, and 59 (control group: G2) did not. Immunosuppression was reduced by one third upon enrollment, by another third the second year of the study and was completely withdrawn the third year. Patient and graft survival were similar between the two groups. Although rejection episodes were significantly less in G1 the first 2 years of the study (35% vs. 57%, p = 0.016), there was no significant difference overall (74% vs. 81%, p = 0.14). Until February 2004, 20 patients, 10 in each group, were immunosuppression free for 1-3 years. Approximately 20% of long-term survivors of liver transplantation can successfully discontinue their immunosuppression. DBMC infusions, do not increase this likelihood.     

The relationship between activity and ions in patients with metal-on-metal bearing hip prostheses

BACKGROUND: Total hip replacements with metal-on-metal bearings are frequently implanted in young, active patients. The relationship between patient activity and cobalt and chromium ion levels has not been investigated, to our knowledge. METHODS: Seven patients with well-functioning metal-on-metal bearing hip prostheses and one control subject (no implants), all with normal renal function, were monitored during a two-week-long activity protocol. Lower-extremity activity was continuously assessed with use of a computerized, two-dimensional accelerometer. During the first week, the subjects were requested to limit physical activity. The subjects then completed an hour-long treadmill test followed by a week in which they were encouraged to be as physically active as practically possible. Serum levels of cobalt and chromium ions and urine levels of chromium were assessed at ten time-points during these two weeks. RESULTS: Regardless of activity, the serum ion levels for a given patient were essentially constant and no correlation was found between patient activity and serum levels of cobalt or chromium, or urine levels of chromium. A mean increase in activity of 28% during the week of high-intensity activity was associated with a mean decrease of 2.7% in the serum cobalt level and a mean increase of 2.0% in the serum chromium level. During the treadmill test, a mean increase in activity of 1621% was associated with a mean increase of 3.0% in the serum cobalt level and a mean increase of 0.8% in the serum chromium level. These results fall within the variability for the measurement accuracy of these tests. CONCLUSIONS: For these patients, serum cobalt and chromium ion levels were not acutely affected by patient activity. Periodic measurements of serum ion levels could be used to monitor the tribologic (lubrication, friction, and wear) performance of a metal-on-metal bearing without adjusting for patient activity. Additional research is needed into the kinetics of ion production, transport, and excretion.     

Role of the thymus and kidney graft in the maintenance of tolerance to heart grafts in miniature swine

BACKGROUND: The authors have examined the mechanism whereby co-transplantation of a kidney and heart from the same donor induces and maintains tolerance to both organs in miniature swine. METHODS: Transplants were performed across a major histocompatibility complex class I mismatch, and recipients received cyclosporine for 12 days. Group 1 animals received heart transplants alone (n=5), and all other groups received both heart and kidney allografts. Group 2 animals received no further intervention (n=2). Group 3 animals underwent transplant nephrectomy 8 days after heart and kidney co-transplantation (n=2). Group 4 animals underwent transplant nephrectomy 100 days after co-transplantation (n=2). Skin grafts were placed on group 4 animals, on one group 3 animal, and on two animals from group 2. Group 5 animals underwent thymectomy 100 days after co-transplantation (n=4). RESULTS: Group 1 animals developed cardiac allograft vasculopathy (CAV) and rejection. Group 2 animals never developed CAV and demonstrated in vitro donor-specific unresponsiveness. Group 3 animals suffered CAV and rejection. Group 4 animals developed CAV without concomitant donor-specific cell-mediated lympholysis reactivity, interstitial rejection, or cessation of graft function. Skin grafts on group 3 and group 4 animals led to fulminant rejection of heart and skin grafts, in contrast to grafts on group 2 animals that had no in vivo effect. Group 5 animals developed CAV but no significant increase in interstitial infiltrates. CONCLUSIONS: Both the kidney and thymus were necessary for maintenance of tolerance to heart allografts.     

The Cost of Intramedullary Nailing for Femoral Shaft Fractures in Dar es Salaam,Tanzania

Background

Femoral shaft fractures are one of the most common injuries seen by surgeons in low- and middle-income countries (LMICs). Surgical repair in LMICs is often dismissed as not being cost-effective or unsafe, though little evidence exists to support this notion. Therefore, the goal of this study is to determine the cost of intramedullary nailing of femoral shaft fractures in Tanzania.

Methods

We used micro-costing methods to estimate the fixed and variable costs of intramedullary nailing of femoral shaft fractures. Variable costs assessed included medical personnel costs, ward personnel costs, implants, medications, and single-use supplies. Fixed costs included costs for surgical instruments and administrative and ancillary staff.

Results

46 adult femoral shaft fracture patients admitted to Muhimbili Orthopaedic Institute between June and September 2014 were enrolled and treated with intramedullary fixation. The total cost per patient was $530.87 (SD $129.99). The mean variable cost per patient was $419.87 (SD $129.99), the largest portion coming from ward personnel $144.47 (SD $123.30), followed by implant $134.10 (SD $15.00) medical personnel $106.86 (SD $28.18), and medications/supplies $30.05 (SD $12.28). The mean fixed cost per patient was $111.00, consisting of support staff, $103.50, and surgical instruments, $7.50.

Conclusions

Our study provides empirical information on the variable and fixed costs of intramedullary nailing of femoral shaft fractures in LMICs. Importantly, the lack of surgical capacity was the primary driver of the largest cost for this procedure, preoperative ward personnel time. Our results provide the cost data for a formal cost-effectiveness analysis on this intervention.

     

Management of non-acute gastrointestinal defects using the over-the-scope clips (OTSCs): a retrospective single-institution experience

Introduction

Advanced endoscopic techniques provide novel therapies for complications historically treated with surgical interventions. Over-the-scope clips (OTSCs) have recently been shown to be effective at endoscopic closure of gastrointestinal (GI) defects. We hypothesize that by following classic surgical principles of fistula management, a high rate of long-term success can be achieved with endoscopic closure of non-acute GI tract defects.

Methods

A retrospective review of a single-institution prospectively maintained database (2012–2015) of all patients referred for the management of GI leaks or fistulae who underwent attempted closure with the OTSC system (Ovesco, Germany) was performed. Acute perforations were excluded. The primary endpoint was long-term success defined by the absence of radiographic or clinical evidence of leak or fistula during follow-up. Patients were stratified by success or failure of OTSC closure and compared with Fisher’s exact and Mann–Whitney U tests.

Results

We identified 22 patients with 28 defects (22 fistulae and 6 leaks). Most patients were female (59 %) with a mean age of 54 years (±14), median BMI of 29, and prior bariatric procedure (55 %). Comorbidities included smoking history (68 %) and diabetes (23 %). The majority of defects were solitary (64 %), involved the upper GI tract (82 %), and had been present for >30 days (50 %). Multiple therapeutic interventions were necessary in 46 % of defects. There were no adverse outcomes related to OTSC placement or misfiring. Endoscopic adjuncts were used in 61 % of cases. Overall success rate was 82 % (100 % for leaks and 76 % for fistulae) at a median follow-up of 4.7 months (IQR 2.1–8.4 months). Predictors of success and failure could not be distinguished due to limited sample size.

Conclusions

Over-the-scope clips can be safely and effectively used in patients presenting with GI leaks and fistulae. Further research is required to characterize the determinants of long-term success and risk factors for failure.