Postpartum management of women at increased risk of thrombosis--results of a Canadian pilot survey

OBJECTIVE: To determine current practice patterns in the postpartum management of women at increased risk of thrombosis. METHODS: Physicians affiliated with the University of Toronto departments of Obstetrics and Gynecology, Rheumatology, Hematology, and Obstetric Medicine who provide care to pregnant women were mailed a questionnaire that presented 6 clinical scenarios involving postpartum management of a woman at risk for thrombosis, with (1) recurrent pregnancy loss and antiphospholipid antibody syndrome (APS) treated with aspirin (ASA) in the pregnancy; (2) 2 pregnancy losses and a low titer antiphospholipid antibody (aPL) treated with ASA and low molecular weight (LMW) heparin with placental insufficiency; (3) known APS and pregnancy loss treated with LMW heparin and delivered by cesarean section; (4) a previous 17 week fetal death and aPL; (5) a previous deep vein thrombosis while on oral contraception; and (6) systemic lupus erythematosus and secondary APS with a history of a stillbirth. Physicians were asked whether they would recommend postpartum coagulation, and if so to choose from a list of treatment options. RESULTS: Of the 71 questionnaires mailed, 44 were returned (62%). Three physicians replied that their practices do not include patients similar to those presented in the cases and chose not to respond to the clinical scenarios. Percentages of responders recommending treatment in each scenario were 29% for Case 1, 49% for Case 2, 63% for Case 3, 41% for Case 4, 51% for Case 5, and 58% for Case 6. Recommendation for treatment differed among medical specialties, with rheumatologists being less likely to treat in all cases. Prophylactic heparin was selected as the treatment of choice most frequently by those recommending anticoagulation 70% (84/120). CONCLUSION: Postpartum treatment recommendations for women at increased risk of thrombosis are variable across different practitioner specializations demonstrating clinical equipoise regarding therapy. More definitive research is needed and broader study of physicians involved in the care of these patients is planned to more accurately describe and understand the decision to treat these patients.     

Interferon-gamma pharmacokinetics and pharmacodynamics in patients with colorectal cancer

Purpose The study objectives were to define subcutaneous (s.c.) interferon gamma (IFN-) disposition in patients with gastrointestinal malignancies receiving 5-fluorouracil (5-FU) and leucovorin (LV) and to examine the relationship between IFN- exposures and Fas upregulation in vivo and in vitro.Methods Patients received IFN- (10, 25, 50, 75, and 100 g/m²) with LV and 5-FU, and serial samples were collected after the first dose. IFN- concentrations were measured by ELISA. A linear one-compartment model with a lag was fitted to the IFN- plasma concentration-time data. To examine the relationship between IFN- systemic exposure and biological activity in vivo, cell surface Fas upregulation was assessed in peripheral blood mononuclear cell (PBMC) subcompartments.Results The median (range) apparent IFN- clearance was 46 l/m² per hour (2.6–92 l/m² per hour). With increasing IFN- dosages, the area under the concentration-time curve (AUC₀) and C_max increased; however, significant interpatient variability was observed. IFN- AUC₀ and time above 33.3 pg/ml significantly correlated with Fas upregulation in several PBMC compartments, but dosage was significantly correlated with this pharmacodynamic marker only in CD4⁺ and CD56⁺ cells. In vitro studies in HT29 cells demonstrated that clinically relevant IFN- concentrations (1 to 10 U/ml for 6.5 h) with 5-FU/LV upregulated Fas expression 3.5-fold, similar to that in PBMC in vivo.Conclusions We characterized IFN- disposition and developed a limited sampling model for use in future pharmacokinetic studies. Our results showed that IFN- upregulates Fas in PBMC in vivo and in HT29 cells in vitro at tolerable, clinically relevant exposures and that monitoring IFN- pharmacokinetics/pharmacodynamics may be warranted in IFN- clinical use.This work was supported in part by US Public Health Service awards CA23099, CA32613 and CA23944, the Wings Cancer Foundation, and American Lebanese Syrian Associated Charities (ALSAC).     

Results of a phase II upfront window of pharmacokinetically guided topotecan in high-risk medulloblastoma and supratentorial primitive neuroectodermal tumor.

PURPOSE: To assess the antitumor efficacy of pharmacokinetically guided topotecan dosing in previously untreated patients with medulloblastoma and supratentorial primitive neuroectodermal tumors, and to evaluate plasma and CSF disposition of topotecan in these patients. PATIENTS AND METHODS: After maximal surgical resection, 44 children with previously untreated high-risk medulloblastoma were enrolled, of which 36 were assessable for response. The topotecan window consisted of two cycles, administered initially as a 30-minute infusion daily for 5 days, lasting 6 weeks. Pharmacokinetic studies were conducted on day 1 to attain a topotecan lactone area under the plasma concentration-time curve (AUC) of 120 to 160 ng/mL.h. After 10 patients were enrolled, the infusion was modified to 4 hours, with dosage individualization. RESULTS: Of 36 assessable patients, four patients (11.1%) had a complete response and six (16.6%) showed a partial response, and disease was stable in 17 patients (47.2%). Toxicity was mostly hematologic, with only one patient experiencing treatment delay. The target plasma AUC was achieved in 24 of 32 studies (75%) in the 30-minute infusion group, and in 58 of 93 studies (62%) in the 4-hour infusion group. The desired CSF topotecan exposure was achieved in seven of eight pharmacokinetic studies when the topotecan plasma AUC was within target range. CONCLUSION: Topotecan is an effective agent against pediatric medulloblastoma in patients who have received no therapy other than surgery. Pharmacokinetically guided dosing achieved the target plasma AUC in the majority of patients. This drug warrants testing as part of standard postradiation chemotherapeutic regimens. Furthermore, these results emphasize the importance of translational research in drug development, which in this case identified an effective drug.     

Neuroprotective effects of testosterone on dendritic morphology following partial motoneuron depletion: Efficacy in female rats

Motoneuron loss is a significant medical problem, capable of causing severe movement disorders and even death. We have previously demonstrated that partial depletion of motoneurons induces dendritic atrophy in remaining motoneurons, with a concomitant reduction in motor activation. Treatment of male rats with testosterone attenuates the regressive changes following partial motoneuron depletion. To test whether testosterone has similar effects in females, we examined potential neuroprotective effects in motoneurons innervating muscles of the quadriceps of female rats. Motoneurons were selectively killed by intramuscular injection of cholera toxin-conjugated saporin. Simultaneously, some saporin-injected rats were given implants containing testosterone or left untreated. Four weeks later, surviving motoneurons were labeled with cholera toxin-conjugated HRP, and dendritic arbors were reconstructed in three dimensions. Compared to normal females, partial motoneuron depletion resulted in decreased dendritic length in remaining quadriceps motoneurons, and this atrophy was greatly attenuated by testosterone treatment. These findings suggest that testosterone has neuroprotective effects on morphology in both males and females, further supporting a role for testosterone as a neurotherapeutic agent in the injured nervous system.     

Sex-specific and race-specific hip fracture rates.

Sex-, race- and age-specific hip fracture rates were determined using Health Care Financing Administration data for Medicare-reimbursed hip fracture hospitalizations from 1980 to 1982. Rates were highest in White women, lowest in Black men, and intermediate in White men and Black women. Proportions of hip fracture patients dying during hospitalization and those discharged to nursing homes, respectively, were: White men (10.5%; 49%); Black men (9.3%; 32%); White women (5.0%; 54%); and Black women (8.2%; 30%).     

Somatic malignant transformation in a sacrococcygeal teratoma in a child and the use of F18FDG PET imaging

A 6-year-old female presented with a subcutaneous sacral mass. Biopsy revealed an adenocarcinoma most likely arising from a sacrococcygeal teratoma (SCT). CT imaging revealed a massive tumour consistent with SCT. F¹⁸FDG Positron Emission Tomography (PET) scan confirmed marked metabolic activity in the tumour mass and regional lymph node involvement. After chemotherapy repeat CT and PET studies revealed a poor response but no evidence of peritoneal or distant metastases. Radical abdomino-pelvic and gluteal surgery was performed with removal of the entire tumour confirmed as a moderately differentiated adenocarcinoma arising in an immature teratoma. Follow up imaging including PET scanning 5 months after her surgery revealed widespread peritoneal, hepatic and pulmonary metastases. Somatic malignant transformation of an SCT in a child of this age has not been previously reported.     

Outcomes of L1-L2 posterior lumbar interbody fusion with the Lumbar I/F cage and the variable screw placement system: reporting unexpected poor fusion results at L1-L2.

BACKGROUND CONTEXT: Posterior lumbar interbody fusion (PLIF) was introduced 50 years ago. The Lumbar I/F cage (DePuy Spine, Raynham, MA) was designed to enhance PLIF results. PLIF with the Lumbar I/F cage and posterior Variable Screw Placement System (VSP) has increased the success of fusion to nearly 100% at the four lowest lumbar levels, L2-L3 through L5-S1. Less commonly, PLIF is indicated for the L1-L2 level. Clinical-results of Lumbar I/F cage fusion and VSP at L1-L2 have-not been reported. PURPOSE: The purpose of this study is to report the functional outcomes, fusion rate, and complications related to PLIF with Lumbar I/F cage and VSP of L1-L2 STUDY DESIGN/SETTING: The setting is a retrospective, single-arm cohort study of consecutive PLIF surgical patients at a single center. PATIENT SAMPLE: A review of 373 of 425 patients who underwent PLIF with Lumbar I/F cage and VSP from 1999 to 2002 identified 12 patients who had PLIF with Lumbar I/F cage and VSP at L1-L2. Mean follow-up was 31 months (range 12-65 months). OUTCOME MEASURES: Clinical success was determined with a modified Prolo score evaluating pain, function, medication usage and economic status. Fusion success, determined by evaluation of plain radiographs, was defined by continuous bone bridging the fusion area with no lucencies. METHODS: The 12 patients were evaluated for clinical success and/fusion success at last follow-up. These results were compared with the results of the 373 patients reviewed, and historical groups of the original Investigational Device Exemption study and the 10-year follow-up study. RESULTS: Previous surgery was reported by 10 of 12 patients, with an average symptom-free period of 3 years after previous fusion and before presentation with severe symptomatology necessitating further surgery at L1-L2. Seven patients had clinical success (59%), and five patients were clinically unsuccessful (41%). This included zero excellent, 2 of 12 (15%) good, 5 of 12 (42%) fair, and 5 of 12 (42%) poor results. Fusion was successful in seven (58%) and failed in five patients (42%). Three failed fusions were associated with L1-L2 subsidence. Two patients required further revision for non-union. CONCLUSIONS: In 12 patients with L1-L2 fusion, we report an unexpected high rate of failed fusion and poor clinical outcome.     

Cost-effectiveness of sirolimus therapy with early cyclosporin withdrawal vs. long-term cyclosporin therapy in Australia

Cyclosporin (CsA) is Australia's most widely used immunosuppressant following renal transplantation. Randomized clinical trials demonstrate that sirolimus use for immunosuppression is associated with significantly lower incidence rates of nephrotoxicity and chronic graft rejection, and lower serum creatinine levels, suggesting long-term benefits if used as a replacement therapy for CsA. The cost-effectiveness of replacing CsA with sirolimus after 2-4 months (as approved by Australian regulatory authorities) was assessed relative to continued CsA plus low-dose sirolimus. A Markov model simulated outcomes over a patient's lifetime from initial transplant. Costs, measured in Australian dollars from the perspective of the Australian healthcare system, included immunosuppressants, dialysis, and inpatient and outpatient treatment. In a cohort with a mean age of 45 yr, the mean lifetime cost per patient is $39,052 greater with the study therapy. However, an average of 272 chronic graft rejections and 91 regrafts are prevented per 1000 patients. The mean predicted survival benefit is 2.086 life-years, or 0.938 quality-adjusted life-years (QALYs) when utility weights and discounting are incorporated. The incremental cost per QALY gained with the study therapy was $41,613. Cost-effectiveness was most sensitive to model duration and dialysis cost. Sirolimus is a cost-effective alternative to CsA for the long-term treatment of patients undergoing renal transplantation.     

Relationship between depression,weight, and patient satisfaction 2 years after bariatric surgery

BackgroundFindings regarding longer term symptoms of depression and the impact of depression on outcomes such as weight loss and patient satisfaction, are mixed or lacking.ObjectivesThis study sought to understand the relationship between depression, weight loss, and patient satisfaction in the two years after bariatric surgery.SettingThis study used data from a multi-institutional, statewide quality improvement collaborative of 45 different bariatric surgery sites.MethodsParticipants included patients (N = 1991) who underwent Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) between 2015–2018. Participants self-reported symptoms of depression (Patient Health Questionnaire-8 [PHQ-8]), satisfaction with surgery, and weight presurgery and 1 year and 2 years postsurgery.ResultsCompared to presurgery, fewer patients’ PHQ-8 scores indicated clinically significant depression (PHQ-8≥10) at 1 year (P < .001; 14.3% versus 5.1%) and 2 years postsurgery (P < .0001; 8.7%). There was a significant increase in the prevalence of clinical depression from the first to second year postsurgery (P < .0001; 5.1% versus 8.7%). Higher PHQ-8 at baseline was related to less weight loss (%Total Weight Loss [%TWL] and %Excess Weight Loss [%EWL]) at 1 year postsurgery (P < .001), with a trend toward statistical significance at 2 years (P = .06). Postoperative depression was related to lower %TWL and %EWL, and less reduction in body mass index (BMI) at 1 year (P < .001) and 2 years (P < .0001). Baseline and postoperative depression were associated with lower patient satisfaction at both postoperative time points.ConclusionsThis study suggests improvements in depression up to 2 years postbariatric surgery, although it appears that the prevalence of depression increases after the first year. Depression, both pre- and postbariatric surgery, may impact weight loss and patient satisfaction.     

Computed tomography angiography to evaluate thoracic outlet neurovascular compression

The objective was to evaluate the efficacy of computed tomography angiography with upper extremity hyperabduction to diagnose thoracic outlet syndrome. Over 5 years, 21 patients were treated surgically for neurogenic symptoms of thoracic outlet syndrome. For patients whose diagnosis was unclear after history and physical examination, adjunctive tests (duplex, magnetic resonance angiography, or computed tomography angiography) were performed to help establish the diagnosis. Five of the 6 computed tomography angiograms were positive. The sixth computed tomography was deemed to be an incomplete study. With mean follow-up of 9.4 months, 95% (n = 19) of patients with a positive hyperabduction test on physical examination were free of symptoms postoperatively. All patients with a positive computed tomography angiogram, with their neurovascular compression localized to the thoracic outlet, had successful operative decompression. Computed tomography angiogram with abduction of the arm can be used as an adjunct to confirm the diagnosis of neurovascular compression and then predict successful operative decompression.