Stereotactic radiosurgery for cavernous malformations

OBJECT: The use of stereotactic radiosurgery to treat cerebral cavernous malformations (CMs) is controversial. To evaluate the efficacy and safety of CM radiosurgery, the authors reviewed the experience at the Mayo Clinic during the past 10 years. METHODS: Seventeen patients underwent radiosurgery for high-surgical-risk CMs in the following sites: thalamus/basal ganglia (four patients), brainstem (12 patients), and corpus callosum (one patient). All patients had experienced at least two documented hemorrhages before undergoing radiosurgery. Stereotactic magnetic resonance (MR) imaging was used for target localization in all cases. The median margin radiation dose was 18 Gy and the median maximum dose was 32 Gy. The median length of follow-up review following radiosurgery was 51 months. The annual hemorrhage rate during the 51 months preceding radiosurgery was 40.1%, compared with 8.8% in the first 2 years following radiosurgery and 2.9% thereafter. In 10 patients (59%) new neurological deficits developed that were associated with regions of increased signal on long-repetition time MR imaging performed a median of 8 months (range 5-16 months) after radiosurgery. Three patients recovered, giving the group a permanent radiation-related morbidity rate of 41%. Compared with 31 patients harboring arteriovenous malformations (AVMs) of sizes and in locations similar to those of the aforementioned CMs, who underwent radiosurgery during the same time period, the patients with CMs were more likely to experience radiation-related complications (any complication, 59% compared with 10%; p < 0.001; permanent complication, 41% compared with 10%; p = 0.02). CONCLUSIONS: It is impossible to conclude that radiosurgery protects patients with CMs against future hemorrhage risk based on the available data, although it appears that some reduction in the bleeding rate occurs after a latency interval of several years. The risk of radiation-related complications after radiosurgery to treat CMs is greater than that found after radiosurgery in AVMs, even when adjusting for lesion size and location and for radiation dose.     

Diet Modification before or during Pregnancy on Maternal and Foetal Outcomes in Rodent Models of Maternal Obesity

The obesity epidemic has serious implications for women of reproductive age; its rising incidence is associated not just with health implications for the mother but also has transgenerational ramifications for the offspring. Increased incidence of diabetes, cardiovascular disease, obesity, and kidney disease are seen in both the mothers and the offspring. Animal models, such as rodent studies, are fundamental to studying maternal obesity and its impact on maternal and offspring health, as human studies lack rigorous controlled experimental design. Furthermore, the short and prolific reproductive potential of rodents enables examination across multiple generations and facilitates the exploration of interventional strategies to mitigate the impact of maternal obesity, both before and during pregnancy. Given that obesity is a major public health concern, it is important to obtain a greater understanding of its pathophysiology and interaction with reproductive health, placental physiology, and foetal development. This narrative review focuses on the known effects of maternal obesity on the mother and the offspring, and the benefits of interventional strategies, including dietary intervention, before or during pregnancy on maternal and foetal outcomes. It further examines the contribution of rodent models of maternal obesity to elucidating pathophysiological pathways of disease development, as well as methods to reduce the impact of obesity on the mothers and the developing foetus. The translation of these findings into the human experience will also be discussed.     

Trams,trains, planes and automobiles: logistics of conducting a statewide audit of medical records

Objective: This paper reports on the logistics of conducting a validation study of a routinely collected dataset against medical records at hospitals to inform planning of similar studies. Method: A stratified random sample of 15 hospitals and two homebirth practitioners was included. Site visits were arranged following consent. In addition to the validation of perinatal data, information was collected regarding logistics. Results: Records at 14 metropolitan and rural hospitals up to 500 km from the research centre, and two homebirth practitioners, were audited. Obtaining consent to participate took between 5 days and 10 months. Auditors visited sites on 101 days, auditing 737 medical record pairs at 16 sites. Median audit time per record was 51.3 minutes; electronic records each took 36 minutes longer than paper. Travel time accounted for nearly one‐quarter of audit time. Conclusions: Delays obtaining consents, long travel times and electronic records prolonged audit duration and expense. Employment of experts maximised use of available audit time. Conducting a validation study is a time‐consuming and expensive exercise; however, confidence in the accuracy of public health data is vital. Implications: Validation studies are unquestionably important. Three alternative strategies have been proposed to make future studies viable.     

ATR inhibition sensitizes liposarcoma to doxorubicin by increasing DNA damage

Liposarcomas account for approximately 20% of all adult sarcomas and have limited therapeutic options outside of surgery. Inhibition of ataxia-telangiectasia and Rad3 related protein kinase (ATR) has emerged as a promising chemotherapeutic strategy in various cancers. However, its activation, expression, and function in liposarcoma remain unkown. In this study, we investigated the expression, function, and potential of ATR as a therapeutic target in liposarcoma. Activation and expression of ATR in liposarcoma was analyzed by immunohistochemistry, which was further explored for correlation with patient clinical characteristics. ATR-specific siRNA and the ATR inhibitor VE-822 were applied to determine the effect of ATR inhibition on liposarcoma cell proliferation and anti-apoptotic activity. Migration activity and clonogenicity were examined using wound healing and clonogenic assays. ATR (p-ATR) was overexpressed in 88.1% of the liposarcoma specimens and correlated with shorter overall survival in patients. Knockdown of ATR via specific siRNA or inhibition with VE-822 suppressed liposarcoma cell growth, proliferation, migration, colony-forming ability, and spheroid growth. Importantly, ATR inhibition significantly and synergistically enhanced liposarcoma cell line chemosensitivity to doxorubicin. Our findings support ATR as critical to liposarcoma proliferation and doxorubicin resistance. Therefore, the addition of ATR inhibition to a standard doxorubicin regimen is a potential treatment strategy for liposarcoma.     

Long-term complications associated with breast-conservation surgery and radiotherapy

Background Breast-conservation surgery plus radiotherapy has become the standard of care for early-stage breast cancer; we evaluated its long-term complications. Methods We selected patients treated with surgery and radiotherapy between January 1990 and December 1992 (an era in which standard radiation dosages were used) with follow-up for at least 1 year. Patients were prospectively monitored for treatment-related complications. Median follow-up time was 89 months. Results A total of 294 patients met the selection criteria. Grade 2 or higher late complications were identified in 29 patients and included arm edema in 13 patients, breast skin fibrosis in 12, decreased range of motion in 4, pneumonitis in 2, neuropathy in 2, fat necrosis in 1, and rib fracture in 1. Arm edema was more common after lumpectomy plus axillary node dissection than after lumpectomy alone. Arm edema occurred in 18% of patients who underwent surgery plus irradiation of the lymph nodes and 10% who underwent surgery without nodal irradiation. Conclusions Breast-conservation surgery plus radiotherapy was associated with grade 2 or higher complications in only 9.9% of patients. Half of these complications were attributable to axillary dissection, it is hoped that lower complication rates can be achieved with sentinel lymph node biopsy.     

Predictors of locoregional recurrence among patients with early-stage breast cancer treated with breast-conserving therapy

Background Our aim was to identify predictors of locoregional recurrence (LRR) in patients with early-stage breast cancer treated with breast-conserving therapy (BCT) and long-term follow-up. Methods From 1970 to 1994, 1153 patients with stage I to II breast cancer underwent BCT and radiotherapy at our institution. Patients with prior breast cancer or other primary malignancies were excluded. Clinical and pathologic characteristics evaluated were age, race, tumor size, stage, pathologic tumor margins, axillary nodal involvement, estrogen and progesterone receptor status, Black's nuclear grade, type of surgery, and use of adjuvant therapy. Results Of 1083 patients, 54% presented with stage I disease and 46% with stage II disease. Median age was 50 years, and median follow-up was 9 years. Axillary nodes were positive in 31% of the patients who underwent axillary dissection. LRR developed in 6%, LRR followed by systemic recurrence in 5%, and systemic recurrence alone in 13%, 76% had no evidence of recurrence at last follow-up. Age, tumor size, positive lymph nodes, and not receiving chemotherapy or hormonal therapy were independent predictors of LRR. Disease-specific survival among patients with LRR was similar to that among patients with no recurrence. Conclusions Multidisciplinary treatment strategies should be used to accomplish durable locoregional control after BCT. Presented at the 54th Annual Cancer Symposium of the Society of Surgical Oncology, Washington, DC, March 15–18, 2001.     

Pre-operative sildenafil and pulmonary endothelial-related complications following cardiopulmonary bypass: a randomised trial in children undergoing cardiac surgery

In a randomised trial, we compared the effects of oral sildenafil (0.5 mg.kg(-1) ) and placebo, administered the day before cardiac surgery, in 24 children. In sildenafil vs placebo patients, pre-cardiopulmonary bypass median (IQR [range]) cyclic-guanosine-monophosphate was not significantly different (29.9 (2.1-208.1 [0.5-391.5]) vs 5.2 (0.3-54.6 [0-628.9]) pmol.ml(-1) , respectively). Post-cardiopulmonary bypass, nitrate/nitrite levels were also not significantly different (0.7 (0-8.0 [0-142.8]) vs 0 (0-2.7 [0-52.7]) μM, respectively). Postoperatively, mean (SD) pulmonary vascular resistance (2.64 (2.28) vs 1.90 (1.12) WU.m(-2) , respectively and oxygenation index (5.29 (4.60) vs 3.38 (2.54), respectively) remained unchanged, whilst oxygen delivery (57.18 (21.24) vs 74.13 (35.46) ml.min(-1) .m(-2) , respectively) and bi-ventricular systolic function (left ventricle 3.78 (0.94) vs 4.55 (1.08) cm.s(-1) , respectively; p=0.002; right ventricle 6.93 (1.47) vs 8.09 (2.25) cm.s(-1) , respectively; p<0.001) were significantly reduced in the sildenafil group. In this trial, pre-operative sildenafil did not affect postoperative pulmonary vascular resistance. There was, however, a negative impact on ventricular function and oxygenation.     

Unintended consequences of policy change to watchful waiting for asymptomatic inguinal hernias

Introduction

In 2009 the Department of Health instructed McKinsey & Company to provide advice on how commissioners might achieve world class National Health Service productivity. Asymptomatic inguinal hernia repair was identified as a potentially cosmetic procedure, with limited clinical benefit. The Birmingham and Solihull primary care trust cluster introduced a policy of watchful waiting for asymptomatic inguinal hernia, which was implemented across the health economy in December 2010. This retrospective cohort study aimed to examine the effect of a change in clinical commissioning policy concerning elective surgical repair of asymptomatic inguinal hernias.

Methods

A total of 1,032 patients undergoing inguinal hernia repair in the 16 months after the policy change were compared with 978 patients in the 16 months before. The main outcome measure was relative proportion of emergency repair in groups before and after the policy change. Multivariate binary logistic regression was used to adjust the main outcome for age, sex and hernia type.

Results

The period after the policy change was associated with 59% higher odds of emergency repair (3.6% vs 5.5%, adjusted odds ratio [OR]: 1.59, 95% confidence interval [CI]: 1.03–2.47). In turn, emergency repair was associated with higher odds of adverse events (4.7% vs 18.5%, adjusted OR: 3.68, 95% CI: 2.04–6.63) and mortality (0.1% vs 5.4%, p<0.001, Fisher’s exact test).

Conclusions

Introduction of a watchful waiting policy for asymptomatic inguinal hernias was associated with a significant increase in need for emergency repair, which was in turn associated with an increased risk of adverse events. Current policies may be placing patients at risk.