Real-world Safety of Bevacizumab with First-line Combination Chemotherapy in Patients with Metastatic Colorectal Cancer: Population-based Retrospective Cohort Studies in Three Canadian Provinces.

AIMS: To examine the real-world safety of adding bevacizumab to first-line irinotecan-based chemotherapy for patients with metastatic colorectal cancer (mCRC). MATERIALS AND METHODS: Patients diagnosed with CRC in three Canadian provinces (Ontario, Saskatchewan and British Columbia) who received publicly funded bevacizumab and/or irinotecan from 2000 to 2016 were identified from cancer registries. Propensity score 1:1 matching (PSM) and inverse probability of treatment weighting (IPTW) were performed to contemporaneous and historical controls, adjusting for baseline demographic and clinical characteristics. Safety end points evaluated during first-line treatment plus 30 days included mortality within 30 days and all-cause-, chemotherapy- and bevacizumab-related hospitalisations. Chemotherapy- and bevacizumab-related visits were defined as hospitalisations for specific conditions commonly associated with chemotherapy (e.g. infections) or bevacizumab (e.g. arteriovenous thromboembolism) using most responsible diagnosis codes. In PSM and IPTW-weighted cohorts, we assessed event frequencies using odds ratios from logistic regressions and event rate ratios using negative binomial regression models. The results from each province and comparison were pooled using random-effects meta-analysis. RESULTS: We identified 16 250 mCRC patients who received first-line irinotecan-based treatment. In PSM cohorts, bevacizumab was associated with fewer deaths within 30 days of treatment compared with contemporaneous (pooled odds ratio = 0.62; 95% confidence interval 0.50-0.75) and historical controls (pooled odds ratio = 0.73; 95% confidence interval 0.58-0.93). Hospitalisations were more frequent among patients treated with bevacizumab compared with historical controls but similar to contemporaneous controls. As patients receiving bevacizumab were exposed to a longer average treatment duration, across their full treatment duration, patients receiving bevacizumab had significantly lower rates of hospitalisations (contemporaneous pooled rate ratio = 0.56; 95% confidence interval 0.47-0.67; historical pooled rate ratio = 0.73; 95% confidence interval 0.56-0.95). Similar trends were observed for chemotherapy- and bevacizumab-related hospitalisations and in IPTW-weighted cohorts. DISCUSSION: We did not observe any increase in rates of hospitalisation or death within 30 days of treatment among mCRC patients treated with bevacizumab plus chemotherapy versus chemotherapy alone; these findings should be interpreted with caution due to the risk of residual confounding.

Estimating the health care costs of non-melanoma skin cancer in Saskatchewan using physician billing data.

Introduction: Given the high occurrence and morbidity of non-melanoma skin cancer (nmsc), its economic burden on the Canadian health care system is a cause for concern. Despite that relevance, few studies have used patient-level data to calculate the cost of nmsc. The objective of the present study was to use physician billing data to describe the health care costs and service utilization associated with nmsc in Saskatchewan. Methods: The Saskatchewan Cancer Agency's cancer registry was used to identify patients diagnosed with nmsc between 2004 and 2008. Treatment services and costs were based on physician billing claims, which detail physician services performed in an outpatient setting. Total and annual outpatient costs for nmsc and mean outpatient cost per person were calculated by skin cell type, lesion site, and geographic location. Service utilization and costs by physician specialty were also explored. Results: Total outpatient costs grew 12.08% annually, to $845,954.98 in 2008 from $527,458.76 in 2004. The mean outpatient cost per person was estimated at $397.86. Differences in the cost-per-person estimates were observed when results were stratified by skin cell type ($403.41 for basal cell carcinoma vs. $377.85 for squamous cell carcinoma), lesion site ($425.27 for the face vs. $317.80 for an upper limb), and geographic location ($415.07 urban vs. $363.48 rural). Investigation of service utilization found that 92.14% of treatment was delivered by general practice and plastic surgery/otolaryngology physicians; dermatology delivered only 6.33% of services. Conclusions: Our results underestimate the direct costs of nmsc because inpatient services and non-physician costs were not included in the calculations. The present research represents a first step in understanding the cost burden of nmsc in Saskatchewan.

Distinct long-term neurocognitive outcomes after equipotent sevoflurane or isoflurane anaesthesia in immature rats.

BACKGROUND: Many anaesthetics when given to young animals cause cell death and learning deficits that persist until much later in life. Recent attempts to compare the relative safety or toxicity between different agents have not adequately controlled for the relative dose of anaesthetic given, thereby making direct comparisons difficult. METHODS: Isoflurane or sevoflurane were given at 1 minimum alveolar concentration (MAC) for 4 h to postnatal day 7 (P7) rat pups. Beginning at P75 these animals underwent fear conditioning and at P83 Morris water maze testing to assess working memory, short-term memory and early long-term memory using delays of 1 min, 1 h, and 4 h. RESULTS: No difference between groups was seen in fear conditioning experiments. Morris water maze learning was equivalent between groups, and no difference was seen in working memory. Sevoflurane-treated animals had a deficit in early long-term memory, and isoflurane-treated animals had a deficit in both short-term and early long-term memory. CONCLUSIONS: Both isoflurane and sevoflurane delivered at 1 MAC for 4 h to immature rats caused a deficit in long-term memory. Isoflurane also caused a deficit in short-term memory. Isoflurane might be more detrimental than sevoflurane in very young animals.

Closed-field titanium magnets for the retention of complex craniofacial prostheses.

Where reconstruction with autogenous tissue is contraindicated in craniofacial reconstruction, or declined by the patient, a prosthesis may be used. Originally made from latex, cellulose or acrylic resins, prostheses are now largely made of silicone. These prostheses were traditionally retained using adhesives, natural undercuts at retention sites or spectacles. However, these methods were unsatisfactory because of frequent loss of retention, skin reactions to adhesives or unnatural movements of the prosthesis. Osseointegration became a popular method of prosthesis retention, initially using a bar-and-clip device. The use of a bar attached to the implant has certain shortcomings, however, including rigidity of the prosthesis and the difficulty in maintaining hygiene at the implant site. We present our experience with the use of magnets to hold the prosthesis in place, which allows ease of use, improved hygiene and a more natural mobility of the prosthesis.

ATP-dependent interaction of yeast U5 snRNA loop 1 with the 5' splice site.

Pre-messenger RNA splicing is a two-step process by which introns are removed and exons joined together. In yeast, the U5 snRNA loop 1 interacts with the 5' exon before the first step of splicing and with the 5' and 3' exons before the second step. In vitro studies revealed that yeast U5 loop 1 is not required for the first step of splicing but is essential for holding the 5' and 3' exons for ligation during the second step. It is critical, therefore, that loop 1 contacts the 5' exon before the first step of splicing to hold this exon following cleavage from the pre-mRNA. At present it is not known how U5 loop 1 is positioned on the 5' exon prior to the first step of splicing. To address this question, we have used site-specific photoactivated crosslinking in yeast spliceosomes to investigate the interaction of U5 loop 1 with the pre-mRNA prior to the first step of splicing. We have found that the highly conserved uridines in loop 1 make ATP-dependent contacts with an approximately 8-nt region at the 5' splice site that includes the invariant GU. These interactions are dependent on functional U2 and U6 snRNAs. Our results support a model where U5 snRNA loop 1 interacts with the 5' exon in two steps during its targeting to the 5' splice site.

Deep dermal burn due to contact with stomach contents.

A patient sustained deep dermal burns from contact with gastric contents following disconnection of his percutaneous endoscopic gastrostomy (PEG) tube. We discuss the complications of gastrostomies and add this as a rare complication, which may be prevented by a modification to the outlet control of a PEG tube.

Twice weekly isoniazid and rifampin treatment of latent tuberculosis infection in Canadian plains Aborigines.

Six months of twice weekly directly observed isoniazid and rifam-picin treatment of latent tuberculosis (TB) infection was implemented to improve the outcome of treatment. A total of 591 infected aborigines without previous tuberculosis or treatment of latent TB infection received twice weekly isoniazid and rifampicin for 6 mo from 1992 to 1995. The outcome was compared with 403 infected aborigines without previous tuberculosis or treatment of latent TB infection who received self-administered isoniazid daily for 1 yr from 1986 to 1989. Of patients, 487 (82%) completed the twice weekly 6-mo regimen compared with 77 (19%) who completed the daily 12-mo regimen. The main reason for incomplete treatment was default. Both groups were followed over a 6-yr period. The rate of tuberculosis in the twice-weekly isoniazid and rifampicin-treated patients was 0.9/1,000 patient-years compared with 9/1,000 patient-years in the daily isoniazid-treated patients. The rate of side effects was higher for directly observed treatment patients, 136/1,000 patient-years of drugs, compared with 39/ 1,000 patient-years for self-administered treatment patients. Life-threatening side effects such as skin allergic reactions and hepatitis were the same in both groups. A regimen of 52 doses of directly observed twice weekly isoniazid and rifampicin is an effective and well-tolerated regimen to improve the outcome of the treatment of latent tuberculosis infection in a population with a high rate of default with daily self-administered isoniazid.

Hypomagnesaemia in postoperative patients: an important contributing factor in postoperative mortality.

Magnesium is the second most abundant intracellular cation and the fourth most abundant cation in the body. Clinical manifestations of hypomagnesaemia include neuromusclar, neurological, psychiatric and cardiac arrhythmias including torsade de pointes resulting in sudden death. Incidence of hypomagnesaemia in hospitalised patients in common and there is a lack of clinical awareness. Clinicians should become familiar with the common conditions and therapeutics that are risk factors for underlying hypomagnesaemia and become familiar with magnesium replacement regimens. Two patients who suffered fatal complications in whom hypomagnesaemia was an important contributing factor are presented. Hypokalaemia and hypocalcaemia are common in severe magnesium deficiency and require concurrent monitoring and correcting.

The safety of topical anaesthetic and analgesic agents in a gel when used to provide pain relief at split skin donor sites.

Post operative pain from split skin donor sites is a recognised problem. This study was carried out to assess the safety of a 'depot' preparation of bupivacaine and ketoprofen when applied to denuded dermis of a split donor site. Two groups of six patients each received either bupivacaine gel (2.5 mg/ml) or ketoprofen gel (1.6 mg/ml). One patient from each group was excluded as protocol was not followed. The mean surface area for bupivacaine was 106 cm2 (range 64-160) and the mean for ketoprofen was 130 cm2 (range 64-180). Blood samples were obtained before application and at 10, 20, 30, 60, 120, 240 and 480 min after application. Serum levels were assayed using Gas Liquid Chromatography and High Pressure Liquid Chromatography. Bupivacaine levels peaked at 120 min, mean level obtained was 0.07 microgram/ml (range 0.03-0.1). Ketoprofen levels also peaked at 120 min and the mean level obtained was 0.20 microgram/ml (range 0.12-0.27). The reported toxic serum level for bupivacaine was 4 micrograms/ml and for ketoprofen is 1128 micrograms/ml. In conclusion, these preparations, when applied to denuded dermis of a split skin donor site, are unlikely to result in toxic levels.

Nipple-bearing inferior flap mammaplasty: a new technique for reducing massive breasts.

Patients with massive breasts may also suffer from concurrent obesity and preexisting cardiac and respiratory problems, thus presenting significant anesthetic and surgical risk. A modified new technique, evaluated by means of three cases, is described. Preliminary findings show a rapid surgical operating time, little blood loss, acceptable aesthetic appearance, and high patient satisfaction.

An evaluation of the Würzburg titanium miniplate osteosynthesis system for mandibular fixation.

We present an 8-year experience with the Würzburg noncompression titanium miniplate system for the rigid fixation of the mandible during elective head and neck cancer surgery in a consecutive series of 100 patients. One half of the miniplates were used to fix mandibulotomies undertaken for surgical access. The remaining half were in patients undergoing reconstruction of segmental mandibular defects, the vast majority (92%) with vascularised bone grafts. One to four variously shaped miniplates were used per patient (mean = 1.5), plate size ranging from 4 to 40 holes. Fifteen patients (15%) developed complications which included 3 mandibular osteoradionecrosis, 8 broken, 5 infected, and 4 exposed plates. Three of the eight fractured plates were associated with nonunion. In this study, the main advantages of titanium miniplate fixation, namely case of application, decreased fixation time and malleability, were accompanied by a level of morbidity which, while comparing well with alternatives, may necessitate a reappraisal of this technique of fixation.