Keith Lim

A study of complications arising from different methods of anesthesia used in high-dose-rate brachytherapy for cervical cancer.

The purpose of this report is to review the complications related to different methods of anesthesia for high-dose-rate (HDR) brachytherapy for cervical carcinoma. All patients diagnosed with cervical cancer between 1999 and 2002 treated with 3-channel HDR brachytherapy were entered. Complications due to anesthesia for each fraction of brachytherapy were graded using the Common Toxicity Criteria. Eighty-four fractions of brachytherapy were delivered to 18 patients: 19 fractions with patients under general anesthesia (GA), 41 with patients under topical anesthesia and sedation, 5 with patients under paracervical nerve block, and 19 with patients under conscious sedation. Thirteen complications were reported: 12 related to GA and 1 due to paracervical nerve block. Of complications due to GA, 7 were grade 1 and 5 were grade 2. The complication due to paracervical nerve block (seizure) was grade 3. GA had significantly more complications than topical anesthesia or conscious sedation (both P < 0.001). HDR brachytherapy for cervical cancer under GA has significantly more complications than other methods. Given the increasing use of fractionated 3-channel brachytherapy, further investigation of risks and benefits of anesthetic techniques is required.

Clinical outcome of palliative radiotherapy for locally advanced symptomatic gastric cancer in the modern era.

AbstractThe purpose of this study was to report the outcomes of patients with symptomatic locally advanced/recurrent gastric cancer treated with radiotherapy (RT) using modern 3-dimensional conformal techniques.We retrospectively reviewed patients who had palliative RT for index symptoms of gastric bleeding, pain, and obstruction. Study endpoints included symptom response, median survival, and treatment toxicity.Of 115 patients with median age of 77 years, 78 (67.8%) patients had metastatic disease at the time of treatment. Index symptoms were gastric bleeding, pain, and obstruction in 89.6%, 9.2%, and 14.3% of patients, respectively. Dose fractionation regimen ranged from 8-Gy single fraction to 40 Gy in 16 fractions. One hundred eleven patients (93.3%) were computed tomography (CT) planned. Median follow-up was 85 days. Response rates for bleeding, pain, and obstruction were 80.6% (83/103), 45.5% (5/11), and 52.9% (9/17), respectively, and median duration of response was 99 days, 233 days, and 97 days, respectively. Median survival was 85 days. Actuarial 12-month survival was 15.3%. There was no difference in response rates between low (⩽39 Gy) and high (>39 Gy) biologically effective dose (BED) regimens (&agr;/&bgr; ratio = 10). Median survival was significantly longer in patients who responded to RT compared with patients who did not (113.5 vs 47 days, P < 0.001). Three patients (2.6%) had grade 3 Common Toxicity Criteria equivalent toxicity (nausea/vomiting/anorexia).External beam RT delivered using 3-dimensional conformal techniques is highly effective and well tolerated in the local palliation of gastric cancer, with palliation lasting the majority of patient’s lives. Short (⩽39 Gy BED) RT schedules are adequate for effective symptom palliation. A phase II study of palliative gastric RT is ongoing.

Liver ergothioneine accumulation in a guinea pig model of non-alcoholic fatty liver disease. A possible mechanism of defence?

ABSTRACT L-ergothioneine (ET), a putative antioxidant compound acquired by animals through dietary sources, has been suggested to accumulate in certain cells and tissues in the body that are predisposed to high oxidative stress. In the present study, we identified an elevation of ET in the liver of a guinea pig model of non-alcoholic fatty liver disease (NAFLD), elucidated a possible mechanism for the increased uptake and investigated the possible role for this accumulation. This increase in liver ET levels correlated with cholesterol accumulation and disease severity. We identified an increase in the transcriptional factor, RUNX1, which has been shown to upregulate the expression of the ET-specific transporter OCTN1, and could consequently lead to the observable elevation in ET. An increase was also seen in heat shock protein 70 (HSP70) which seemingly corresponds to ET elevation. No significant increase was observed in oxidative damage markers, F2-isoprostanes, and protein carbonyls, which could possibly be attributed to the increase in liver ET through direct antioxidant action, induction of HSP70, or by chelation of Fe2+, preventing redox chemistry. The data suggest a novel mechanism by which the guinea pig fatty liver accumulates ET via upregulation of its transporter, as a possible stress response by the damaged liver to further suppress oxidative damage and delay tissue injury. Similar events may happen in other animal models of disease, and researchers should be aware of the possibility.

Ergothioneine levels in an elderly population decrease with age and incidence of cognitive decline; a risk factor for neurodegeneration?

Ergothioneine (ET), a naturally occurring thione, can accumulate in the human body at high concentrations from diet. Following absorption via a specific transporter, OCTN1, ET may accumulate preferentially in tissues predisposed to higher levels of oxidative stress and inflammation. Given its potential cytoprotective effects, we examined how ET levels change with age. We found that whole blood ET levels in elderly individuals decline significantly beyond 60 years of age. Additionally, a subset of these subjects with mild cognitive impairment had significantly lower plasma ET levels compared with age-matched subjects. This decline suggests that deficiency in ET may be a risk factor, predisposing individuals to neurodegenerative diseases.

Does radiotherapy increase oxidative stress? A study with nasopharyngeal cancer patients revealing anomalies in isoprostanes measurements

Abstract This study aimed to examine if exposure to ionizing radiation during clinical radiotherapy (RT) causes increased oxidative damage. Seven patients with nasopharyngeal cancer (NPC) who underwent RT took part in this controlled-trial study. Blood and urine samples were obtained for F2-isoprostanes (F2-IsoPs) measurement. Urinary F2-IsoPs levels were elevated pre-treatment and remained high (but did not increase) during treatment, but decreased to the normal range after treatment. Plasma F2-IsoPs decreased significantly after the start of treatment before rising midway through treatment. Levels decreased significantly to below baseline following treatment. However, the patients were observed to have substantially lower levels of plasma esterified arachidonic acid (AA) residues than controls. The data shows that NPC is associated with elevated F2-isoprostanes in urine and in plasma after correction for decreased AA levels. RT did not increase these levels and, indeed, was associated with falls in F2-IsoPs. The validity and usefulness of correction of plasma F2-IsoPs for lowered AA levels is discussed.

Palliative radiotherapy for gastric cancer: a systematic review and meta-analysis

Background/Purpose To review the efficacy and toxicity of palliative radiotherapy (RT) for symptomatic locally advanced gastric cancer (GC) and to determine the optimal RT schedule for symptom palliation. Methods We searched MEDLINE and CENTRAL for eligible studies published from 1995 to 2015. Outcomes of interest were relief of bleeding, pain and obstruction. RESULTS Seven non-comparative observational studies were included. There were large variations in RT dose and fractionation. The pooled overall response rates for bleeding, pain and obstruction symptoms were 74%, 67% and 68% respectively. There was no difference in response rate of bleeding between regimens with high biological equivalent dose (BED) of = 39Gy versus regimens with low BED<39Gy regimens (p value =0.39). Grade 3 to 4 toxicities occurred in up to 15% of patients for patients treated with RT alone and up to 25% of patients treated with chemoradiotherapy. Health-related quality of life (HRQL) outcomes were not reported. Conclusion More than two-thirds of patients receiving RT would have a clinical benefit. Low BED regimens appear to be adequate for symptom palliation. Toxicity rates appear acceptable for patients treated with RT alone. The optimal dose fractionation regimen for symptom palliation remains unclear. Prospective studies to determine the effects of palliative gastric RT on HRQL outcomes are warranted.

Influence of the Way Results Are Presented on Research Interpretation and Medical Decision Making: The PRIMER Collaboration Randomized Studies:

Background. The manner of presentation of research results may affect how clinicians interpret research and make clinical decisions. The authors evaluate whether the use of confidence levels improve research interpretation and decision making compared with P values and 95% confidence intervals. Methods. The 2 Presentation and Interpretation of Medical Research (PRIMER) studies were 3-arm randomized trials. PRIMER 1 presented results of 5 fictitious scenarios with P values (P), P plus 95% confidence intervals (P + CI), or P, CI, and confidence levels (P + CI + CL); PRIMER 2 compared P + CI + CL, P + CI, and P + CL. Clinicians were asked to identify the correct interpretation of scenarios in terms of statistical and clinical significance and then indicate the intended decision making in terms of treatment recommendation. Results. Seventy-five and 246 clinicians participated in PRIMER 1 and PRIMER 2, respectively. In PRIMER 1, P+CI+CL was superior to P + CI and P (P < 0.05); the latter 2 arms did not differ significantly. Decision making was not significantly different between arms. In PRIMER 2, P+CI+CL resulted in better interpretation than P + CI (P = 0.03), with no difference between P + CI and P + CL. In combined analysis, the odds of correct interpretation were higher for P+CI+CL than P+CI (odds ratio = 1.73, P=0.005, 95% CI= 1.19--2.52). Decision making was better for P + CI+ CL (P = 0.03). On multivariate analysis, the P + CI+ CL arm and clinicians with statistics training, not in private practice, or participating in PRIMER 1 had better interpretation. The P + CI+ CL arm was the only factor improving decision making. Conclusions. Presenting research with a combination of P values, confidence intervals, and confidence levels leads to better interpretation and decision making by clinicians.

Outcome of 6 fractions of 5.3 Gray HDR brachytherapy in combination with external beam radiotherapy for treatment of cervical cancer

OBJECTIVE To review the characteristics, outcomes and toxicities of cervical cancer patients treated with 6 fractions of brachytherapy after external beam radiotherapy (EBRT). METHODS All patients diagnosed with cervical cancer from 2000 to 2009 who were referred for radical treatment and who received 6 fractions of brachytherapy were retrospectively reviewed. Overall survival (OS), disease free survival (DFS), local control (LC), distant control (DC) rate, acute and late toxicities were the primary endpoints. RESULTS Thirty-two patients with mainly advanced stage squamous cell carcinoma were identified and reviewed. Patients received EBRT of 45 to 50.4 Gy in 1.8 Gy daily fractions followed by 6 sessions of 3 channel brachytherapy of 5.3 Gy prescribed to point H. Response rates to treatment were good, with no residual disease in 84% six weeks after the completion of treatment. With a median follow up time of 8.1 years, the five-year OS, DFS, LC and distant control rates were 75%, 68.5%, 92.8% and 76.9% respectively. None of the patients developed any G3-4 acute toxicity but one patient who had advanced disease developed G3-4 proctitis with a fistula formation. CONCLUSIONS HDR brachytherapy utilizing 6 fractions of 5.3 Gy prescribed to point H with concurrent chemo-radiation is superior in terms of OS and LC to regimens that deliver a lower EQD2 dose to point A/H and is associated with very low rates of toxicities.

Outcomes of Asian patients with localized prostate cancer treated with combined intensity modulated radiation therapy (IMRT) and high dose rate (HDR) brachytherapy: A single institution experience

External beam radiotherapy (EBRT) followed by high dose rate (HDR) brachytherapy boost has demonstrated minimal toxicities and improved disease control rate compared with EBRT alone in observational and randomized studies with predominantly Caucasian patients. This study aims to report the outcomes of patients treated with this approach in our predominantly Asian population.