Managing the COVID-19 Pandemic as a National Radiation Oncology Centre in Singapore.

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a global pandemic in March 2020. It has impacted the world medically, financially, politically and socially, with countries such as China and Italy adopting a full lockdown of their cities to mitigate the transmission. The current mortality rate is 5.4%, with 1 056 159 people infected worldwide. The disease is reminiscent of SARS in 2002, from which the healthcare system of Singapore has garnered many lessons and applied them in the current climate. As a result of the high transmissibility of the virus, hospitals in Singapore have reduced clinic loads and elective treatments to halt propagation of the virus and also to allow redistribution of healthcare workforce to the frontline. Cancer patients, who are often immunocompromised, are at risk of contracting the disease and becoming seriously ill. At the same time, delaying treatment such as radiotherapy in cancer patients can be detrimental. Here, we describe our experience as a large radiation oncology department in Singapore, including the challenges we encountered and how we managed our patient flow.

Graft-vs-tumor effect in patients with advanced nasopharyngeal cancer treated with nonmyeloablative allogeneic PBSC transplantation.

While nonmyeloablative peripheral blood stem cell transplantation (NST) has shown efficacy against several solid tumors, it is untested in nasopharyngeal cancer (NPC). In a phase II clinical trial, 21 patients with pretreated metastatic NPC underwent NST with sibling PBSC allografts, using CY conditioning, thymic irradiation and in vivo T-cell depletion with thymoglobulin. Stable lymphohematopoietic chimerism was achieved in most patients and prophylactic CYA was tapered at a median of day +30. Seven patients (33%) showed partial response and three (14%) achieved stable disease. Four patients were alive at 2 years and three showed prolonged disease control of 344, 525 and 550 days. With a median follow-up of 209 (4-1147) days, the median PFS was 100 days (95% confidence interval (CI), 66-128 days), and median OS was 209 days (95% CI, 128-236 days). Patients with chronic GVHD had better survival-median OS 426 days (95% CI, 194-NE days) vs 143 days (95% CI, 114-226 days) (P=0.010). Thus, NST may induce meaningful clinical responses in patients with advanced NPC.

Molecular and pharmacodynamic properties of estrogenic extracts from the traditional Chinese medicinal herb, Epimedium.

The Chinese medicinal herb, Epimedium, used traditionally for bone health exerts estrogenic activity (EA) in vitro. A genetically characterized Epimedium brevicornum (EB) extract induced biphasic responses in the mRNA and protein expression of the estrogen-regulated progesterone receptor gene in breast cancer (MCF-7) cells. These changes were mirrored changes in estrogenic receptor (ERalpha) content. In male Sprague-Dawley rats, administration of the estrogenic prodrug, estradiol valerate increased area-under-curve of serum effects for ERalpha (AUC difference: 18,900EA(ERalpha) min; 95% CI: 0-37,800; p = 0.05) and breast cancer cell (MCF-7) growth (AUC difference: 30,200EA(MCF-7) min; 95% CI: 24,200-36,200; p<0.001), compared to placebo. Oral administration of Epimedium brevicornum increased ERalpha activity (1320EA(ERalpha) min, p<0.01). Our data indicate that estrogen-responsive bioassays can measure the pharmacokinetic/pharmacodynamics of estrogenic activity in serum. Epimedium brevicornum extract increases estrogenic activity in serum and human studies are required to evaluate whether Epimedium extracts have utility for estrogen replacement therapy.

Concurrent chemoradiotherapy followed by surgery in locally advanced squamous cell carcinoma of the oesophagus: a single centre experience.

INTRODUCTION: Data on combined modality treatment for locally advanced squamous cell carcinoma of the oesophagus involving Asian patients are limited. MATERIALS AND METHODS: A retrospective study of 56 consecutive patients with this condition treated with concurrent chemoradiotherapy followed by surgery in a single tertiary institution in Singapore was performed. RESULTS: The median overall survival of the entire cohort was 14.1 months [95% confidence interval (CI); range, 8.6 to 19.6 months]. In patients who underwent successful oesophagectomy after chemoradiotherapy (n = 17), the median survival was 27.8 months compared to 9.8 months for those who did not have surgery (n = 39) (P = 0.046, log-rank test). The median time to first relapse for the entire cohort was 16.1 months (95% CI, 7.7 to 24.5 months). The time to first relapse was 23.9 months in the subgroup of patients with successful surgery and 12.1 months in the group which did not (P = 0.147, log-rank test). The high proportion of patients who were medically unfit for surgery or declined surgery may have conferred a selection bias. CONCLUSION: Concurrent chemoradiotherapy followed by surgery is feasible in selected patients. The benefit of adding of surgery to chemoradiotherapy is still controversial and we await the results of randomised controlled trials comparing chemoradiotherapy with surgery versus chemoradiotherapy alone.

Adjuvant sequential chemotherapy and radiotherapy in uterine papillary serous carcinoma.

PURPOSE: To evaluate the efficacy and toxicity of adjuvant combination of sequential chemotherapy followed by radiotherapy in uterine papillary serous carcinoma (UPSC). METHODS AND MATERIALS: From April 1994 to June 2003, 26 patients (median age 61.7 years, range 46.9-78.4) with UPSC were treated with a platinum-based chemoradiation protocol after definitive surgery. 9 patients were assigned as stage I (35%), 4 were stage II (15%), 11 were stage III (42%), and 2 were stage IV (8%) according to the FIGO staging for gynecological cancers. All patients underwent total hysterectomy, salpingo-oophorectomy, pelvic +/- perioartic lymph nodes dissection/sampling, omentectomy, and peritoneal washing. The adjuvant chemoradiation protocol consists of 4 cycles of platinum-based chemotherapy followed by pelvic irradiation and vaginal vault brachytherapy. In selected stage I patients with no or minimal myometrial invasion, only vault brachytherapy was given after adjuvant chemotherapy. RESULTS: After a median follow-up of 28 months (range 9-113 months), 14 (54%) patients were alive and free of disease. 12 out of these 14 patients were FIGO stage I/II. 9 patients (35%) had died (8 from distant metastases). The Kaplan-Meier 2-year and 5-year survival estimates were 69.5% and 57%, respectively. Only 4 (15%) patients had pelvic recurrence. None of the patients developed local vault recurrence. The treatment was well tolerated, only 1 patient developed congestive cardiac failure from the chemotherapy and 6 patients had grade 2 peripheral neuropathy on follow-up. CONCLUSION: In our series of UPSC patients treated with adjuvant chemotherapy followed by radiotherapy, local control can be achieved in a majority of patients. Distant failure remains the major cause of mortality. Further investigations into finding a more effective systemic therapy are required if improvement in outcome for this form of uterine cancer is to be achieved.

An investigation into the structure and bioavailability of alpha-tocopherol dispersions in Gelucire 44/14.

In this investigation we describe the preparation, physical characterisation and in vivo behaviour of solid dispersions of a liquid nutraceutical, alpha-tocopherol, in Gelucire 44/14 with a view to establishing whether dispersion in this matrix may provide a means of formulating a liquid drug in a solid dosage form while also improving the oral bioavailability. Using Vitamin E Preparation USP as the source of alpha-tocopherol, dispersions were prepared using a melt-fusion method with active loadings up to 50% (w/w) and characterised using differential scanning calorimetry and optical microscopy. Capsules containing 300 IU alpha-tocopherol were manufactured and the absorption profiles compared to a commercial soft gelatin capsule preparation in healthy human volunteers. Confocal laser scanning microscopy (CLSM) studies were performed in order to elucidate the mechanism by which drug release may be occurring. Differential scanning calorimetry studies indicated that the presence of the active had a negligible effect on the melting profile of the carrier, indicating limited miscibility between the two components, a conclusion supported by the microscopy studies. Similarly, the dispersions were shown to exhibit a glass transition corresponding to the incorporated drug, indicating molecular cooperativity and hence phase separation from the lipid base. Despite the phase separation, it was noted that capsules stored for 18 months under ambient conditions showed no evidence of leakage. Bioavailability studies in six healthy male volunteers indicated that the Gelucire 44/14 formulation showed an approximately two-fold increase in total alpha-tocopherol absorption compared to the commercial preparation. Confocal laser scanning microscopy studies indicated that, on contact with water, the dispersions formed two interfacial layers, from which the Gelucire 44/14 disperses in the liquid medium as small particles. Furthermore, evidence was obtained for the dispersed material becoming incorporated into the hydrated lipid. In conclusion, the dispersion of the liquid drug in Gelucire 44/14 appears to allow the dual advantages of the preparation of a solid formulation and improved bioavailability of this material.

Improved high performance liquid chromatographic analysis of omeprazole in human plasma.

A simple high-performance liquid chromatographic method was developed for the determination of omeprazole in human plasma. Omeprazole and the internal standard, chloramphenicol, were extracted from alkalinized plasma samples using dichloromethane. The mobile phase was 0.05 M Na2HPO4-ACN (65:35, v/v) adjusted to pH 6.5. Analysis was run at a flow rate of 1.0 ml/min at a detection wavelength of 302 nm. The method was specific and sensitive with a detection limit of 2.5 ng/ml at a signal-to-noise ratio of 4:1. The limit of quantification was set at 5 ng/ml. The calibration curve was linear over a concentration range of 5-1280 ng/ml. Mean recovery value of the extraction procedure was about 96%, while the within and between day coefficient of variation and percent error values of the assay method were all less than 14%.

Estimated coefficient of variation values for sample size planning in bioequivalence studies.

OBJECTIVE: The aim of the present communication is to provide information regarding the intrasubject coefficent of variation obtained from 30 bioequivalence studies covering 16 drugs which can be used for estimation of sample size. Additionally, an attempt was also made to estimate the test power of each of the studies conducted. METHODS: The intrasubject coefficient of variation was estimated from the residual mean square error obtained from analysis of variance of the parameters AUC0-infinity, Cmax and Cmax/AUC0-infinity after logarithmic transformation. The test power in the analyses of the above parameters was subsequently estimated using nomograms provided by Diletti et al. [1991]. RESULTS AND CONCLUSION: Thirty products covering 16 drugs were studied in which 22 were immediate-release (including one dispersible tablet) and 8 were sustained-release formulations. The intrasubject coefficient of variation for the parameter AUC0-infinity was smaller than Cmax, and hence considerably more studies were able to attain a power of greater than 80% using 12 volunteers for the AUC0-infinity, compared to the Cmax. However, the variability in the Cmax could be reduced by using the parameter Cmax/ AUC0-infinity, and thus, provide a more realistic estimation of sample size, since the latter reflects only the rate of absorption and not both the rate and extent as in the case of Cmax [Endrenyi et al. 1991].

Pharmacokinetics and bioavailability of alpha-, gamma- and delta-tocotrienols under different food status.

We have investigated the pharmacokinetics and bioavailability of alpha-, gamma- and delta-tocotrienols under fed and fasted conditions in eight healthy volunteers. The volunteers were administered a single oral dose of mixed tocotrienols (300 mg) under fed or fasted conditions. The bioavailability of tocotrienols under the two conditions was compared using the parameters peak plasma concentration (Cmax), time to reach peak plasma concentration (Tmax) and total area under the plasma concentration-time curve (AUC(o-infinity)). A statistically significant difference was observed between the fed and fasted logarithmic transformed values of Cmax (P < 0.01) and AUC(0-infinity) (P < 0.01) for all three tocotrienols. In addition, the 90% confidence intervals for the ratio of the logarithmic transformed AUC(0-infinity) values of alpha-, gamma- and delta-tocotrienols under the fed state over those of the fasted state were found to lie between 2.24-3.40, 2.05-4.09 and 1.59-3.81, respectively, while those of the Cmax were between 2.28-4.39, 2.31-5.87 and 1.52-4.05, respectively. However, no statistically significant difference was observed between the fed and fasted Tmax values of the three homologues. The mean apparent elimination half-life (t(1/2)) of alpha-, gamma- and delta-tocotrienols was estimated to be 4.4, 4.3 and 2.3 h, respectively, being between 4.5- to 8.7-fold shorter than that reported for alpha-tocopherol. No statistically significant difference was observed between the fed and fasted t(1/2) values. The mean apparent volume of distribution (Vd/f) values under the fed state were significantly smaller than those of the fasted state, which could be attributed to increased absorption of the tocotrienols in the fed state.

Simple high-performance liquid chromatographic method for the determination of tocotrienols in human plasma.

A simple high-performance liquid chromatographic method using fluorescence detection was developed for the determination of vitamin E especially delta-, gamma- and alpha-tocotrienols in human plasma. The method entailed direct injection of plasma sample after deproteinization using a 3:2 mixture of acetonitrile-tetrahydrofuran. The mobile phase comprised 0.5% (v/v) of distilled water in methanol. Analyses were run at a flow-rate of 1.5 ml/min with the detector operating at an excitation wavelength of 296 nm and emission wavelength of 330 nm. This method is specific and sensitive, with a quantification limit of approximately 40, 34 and 16 ng/ml for alpha-, gamma- and delta-tocotrienol, respectively. The mean absolute recovery values were about 98% while the within-day and between-day relative standard deviation and percent error values of the assay method were all less than 12.0% for alpha-, gamma- and delta-tocotrienol. The calibration curve was linear over a concentration range of 40-2500, 30-4000 and 16-1000 ng/ml for alpha-, gamma- and delta-tocotrienol, respectively. Application of the method in a bioavailability study for determination of the above compounds was also demonstrated.