An Unconventional Regimen of Carboplatin and Paclitaxel in Metastatic Colorectal Carcinosarcoma: A Case Report and Review of Literature.

Colorectal carcinosarcoma is an exceedingly rare subtype of colorectal cancer that displays the histological and molecular features of both mesenchymal and epithelial tumors. Due to its rarity, there are no guidelines regarding the systemic treatment of this disease. This report describes a case of a 76-year-old woman with colorectal carcinosarcoma with extensive metastatic burden treated with carboplatin and paclitaxel. After four cycles of chemotherapy, the patient had an excellent clinical and radiographical response to treatment. To the best of our knowledge, this is the first report addressing the use of carboplatin and paclitaxel in this disease. We reviewed seven published case reports of metastatic colorectal carcinosarcoma where various systemic treatments were offered. Remarkably, there are no previously published reports where even a partial response was noted, which underscores the aggressiveness of this disease. While further studies are required to validate our experience and assess long-term outcomes, this case suggests an alternative treatment regimen for metastatic colorectal carcinosarcoma.

The role of the mass vaccination programme in combating the COVID-19 pandemic: An LSTM-based analysis of COVID-19 confirmed cases.

The COVID-19 virus has impacted all facets of our lives. As a global response to this threat, vaccination programmes have been initiated and administered in numerous nations. The question remains, however, as to whether mass vaccination programmes result in a decrease in the number of confirmed COVID-19 cases. In this study, we aim to predict the future number of COVID-19 confirmed cases for the top ten countries with the highest number of vaccinations in the world. A well-known Deep Learning method for time series analysis, namely, the Long Short-Term Memory (LSTM) networks, is applied as the prediction method. Using three evaluation metrics, i.e., Mean Absolute Error (MAE), Root Mean Square Error (RMSE), and Mean Absolute Percentage Error (MAPE), we found that the model built by using LSTM networks could give a good prediction of the future number and trend of COVID-19 confirmed cases in the considered countries. Two different scenarios are employed, namely: 'All Time', which includes all historical data; and 'Before Vaccination', which excludes data collected after the mass vaccination programme began. The average MAPE scores for the 'All Time' and 'Before Vaccination' scenarios are 5.977% and 10.388%, respectively. Overall, the results show that the mass vaccination programme has a positive impact on decreasing and controlling the spread of the COVID-19 disease in those countries, as evidenced by decreasing future trends after the programme was implemented.

Examining operational efficiency with prudent risks of Covid-19: a contextual DEA analysis with an undesirable intermediate measure.

In the wake of the losses of human lives and disruption to the world economy caused by the spread of the COVID-19 pandemic, it has become imperative to assess the effectiveness of containment strategies adopted by countries. The success of any containment strategy of achieving low mortality and high recovery rate depends on the efficient utilization of available but limited resources, such as number of hospital beds and healthcare workers. While the spreading pattern of the pandemic has been researched heavily, there is limited research that comprehensively focuses on the efficient utilization of available resources to achieve the desired aims of low mortality and high recovery. In order to close this research gap, we employ a two-stage network data envelopment analysis (DEA) to identify the inefficiency in the process and resolve the resource constraints by considering medical and non-medical (administrative) interventions as two serial stages. The number of infected people is treated as the intermediate product, which is an undesirable output of the first stage and subsequently enters the second stage as an input. This network DEA model successfully addresses the conflict between the two stages over the handling of infected people and assesses the vulnerabilities of the countries against the transmission rates of the disease in the respective countries. Thus, the objective of this study is to develop a well-coordinated plan for different government agencies to jointly mitigate the risk under constrained resources. The findings reveal that almost 60 % of the Organization for Economic Cooperation and Development (OECD) countries have used their resources suboptimally and are producing, on average, almost half the amount of the maximum possible outputs. As a sizeable amount of inefficiency can be explained by varying economic and demographic factors, such as health expenditure and the proportion of the aged population, the efficiency evaluation has been revisited with adjustments for unfavorable externalities. The analysis and its implications can help policymakers formulate optimal resource plans and identify potential areas for improvement.

A critical analysis of the integration of blockchain and artificial intelligence for supply chain.

The integration between blockchain and artificial intelligence (AI) has gained a lot of attention in recent years, especially since such integration can improve security, efficiency, and productivity of applications in business environments characterised by volatility, uncertainty, complexity, and ambiguity. In particular, supply chain is one of the areas that have been shown to benefit tremendously from blockchain and AI, by enhancing information and process resilience, enabling faster and more cost-efficient delivery of products, and augmenting products' traceability, among others. This paper performs a state-of-the-art review of blockchain and AI in the field of supply chains. More specifically, we sought to answer the following three principal questions: Q1-What are the current studies on the integration of blockchain and AI in supply chain?, Q2-What are the current blockchain and AI use cases in supply chain?, and Q3-What are the potential research directions for future studies involving the integration of blockchain and AI? The analysis performed in this paper has identified relevant research studies that have contributed both conceptually and empirically to the expansion and accumulation of intellectual wealth in the supply chain discipline through the integration of blockchain and AI.

Experimental and theoretical investigations of 4-hydroxy L-proline cadmium chloride nonlinear optical crystal.

The solution grown structure 4-hydroxy L-proline cadmium chloride (4HLPCC) single crystal has been done by means of X-ray diffraction method. The computational quantum mechanical modelling method was performed with B3LYP level and LanL2DZ basis set to determine optimized geometry, dipolar moment, linear polarizability, first order hyperpolarizability, atomic charges of various atoms, thermodynamic parameters, HOMO-LUMO energy gap and vibrational frequencies of 4HLPCC. The vibrational frequencies of 4HLPCC were observed experimentally through FTIR and FT-RAMAN analyses and compared with theoretical frequencies. The electric properties were detected by dielectric studies. The frequency doubling of the grown crystal was made with Kurtz-Perry powder technique.

Clinico-pathologic profile and clinical outcomes of patients with indolent lymphoma at the Cancer Institute of the Philippine General Hospital: A seven-year experience

@#<p style="text-align: justify;"><strong>INTRODUCTION:</strong> Indolent lymphoma (IL) is a slowly growing lymphoma, generally refractory to conventional chemotherapy. There are several types of IL, which includes follicular lymphoma (FL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), and waldenstrom macroglobulinemia/ lymphoplasmacytic lymphoma (WM/LPL). Presently, there are no known data in the Philippines on IL. This study is done to determine the clinico-pathologic profile and outcomes of Filipino patients with IL.</p><p style="text-align: justify;"><strong>METHODS:</strong> This study is a retrospective chart review of outpatient department cases of IL seen at the Philippine General Hospital-Cancer Institute from January 2009 to January 2016. The following were documented: age; gender; primary location; presence or absence of B symptoms; type of IL; Ann-arbor stage; prognostic indices for FL and MCL; and staging with bone marrow aspiration and whole body CT scan. Treatment intervention and clinical outcomes were documented.</p><p style="text-align: justify;"><strong>RESULTS:</strong> This study showed that SLL was the most common IL. Most were elderly (>40 years old); male; lacked B symptoms; limited disease; and primary location at or near the orbital area. MCL were seen in all risk groups. Follicular lymphoma (FL) were mostly low risk and had grade one histology. Majority had disease control regardless of treatment intervention. Most patients with recurrence/progression after initial treatment had limited disease but were understaged. Most of the patients were not staged with bone marrow aspiration or whole body computed tomography.</p><p style="text-align: justify;"><strong>CONCLUSION: </strong>The results of this study are mostly consistent with known literature on IL. Absence of B symptoms and limited disease may indicate a low-grade histology. Observation was the most common option for asymptomatic patients.</p><p style="text-align: justify;"> </p>

Clinico-pathologic profile and clinical outcomes of patients with indolent lymphoma at the Cancer Institute of the Philippine General Hospital: A seven-year experience

INTRODUCTION: Indolent lymphoma (IL) is a slowly growing lymphoma, generally refractory to conventional chemotherapy. There are several types of IL, which includes follicular lymphoma (FL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), and waldenstrom macroglobulinemia/ lymphoplasmacytic lymphoma (WM/LPL). Presently, there are no known data in the Philippines on IL. This study is done to determine the clinico-pathologic profile and outcomes of Filipino patients with IL.METHODS: This study is a retrospective chart review of outpatient department cases of IL seen at the Philippine General Hospital-Cancer Institute from January 2009 to January 2016. The following were documented: age; gender; primary location; presence or absence of B symptoms; type of IL; Ann-arbor stage; prognostic indices for FL and MCL; and staging with bone marrow aspiration and whole body CT scan. Treatment intervention and clinical outcomes were documented.RESULTS: This study showed that SLL was the most common IL. Most were elderly (>40 years old); male; lacked B symptoms; limited disease; and primary location at or near the orbital area. MCL were seen in all risk groups. Follicular lymphoma (FL) were mostly low risk and had grade one histology. Majority had disease control regardless of treatment intervention. Most patients with recurrence/progression after initial treatment had limited disease but were understaged. Most of the patients were not staged with bone marrow aspiration or whole body computed tomography.CONCLUSION: The results of this study are mostly consistent with known literature on IL. Absence of B symptoms and limited disease may indicate a low-grade histology. Observation was the most common option for asymptomatic patients. 

Clinico-pathologic profile and clinical outcomes of patients with indolent lymphoma at the Cancer Institute of the Philippine General Hospital: A seven-year experience

INTRODUCTION: Indolent lymphoma (IL) is a slowly growing lymphoma, generally refractory to conventional chemotherapy. There are several types of IL, which includes follicular lymphoma (FL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), and waldenstrom macroglobulinemia/ lymphoplasmacytic lymphoma (WM/LPL). Presently, there are no known data in the Philippines on IL. This study is done to determine the clinico-pathologic profile and outcomes of Filipino patients with IL. METHODS: This study is a retrospective chart review of outpatient department cases of IL seen at the Philippine General Hospital-Cancer Institute from January 2009 to January 2016. The following were documented: age; gender; primary location; presence or absence of B symptoms; type of IL; Ann-arbor stage; prognostic indices for FL and MCL; and staging with bone marrow aspiration and whole body CT scan. Treatment intervention and clinical outcomes were documented. RESULTS: This study showed that SLL was the most common IL. Most were elderly (>40 years old); male; lacked B symptoms; limited disease; and primary location at or near the orbital area. MCL were seen in all risk groups. Follicular lymphoma (FL) were mostly low risk and had grade one histology. Majority had disease control regardless of treatment intervention. Most patients with recurrence/progression after initial treatment had limited disease but were understaged. Most of the patients were not staged with bone marrow aspiration or whole body computed tomography. CONCLUSION: The results of this study are mostly consistent with known literature on IL. Absence of B symptoms and limited disease may indicate a low-grade histology. Observation was the most common option for asymptomatic patients.  

Metabolic activation of furan moiety makes Diosbulbin B hepatotoxic.

Diosbulbin B (DIOB), a furanoid, is a major constituent of herbal medicine Dioscorea bulbifera L. Exposure to DIOB caused liver injury in humans and experimental animals. The mechanisms of DIOB-induced hepatotoxicities remain unknown. The present study demonstrated that DIOB induced hepatotoxicities in a time- and dose-dependent manner in mice. H&E stained histopathologic image showed the occurrence of necrosis in the liver obtained from the mice treated with DIOB at dose of 200 mg/kg. Pretreatment with KTC protected the animals from hepatotoxicities and hepatic GSH depletion induced by DIOB, increased area under the concentration-time curve of blood DIOB, decreased urinary excretion of GSH conjugates derived from DIOB, and increased urinary excretion of parent drug. Pretreatment with BSO exacerbated DIOB-induced hepatotoxicities. In order to define the role of furan moiety in DIOB-induced liver toxicities, we replaced the furan of DIOB with a tetrahydrofuran group by chemical hydrogenation of the furan ring of DIOB. No liver injury was observed in the animals given the same doses of tetrahydro-DIOB. The furan moiety was essential for DIOB-induced hepatotoxicities. The results implicate the cis-enedial reactive metabolite of DIOB was responsible for the observed toxicities. The observed modest depletion of hepatic GSH in DIOB-treated animals suggests the actions of one or more reactive metabolites, and the hepatic injury observed could be due at least in part to reactions of these metabolites with crucial biomolecules. Cytochrome P450 3A enzymes are implicated in DIOB-induced hepatotoxicities by catalyzing the formation of the reactive metabolite of DIOB.

Efficacy of tiotropium as add-on therapy for adults with uncontrolled asthma

@#<p style="text-align: justify;"><strong>OBJECTIVE:</strong> The study aimed to evaluate efficacy of tiotropium as add-on therapy on top of standard regimens for uncontrolled asthma, specifically in terms of FEV1, morning and evening PEF, reduction in exacerbations, rescue medication use, and quality of life improvement.<br /><strong>METHODS:</strong> A search was done for eligible trials after which validity screen and data extraction was performed. Results were presented as mean differences, standard errors, and 95% confidence intervals, and graphically as forest plots. Estimates were pooled using the random effects model with I2 and Chi2 tests used to assess heterogeneity. Adverse events were reported as dichotomous variables.<br /><strong>RESULTS:</strong> Four studies were included totaling 1617 participants. The tiotropium group had statistically significant improvement in FEV1 (95% Cl, 0.14 [0.09, 0.19], p<0.00001), morning (95% Cl, 20.03 [11.71, 28.35], p<0.00001) with trend towards benefit in reduction of rescue medications (95% Cl, 0.12 [-0.17,0.4],p=0.42) and quality of life improvements (95% Cl, 0.1 [-0.05,0.25], p=0.20). Homogeneity (I2= 0%, Chi2= 0.47-3.22) was found across studies.<br /><strong>CONCLUSION:</strong> Tiotropium is associated with significant improvement in pulmonary function among patients with uncontrolled asthma, with possible benefit in reduction of rescue medications and quality of life improvement.</p>

Determinants and prognosis of atrial fibrillation in patients with aortic stenosis.

Atrial fibrillation (AF) is frequently encountered in patients with aortic stenosis (AS) and its incidence also increases with age. In the general population, AF is known to increase cardiovascular risk. We sought to investigate the prognostic importance of AF associated with AS in the context of routine clinical practice. This analysis was based on 809 patients (75 ± 12 years) diagnosed with AS (aortic valve area <2 cm(2)) and normal (≥50%) ejection fraction (EF). Patients were grouped according to the presence of sinus rhythm (SR) or AF at study enrollment. The AF group comprised 141 patients (17.5%) with AF, whereas 668 patients (82.5%) were in SR at inclusion. Four-year estimates of all-cause mortality with medical and surgical management were 60 ± 5% for the AF group compared with 24 ± 2% for the SR group (p = 0.0001). On multivariate analysis, the risk of all-cause mortality was higher in the AF group than in the SR group (adjusted hazard ratio [HR] 2.47 [1.83 to 3.33], p = 0.0001). AF remained associated with excess mortality risk when the analysis was limited to asymptomatic patients (adjusted HR 2.31 [1.38 to 3.89], p = 0.002) and, respectively, patients with severe AS (adjusted HR 2.22 [1.41 to 3.49], p = 0.001). Among patients managed medically, AF was independently associated with increased risk of death in the overall study population (adjusted HR 2.52 [1.81 to 3.51], p = 0.0001), in asymptomatic AS (adjusted HR 2.12 [1.19 to 3.76], p = 0.01), and in severe AS (adjusted HR 2.23 [1.30 to 3.81], p = 0.004). In conclusion, AF is a major predictor of mortality, in both medically and surgically managed patients with AS, irrespective of the functional status and the severity. AF is, therefore, a strong marker of risk in AS and should be considered for clinical decision making.

Progression of Low-Gradient, Low-Flow, Severe Aortic Stenosis With Preserved Left Ventricular Ejection Fraction.

Low-gradient (LG), low-flow (LF), severe aortic stenosis (AS) with preserved ejection fraction (PEF) is considered by some authors as an advanced form of AS associated with very poor outcome. The aim of this Doppler echocardiographic study was to investigate changes over time in the hemodynamic severity of LG/LF AS with PEF. We retrospectively identified in 2 academic centers 59 patients who had 2 Doppler echocardiographic examinations without an intervening event. After a median follow-up of 2 (interquartile range [IQR] 1.3 to 3.5) years, progression was observed with increase in mean Doppler gradient (MDG; from 27 [23 to 32] to 37 [28 to 44] mm Hg; p <0.001), peak aortic jet velocity (from 330 [314 to 366] to 373 [344 to 423] cm/s; p <0.001), and decrease in aortic valve area (AVA; from 0.73 [0.63 to 0.92] to 0.64 [0.56 to 0.75] cm(2); p = 0.001). Annual rates were, respectively, 8 mm Hg/year, 36 cm/s/year, and -0.04 cm(2)/year. EF decreased from 62% (55% to 69%) to 58% (51% to 65%), p = 0.001. At follow-up, MDG increase was observed in 51 patients (86%), and 24 patients (41%) acquired the features of classical high-gradient (HG) severe AS (MDG ≥40 mm Hg and peak aortic jet velocity ≥400 cm/s). There were no differences as regard to baseline hemodynamic parameters between patients who displayed ≥5 mm Hg MDG increase and those in whom such increase was not observed. In conclusion, most patients with LG/LF AS with PEF exhibit over time increase in MDG and decrease in AVA with slight EF impairment. This result suggests that LG/LF AS with PEF is an intermediate stage between moderate AS and HG AS rather than an advanced form of the disease.

Sexual Dysfunction among Filipino breast cancer patients

INTRODUCTION: Sexual function is an important aspect of quality of life, and can be drastically affected in ill patients. Very few studies (and apparently none among Filipinas) looked into sexual dysfunction among females with breast cancer (BrCa); prevalence also is not well defined. This study evaluates the prevalence of sexual dysfunction among Filipino patients with BrCa, and assesses which treatment or if duration of illness, age, BMI, smoking history, diabetes, hypertension significantly contributed to the dysfunction.METHODS: A cross sectional study was conducted among BrCa patients consulting at the outpatient medical oncology clinic of a government tertiary hospital. Study population included those diagnosed and was with breast cancer over a 3-months period, with a calculated sample size of 60 (within 81±10% prevalence rate, Cl 95%). A validated translated version of the Female Sexual Function Index (FSFI) 19-item questionnaire that looked into 6 domains (arousal, lubrication, desire, pain, orgasm, and satisfaction) was used. Sexual dysfunction was defined as an FSFI score of RESULTS: Of the 97 respondents, mean age was 49.4 years old and mean BMI of 24.8. About 78% received chemotherapy, 26% hormonal therapy. 15% radiotherapy, 82% modified radical mastectomy (MRM), and 71% received both MRM and chemotherapy at the time of interview. Duration of cancer wasmonths in 72% of subjects. There were 97.9% who had sexual dysfunction which is similar to prevalence rates (64-98%) in other studies. Age, BMI, smoking history, hypertension, diabetes mellitus, chemotherapy, surgery, hormonal therapy, radiation therapy, and duration of illness were shown not to be significant predictors of sexual dysfunction among Filipinas with BrCa by bivariate analysis.CONCLUSION: Sexual dysfunction is highly prevalent among female Filipino BrCa patients. Knowing such high prevalence should prompt health care providers to include interventions to improve quality of life of BrCa patients, including their sexual life.

Breast cancer anti-estrogen resistance 3 inhibits transforming growth factor ß/Smad signaling and associates with favorable breast cancer disease outcomes.

INTRODUCTION: This study helps to define the implications of breast cancer anti-estrogen resistance 3 (BCAR3) in breast cancer and extends the current understanding of its molecular mechanism of action. BCAR3 has been shown to promote cell proliferation, migration and attachment to extracellular matrix components. However, in a cohort of metastatic breast cancer patients who received tamoxifen treatment, high BCAR3 mRNA levels were associated with favorable progression-free survival outcome. These results suggest that, besides its established roles, BCAR3 may have additional mechanisms of action that regulate breast cancer aggressive phenotype. In this study, we investigated whether BCAR3 is a novel antagonist of the canonical transforming growth factor ß (TGFß) pathway, which induces potent migration and invasion responses in breast cancer cells. METHODS: We surveyed functional genomics databases for correlations between BCAR3 expression and disease outcomes of breast cancer patients. We also studied how BCAR3 could regulate the TGFß/Smad signaling axis using Western blot analysis, coimmunoprecipitation and luciferase assays. In addition, we examined whether BCAR3 could modulate TGFß-induced cell migration and invasion by using an automated imaging system and a confocal microscopy imaging-based matrix degradation assay, respectively. RESULTS: Relatively low levels of BCAR3 expression in primary breast tumors correlate with poor distant metastasis-free survival and relapse-free survival outcomes. We also found a strong correlation between the loss of heterozygosity at BCAR3 gene alleles and lymph node invasion in human breast cancer, further suggesting a role for BCAR3 in preventing disease progression. In addition, we found BCAR3 to inhibit Smad activation, Smad-mediated gene transcription, Smad-dependent cell migration and matrix digestion in breast cancer cells. Furthermore, we found BCAR3 to be downregulated by TGFß through proteasome degradation, thus defining a novel positive feedback loop mechanism downstream of the TGFß/Smad signaling pathway. CONCLUSION: BCAR3 is considered to be associated with aggressive breast cancer phenotypes. However, our results indicate that BCAR3 acts as a putative suppressor of breast cancer progression by inhibiting the prometastatic TGFß/Smad signaling pathway in invasive breast tumors. These data provide new insights into BCAR3's molecular mechanism of action and highlight BCAR3 as a novel TGFß/Smad antagonist in breast cancer.

Synergistic effects of pyrrolizidine alkaloids and lipopolysaccharide on preterm delivery and intrauterine fetal death in mice.

Preterm birth is the leading cause of death for newborn infants, and lipopolysaccharide (LPS) is commonly used to induce preterm delivery in experimental animals. Pyrrolizidine alkaloids (PAs) are widespread and occur in foods, herbs, and other plants. This study was to investigate the synergistic effects of LPS and two representative PAs, retrorsine (RTS) and monocrotaline (MCT), on preterm delivery and fetal death. Pregnant Kunming mice were divided into seven groups: control, RTS, MCT, LPS, RTS+LPS and two MCT+LPS groups. Animals in PAs and PAs+LPS groups were dosed intragastrically with RTS (10mg/kg) or MCT (20 mg/kg or 60 mg/kg) from gestational day (GD) 9 to GD16; mice given LPS were injected intraperitoneally with 150 µg/kg on GD15.5. Latencies to delivery, numbers of pups live and dead at birth were recorded, and livers of live neonates were collected. The incidence of LPS-induced preterm birth was enhanced in dams pretreated with MCT, and combination of PAs and LPS increased fetal mortality from PAs. The enhancement of LPS-induced preterm delivery and fetal demise in animals exposed chronically to PAs and other substances found in foods and beverages consumed widely by humans merits further focused investigation.

What Kind of Control Condition should we use in Trials of Acupuncture? / 全日本鍼灸学会雑誌

Disappointingly little has been achieved by literally hundreds of attempts to evaluate acupuncture for chronic pain. Major methodological flaws are apparent in the vast majority of studies. Controlled studies have shown positive findings for low back pain, and equivocal results for migraine and asthma. Nevertheless larger scale studies are warranted for all these disorders, though other types of musculo-skeletal pain, tension headache and arthritis are also possible candidates.<br>Controlled trials of any treatment have become an immensely difficult and technical undertaking. They are expensive, time-consuming and ideally require the collaboration between practitioners and researchers and consultation with a statistician. It is not really possible for acupuncturists in private practice to mount such trials, and it is very difficult for a professional association or college. However, it is clear that there is no longer any point in conducting small, preliminary studies of acupuncture treatment. There are dozens of such studies, with some encouraging findings. The only way acupuncture can gain full acceptance as a valid form of treatment is through good controlled trials that are large enough to answer the questions they pose.<br>Ter Riet's list of criteria as a good starting point for anyone designing a trial of acupuncture. Specific points I would emphasize after reviewing the existing research on acupuncture are:<br>1. Trials should be single blind; it is not feasible to conduct double-blind trials. Some trials are nevertheless incorrectly described as double blind.<br>2. A range of outcome measures should be used, preferably with some independent assessment. An adequate follow-up is essential.<br>3. Considerable care needs to be taken in the choice of control group, especially with placebo controls. For a placebo I suggest a form of acupuncture treatment that is designed to have minimal effects. It will be the option that is the closest match to the true treatment and avoids the difficulties inherent in randomizing patients to a non-acupuncture treatment.<br>4. It is very useful to check the adequacy of any control treatment with a measure of credibility, or similar assessment, as the choice of control is frequently a matter for criticism.<br>5. Trials have generally been too small to permit firm conclusions. Ter Riet (Ter Riet, Kleijnen et al. 1990) implies that 50 patients per group are needed. This may not be necessary. However preliminary calculations of the necessary size for a reasonable power need to be carried out.