As adaptive clinical trials (ACTs) receive growing attention and exhibit promising performance in practical trials during last decade, they also present challenges to drug supply chain management. As indicated by Burnham et al. (2015), the challenges include the uncertainty of maximum drug supply needed, the shifting of supply requirement, and rapid availability of new supply at decision points. To facilitate drug supply decision making and the development of mathematical analysis tools, we propose two trial supply chain optimization problems that represent different mindsets in response to trial adaptations. In the first problem, we treat the impacts of ACTs as exogenous uncertainties and study important aspects of trial supply, including drug wastage, resupply policy, trial length, and costs minimization, via a two-stage stochastic program. In the second problem, we incorporate the adaptation rules of ACTs with supply chain management and numerically study the impact of joint optimization on the trial and drug supply planning through a mixed-integer nonlinear program (MINLP). For solution approaches to the problems, we use progressive hedging algorithm (PHA) and particle swarm optimization (PSO) respectively, and take advantages of the problem structures to enhance the solution efficiency. With case studies, we see that the proposed models capture the features of ACT drug supply and the mechanisms of trial conduction well. The solutions not only reflect the impact of trial adaptations but also provide managerial suggestions, e.g. the prediction of needed production amount, storage capacity at clinical sites, and resupply schemes. The joint optimization also suggests a new angle and research extension in the field of ACT design and supply.

Migraine affects 8 -16% of population in different countries resulting in significant economic and social impacts. Current pharmacological treatment provides symptomatic relief, but not without side effects. Hence, an increasing proportion of patients prefer complementary therapies including acupuncture for migraine relief. Randomised controlled trials (RCTs) of acupuncture treatment for migraine have produced conflicting evidence due to methodological and reporting deficiencies, including small sample sizes and inappropriate outcome measures. Furthermore, systematic reviews on acupuncture for headache failed to adequately represent non-English studies such as those conducted in China. This project aimed to: (1) systematically review studies of acupuncture for migraine; and (2) conduct a RCT addressing key deficiencies identified from the systematic reviews (SRs). Two SRs were conducted based onfollowing Cochrane review protocols. Major English, Chinese, Japanese and Korean databases were searched. The first SR included 15 English studies and the second SR had 17 Chinese studies. No Japanese or Korean RCTs were identified. Overall, those two SRs supported the value of acupuncture in the treatment and prevention of migraine when compared with western medications. However, conflicting results were found when real acupuncture treatments were compared with sham/placebo procedures. When compared with the studies published in English, Chinese studies had a higher frequency of acupuncture treatment, displayed poor methodological quality, and commonly used pharmacotherapy as a comparator. The SRs revealed that there was limited evaluation of acupuncture for frequent migraine. In the RCT, fifty participants with a minimum of eight migraine days per four weeks were randomly allocated to receive real (RA, n = 26) and sham (SA, n = 24) acupuncture for a total of 16 sessions over 20 weeks in a gradually decreasing treatment frequency. Fixed and supplementary acupoints were used. Participants were followed up for further assessment at three months and one year. Results showed that at the end of the treatment period, the mean (SD) migraine attack days per four weeks decreased from 11.81 (5.76) to 5.17 (5.02) in the RA group and from 12.41 (6.4) to 10.08 (7.11) in SA (group difference: p = .008). Intensity of migraine assessed using a Six-point Likert scale was lower in the RA (2.18 ±1.05) than that in the SA group (2.93 ± 0.61, p = 0.004). The percentile changes of pressure pain threshold (PPTs) detected at the bilateral points of TaiYang (Ex-HN5) were significantly higher in the RA group (RA 228.48% vs. SA -0.66 % on the left and 92.69% vs. -2.52% on the right). However, there was no s tatistically significant difference between the two groups with respect to Migraine Specific Quality of Life (MSQOL). At the end of the three-month follow up, medication consumption was less in the RA group, but not at the one-year follow up. In conclusion, this project demonstrates that acupuncture is a potentially effective and safe option for adult patients with frequent migraine headache with the effects lasting up to three months. Further studies are needed to confirm these therapeutic benefits with adequate sample sizes and the potential mechanism for this action.

No description available.

Despite progress through expanded use of bed nets and anti-malarial drugs, Plasmodium falciparum (Pf) malaria caused about 200 million cases and 500,000 deaths in 2015. An ideal vaccine would reduce the burden of disease and interrupt transmission. Despite decades of effort, there is no vaccine that can adequately address the global burden of malaria. This thesis focuses on two potential weaknesses in the parasite life-cycle. First, I investigate two vaccination strategies aimed at improving the antibody response to RH5, an essential and conserved protein for erythrocyte invasion. Due to instability of the resultant recombinant vaccine constructs, these efforts have required re-engineering of the vaccine platform, which remains an ongoing effort. Second, the immunogenicity and mechanism of protection of a live-attenuated whole sporozoite vaccine, PfSPZ Vaccine, was assessed. In a study that examined PfSPZ Vaccine at intravenous (IV) doses between 1.35 &tiles; 10⁵ to 4.5 &tiles; 10⁵ PfSPZ, I demonstrate that PfSPZ antibody responses correlated with durable sterile protection against controlled human malaria infection (CHMI). Surprisingly, the pre-vaccine frequency of Vγ9⁺Vδ2⁺ T cells, an innate T cell that recognizes conserved Plasmodium phosphoantigens, also correlated with durable sterile protection. Regarding the mechanism of protection, PfSPZ-specific antibodies as well as CD8 and CD4 T cells in the blood decreased substantially over time, yet sterile protection was maintained. In non-human primates, the CD8 T cell response in the liver at a memory time point was measured to be about 100-fold higher than found in the blood. Collectively, these data suggest that PfSPZ Vaccine confers durable protection in humans by long-lived, tissue-resident CD8 T cells. These findings were extended with a study using 9.0 x 10⁵ PfSPZ, wherein I demonstrate that T cell responses peaked immediately after the first vaccination with minimal T cell activation despite additional immunizations. This suggests that anti-PfSPZ immunity may be limiting the effectiveness of subsequent immunizations. Finally, I examined the T cell response to PfSPZ attenuated by chloroquine (termed PfSPZ-CVac). T cell responses were substantially higher than achieved with comparable PfSPZ Vaccine doses. Additionally, a significantly higher proportion of PfSPZ-specific CD4 T cells were polyfunctional, simultaneously expressing IFN-γ, IL-2, and TNF-α, in subjects that were protected from CHMI. In sum, these studies provide insight into the immunobiology of a protective immune response that may guide future malaria vaccine development efforts.

nÃo hà / A periodontite agressiva representa um tipo de doenÃa periodontal inflamatÃria que, embora rara, geralmente acomete indivÃduos em idade precoce e à caracterizada pela destruiÃÃo rÃpida e debilitante do periodonto de suporte. A patogÃnese desta doenÃa vincula-se a um fator etiolÃgico primÃrio, o biofilme dental e tambÃm à resposta inflamatÃria do hospedeiro susceptÃvel à agressÃo bacteriana. O objetivo deste estudo foi avaliar o efeito do tratamento a curto prazo com etoricoxib como adjuvante à terapia de raspagem e alisamento radicular (RAR) sobre os nÃveis de PGE2 e sobre os parÃmetros clÃnicos e radiogrÃficos em pacientes portadores de periodontite agressiva. Os pacientes foram randomicamente alocados para TESTE e CONTROLE (n=10 em cada grupo) e submetidos ao tratamento com etoricoxib (120 mg/dia) ou placebo durante 7 dias. Profundidade de sondagem (PS), nÃvel de inserÃÃo clÃnica (NIC), recessÃo gengival (RG), Ãndice de placa visÃvel (IP), sangramento à sondagem (SS), mensuraÃÃo da distÃncia linear (DL) e anÃlise dos nÃveis de cinza (NC) foram registrados antes e um mÃs apÃs a instituiÃÃo das terapias. A anÃlise visual por vÃdeo e por negatoscÃpio bem como a anÃlise por subtraÃÃo radiogrÃfica digital foram feitas no inÃcio e ao final do perÃodo experimental. A dosagem de PGE2 no fluido crevicular gengival (FCG) foi avaliada por radioimunoensaio no inÃcio, com 7 dias apÃs o inÃcio dos tratamentos e 30 dias apÃs a finalizaÃÃo dos mesmos. Ao final do perÃodo experimental, nÃo foram observadas diferenÃas estatisticamente significantes entre os grupos em relaÃÃo aos parÃmetros clÃnicos, embora ambos os grupos tenham apresentado melhora significativa em todas as variÃveis avaliadas. Houve um decrÃscimo no NIC de 5,54Â0,47 mm para 3,59Â0,53 mm no grupo TESTE e de 5,92Â1,10 para 3,69Â0,80 mm no grupo CONTROLE. Uma significativa reduÃÃo nos nÃveis de PGE2 foi observada apÃs 7 dias de tratamento. A mensuraÃÃo da DL evidenciou diferenÃa entre os grupos. Em conclusÃo, etoricoxib nÃo foi capaz de promover benefÃcio adicional nos parÃmetros clÃnicos, contudo, promoveu reduÃÃo inicial nos nÃveis de PGE2 e discreta melhora na condiÃÃo Ãssea. / Aggressive periodontitis is an inflammatory type of periodontal disease which, although rare, generally affects individuals at an early age and is characterized by the rapid and debilitating destruction of the support periodontium. The pathogenesis of this pathology is related to primary etiologic factor, dental biofilm, associated to the immunoinflammatory response of susceptible host to this aggression. The purpose of this study was to assess the effect of short duration treatment with etoricoxib as adjuvant therapy to scaling and root planing (SRP) on prostaglandin E2 (PGE2) levels and the clinical and radiographic parameters in aggressive periodontitis. Patients were randomly allocated to TEST or CONTROL (N=10 in each group) and submitted to SRP and treatment with 120 mg/day of etoricoxib or placebo during 7 days. Probing depth (PD), clinical attachment level (CAL), gingival recession (GR), visible plaque index (VPI), bleeding on probing (BOP), measurement of the linear distance (LD) and analysis of the gray levels (GL) were recorded before and one month after the therapies. The visual analysis from video and negatoscope and digital subtraction radiographic was made in beginning and in the final experimental period (30 days). The PGE2 dosage in the gingival crevicular fluid (GCF) was measured by radioimmunoassay at the beginning, and 7 and 30 days afterwards. No significant difference was observed between the groups in the clinical parameters at the end of the experimental period, although both groups presented significant improvement in all the variables examined. There was a decrease in CAL from 5.54Â0.47 mm to 3.59Â0.53 mm in the TEST group and from 5.92Â1.10 to 3.69Â0.80 mm in the CONTROL group. A significant reduction in PGE2 was found after 7 days of treatment. The LD measurement was shown to differ between the groups. In conclusion, etoricoxib did not promote additional improvement in the clinical parameters, however it produced an initial reduction in the PGE2 levels in the GCF, which could be related to the discrete improvement in the bone condition.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / The Systemic Inflammatory Response Syndrome (SIRS) is characterized by an excessive release of inflammatory mediators as a systemic inflammatory response to a serious clinical injuries. The use of glutamine in nutraceutical doses has been studied as a strategy in tissue protection and preservative of tissue metabolic function in stressful situations, helping to improve the immune response of patients. The effects of enteral glutamine supplementation in nutraceutical doses on the inflammatory markers, of glycolytic metabolism, of immune system and of oxidative stress were studied in adult and elderly patients with SIRS in a prospective, clinical, randomized, controlled, double-blind crossover study. Thirty six moderately severe patients admitted to the Intensive Care Unit were selected according to pre-defined criteria, diagnosis of SIRS and the APACHE II score (>10<20), distributed into two groups and submitted to the supplementation with 1 litre of enteral nutrition with addition of 30g of L-glutamine or calcium caseinate or 1 litre of enteral nutrition with addition of 30g of calcium caseinate or L-glutamine for two days, pause for one day only with diet, followed by four days of supplementation. Blood samples were collected before (T0) and after (T1) each supplementation. For evaluation blood parameters (hematocrit, leukocytes, lymphocytes, monocytes, prealbumin, blood urea nitrogen, creatinine, glucose, lactate, C-peptide and insulin), IL-1, IL-6, IL-10 and TNF&#945; were also assayed. Glutathione, TBARS, and glutamine and glutamate amino acids were measured. Six patients died during the study. Thirty patients finished the study, 16 men (53%) and 14 (47%) women, median age 74.4 years (30-92 years) in moderately severe state of health (APACHE II 13.1 - range 10-19). All patients developed SIRS and were given enteral nutrition supplemented with L-glutamine or calcium caseinate, 1464kcal/day (range 792-1914kcal/day). The use of L-glutamine in nutraceutical dose of 30g/day showed no changes in blood parameters. All laboratory parameters remained within normal values except the blood urea [Calcium Caseinate T1=47.0mg/dL (range 34.0-69.0 mg/dL) versus Glutamine T1=50.0mg/dL (36.75-75.0mg/dL); p=0.030]. Creatinine concentrations were not statistically different. There was no statistically significant difference in assessment of inflammatory parameters (IL-1, IL-6, IL-10 E TNF&#945;). Leukocytes count decreased significantly in both groups [Calcium Caseinate T0=13.650 1/mm3 (10.148-18.250 1/mm3) versus T1=11.500 1/mm3 (8.050-29.100 1/mm3); p=0,019] and [Glutamine T0=12.850 1/mm3 (11.155-15.550 1/mm3) versus T1=11.000 1/mm3 (9.200-16.325 1/mm3); p=0.046]. There was increase statistically significant difference in lymphocytes count between groups [Calcium Caseinate T1=1085 1/mm3 (range 805-1363 1/mm3) versus Glutamine T1=1916 1/mm3 (1301-2517 l/mm3); p<0.0001] and Calcium Caseinate group decreases [T0=1288 1/mm3 (range 834-2209 1/mm3) versus T1=1085 1/mm3 (range 805-1363 1/mm3); p=0.0324] and Glutamine group increases [T0=954 1/mm3 (range 785-1442 1/mm3) versus T1=1916 1/mm3 (range 1301-2517 l/mm3); p<0.0001]. Blood concentration of TBARS decreased significantly in both groups [Calcium Caseinate T0=20.56&#61549;mol MDA/ml (range 13.64-20.56&#61549;mol MDA/ml); p=0.001] and [Glutamine T0=17.67 &#61549;mol MDA/ml (range 8.11-34.98 &#61549;mol MDA/ml) versus T1=16.52 &#61549;mol MDA/ml (range 5.41-21.86 &#61549;mol MDA/ml); p=0.020]. The blood concentrations of Gluthatione showed a statistically significant reduction in caseinate group (T0=486.0&#61549;mol/ml (range 486.0Â165.8&#61549;mol/ml versus T1=451.0Â167.4&#61549;mol/ml; p=0.047) and no statistically significant difference in the glutamine group, nor between groups. However, there were no differences between groups. Glutamine and glutamate were not statistically different. Enteral nutrition supplemented with glutamine in nutraceutical doses of 30g/day increase lymphocyte count, helps to reduce lipid peroxidation and maintains the antioxidant glutathione capacity, interfering beneficially modulating the inflammatory response and stress, but present no effect upon cytokines concentrations or glycolytic parameters. / A SÃndrome da Resposta InflamatÃria SistÃmica (SRIS) caracteriza-se por uma liberaÃÃo excessiva de mediadores inflamatÃrios a uma sÃrie de situaÃÃes clÃnicas graves. A utilizaÃÃo da glutamina em doses nutracÃuticas tem sido estudada como uma estratÃgia de proteÃÃo tecidual e metabÃlica em situaÃÃes de estresse, melhorando a resposta imune de pacientes. Os efeitos da nutriÃÃo enteral suplementada com 30g/dia de glutamina sobre os marcadores inflamatÃrios, do metabolismo glicolÃtico, da funÃÃo imune e do estresse oxidativo foram estudados em pacientes adultos e idosos com SRIS. Foi realizado estudo clÃnico prospectivo, randomizado, controlado, duplo-cego, cruzado. Trinta e seis pacientes internados em Unidade de Terapia Intensiva foram selecionados pelos critÃrios do estudo, diagnÃstico da SRIS e score APACHE II (>10<20), distribuÃdos em dois grupos e submetidos à suplementaÃÃo com 1 litro de dieta enteral suplementada com 30g de L-glutamina ou caseinato de cÃlcio ou 1 litro de dieta enteral suplementada com 30g de caseinato de cÃlcio ou L-glutamina por dois dias, intervalo de um dia somente com dieta, perfazendo quatro dias de dieta com suplementaÃÃo. Amostras de sangue foram coletadas antes (T0) e apÃs (T1) cada suplementaÃÃo. Foram realizadas anÃlises do hematÃcrito, leucÃcitos, linfÃcitos, monÃcitos, prÃ-albumina, urÃia, creatinina, glicose, lactato, peptÃdeo-C e insulina, das IL-1, IL-6, IL-10, TNF&#945;, glutationa, TBARS e dos aminoÃcidos glutamina e glutamato. Seis pacientes foram a Ãbito durante o estudo e trinta pacientes concluÃram o estudo, sendo 16(53%) homens e 14(47%) mulheres, mediana de idade 74,4 anos (30-92 anos), moderadamente graves, mediana de APACHE II 13,1 (10-19) e mediana de ingestÃo calÃrica de 1464kcal/dia (792-1914kcal/dia). O uso L-glutamina em dose nutracÃutica de 30g/dia nÃo mostrou alteraÃÃes nos parÃmetros hematolÃgicos. Houve aumento da urÃia [Caseinato T1=47,000mg/dL (34,000-69,000mg/dL) versus Glutamina T1=50,000mg/dL (36,750-75,000mg/dL); p=0,030] na comparaÃÃo intergrupos, mas nÃo houve diferenÃa estatisticamente significante de creatinina em nenhum dos grupos. NÃo houve alteraÃÃo estatisticamente significante nos parÃmetros inflamatÃrios (IL-1, IL-6, IL-10 e TNF&#945;). A contagem de leucÃcitos diminuiu significantemente em ambos os grupos [Caseinato T0=13.650 1/mm3 (10.148-18.250 1/mm3) versus T1=11.500 1/mm3 (8.050-29.100 1/mm3); p=0,019] e [Glutamina T0=12.850 1/mm3 (11.155-15.550 1/mm3) versus T1=11.000 1/mm3 (9.200-16.325 1/mm3); p=0,046]. Houve aumento estatisticamente significante na contagem de linfÃcitos na comparaÃÃo intergrupos [Caseinato T1=1.085 1/mm3 (805-1.363 1/mm3) versus Glutamina T1=1.916 1/mm3 (1.301-2.517 l/mm3); p<0,0001], uma diminuiÃÃo estatisticamente significante no grupo Caseinato [T0=1.288 1/mm3 (834-2.209 1/mm3) versus T1=1.085 1/mm3 (805-1.363 1/mm3); p=0,0324] e aumento no grupo Glutamina [T0=954 1/mm3 (785-1.442 1/mm3) versus T1=1.916 1/mm3 (1.301-2.517 l/mm3); p<0,0001]. Observou-se reduÃÃo estatisticamente significante na dosagem do TBARS na comparaÃÃo intragrupos [Caseinato T0=20,56&#61549;mol MDA/ml (13,64-20,56&#61549;mol MDA/ml) versus T1=15,08 &#61549;mol MDA/ml (13,64-20,56 &#61549;mol MDA/ml); p=0,001] e [Glutamina T0=17,67 &#61549;mol MDA/ml (8,11-34,98 &#61549;mol MDA/ml) versus T1=16,52 &#61549;mol MDA/ml (5,41-21,86 &#61549;mol MDA/ml); p=0,020], mas nÃo houve diferenÃas intergrupos. A concentraÃÃo sanguÃnea de glutationa apresentou uma reduÃÃo estatisticamente significante no grupo Caseinato (T0=486,00&#61549;mol/mlÂ165,80&#61549;mol/ml) versus T1=451,00Â167,40&#61549;mol/ml; p=0,047) e nÃo houve diferenÃa no grupo Glutamina, tampouco entre os grupos. Glutamina e glutamato nÃo demonstraram diferenÃas estatisticamente significantes. Conclui-se que a nutriÃÃo enteral suplementada com glutamina em dose nutracÃutica de 30g/dia em pacientes moderadamente graves promove um aumento dos linfÃcitos, contribui para reduzir a peroxidaÃÃo lipÃdica e mantÃm a capacidade antioxidante da glutationa, interferindo de forma benÃfica na modulaÃÃo da resposta inflamatÃria e do estresse, mas nÃo apresenta nenhum efeito sobre a concentraÃÃo de citocinas ou parÃmetros glicolÃticos.

Tumor biopsies may help to reliably distinguish hepatocellular carcinoma (HCC) from other tumors, mostly cholangiocarcinoma as well as to identify the patient populations who most benefit from target-driven HCC treatments, in order to improve the success rate of experimental therapies. Clarifying tumor biology may also lead to identify biomarkers with prognostic role and/or enabling to predict response or resistance to therapies. Recently, clinical trials have more efficiently included biomarker endpoints and increasingly collected tumor tissue from enrolled patients. Due to their frail status and sometimes fast-progressing disease, the performance status of patients with HCC progressing on first-line therapy can deteriorate quickly, preventing their enrollment in clinical trials. However, the challenge of identifying the proper patient at the proper time can be overcome by periodic inter-department meetings involving the key specialists taking care of HCC patients, and solid networks between research centers and referring institutions. An early planned biopsy would also facilitate timely inclusion of patients in biology-driven clinical trials. Ultimately, institution of multidisciplinary teams can optimize treatment choice, biopsy timing, and quick enrollment of patients in clinical trials, before their performance status deteriorates.

Background: People with Multiple Sclerosis experience difficulties with balance and mobility. Pilates exercises are often used to address these difficulties. Design: This was a multi-centre, double blind, block randomised, controlled trial. Eligible participants were recruited from seven UK centres. Participants were randomly allocated to either: Pilates based core stability training (Pilates), Standardised Exercise (SE) or Relaxation (placebo). All received face-to-face training sessions over a 12 week period; together with a home exercise programme. Blinded assessments were taken before training, at the end of the 12 week programme and at 16 weeks (follow-up). The primary outcome measure was the 10metre timed walk (10mtw). Secondary outcome measures were the MS walking Scale (MSWS-12), Functional Reach Test (FRT ) (forwards and lateral), a 10 point Visual Analogue Scale (VAS) to determine “Difficulty in carrying a drink when walking”, and the Activities-specific Balance Confidence (ABC) Scale. Effects on deep abdominal muscles were measured with ultrasound imaging (USI) in a subgroup of patients. Independent t-tests were performed to compare groups. Sensitivity analyses were undertaken to confirm the results. A mixed factorial ANOVA analysed the effect of intervention over time upon TrAb and IO upon USI. Results: Of the 100 participants recruited, 13 relapsed leaving 94 for intention to treat analysis. At 12 weeks there were significant differences between: (1) Pilates and Relaxation for walking velocity (p=0.04), forward (p=0.04) and lateral (p=0.04) FRT. (2) SE and Relaxation for all measures (p < 0.05) apart from the VAS. These remained at 16 weeks for 10mtw (p=0.04), LFR (p < 0.01) MSWS-12 (p=0.03) and ABC (p = 0.03). There were no significant interactions (p > 0.05) between groups or over time for TrAb and IO. Conclusions: Participants improved with both Pilates and SE in the short term; with broader and longer-lasting effects in the SE group. USI did not detect any effect of group over time.

BACKGROUND: Multiple myeloma is a rare form of cancer that affects the proper function of plasma cells in the immune system. Patients experience symptoms ranging from bone pain to otherwise avoidable infections that can have negative effects on quality of life. Despite advances in multiple myeloma treatment leading to longer patient survival, it is still an incurable form of blood cancer. As a result, it is important for researchers to constantly investigate new avenues of treatment in order to delay disease progression. This study investigated whether the next generation proteasome inhibitor, ixazomib, could safely delay disease progression in patients who failed a combination regimen that included either the proteasome inhibitor bortezomib or carfilzomib. METHODS: This study is a phase 1/2, 3+3 design, intra-patient, multicenter, open-label, and non-randomized clinical trial that recruited patients that were previously on one of ten combination treatments containing the proteasome inhibitors bortezomib or carfilzomib. Patients must have shown progressive disease while on this treatment in order to qualify. They were given the same drugs and doses they were previously taking except that the proteasome inhibitor was replaced with ixazomib. The safety and efficacy measurements were taken periodically to assess patients’ disease burden. To assess safety, adverse events (AEs) and serious adverse events (SAEs) were recorded, codified, and quantified for analysis. In addition, the maximum tolerated dose (MTS) of ixazomib for three regimens for which it was unknown was investigated through the analysis of dose limiting toxicities (DLTs). Clinical benefit rate (CBR) and overall response rate (ORR) using response data were also determined. Lastly, Kaplan-Meir statistical analysis was used to calculate the secondary efficacy endpoints such as progression free survival (PFS) using data collected throughout the trial. RESULTS: Safety: 24.4% of patients experienced at least one ≥ Grade 3 serious adverse event, 33.3% experienced at least one ≥ Grade 3 adverse event, and two experienced dose limiting toxicities. Efficacy: ORR was 13.2% and the CRR was 18.4%. Median PFS was 2.1 months, duration of response (DOR) was 2.0 months, and overall survival (OS) was 7.9 months. However, the MTD of ixazomib for the three regimens which it was unknown for was not found due to the nature of the data distribution. CONCLUSION: The results indicated that ixazomib is not an effective replacement for bortezomib or carfilzomib in combination treatments containing these drugs, which is apparent from low primary and secondary efficacy endpoints. However, due to a low occurrence of adverse events, serious adverse events, and dose limiting toxicities safety was confirmed. In addition, physicians should determine the MTD on a case by case basis through individual dose escalations if ixazomib is to be used in this context.

Treatment of duodenal ulcer with the histamine H2-receptor antagonist, ranitidine, was assessed in a double-blind, randomized, multicenter trial in which patients were treated for two consecutive 4-week periods with ranitidine 150 mg b.i.d. or a placebo. All patients were allowed to take antacids as necessary for symptoms. Three hundred eighty-two patients were entered and 355 completed the first 4-week trial period. Ranitidine significantly improved healing at 2 weeks (37 versus 19%, p < 0.01) and at 4 weeks (73 versus 45%, p < 0.01), with better relief of pain and lower use of antacids. In the second 4-week trial period, 124 unhealed patients from the first 4 weeks were re-randomized. Ranitidine treatment resulted in a greater healing rate regardless of previous treatment (p < 0.05). In this trial, side effects were uncommon and not different between placebo and the tested drug. One case of hepatitis in the ranitidine treated group was presumed on the evidence to be non-A non-B. Ranitidine is effective and appears to be safe in the treatment of duodenal ulcer and its symptoms.