gemcitabine

fluorouracil

Current and emerging treatments for pancreatic cancer. The worldwide annual pancreatic cancer death rate equals its estimated annual incidence. Surgery has been considered the only curative modality for this disease, but only 5 to 15% of patients are candidates for potentially curative resection. Evidence that postoperative adjuvant treatment improves outcome has been limited to a single randomised trial of a well tolerated split-course chemoradiation regimen. More intensive regimens have since been developed and are associated with, at best, a modest improvement in patient outcome. The potentially significant morbidity associated with pancreaticoduodenectomy, which can compromise the delivery of postoperative adjuvant chemoradiation, has led to the development of preoperative adjuvant ('neoadjuvant') chemoradiation in these patients. Although experience suggests that such an approach is feasible, its ultimate impact awaits further evaluation. Combined modality therapy has produced the most promising results in patients with unresectable or locally advanced disease. However, only modest improvements in median survival and minimal increases in long term survival have so far been achieved. This observation has encouraged many investigators to devise innovative methods of delivering therapy, including radioisotope implantation and intraoperative radiation therapy (IORT). Combined modality therapy with radioisotope implantation appears to have the greatest potential for improving local control and survival in these patients. IORT may be associated with lower morbidity than radioisotope implantation, but its impact may be limited by the radiobiological disadvantage associated with single dose boost therapy. Although new radiosensitising drugs are being tested, the problem of distant metastasis remains significant. New chemotherapeutic agents such as gemcitabine appear to have the potential to produce better results than those achieved over the last 35 years with fluorouracil . Investigations into the optimal integration of different therapeutic modalities, along with continued advances in surgery, radiation and systemic therapy, should lead to the increased use of modern multimodality interventions. In turn, this will lead us towards further improvements in outcomes for patients with pancreatic carcinoma.


rituximab

abatacept

tocilizumab

Comparative effectiveness of rituximab , abatacept , and tocilizumab in adults with rheumatoid arthritis and inadequate response to TNF inhibitors : prospective cohort study . To compare the effectiveness and safety of three non-tumour necrosis factor (TNF) α inhibitors (rituximab, abatacept, and tocilizumab) in the treatment of rheumatoid arthritis. ### design Population based prospective study. ### setting 53 university and 54 non-university clinical centres in France. ### participants 3162 adults (>18 years) with rheumatoid arthritis according to 1987 American College of Rheumatology criteria, enrolled in one of the three French Society of Rheumatology registries; who had no severe cardiovascular disease, active or severe infections, or severe immunodeficiency, with follow-up of at least 24 months. ### intervention Initiation of intravenous rituximab, abatacept, or tocilizumab for rheumatoid arthritis. ### Main Outcome Measure The primary outcome was drug retention without failure at 24 months. Failure was defined as all cause death; discontinuation of rituximab, abatacept, or tocilizumab; initiation of a new biologic or a combination of conventional disease modifying antirheumatic drugs; or increase in corticosteroid dose >10 mg/d compared with baseline at two successive visits. Because of non-proportional hazards, treatment effects are presented as life expectancy difference without failure (LED ### results Average durations of survival without failure were 19.8 months for rituximab, 15.6 months for abatacept, and 19.1 months for tocilizumab. Average durations were greater with rituximab (LED ### conclusion Among adults with refractory rheumatoid arthritis followed-up in routine practice, rituximab and tocilizumab were associated with greater improvements in outcomes at two years compared with abatacept.


halothane

reserpine

halothane

haloperidol

veratridine

raclopride

Extracellular levels of glutamate and aspartate in the entopeduncular nucleus of the rat determined by microdialysis: regulation by striatal dopamine D2 receptors via the indirect striatal output pathway? This study used intracerebral microdialysis to monitor the outputs of excitatory amino acids in the entopeduncular nucleus (EPN) of conscious or halothane-anaesthetized rats, in an attempt to obtain direct biochemical evidence for the theory that neuronal inputs to the EPN by the indirect striatal output pathway are glutamatergic and regulated primarily by dopamine D2 receptors in the striatum. In dopamine-intact animals, both glutamate and asparate were readily detectable in EPN dialysates. Recoveries of both amino acids were increased bilaterally by local perfusion with veratridine ( 100 microM , given under halothane anaesthesia ) , pretreatment with reserpine ( 4 mg/kg , i.p . , 24 h beforehand ) , unilateral pretreatment of the medial forebrain bundle with 6-OHDA ( 8 microg/4 microl ) , and by the systemic ( 1 mg/kg , i.p . ) or bilateral intrastriatal ( 7 microg/0.5 microl under halothane anaesthesia ) administration of the dopamine D2 receptor antagonist haloperidol , but not raclopride ( 2 mg/kg , i.p . ) . The dopamine D1 receptor antagonist SCH 23390 was ineffective both systemically (0.25 mg/kg, i.p.) and intrastriatally (0.125 microg/0.5 microl/side), as also were control intrastriatal injections of saline (0.5 microl/side). By contrast, the dopamine D2/3 receptor agonist quinpirole (4 mg/kg, i.p.) lowered the outputs of glutamate and aspartate in the EPN of reserpine-treated and normal individuals, whilst the dopamine D1 receptor agonist SKF 38393 (30 mg/kg, i.p.) was inactive; however, both drugs caused behavioural arousal. The dopamine D2/3 receptor agonist RU 24213 reversed reserpine-induced akinesia, yet paradoxically increased glutamate (not aspartate) output in the EPN still further. The combination of benserazide (30 mg/kg, i.p.) and L-DOPA (50 mg/kg, i.p.) evoked intense contraversive circling in unilaterally 6-OHDA-lesioned rats, together with a drop in EPN glutamate (but not aspartate) output in the intact but not lesioned hemisphere. These results offer biochemical support for the hypothesis that excitatory neurones innervating the EPN via the indirect striatal output pathway, may utilise glutamate and/or aspartate as their neurotransmitter. They further endorse the view that the EPN receives information from striatal D2 and not D1 receptors via excitatory synapses, which become hyperactive following dopamine depletion or inactivation, and which are subject to control by the contralateral as well as by the ipsilateral hemisphere. The results obtained with RU 24213 and L-DOPA, however, indicate that dopaminergic behaviours can also occur independently of glutamate or aspartate release in the EPN.


cyclophosphamide

methylprednisolone

Combined initial cyclophosphamide with repeated methylprednisolone pulse therapy for severe paraquat poisoning from dermal exposure . The article presents a patient with severe paraquat poisoning from dermal exposure, who had chemical bums to more than 10% of his body surface area, serum paraquat level 0.13 microg/mL 60 hr after exposure, and severe hypoxemia (PaO2 41.6 mmHg). The patient was successfully treated with combined initial megadoses of cyclophosphamide (15 mg/kg/day, total 2 days) with repeated methylprednisolone pulse therapy (15 mg/kg/day, total 6 days) and continuous dexamethasone administration (5 mg every 8 hr), and recovered completely without sequelae 3 months later. This treatment deserves further investigation in future clinical trials.


docetaxel

pemetrexed

Crizotinib. Patients with advanced-stage or metastatic non-small cell lung cancer have a grim prognosis when first-line chemotherapy fails. Some cytotoxic drugs such as docetaxel and pemetrexed prolong overall survival by a few months, but at a cost of severe toxicity. crizotinib (Xalkori*, Pfizer), a drug that inhibits ALK (among other tyrosine kinases) has been authorised for use in patients whose tumours overexpress this tyrosine kinase. Preliminary results of a comparative, randomised but unblinded trial in 347 patients suggest that crizotinib delays cancer progression and death more effectively than pemetrexed or docetaxel (median 7.7 months versus 3 months). However, it remains to be seen whether or not this translates into longer overall survival. Two uncontrolled trials including 136 and 119 patients also suggest that crizotinib delays tumour progression and death by about 8 months. crizotinib is highly toxic, causing gastrointestinal, visual and hepatic disorders, cardiac arrhythmias (including QT prolongation) and pneumonia. These adverse effects were all more frequent than with docetaxel or pemetrexed . Some of these effects are more difficult to predict and manage than haematological disorders, which are the main adverse effects of docetaxel and pemetrexed. crizotinib is extensively metabolised by cytochrome P450 isoenzymes and also inhibits P-glycoprotein, creating a risk of numerous pharmacokinetic interactions. Other interactions, with drugs that prolong the QT interval, may increase the risk of serious adverse effects. In practice, in patients with non-small cell lung cancer overexpressing ALK tyrosine kinase in whom first-line chemotherapy has failed, crizotinib appears to delay cancer progression and death, but at a cost of serious adverse effects. Further evaluation of crizotinib in well-designed comparative trials is needed before deciding whether or not to include it in the therapeutic arsenal.


methotrexate

cytarabine

Relation between the duration of remission and hyperglycemia during induction chemotherapy for acute lymphocytic leukemia with a hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone/methotrexate-cytarabine regimen. Hyperglycemia, which is not uncommon during the treatment of acute lymphocytic leukemia (ALL), has been shown to be an independent predictor of adverse outcomes among hospitalized patients with undiagnosed diabetes; it also may have the potential to affect leukemic cell proliferation through altered metabolism. The purpose of the current study was to determine the prevalence of hyperglycemia during induction chemotherapy for ALL using a regimen comprised of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD) and to determine its effect on survival, duration of disease remission, and treatment-related complications. ### methods Two hundred seventy-eight adult patients with previously untreated ALL who achieved a complete remission with the hyper-CVAD regimen were evaluated. Hyperglycemia was defined as > or = 2 glucose determinations of > or = 200 mg/dL during the first 30 days of induction chemotherapy. Induction chemotherapy was comprised of fractionated cyclophosphamide at a dose of 300 mg/m2 twice daily on Days 1-3, doxorubicin at a dose of 50 mg/m2 on Day 4, vincristine at a dose of 2 mg on Days 4 and 11, and dexamethasone at a dose of 40 mg on Days 1-4 and Days 11-14 (hyper-CVAD). Hyper-CVAD , given in odd-number courses ( Courses 1 , 3 , 5 , and 7 ) , was alternated with methotrexate and cytarabine ( MTX/Ara-C ) , given in even-number courses ( Courses 2 , 4 , 6 , and 8) . MTX/Ara-C was comprised of MTX at a dose of 200 mg/m2 over 2 hours followed by 800 mg/m2 over 22 hours on Day 1, Ara-C at a dose of 3 g/m2 every 12 hours for 4 doses over 2 days (Days 2 and 3), and intravenous methylprednisolone given at a dose of 50 mg twice daily on Days 1-3. The complete remission duration (CRD), survival, and treatment-related complications were determined for patients with and without hyperglycemia; differences between the two groups were assessed using standard statistical methods. ### results Hyperglycemia was found to occur in 103 patients (37%). Patients with hyperglycemia had a shorter median CRD (24 months vs. 52 months; P = 0.001) and a shorter median survival (29 months vs. 88 months; P < 0.001); they also were more likely to develop sepsis (16.5% vs. 8.0%; P = 0.03) or any complicated infection (sepsis, pneumonia, or fungal) (38.8% vs. 25.1%; P = 0.016) compared with patients without hyperglycemia. ### conclusions Patients with hyperglycemia during induction chemotherapy for ALL with the hyper-CVAD regimen were found to have a shorter CRD, experience a significant increase in overall mortality, and be at an increased risk for developing complicated infections.


pemetrexed

bevacizumab

Cisplatinum

The necessity of a more aggressive initial surgical treatment in patients with mesothelioma of the testicular tunica vaginalis. Mesothelioma of the tunica vaginalis of the testis (MTVM) is a rare tumor encountering for less than 1% of mesothelioma. Patients suffering from these tumors have poor survival due to local and distant metastasis despite treatment. Actually, no specific treatment recommendations exist for this tumor, yet radical orchidectomy is the gold standard in limited disease. We herein report the case of a 71 patient with MTVM who underwent radical orchidectomy without inguinal lymph node dissection and recurred 2 years later with metastasis in pelvic and mediastinal lymph nodes. Despite systemic chemotherapy combining pemetrexed , bevacizumab and Cisplatinum , the disease relapsed eight months later with multiple metastatic lung nodules leading to a treatment shift . We believe that systematic inguinal-iliac lymph node resection should be included in the initial treatment of this tumor.


Trastuzumab

lapatinib

Effects of lapatinib or trastuzumab, alone and in combination, in human epidermal growth factor receptor 2-positive breast cancer: a meta-analysis of randomized controlled trials. This meta-analysis compared the efficiency and safety of lapatinib and trastuzumab, alone or in combination, administered with neoadjuvant chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. For dichotomous variables, the relative risk ratio (RR) and 95% confidence interval (CI) were used to investigate outcome measures: pathological complete response (pCR), neutropenia, diarrhea, dermatologic toxicity, and congestive heart failure (CHF). Eight randomized controlled trials of 2350 participants (837 receiving lapatinib, 913 trastuzumab, and 555 combination therapy) were selected to compare the efficiency and safety of lapatinib to trastuzumab. A significant difference was found between lapatinib and trastuzumab for pCR (RR = 0.82, 95% CI: 0.73-0.93; Z = 3.00; P = 0.003). In six studies, a significant difference was found between trastuzumab and combination therapy for pCR (RR = 1.33, 95% CI: 1.18-1.50; Z = 4.70; P < 0.00001), diarrhea (RR = 14.59, 95% CI: 7.69-27.67; Z = 8.20; P < 0.00001), and dermatologic toxicity (RR = 3.10, 95% CI: 1.61-5.96; Z = 3.39; P = 0.007), but none was found for neutropenia (RR = 1.38, 95% CI: 0.82-2.31; Z = 1.22; P = 0.22) or CHF (RR = 0.14, 95% CI: 0.02-1.17; Z = 1.02; P = 0.07). Combination therapy compared to trastuzumab alone increases the pCR rate of HER2-positive breast cancer patients with no additional cardiac events. Trastuzumab , which is still the first-line therapy in breast cancer , increases the pCR rate more than lapatinib .


irinotecan

oxaliplatin

raltitrexed

Novel agents for colorectal cancer. The compound 5-fluorouracil (5-FU) has been investigated for over four decades; research has focussed on examining various schedules and biochemical modulators in an attempt to improve its therapeutic activity in advanced colorectal cancer. Combination chemotherapy regimens have not been developed because of the lack of other active agents. Recently , several novel agents are under clinical development for advanced colorectal cancer , including irinotecan , oxaliplatin , oral fluoropyrimidines , raltitrexed , monoclonal antibody 17 - 1A and tumour vaccines . Both irinotecan and oxaliplatin have uniquely different mechanisms of action compared to 5-FU, and have demonstrated activity in patients whose disease has progressed with 5-FU treatment. Recent randomised trials comparing 5-FU plus leucovorin (5-FU/LV) to combinations of either irinotecan or oxaliplatin plus 5-FU/LV have demonstrated that the addition of these novel agents to 5-FU improve response rates (RRs) and time to progression (TTP). The role and acceptance of these combinations need to be defined, but are rapidly being introduced into the adjuvant therapy of colorectal cancer. Oral fluoropyrimidines (UFT plus leucovorin, capecitabine, eniluracil plus oral 5-FU, and S-1) provide the convenience of oral delivery with a marked reduction in febrile neutropenia and mucositis. To gain clinical acceptance, oral fluoropyrimidines must provide not only convenience and toxicity reduction, but also maintenance of survival advantages associated with optimal use of iv. 5-FU/LV regimens. These novel agents discussed herein provide treatment options which may allow for more individualised treatment strategies.


SKF 525A

piperonyl butoxide

progesterone

cysteamine

phenobarbital

metyrapone

Inhibition by metyrapone of the accumulation of nicotine-14C in bronchial epithelium of mice. Further studies have been conducted in an attempt to define the mechanism of the intense accumulation of radioactivity in bronchial epithelium following the administration of nicotine-14C to mice. Male and female pigmented (C57B1/6J) and nonpigmented (A/HeJ) mice were studied by whole-body autoradiography following administration of either nicotine-14C (methyl- or 2'-labeled) or nicotine-1'-N-oxide-14C. When each of these compounds was administered at the same specific activity the radioactivity retained in the bronchial epithelium was much greater for the methyl-labeled nicotine-14C than for the ring-labeled. Following administration of the N-oxide very little radioactivity was retained at this site and this was seen only at a few time intervals. Pretreatment with NaHCO3 , NH4Cl , SKF 525A , piperonyl butoxide , progesterone , cysteamine , phenobarbital or metyrapone prior to the administration of [methyl-14C]nicotine was studied . metyrapone totally prevented the accumulation of radioactivity in the bronchial epithelium and progesterone reduced this accumulation; the other substances used for pretreatment had no effect on the uptake of radioactivity. These results are interpreted to indicate that the accumulation of nicotine in bronchial epithelium is not accounted for by transcellular pH gradients but is due to a high affinity of nicotine for a cytochrome P-450 in this tissue which demethylates the nicotine. The relationship and significance of metabolism of nicotine in this tissue to metabolism at other sites in the body are discussed.


Capecitabine

fluorouracil

[New drugs for colorectal cancer]. Drug treatment of colorectal cancer has made impressive progress during the past 10 years. In addition to fluorouracil new anticancer drugs like irinotecan and oxaliplatin have become available. The activity of fluorouracil was optimized by using schedules of prolonged infusion. Capecitabine is an oral pro-drug of fluorouracil . When colorectal metastases are limited to the liver they should be resected if possible. Sometimes they can be reduced in size by primary chemotherapy (downstaging) and resected later. Very new and exciting are reports with the monoclonal antibody bevacizumab in combination with chemotherapy. bevacizumab blocks angiogenesis. So far it is available only in the USA.


artemisinin

lumefantrine

A rapid stability-indicating, fused-core HPLC method for simultaneous determination of β-artemether and lumefantrine in anti-malarial fixed dose combination products. artemisinin-based fixed dose combination (FDC) products are recommended by World Health Organization (WHO) as a first-line treatment. However , the current artemisinin FDC products , such as β-artemether and lumefantrine , are inherently unstable and require controlled distribution and storage conditions , which are not always available in resource-limited settings . Moreover, quality control is hampered by lack of suitable analytical methods. Thus, there is a need for a rapid and simple, but stability-indicating method for the simultaneous assay of β-artemether and lumefantrine FDC products. ### methods Three reversed-phase fused-core HPLC columns (Halo RP-Amide, Halo C18 and Halo Phenyl-hexyl), all thermostated at 30°C, were evaluated. β-artemether and lumefantrine (unstressed and stressed), and reference-related impurities were injected and chromatographic parameters were assessed. Optimal chromatographic parameters were obtained using Halo RP-Amide column and an isocratic mobile phase composed of acetonitrile and 1 mM phosphate buffer pH 3.0 (52:48; V/V) at a flow of 1.0 ml/min and 3 μl injection volume. Quantification was performed at 210 nm and 335 nm for β-artemether and for lumefantrine, respectively. In-silico toxicological evaluation of the related impurities was made using Derek Nexus v2.0®. ### results Both β-artemether and lumefantrine were separated from each other as well as from the specified and unspecified related impurities including degradants. A complete chromatographic run only took four minutes. Evaluation of the method, including a Plackett-Burman robustness verification within analytical QbD-principles, and real-life samples showed the method is suitable for quantitative assay purposes of both active pharmaceutical ingredients, with a mean recovery relative standard deviation (± RSD) of 99.7 % (± 0.7%) for β-artemether and 99.7 % (± 0.6%) for lumefantrine. All identified β-artemether-related impurities were predicted in Derek Nexus v2.0® to have toxicity risks similar to β-artemether active pharmaceutical ingredient (API) itself. ### conclusions A rapid, robust, precise and accurate stability-indicating, quantitative fused-core isocratic HPLC method was developed for simultaneous assay of β-artemether and lumefantrine. This method can be applied in the routine regulatory quality control of FDC products. The in-silico toxicological investigation using Derek Nexus® indicated that the overall toxicity risk for β-artemether-related impurities is comparable to that of β-artemether API.


vincristine

doxorubicin

cyclophosphamide

ifosfamide

etoposide

A case of desmoplastic small round cell tumor diagnosed in a young female patient. Desmoplastic small round cell tumor is a very rare malignancy. We report the case of a 26-year-old woman who suffered from dyspepsia and abdominal pain for 2 months. We performed an endoscopic biopsy of the duodenal mass and diagnosed her disease as desmoplastic small round cell tumor using immunohistochemical staining, fluorescence in situ hybridization, and reverse transcriptase polymerase chain reaction. Because the mass invaded the pancreas and superior mesenteric vein as well as duodenum and the disease was disseminated to liver and peritoneum , she received palliative chemotherapy using vincristine , doxorubicin , cyclophosphamide , ifosfamide , and etoposide . The maximal response to chemotherapy was stable disease. The patient expired 9 months after diagnosis.


boceprevir

telaprevir

pegylated interferon

ribavirin

[Treatment of chronic hepatitis C in human immunodeficiency virus infected patients]. Treatment of HCV infection offers the possibility of viral eradication, thus every person with a detectable HCV viral load is a candidate for treatment. Treatment is recommended to all HCV/HIV co-infected patients with: 1) repeatedly elevated aminotransferase levels; 2) F2 stage of liver fibrosis or higher, regardless of alanine aminotransferase values; and 3) more than 200 CD4+ lymphocytes per microL of blood. Treatment with a combination of pegylated interferon and weight-based ribavirin (1000 mg/day if < 75 kg and 1200 mg/day if > 75 kg) is recommended. Pegylated interferon is used as 180 microg for the alfa-2a form and 1.5 mg/kg for the alfa-2b form once weekly subcutaneously. HCV RNA should be measured after 4 weeks of treatment, and later as needed, in weeks 12, 24, 48 or 72. For evaluation of a sustained virologic response, HCV RNA should be measured 24 weeks after the end of treatment. Treatment duration for patients who have a rapid viral response (undetectable levels of HCV RNA after 4 weeks of treatment) is 24 weeks (genotypes 2 and 3) or 48 weeks (genotypes 1 and 4). For patients without a rapid virologic response, but with an adequate response after 12 and 24 weeks, we generally recommend treatment for 48 weeks. Treatment discontinuation is recommended for patients with < 2 log viral load decline after 12 weeks or with a detectable viral load after 24 weeks of treatment. In HCV genotype 1 infection and F3 or F4 liver fibrosis , treatment with boceprevir or telaprevir in addition to pegylated interferon and ribavirin is recommended . In case of persistent HCV replication during therapy stopping rules should be applied.


reserpine

nicardipine

verapamil

trifluoperazine

[Possibility of overcoming of ACNU resistance in an ACNU-resistant subline of C6 rat glioma].  Membrane-modifying agents such as reserpine , calcium antagonists ( nicardipine , verapamil ) and calmodulin inhibitor ( trifluoperazine ) were found to enhance the cytotoxicity of ACNU in vitro and in vivo in ACNU-resistant C 6 ( C 6/ACNU ) glioma . In in vitro experiments, uptake and retention studies with [14C] ACNU revealed that intracellular uptake and retention of ACNU in C 6 cells were larger than those in C 6/ACNU cells, and that these membrane-modifying agents increased the cellular uptake and retention of ACNU in C 6, especially in C 6/ACNU cells. The amount of ACNU in C 6/ACNU cells reached the same level as that detected in C 6/ACNU cells. When these drugs were added along with ACNU at the concentration of 10 to 20 microM to the culture in vitro, ACNU resistance was completely overcome. In in vivo experiment, reserpine, nicardipine, verapamil and trifluoperazine in doses 250 to 500 micrograms/kg intrathecally administered with 1 mg/kg ACNU 1 day after the tumor inoculation significantly enhanced the chemotherapeutic effect of ACNU in C 6/ACNU bearing (C 6/ACNU-MG) rats. It might be concluded that the mechanism of enhancement of ACNU cytotoxicity presented in in vitro and in vivo is explained by the enhanced accumulation of ACNU by these membrane-modifying agents in C 6, especially in ACNU-resistant (C 6/ACNU) cells, and, furthermore, that combination chemotherapy with ACNU and such membrane interacting drugs as reserpine, calcium antagonists (nicardipine, verapamil) and calmodulin inhibitor (trifluoperazine) could lead to the capability of overcoming resistance to ACNU in glioma.


temozolomide

procarbazine

vincristine

Temozolomide as a second-line systemic regimen in recurrent high-grade glioma: a phase II study.  To investigate the efficacy of temozolomide in relation to response rate , toxicity , time to progression . and median survival time , a phase II study was conducted in patients with recurrent high-grade glioma following surgery plus radiotherapy and first-line chemotherapy based on nitrosourea , procarbazine and vincristine . ### Patients And Methods Forty-one patients with high-grade glioma, at second recurrence or progression, of which twenty-two (54%) had glioblastoma multiforme, ten (24%) anaplastic astrocytoma, and nine (22%) anaplastic oligodendroglioma were administered temozolomide, 150 mg/m2/daily for five days every four weeks. ### results Response was assessed in 40 patients. The overall response rate (complete + partial response) was 22.5% (95% confidence interval (CI): 9.5%-35%). The median time to progression for all 41 patients was 22.3 weeks; progression-free survival at 6 and 12 months was 48.5% and 34.7%, respectively. Median survival time was 37.1 weeks with 80.2% at 6 and 34.9% survival at 12 months. ### conclusions On multivariate analysis, response to previous treatment was significant (P = 0.03) for time to progression and Karnofsky performance score for overall survivall (P = 0.002). temozolomide gave a moderate response rate with acceptable toxicity as second-line chemotherapy in patients with recurrent high-grade glioma.


Ketoconazole

genistein

H295R cells as a model for steroidogenic disruption: a broader perspective using simultaneous chemical analysis of 7 key steroid hormones. The effects of three model endocrine disruptors, prochloraz, ketoconazole and genistein on steroidogenesis were tested in the adrenocortical H295R cell line to demonstrate that a broader mechanistic understanding can be achieved in one assay by applying chemical analysis to the H295R assay. Seven key steroid hormones (pregnenolone, progesterone, dehydroepiandrosterone, androstenedione, testosterone, estrone and 17β-estradiol) were analyzed using a novel and thoroughly validated GC-MS/MS method. In addition to the simultaneous quantification of 7 steroid hormones, the present method also negates the potential problems of cross-reactivity that can be encountered in some immunoassays. Although all 3 test compounds decrease the concentrations of the main sex steroids, the chemicals exerted different effects upstream in the pathway. Exposure to prochloraz resulted in increased hormone levels upstream of steroid 17 alpha-hydroxylase/17,20 lyase (P450c17) and decreases downstream. Ketoconazole inhibited the entire pathway , while exposure to genistein resulted in increased hormone levels upstream of 3-β-hydroxysteroid dehydrogenase ( 3β-HSD ) and decreases downstream . The results demonstrate that chemical analysis combined with the H295R cell assay is an useful tool for studying the mechanisms by which endocrine disruptors interfere with the steroidogenic pathway.


Melphalan

cisplatin

carboplatin

doxorubicin

etoposide

Drug resistance in human neuroblastoma cell lines correlates with clinical therapy. To determine if neuroblastoma acquires a sustained drug-resistant phenotype from patient exposure to therapy, we studied neuroblastoma cell lines established at different points of therapy: at diagnosis prior to therapy, at progressive disease after induction therapy and at relapse after intensive chemoradiotherapy and bone marrow transplantation (post-BMT). Melphalan , cisplatin , carboplatin , doxorubicin , and etoposide cytotoxicities were determined by DIMSCAN assay . Drug resistance progressively increased with therapy and 3/5 post-BMT lines showed high resistance to most drugs. IC 90s 37, 78, 719 and 256 times higher than clinically achievable drug levels were obtained in post-BMT cell lines for melphalan, cisplatin, doxorubicin and etoposide, respectively. Resistance correlated with the therapies patients received: considerable etoposide and doxorubicin resistance (> 1000-fold resistance) was seen in cell lines obtained from patients treated with these drugs. These cell lines indicate that neuroblastoma acquires resistance to cytotoxic drugs that is probably due to stable genetic alterations occurring during therapy.


erlotinib

docetaxel

Clinical and biological significance of erlotinib therapy after pemetrexed in non-small cell lung cancer with wild-type EGFR. pemetrexed is a multi-targeted anti-folate agent that confers favorable benefits to patients with non-small cell lung cancer (NSCLC). However, the optimal use including treatment schedule of pemetrexed and other drugs in clinical practice remains to be determined, particularly for NSCLC with wild-type epidermal growth factor receptor (EGFR). The present study investigated a potential therapeutic strategy for NSCLC patients with wild-type EGFR who were treated with pemetrexed. To identify factors associated with a survival, medical record data from 130 patients were retrospectively reviewed, using the Kaplan-Meier method with log-rank test. Factors identified in the clinical analysis were further investigated within in vitro studies. Patients who underwent the treatment schedule of erlotinib at the time of progression after pemetrexed-based chemotherapy prolonged overall survival, compared to those treated with other schedules (p=0.010; hazard ratio, 0.418). This survival benefit was also observed in the treatment schedule of pemetrexed monotherapy and subsequent erlotinib (p=0.008; hazard ratio, 0.220). As a treatment at the time of progression after pemetrexed-based chemotherapy , erlotinib conferred a survival benefit when compared to docetaxel ( p=0.024 ; hazard ratio , 0.377 ) . The cell growth assay confirmed that treatment with pemetrexed followed by erlotinib significantly inhibited proliferation of NSCLC cells regardless of EGFR mutation status. In conclusion, use of erlotinib at the time of progression after pemetrexed therapy confers a survival benefit in NSCLC patients with wild-type EGFR. The result of this study provides an important clue to the optimal treatment schedule for NSCLC.


ifosfamide

etoposide

Ifosfamide plus oral etoposide salvage chemotherapy for platinum-resistant paclitaxel-pretreated ovarian cancer. The prognosis of platinum resistant ovarian cancer is very poor and the treatment of choice has not been clearly defined. ### Patients And Methods We conducted a phase II study with the combination of ifosfamide i.v. at 2.25 g/m2 (days 1, 2) and etoposide per os at 100 mg daily (days 1-10) every four weeks. To be eligible for the study patients had to be resistant to platinum and paclitaxel pretreated. ### results Forty-one patients entered the study. The median interval from the previous chemotherapy was 3.9 months. The median number of previous chemotherapeutic regimens was 2. Severe toxicities included neutropenia (41% of patients), leukopenia (29%) and thrombocytopenia (13%). Thirty-five patients are assessable for response. Nine patients responded (22% of the eligible, 26% of the assessable), four of them demonstrated complete response to chemotherapy (10% and 12%, respectively), while three patients demonstrated stabilization of their progressive disease. After a median follow-up of 18 months, time to progression is 3 months (range 0.9-14.4), duration of response is 9 months (2.5-11) and median survival is 13 months (2.5-37.4+). ### conclusions The combination of ifosfamide with oral etoposide appears to have significant but manageable toxicity and encouraging efficacy in platinum resistant ovarian cancer .


ranibizumab

aflibercept

Evaluation of outer retinal tubulations in eyes switched from intravitreal ranibizumab to aflibercept for treatment of exudative age-related macular degeneration. To evaluate the changes of outer retinal tubulations (ORTs) as seen on spectral-domain optical coherence tomography (SD OCT) in eyes with neovascular age-related macular degeneration (AMD) where treatment was switched from intravitreal ranibizumab to intravitreal aflibercept. ### methods This was a prospective study of eyes diagnosed with neovascular AMD and previously treated with >6 intravitreal ranibizumab injections and switched to aflibercept, conducted at a single centre (Department of Ophthalmology at Pitié Salpetriere Hospital, Paris VI University) from January to July 2015. Before and after treatment was switched from ranibizumab to aflibercept, SD-OCT was used to evaluate the presence of ORTs. Additional assessments in this patient group included best-corrected visual acuity (BCVA), fluorescein angiography (FA), indocyanine green angiography (ICGA). Changes in pigment epithelium detachments (PED), presence of intraretinal cysts, and presence of subretinal fluid (SRF) were also noted. ### results Twenty-four eyes of 24 consecutive patients (15 female/nine male, mean age 70 years) diagnosed with neovascular AMD and previously treated with >6 intravitreal ranibizumab injections and switched to aflibercept were included in the analysis. After receiving aflibercept, patients were followed for a mean of 6.1 months. Prior to treatment switch, 97 % of eyes showed ORTs, while after treatment switch to aflibercept, at the end of the study period, 75 % had ORTs (p =  0.219). Changes in BCVA (LogMAR) were not statistically significant (1.16 ± 0.44 to 1.18 ± 1.06, p =  0.12), however, a significant reduction in central macular thickness (CMT) (from 406 μm ± 112 to 263 μm ± 68, p =  0.001), PED (from 70.8 % to 41.7 % , p =  0.016), presence of intraretinal cysts (from 83.3 % to 33.3 %, p =  0.002) and SRF (from 91.7 % to 25 %, p = 0.001 ) were noted. ### conclusion After switching from ranibizumab treatment to aflibercept , ORTs remained present in 75 % of eyes , and significant reductions in CMT , PED , and SRF , and presence of intraretinal cysts were observed .


Vinorelbine

gemcitabine

docetaxel

paclitaxel

irinotecan

A brief historical review of the development of chemotherapy for the treatment of advanced non-small cell lung cancer: why we should look beyond platinum. We are approaching the end of the fifth decade and the most productive period in the development of chemotherapy for the treatment of advanced non-small cell lung cancer. We began this decade by establishing cisplatin-based combination chemotherapy regimens of the 1980s as effective at improving survival for patients with advanced disease. The observed improvement in survival from these trials appears to be primarily attributed to cisplatin. Furthermore, this decade, unlike the prior, has identified an abundance of novel active agents for the treatment of this disease. Vinorelbine , gemcitabine , docetaxel , paclitaxel , and irinotecan are all new chemotherapeutic agents which have shown promising activity in this disease . In contrast to the cisplatin-based chemotherapy trials of the 1980s, these newer chemotherapeutic agents when given in combination with cisplatin add to the survival outcomes for these patients. With these survival advances has come a focus on chemotherapy-induced adverse events, lung cancer symptom management, and overall quality of life. The results of the cisplatin combination trials will be discussed.


omeprazole

ritonavir

Effects of omeprazole and ritonavir on absorption and elimination of the hepatitis C virus NS5A inhibitor GSK2336805 in healthy adults.  This Phase I , randomized , open-label study evaluated the gastric pH-altering effects of omeprazole , a proton pump inhibitor , and the CYP3A enzyme/P-glycoprotein (Pgp)-inhibitory effects of ritonavir , an HIV protease inhibitor , on the pharmacokinetics and safety of the hepatitis C virus ( HCV ) non-structural protein 5A ( NS5A ) inhibitor GSK2336805 in healthy male and female subjects . Co-administration of GSK2336805 60 mg with omeprazole decreased GSK2336805 plasma AUC(0-∞) by 10% and Cmax by 18%; no marked effect was observed on t½ . Co-administration of GSK2336805 30 mg with ritonavir increased GSK2336805 plasma AUC(0-∞) by 52%, Cmax by 43%, and t½ by 40%; CL/F was decreased by 34%. All adverse events were minor in intensity. The gastric acid-suppressive effect of omeprazole had minimal impact on the extent and rate of GSK2336805 absorption in vivo; therefore, GSK2336805 may be co-administered with omeprazole without concern about lower GSK2336805 exposures and compromised antiviral efficacy. The modest increases in AUC and Cmax following co-administration of GSK2336805 plus ritonavir suggest that GSK2336805 when given concomitantly with a single CYP3A/Pgp inhibiting drug will not likely require dose adjustment. Final dose recommendation will be based on GSK2336805 efficacy and safety profiles from Phase III trials in HCV-infected patients.


chloroquine

hydroxychloroquine

azithromycin

Guidance on Minimizing Risk of Drug-Induced Ventricular Arrhythmia During Treatment of COVID-19: A Statement from the Canadian Heart Rhythm Society. The COVID-19 pandemic has led to efforts at rapid investigation and application of drugs which may improve prognosis but for which safety and efficacy are not yet established. This document attempts to provide reasonable guidance for the use of antimicrobials which have uncertain benefit but may increase risk of QT interval prolongation and ventricular proarrhythmia , notably , chloroquine , hydroxychloroquine , azithromycin , and lopinavir/ritonavir . During the pandemic, efforts to reduce spread and minimize effects on health care resources mandate minimization of unnecessary medical procedures and testing. We recommend that the risk of drug proarrhythmia be minimized by 1) discontinuing unnecessary medications that may also increase the QT interval, 2) identifying outpatients who are likely to be at low risk and do not need further testing (no history of prolonged QT interval, unexplained syncope, or family history of premature sudden cardiac death, no medications that may prolong the QT interval, and/or a previous known normal corrected QT interval [QTc]), and 3) performing baseline testing in hospitalized patients or those who may be at higher risk. If baseline electrocardiographic testing reveals a moderately prolonged QTc, optimization of medications and electrolytes may permit therapy. If the QTc is markedly prolonged, drugs that further prolong it should be avoided, or expert consultation may permit administration with mitigating precautions. These recommendations are made while there are no known effective treatments for COVID-19 and should be revisited when further data on efficacy and safety become available.


paclitaxel

sorafenib

Phase II study of weekly paclitaxel and sorafenib as second/third-line therapy in patients with adrenocortical carcinoma . There is a strong rationale in the use of antiangiogenic therapy in the management of adrenocortical carcinoma (ACC). Metronomic administration of chemotherapy and antiangiogenic drugs can be synergistic in targeting endothelial cells. ### objective We assessed the activity of sorafenib plus metronomic paclitaxel as second/third-line therapy in advanced ACC patients. We also tested the activity of sorafenib and paclitaxel against NCI-H295R in vitro. ### design Multicenter, prospective phase II trial. Setting Referral centers for ACC. ### methods Twenty-five consecutive metastatic ACC patients who progressed after mitotane plus one or two chemotherapy lines were planned to be enrolled. The patients received a combination of i.v. paclitaxel (60 mg/m(2) every week) and oral sorafenib (400 mg twice a day) till progression. The primary aim was to measure the progression-free survival rate after 4 months and the secondary aims were to assess the objective response rate and toxicity. ### results Tumor progression was observed in nine evaluable patients at the first assessment. These results led to the premature interruption of the trial. The treatment was well tolerated. The most relevant toxicities were fatigue, being grade 2 or 3 in four patients, and hypophosphatemia, being grade 3 in three patients. In the in vitro study, sorafenib impaired the viability of H295R cells with dose-response and time-response relationships. The in vitro sorafenib activity was not increased in combination with paclitaxel. ### conclusions Despite the in vitro activity, sorafenib plus weekly paclitaxel is an inactive salvage treatment in patients with advanced ACC and should not be recommended.


cyclophosphamide

doxorubicin

methotrexate

Random prospective study cyclophosphamide, doxorubicin, and methotrexate (CAM) combination chemotherapy versus single-agent sequential chemotherapy in non small cell lung cancer. A group of 104 patients with unresectable non-small cell lung cancer were randomized to receive combination chemotherapy with cyclophosphamide, doxorubicin, and methotrexate (CAM) or single-agent sequential chemotherapy with the same three agents. CAM combination chemotherapy produced a 22% objective response rate, including two complete remissions, compared to a 9% response rate, including one complete remission, produced by single-agent therapy (P = 0.16). The median survival time was 32 weeks (range, 3-116) for CAM, compared to 25 weeks (range, 4-179 +) for sequential single agents (P = 0.24). Overall survival was 31% (1-year), (16%) (1 1/2-year), and 5% (2-year), with no difference between the study arms. Although there was no statistically significant survival advantage for the CAM arm, both arms had survival superior to that in historical controls, presumably because of better patient selection. This study indicates that cyclophosphamide , doxorubicin , and methotrexate are , at best , marginally active as single agents , and new drugs with more efficacy are needed before combination chemotherapy can be expected to result in any meaningful prolongation of survival in non-small cell lung cancer .


curcumin

docetaxel

curcumin

Combinatorial effect of curcumin with docetaxel modulates apoptotic and cell survival molecules in prostate cancer. docetaxel is the most commonly used chemotherapeutic agent to target androgen signaling in metastatic prostate cancer (PCa); however, prolonged treatment with docetaxel results in drug-resistant cancer cells. Combination therapies have the potential of increasing the effectiveness of drug treatment as well as decreasing the side effects. curcumin is a nontoxic organic compound with multifaceted chemopreventive potential. In this study, we evaluated whether curcumin can reinforce the effect of docetaxel on PCa cells. The PCa cell lines DU145 and PC3 were treated with curcumin and docetaxel alone or in combination. After completion of the treatment cell proliferation and the expression of pro-survival and anti-apoptotic markers and the signaling molecules were analyzed. The combined treatment of curcumin and docetaxel inhibited the proliferation and induced apoptosis significantly higher than the curcumin and docetaxel-treated group alone . Interestingly, the combined treatment with curcumin and docetaxel modulates the expression of RTKs, PI3K, phospho-AKT, NF-kappa B, p53, and COX-2. These results suggest that curcumin can be a potential therapeutic contender in enhancing the efficacy of docetaxel in PCa treatment.


dabrafenib

trametinib

dabrafenib

Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial.  Previously , a study of ours showed that the combination of dabrafenib and trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF Val600Lys/Glu mutation-positive metastatic melanoma . The study was continued to assess the secondary endpoint of overall survival, which we report in this Article. ### methods We did this double-blind phase 3 study at 113 sites in 14 countries. We enrolled previously untreated patients with BRAF Val600Glu or Val600Lys mutation-positive unresectable stage IIIC or stage IV melanoma. Participants were computer-randomised (1:1) to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily), or dabrafenib and placebo. The primary endpoint was progression-free survival and overall survival was a secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT01584648. ### findings Between May 4, 2012, and Nov 30, 2012, we screened 947 patients for eligibility, of whom 423 were randomly assigned to receive dabrafenib and trametinib (n=211) or dabrafenib only (n=212). The final data cutoff was Jan 12, 2015, at which time 222 patients had died. Median overall survival was 25·1 months (95% CI 19·2-not reached) in the dabrafenib and trametinib group versus 18·7 months (15·2-23·7) in the dabrafenib only group (hazard ratio [HR] 0·71, 95% CI 0·55-0·92; p=0·0107). Overall survival was 74% at 1 year and 51% at 2 years in the dabrafenib and trametinib group versus 68% and 42%, respectively, in the dabrafenib only group. Based on 301 events, median progression-free survival was 11·0 months (95% CI 8·0-13·9) in the dabrafenib and trametinib group and 8·8 months (5·9-9·3) in the dabrafenib only group (HR 0·67, 95% CI 0·53-0·84; p=0·0004; unadjusted for multiple testing). Treatment-related adverse events occurred in 181 (87%) of 209 patients in the dabrafenib and trametinib group and 189 (90%) of 211 patients in the dabrafenib only group; the most common was pyrexia (108 patients, 52%) in the dabrafenib and trametinib group, and hyperkeratosis (70 patients, 33%) in the dabrafenib only group. Grade 3 or 4 adverse events occurred in 67 (32%) patients in the dabrafenib and trametinib group and 66 (31%) patients in the dabrafenib only group. ### interpretation The improvement in overall survival establishes the combination of dabrafenib and trametinib as the standard targeted treatment for BRAF Val600 mutation-positive melanoma. Studies assessing dabrafenib and trametinib in combination with immunotherapies are ongoing. ### funding GlaxoSmithKline.


clindamycin

gentamicin

In vivo efficacy of trovafloxacin (CP-99,217), a new quinolone, in experimental intra-abdominal abscesses caused by Bacteroides fragilis and Escherichia coli. The efficacy of trovafloxacin in treating Bacteroides fragilis and Escherichia coli infections was investigated and compared to the efficacy of combined clindamycin and gentamicin therapy in an experimental model of intra-abdominal abscesses in rats. Rats were treated with different doses of CP-116,517-27, a parenteral prodrug of trovafloxacin. Response to treatment was evaluated by mortality rate and elimination of infection (cure rate). Mortality in the control group was 85.4%, whereas in rats treated with trovafloxacin, it was close to 0%. The highest cure rate (89.3%) resulted from the administration of 40 mg of CP-116,517-27 per kg of body weight three times a day (TID) for 10 days (equivalent to 18.15 mg of active drug trovafloxacin per rat per day). The therapeutic response with trovafloxacin was comparable to that of a combination therapy of clindamycin (75 mg/kg) plus gentamicin (20 mg/kg) TID (cure rate, 74%; mortality rate, 5%). The measured peak levels of trovafloxacin in serum and abscess pus were 2.6 +/- 0.3 and 5.2 micrograms/ml, respectively. The tumor necrosis factor alpha levels in the untreated animals were high compared to those for rats treated with trovafloxacin or clindamycin plus gentamicin. These results demonstrate that trovafloxacin as a single agent appears to be as successful as clindamycin plus gentamicin in the treatment of experimental intra-abdominal abscesses in rats.


trovafloxacin

doxorubicin

etoposide

Topoisomerase II inhibition involves characteristic chromosomal expression patterns. The phenomenon of co-localization of transcriptionally upregulated genes showing similar expression levels is known across all eukaryotic genomes. We recently mapped the Aroclor 1254-regulated transcriptome back onto the genome and provided evidence for the statistically significant co-localization of regulated genes. They did, however, not always show similar expression levels, and many of the regulated genes were, in fact, repressed. ### results In this study, we were able to reproduce this observation with microarray data stemming from 1) human hepatocytes treated with the gyrase and potential topoisomerase II inhibitor trovafloxacin, 2) human hepatocytes treated with the topoisomerase II inhibitor doxorubicin and 3) mouse lymphoma cells treated with the topoisomerase II inhibitor etoposide. We found statistically significant co-localization of regulated gene pairs--induced and repressed--within the window size of 0-100 kbp. Notably, by using microarray data stemming from lung tissue of a mouse transgenic line overexpressing the transcription factor c-myc, which served as a negative control, we found regulated genes to be located with regard to each other nearly in the same way as genes distributed randomly all over the genome (0-100 kbp). ### conclusion We suggest topoisomerase II inhibition by Aroclor 1254 , trovafloxacin , doxorubicin , and etoposide to be responsible for significant co-localization of regulated genes through the inability of the stabilized enzyme complexes to religate DNA . Within the permanently opened chromatin domains, neighbored genes might be allowed to be regulated. Overexpression of c-myc, however, does not inhibit topoisomerase II activity. Consequently, the enzyme is able to perform its normal function of transiently breaking and rejoining the DNA double strand. As a result, exclusively target genes are regulated.


doxorubicin

etoposide

ifosfamide

The prognostic value of etoposide area under the curve (AUC) at first chemotherapy cycle in small cell lung cancer patients: a multicenter study of the groupe Lyon-Saint-Etienne d'Oncologie Thoracique (GLOT). To assess the potential relationships between systemic exposure to doxorubicin, etoposide and ifosfamide at first chemotherapy cycle and therapeutic effect, tumor response, toxicity, and survival, in small cell lung cancer (SCLC) patients. ### Patients And Methods Twenty-four patients referred to five different centers with either thorax-limited or metastatic SCLC entered the study. All but one received two induction courses of the 3 day-AVI ( doxorubicin 50 mg/m(2 ) day 1 , etoposide 120 mg/m(2 ) day 1 , 2 , 3 , ifosfamide 2000 mg/m(2 ) day 1 , 2 ) regimen . Individual plasma samples were collected at the first course and complete concentration data on 24 courses were available. Drugs exposures were estimated using a population pharmacokinetic method and expressed as clearance (Cl), area under the curve (AUC), and AUC-intensity (AUC/cycle duration). Responding patients received thoracic irradiation+concomitant cisplatinum-etoposide (limited disease) or four more courses of AVI (extensive disease). The impact of exposure parameters on haematological toxicity, tumor response and overall survival was assessed using linear regression, the Mann-Whitney U-test and the log-rank test/Kaplan-Meier estimation, respectively. ### results Twenty-three patients could be evaluated for response and survival. We found no relationship between drug exposure and haematological toxicity but all patients had received Granulocyte-Colony Stimulating Factor support. Tumor response was marginally influenced by ifosfamide AUC. In patients with etoposide AUC>254.8 mg h/l, 1-year survival was 50.0 vs. 9.1% in the other group (median 11.4 vs. 7.1 months, P=0.02), with respect to established prognostic factors. In patients with extensive disease only (n=15), 1-year survival was 42.9 vs. 0% (median 11.3 vs. 5.3 months, P=0.01). ### conclusion This study strongly suggests that SCLC patients should benefit from sufficient etoposide exposure at first cycle to improve survival. Adaptative control based on plasma concentration measurements should be tested in further studies assessing various polychemotherapy regimens.


trastuzumab

ramucirumab

Recent insights in the therapeutic management of patients with gastric cancer. Gastric cancer remains frequent and one of the most lethal malignancies worldwide. In this article, we aimed to comprehensively review recent insights in the therapeutic management of gastric cancer, with focus on the surgical and perioperative management of resectable forms, and the latest advances regarding advanced diseases. Surgical improvements comprise the use of laparoscopic surgery including staging laparoscopy, a better definition of nodal dissection, and the development of hyperthermic intraperitoneal chemotherapy. The best individualized perioperative management should be assessed before curative-intent surgery for all patients and can consists in perioperative chemotherapy, adjuvant chemo-radiation therapy or adjuvant chemotherapy alone. The optimal timing and sequence of chemotherapy and radiation therapy with respect to surgery should be further explored. Patients with advanced gastric cancer have a poor prognosis. Nevertheless, they can benefit from doublet or triplet chemotherapy combination, including trastuzumab in HER2-positive patients. Upon progression, second-line therapy can be considered in patients with good performance status. Although anti-HER2 ( trastuzumab ) and anti-VEGFR ( ramucirumab ) may yield survival benefit , anti-EGFR and anti-HGFR therapies have failed to improve outcomes . Nevertheless, combination regimens containing cytotoxic drugs and targeted therapies should be further evaluated; keeping in mind that gastric cancer biology is different between Asia and the Western countries.


doxorubicin

paclitaxel

Paclitaxel plus doxorubicin in breast cancer: an Italian experience. Based on preclinical data, phase I/II clinical trials were performed at Istituto Oncologico Romagnolo (IOR) Operative Units (Medical Oncology Departments of Forlì, Rimini, and Ravenna, Italy) to determine the efficacy and toxicity of sequential administration of doxorubicin followed by paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in the treatment of patients with advanced breast cancer that either had been previously untreated or that had relapsed after adjuvant therapy. In the phase I trial , 19 patients received bolus doxorubicin ( 50 mg/m2 ) followed after a 16-hour interval by paclitaxel ( given at dose levels ranging from 130 to 250 mg/m2 ) by 3-hour infusion every 3 weeks , for a maximum of eight cycles . paclitaxel doses were escalated in 30-mg/m2 increments if the maximum tolerated dose had not been reached in the previous dose level. Analysis of the 128 cycles assessable for toxicity demonstrated neutropenia (<500/microL) in 26 courses (20.3%), with no significant clinical events. No relevant clinical cardiotoxicity was observed. The paclitaxel maximum tolerated dose was not reached at the 250-mg/m2 dose level (no grade 3 or 4 extramedullary toxicity). In the IOR phase II trial, 13 patients were treated with fixed doses of both drugs (doxorubicin 50 mg/m2 and paclitaxel 220 mg/m2). Grade 4 neutropenia occurred in 39 of the 95 cycles, but was complicated by fever in only eight cycles (8.4%); three cycles required granulocyte colony-stimulating factor support. Peripheral neurotoxicity was the most common extramedullary side effect noted. Overall clinical responses in the IOR trials included 10 complete responses (31.3%) and 15 partial responses (46.9%), with an objective response rate of 78.1%. Comparison of these results with those obtained from a phase I trial using the opposite drug sequence showed comparable overall response rates, but IOR's sequence was associated with a higher complete response rate, as well as less frequent and less severe nonhematologic toxicity.


ofatumumab

carfilzomib

rapamycin

Treatment recommendations for patients with Waldenström macroglobulinemia (WM) and related disorders: IWWM-7 consensus. Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of International Workshops on WM (IWWM). As part of the IWWM-7 and based on recently published and ongoing clinical trials, the panels updated treatment recommendations. Therapeutic strategy in WM should be based on individual patient and disease characteristics (age, comorbidities, need for rapid disease control, candidacy for autologous transplantation, cytopenias, IgM-related complications, hyperviscosity, and neuropathy). Mature data show that rituximab combinations with cyclophosphamide/dexamethasone, bendamustine, or bortezomib/dexamethasone provided durable responses and are indicated for most patients. New monoclonal antibodies ( ofatumumab ) , second-generation proteasome inhibitors ( carfilzomib ) , mammalian target of rapamycin inhibitors , and Bruton 's tyrosine kinase inhibitors are promising and may expand future treatment options . A different regimen is typically recommended for relapsed or refractory disease. In selected patients with relapsed disease after long-lasting remission, reuse of a prior effective regimen may be appropriate. Autologous stem cell transplantation may be considered in young patients with chemosensitive disease and in newly diagnosed patients with very-high-risk features. Active enrollment of patients with WM in clinical trials is encouraged.


hydrogen peroxide

cimetidine

ranitidine

Role of cytochrome P-450 in hydrogen peroxide-induced cytotoxicity to LLC-PK1 cells. The current study was designed to test the role of cytochrome P-450 in hydrogen peroxide-induced cytotoxicity, and to determine whether it may serve as a source of catalytic iron. Hydrogen peroxide led to iron release (as measured by iron/bathophenanthroline complex) from the microsomes prepared from LLC-PK1 cells. cimetidine, which inhibits cytochrome P-450 by interacting with the heme iron, significantly blocked iron release, whereas ranitidine, which has a similar structure as cimetidine but is a weak inhibitor of P-450, did not have an effect (H2O2, 0.42 +/- 0.04; H2O2 + cimetidine, 0.23 +/- 0.02 nmol/mg protein; N = 4, P < 0.01). Exposure of LLC-PK1 cells to hydrogen peroxide ( 2.5 mM ) resulted in a significant increase in the bleomycin-detectable iron ( iron capable of catalyzing free radical reactions ) content that was prevented by cimetidine , but not ranitidine . We then examined the effect of the inhibitors of cytochrome P-450 on cell death (as measured by Trypan blue exclusion) after exposure of LLC-PK1 cells to 2.5 mM hydrogen peroxide for 120 minutes. Inhibition of cytochrome P-450 by cimetidine significantly reduced the cell death; the effect was observed with 0.05 mM and was concentration dependent with 1 mM affording almost complete protection (H2O2, 59 +/- 1.3% vs. H2O2 + cimetidine, 11 +/- 0.7%; N = 5, P < 0.01). In contrast, ranitidine did not show any protection. We confirmed that the protective effect of cimetidine was not related to scavenging hydrogen peroxide or hydroxyl radicals or chelating iron. A second inhibitor of cytochrome P-450, piperonyl butoxide, had a similar dose-dependent beneficial effect against hydrogen peroxide-induced cell injury. Our data thus indicate an important role of cytochrome P-450 in hydrogen peroxide-induced cytotoxicity to LLC-PK1 cells and suggest that cytochrome P-450 may serve as a source of catalytic iron.


Chloroquine

Auranofin

Longterm results of auranofin therapy. The results of longterm therapy with the oral gold preparation auranofin in patients with rheumatoid arthritis (RA) were evaluated based on the following data: 1) Two multicenter open uncontrolled studies (MTC06) and (162EMUA-RA), 2) the reevaluation of these data for the MTC06 study after 4 years from the beginning of the study and 3) the results of a postmarketing surveillance program (PMSP) of patients on auranofin therapy. The specific rheumatologic documentation and information system (IKR inhaltkodierte rheumatologic) serves as the basis of the follow-up studies and longterm observations. The first year data on 207 patients (MTC06) indicating that duration of the disease less than 2 years was the only discriminating factor regarding a positive treatment outcome were confirmed by the two-year (151 patients). Patients, who responded favourably to auranofin did usually well for the four-year or longer observation period. The data base of these two studies and the PMSP failed to outline any new severe or threatening side effects. Diarrhea and loose stools were more common at the beginning of the treatment. The overall withdrawal for untoward events was 11.2%. Patients who did or did not respond to previous DIMARD therapy either on i.m . gold , D-Penicillamine or Chloroquine , did usually well when treated with Auranofin , even if severe side effects leading to withdrawal had occurred on previous therapy . The favourable safety profile was confirmed by the PMSP data.


docetaxel

prednisone

custirsen

docetaxel

prednisone

Custirsen in combination with docetaxel and prednisone for patients with metastatic castration-resistant prostate cancer (SYNERGY trial): a phase 3, multicentre, open-label, randomised trial. Clusterin is a chaperone protein associated with treatment resistance and upregulated by apoptotic stressors such as chemotherapy. Custirsen is a second-generation antisense oligonucleotide that inhibits clusterin production. The aim of the SYNERGY trial was to investigate the effect of custirsen in combination with docetaxel and prednisone on overall survival in patients with metastatic castration-resistant prostate cancer. ### methods SYNERGY was a phase 3, multicentre, open-label, randomised trial set at 134 study centres in 12 countries. Patients were eligible for participation if they had: metastatic castration-resistant prostate cancer and had received no previous chemotherapy; prostate-specific antigen greater than 5 ng/mL; and a Karnofsky performance score of 70% or higher. Patients were randomly assigned 1:1 centrally to either the docetaxel , prednisone , and custirsen combination or docetaxel and prednisone alone . Patients were not masked to treatment allocation. Randomisation was stratified by opioid use for cancer-related pain and radiographic evidence of progression. All patients received docetaxel 75 mg/m ### findings Between Dec 10, 2010, and Nov 7, 2012, 1022 patients were enrolled to the trial, of whom 510 were assigned docetaxel, prednisone, and custirsen and 512 were allocated docetaxel and prednisone. No difference in overall survival was recorded between the two groups (median survival 23·4 months [95% CI 20·9-24·8] with docetaxel, prednisone, and custirsen vs 22·0 months [19·5-24·0] with docetaxel and prednisone; hazard ratio [HR] 0·93, 95% CI 0·79-1·10; p=0·415). The most common adverse events of grade 3 or worse in the docetaxel, prednisone and custirsen group (n=501) compared with the docetaxel and prednisone alone group (n=499) were neutropenia (grade 3, 63 [13%] vs 28 [6%]; grade 4, 98 [20%] vs 77 [15%]), febrile neutropenia (grade 3, 52 [10%] vs 31 [6%]; grade 4, four [1%] vs two [<1%]), and fatigue (grade 3, 53 [11%] vs 41 [8%]; grade 4, three [1%] vs one [<1%]). One or more serious adverse events were reported for 214 (43%) of 501 patients treated with docetaxel, prednisone, and custirsen and 181 (36%) of 499 receiving docetaxel and prednisone alone. Adverse events were attributable to 23 (5%) deaths in the docetaxel, prednisone, and custirsen group and 24 (5%) deaths in the docetaxel and prednisone alone group. ### interpretation Addition of custirsen to first-line docetaxel and prednisone was reasonably well tolerated, but overall survival was not significantly longer for patients with metastatic castration-resistant prostate cancer treated with this combination, compared with patients treated with docetaxel and prednisone alone. ### funding OncoGenex Technologies.


Carboplatin

etoposide

[ Carboplatin and etoposide combination for the treatment of recurrent epithelial ovarian cancer ] . The objective of this phase II study was to determine the efficacy and toxicity of a combination of carboplatin and etoposide as salvage treatment, in previously treated patients with persistent or recurrent ovarian cancer following first-line cisplatin-based chemotherapy. ### Patients And Methods From July 1990 to August 1994, 58 patients were treated with 3-week cycles of chemotherapy consisting of carboplatin (200 mg/m2, D1) and etoposide (120 mg/m2, D1, D2). Criteria for evaluating previous response to cisplatin were strictly defined. ### results The overall response rate was 36%, with five complete responses (CR, 9%), 16 partial responses (PR, 27%) and the median duration of response was 10 months (range: 4 to 38). In the group of patients who progressed during the first year following the diagnosis, the response was 1 CR and 2 PR (12%) and in the group of patients who progressed from the second year after diagnosis, 4 CR and 14 PR (56%), with a median survival of 8.5 and 21 months respectively (p = 0.0013). The response rate was 59% in the potentially platinum sensitive group versus 8.7% in the primary resistant group (0.02 < p < 0.05). Myelotoxicity was the main side-effect but did not appear to be cumulative. Grade 3 and grade 4 anemia were observed in 26% and 3% of the patients respectively, neutropenia in 14% and 2% and thrombocytopenia in 14% and 8.5%. One patient died of sepsis associated with neutropenia. ### conclusion Treatment was easily manageable and well tolerated. The advantage of carboplatin and etoposide combination in potentially responsive patients is represented by the reduced nephrotoxicity, neurotoxicity and ototoxicity as compared with cisplatin containing regimen, with durable feasibility in outpatients. This second-line chemotherapy for ovarian cancer is effective as salvage treatment in potentially responsive patients with late recurrent tumors, while paclitaxel is the drug of choice for patients who have developped primary or secondary resistance to platin therapy.


paclitaxel

carboplatin

One-hour paclitaxel plus carboplatin in the treatment of advanced non-small cell lung cancer : results of a multicentre , phase II trial . The aim of this phase II study was to determine the activity and toxicity of paclitaxel (administered by 1-h infusion) and carboplatin in advanced non-small cell lung cancer when used in a multicentre, community-based treatment setting. 100 chemotherapy-naive patients with stage IIIB or IV non-small cell lung cancer were treated between March 1995 and February 1996. All patients had Karnofsky performance status 70-100, measurable disease and adequate bone marrow, kidney and liver function. All patients received intravenous (i.v.) paclitaxel 225 mg/m2 by 1-h infusion followed immediately by carboplatin at a targeted area under the concentration time curve (AUC) of 6.0 using the Calvert formula. Courses were repeated every 21 days. Colony stimulating factors were not used routinely. 38 of 94 evaluable patients (40%) had objective responses to treatment (3 complete responses, 35 partial responses). An additional 32 patients had stable disease at initial re-evaluation. Weight gain during treatment was experienced by 47% of patients with objective response or stable disease. The median survival in this group of 100 patients was 8 months, with an actuarial 1-year survival of 42%. Leucopenia was common, but hospitalisation for treatment of neutropenia and fever occurred in only 3% of courses. Cumulative peripheral neuropathy was common, but usually appeared after the third or fourth course and was severe (grade 3) in only 15% of patients. Other grade 3 and 4 toxicity was uncommon. There was one treatment-related death due to sepsis. This large multicentre community-based phase II trial demonstrated the efficacy of paclitaxel and carboplatin combination chemotherapy in advanced non-small cell lung cancer. When paclitaxel is given by 1-h infusion, this regimen is easily administered in the outpatient setting.


trastuzumab

bevacizumab

The role of trastuzumab in early stage breast cancer: current data and treatment recommendations. Treatment of early stage breast cancer requires a multimodality approach in order to eradicate residual cancer and prevent recurrent disease. Targeting the pathways that promote or sustain cancer cell growth and invasion is critical to the effective treatment of breast and other cancers. Overexpression of the family of HER receptors have been associated with a variety of malignancies; the first and best studied is the association of overexpression of the HER2/neu receptor with a more aggressive breast cancer phenotype and poorer survival. A humanized antibody to HER2/neu, trastuzumab, is now FDA approved for the treatment of early stage, HER2/neu overexpressing breast cancer sequenced with chemotherapy including doxorubicin, cyclophosphamide, and paclitaxel. Additional international and national studies support the significant impact of trastuzumab on both disease free and overall survival in women with this aggressive form of breast cancer. Toxicity includes a low but clear risk of congestive heart failure, and the large phase III trials have helped to determine which patients are at higher risk for this complication. Non-anthracycline containing regimens are an alternative therapy associated with reduced cardiac toxicity. trastuzumab therapy is now the standard of care for the treatment of early stage, HER2/neu positive breast cancer given in combination with one of several chemotherapy regimens. Ongoing questions include the appropriate duration of trastuzumab treatment as well as the optimal chemotherapy regimen and sequence. The next large phase III adjuvant trial for this subset of breast cancer is an international collaboration designed to evaluate the added or alternative benefit of an oral tyrosine kinase inhibitor targeting HER2/neu as well as the epidermal growth factor receptor (EGFR), lapatinib. Other trials are investigating differences in duration. Studies in the neoadjuvant setting should help to define markers of trastuzumab and lapatinib sensitivity and resistance. Preliminary data combining trastuzumab with the antiangiogenic antibody bevacizumab is encouraging ; this combination will be tested in both early stage and late stage disease .


nivolumab

pembrolizumab

atezolizumab

durvalumab

ipilimumab

tremelimumab

bevacizumab

lenvatinib

cabozantinib

The New Immuno-Oncology-Based Therapies and Their Perspectives in Hepatocellular Carcinoma. Hepatocellular carcinoma is a poor prognosis tumor. Systemic therapies are frequently used due to frequent recurrences after surgical or radiologic treatments. Anti-angiogenic tyrosine kinase inhibitors have shown efficacy in monotherapy, but with very low rates of long survival and exceptional recovery. Immuno-oncology based on immune checkpoint inhibitors has revolutionized the systemic therapies since showing long survival rates without any tumor progression or recurrence for some patients in partial or complete response, and possibly for some patients in stable disease. However, the rate of responders under immuno-oncology monotherapy is too low to increase significantly the median overall survival of the treated patients. The immuno-oncology-based combinations with different types of immune checkpoint inhibitors ( PD-1/PD-L1 and CTLA-4 inhibitors such as nivolumab , pembrolizumab , atezolizumab , durvalumab , ipilimumab , tremelimumab ) , or the association of immune checkpoint inhibitors plus anti-angiogenic agents ( bevacizumab , lenvatinib , cabozantinib ) , have led to a breakthrough in the treatment of hepatocellular carcinoma . Indeed, the first phase-3 trial, combining atezolizumab with bevacizumab, has dramatically changed the outcome of patients. Data from several other types of combinations assessed in phase-3 trials are pending, and if positive, will drastically arm the physicians to efficiently treat the patients, and disrupt the current algorithm of hepatocellular carcinoma treatment.


melatonin

cyclophosphamide

Expression of vascular endothelial growth factor (VEGF-A) in rat mandibular salivary gland during paraneoplastic process and treatment with cyclophosphamide and melatonin. Expression of VEGF-A in Walker 256 carcinosarcoma and mandibular salivary gland of rats during paraneoplastic process and various regimens of chemotherapy with melatonin and cyclophosphamide were studied by immunohistochemical methods. VEGF-A expression increased in the tumor node and salivary gland after monotherapy with melatonin and cyclophosphamide during progression of tumor growth and paraneoplastic syndrome. A decrease in VEGF-A expression in the tumor node and salivary gland was found after monotherapy with melatonin and cyclophosphamide and , especially , after combined treatment , which proves maximum therapeutic efficiency of combined administration of chemical agents with various mechanisms of action . Overexpression of VEGF-A in the mandibular salivary gland can have diagnostic and predictive value in early diagnostics of neoplasms.


rituximab

bendamustine

cytarabine

Rituximab, bendamustine, and low-dose cytarabine as induction therapy in elderly patients with mantle cell lymphoma: a multicentre, phase 2 trial from Fondazione Italiana Linfomi.  The combination of rituximab , bendamustine , and cytarabine ( R-BAC ) was highly active in a pilot trial of mantle cell lymphoma , but its use was restricted by high haematological toxicity . We aimed to assess the efficacy and safety of an R-BAC regimen with low-dose cytarabine (RBAC500). ### methods In this multicentre, phase 2 trial, we recruited previously untreated patients with an established histological diagnosis of mantle cell lymphoma from 29 Fondazione Italiana Linfomi centres in Italy. Patients had to be older than 65 years and fit according to the comprehensive geriatric assessment, or aged 60-65 years if they were ineligible for high-dose chemotherapy plus autologous stem-cell transplantation and were fit or unfit. All patients received RBAC500 (rituximab 375 mg/m ### findings Between May 2, 2012, and Feb 25, 2014, we enrolled 57 patients (median age 71 years, IQR 67-75). 54 (95%) patients received at least four RBAC500 cycles (three discontinued because of toxicity), and 38 (67%) completed six cycles. Two (4%) had disease progression (one after the fourth cycle and one after the sixth cycle). All 52 (91%, lower limit of one-sided 95% CI 85%) remaining patients achieved complete response at the end of treatment. 23 (40%, upper limit of one-sided 95% CI 53%) of 57 patients had at least one episode of relevant toxicity. The most frequent grade 3-4 haematological toxicities were neutropenia (149 [49%] of 304 cycles) and thrombocytopenia (158 [52%]). Most treatment-related non-haematological adverse events were of grade 1-2, with the most frequent ones being fatigue (14 [25%] patients), nausea or vomiting (12 [21%]), and infusion-related reactions or tumour lysis syndrome (12 [21%]). 41 (72%) patients required a dose reduction. 12 patients died during the study, but no deaths were related to treatment. ### interpretation RBAC500 is an effective treatment for elderly patients with mantle cell lymphoma and, despite not meeting our prespecified safety boundary, haematological toxicity was manageable with appropriate supportive care and dose reduction. Since maintenance therapy is not required, RBAC500 could be considered an option and should be studied in phase 3 trials. ### funding Fondazione Italiana Linfomi and Mundipharma.


sildenafil

ambrisentan

epoprostenol

Subacute right heart failure revealing three simultaneous causes of post-embolic pulmonary hypertension in metastatic dissemination of breast cancer. A 72-year-old woman with history of breast cancer only treated surgically was referred to our department for pulmonary hypertension (PH) suspicion. Echocardiogram revealed elevated right ventricular systolic pressure. Computed tomography (CT) angiogram showed no pulmonary embolism (PE), but lung scan revealed two ventilation-perfusion mismatch areas. Right cardiac catheterization established precapillary PH. Despite treatment with PH specific therapy ( sildenafil , ambrisentan , and epoprostenol ) , her condition worsened rapidly with acute right heart failure ( RHF ) . She died 22 days after admission. Post-mortem microscopic examination showed a rare combination of PH etiologies consistent with metastasis of breast cancer in pulmonary vasculature including the rare pulmonary tumour thrombotic microangiopathy (PTTM).


ixabepilone

carboplatin

ixabepilone

A phase I and pharmacokinetic study of ixabepilone in combination with Carboplatin in patients with advanced solid malignancies. To determine the recommended phase II dose of combination ixabepilone plus carboplatin based on the maximum tolerated dose, pharmacokinetics, optimum schedule, and safety. ### Experimental Design Patients with advanced solid malignancies were treated with escalating doses of carboplatin plus ixabepilone administered on day 1 (schedule A) or days 1 and 8 (schedule B) of a 21-day cycle. Blood was sampled during cycle 1 for pharmacokinetic analysis of ixabepilone (both schedules) and carboplatin (schedule B). ### results Fifty-two patients were treated with ixabepilone doses ranging from 30 to 50 mg/m2 per 21-day cycle plus carboplatin area under curve (AUC) 5 or 6 (Calvert formula). On schedule A (ixabepilone 40 mg/m2 over 1 hour plus carboplatin AUC 6), 2 of 2 patients experienced dose-limiting toxicity (DLT). On schedule B (ixabepilone 25 mg/m2 over 1 hour on days 1 and 8 plus carboplatin AUC 6), 3 of 3 patients experienced DLT. DLT was myelosuppression; however, cumulative sensory neuropathy limited extended dosing on schedule A. ixabepilone and carboplatin pharmacokinetics were similar to those using either drug as monotherapy, indicating an absence of pharmacokinetic drug interactions. Based on DLTs and tolerability with repeated dosing, the recommended doses were 30 mg/m2 ixabepilone (1-hour infusion) d1 q3w plus carboplatin AUC 6 (schedule A) and 20 mg/m2 ixabepilone (1 hour infusion) d1, d8 q3w plus carboplatin AUC 6 (schedule B). ### conclusions Data from the present study show the feasibility and tolerability of combination ixabepilone plus carboplatin , with ixabepilone administered on day 1 or on days 1 and 8 on a 21-day cycle .


metformin

gliclazide

Safety and efficacy of gliclazide as treatment for type 2 diabetes: a systematic review and meta-analysis of randomized trials. gliclazide has been associated with a low risk of hypoglycemic episodes and beneficial long-term cardiovascular safety in observational cohorts. The aim of this study was to assess in a systematic review and meta-analysis of randomized controlled trials the safety and efficacy of gliclazide compared to other oral glucose-lowering agents (PROSPERO2013:CRD42013004156). ### Data Sources Medline, EMBASE, Clinicaltrials.gov, Trialregister.nl, Clinicaltrialsregister.eu and the Cochrane database. ### selection Included were randomized studies of at least 12 weeks duration with the following outcomes: HbA1c change, incidence of severe hypoglycemia, weight change, cardiovascular events and/or mortality when comparing gliclazide with other oral blood glucose lowering drugs. Bias was assessed with the Cochrane risk of bias tool. The inverse variance random effects model was used. ### results Nineteen trials were included; 3,083 patients treated with gliclazide and 3,155 patients treated with other oral blood glucose lowering drugs. There was a considerable amount of heterogeneity between and bias in studies. Compared to other glucose lowering agents except metformin , gliclazide was slightly more effective ( -0.13 % ( 95%CI : -0.25 , -0.02 , I(2 ) 55 % ) ) . One out of 2,387 gliclazide users experienced a severe hypoglycemic event, whilst also using insulin. There were 25 confirmed non-severe hypoglycemic events (2.2%) in 1,152 gliclazide users and 22 events (1.8%) in 1,163 patients in the comparator group (risk ratio 1.09 (95% CI: 0.20, 5.78, I² 77%)). Few studies reported differences in weight and none were designed to evaluate cardiovascular outcomes. ### conclusions The methodological quality of randomized trials comparing gliclazide to other oral glucose lowering agents was poor and effect estimates on weight were limited by publication bias. The number of severe hypoglycemic episodes was extremely low, and gliclazide appears at least equally effective compared to other glucose lowering agents. None of the trials were designed for evaluating cardiovascular outcomes, which warrants attention in future randomized trials.


ifosfamide

carboplatin

etoposide

Phase II study with ifosfamide, carboplatin, etoposide (ICE regimen) at intermediate dosage for advanced non small cell lung cancer (NSCLC). We have evaluated the combination of ifosfamide, carboplatin and etoposide (ICE regimen) along with mesna in 26 previously untreated patients with non small cell lung cancer (NSCLC). Thirteen stage III B and 13 stage IV patients received intermediate doses of ifosfamide ( 1000 mg/m2 ) , carboplatin ( 120 mg/m2 ) and etoposide ( 120 mg/m2 ) given intravenously on day 1 to 3 every 4 weeks . Except for one patient who experienced grade 3 transient thrombocytopenia no major events of hematological or systemic toxicity were observed. Response rate (27%, 95% C.I., 10 to 44%), median duration of response (9 months, range 6-15), and survival (9.5 months, range 2-44+) were comparable to those achieved with conventional cisplatin-containing regimens. Our ICE combination, as compared to standard or high dose schedules appears effective, safe, well tolerated, and devoid of severe hematological toxicity.


oxcarbazepine

carbamazepine

Immediate (overnight) switching from carbamazepine to oxcarbazepine monotherapy is equivalent to a progressive switch.  This study compared immediate ( overnight ) and progressive switching to oxcarbazepine monotherapy in patients with partial seizures unsatisfactorily treated with carbamazepine monotherapy . Patients were randomised to either an overnight (n = 140) or a progressive switch (n = 146) from carbamazepine to oxcarbazepine monotherapy at a dose ratio of 1:1.5. The difference between the two switch groups in the mean monthly seizure frequency supported the equivalence of overnight and progressive switching (difference of 0.02 excluding outliers; 95% confidence interval (CI) -0.74, 0.78). Following the switch from carbamazepine to oxcarbazepine, there was a reduction in median monthly seizure frequency in both the overnight group (from 1.5 to 0; P = 0.0005) and the progressive group (from 1.0 to 0.4; P = 0.003). The proportion of seizure-free patients increased from 38 to 51% (P = 0.002) and 39 to 49% (P = -0.01) in the overnight and progressive groups, respectively. In addition, the proportion of patients experiencing no clinically significant adverse events did not differ between the two switch methods (difference of 2.5; 95% CI -4.1, 9.0). For patients who are unsatisfactorily treated with carbamazepine monotherapy, overnight switch to oxcarbazepine monotherapy is as effective and well tolerated as a progressive switch, therefore allowing simple and flexible individualised treatment. Switching to oxcarbazepine monotherapy appears to be beneficial for patients who are unsatisfactorily treated with carbamazepine monotherapy, independently of the switch method used.


prasugrel

clopidogrel

Use of prasugrel in the setting of clopidogrel hypersensitivity: Case report and systematic review of the literature. Allergic reactions to clopidogrel soon after coronary stent implantation pose an important and challenging clinical problem. We describe a 44-year-old man who developed a diffuse maculopapular rash four days after initiation of clopidogrel with drug-eluting coronary stent placement. An initial treat-through strategy was unsuccessful due to patient intolerance to corticosteroids. Because of persistent hypersensitivity, clopidogrel was substituted with prasugrel which was continued successfully for one year without reaction. A systematic review of the literature was performed which identified 10 prior case reports of patients with clopidogrel hypersensitivity who were subsequently treated with prasugrel. Patient characteristics and clinical outcomes of these patients plus the current case were reviewed. There were 9 men and 2 women with ages from 44 to 76 years. All patients had undergone coronary stent procedures. prasugrel was successfully used without cross-reactivity in 9 of the 11 patients (82%). Cross-reactivity was reported in two patients who developed hypersensitivity reactions to prasugrel similar to those experienced on clopidogrel. In conclusion , prasugrel can be used successfully in most patients with a history of clopidogrel hypersensitivity . However, potential cross-reactivity between these two thienopyridines may occur in some patients.


chloroquine

mefloquine

quinine

halofantrine

atovaquone

The microculture tetrazolium assay (MTA): another colorimetric method of testing Plasmodium falciparum chemosensitivity. Malarial lactate dehydrogenase (LDH), which uses 3-acetyl pyridine adenine dinucleotide as coenzyme in a reaction leading to the formation of pyruvate from L-lactate, may be used to study the susceptibility of Plasmodium falciparum to a drug in vitro. Several methods to determine the activity of this enzyme are available. One, the colorimetric method of Makler and colleagues, was modified slightly, by using sodium-2,3-bis-[2-methoxy-4-nitro-5-sulphophenyl]-2H-tetrazolium-5 - carboxanilide (XTT) and following the reaction by measuring the optical density at 450 nm. Using two, culture-adapted strains of P. falciparum, this LDH assay was compared with the unmodified Makler's assay and with the isotopic microtest based on the incorporation of tritium-labelled hypoxanthine. Fresh , clinical P. falciparum isolates were also tested in the presence of several drugs , including chloroquine , mefloquine , quinine , halofantrine , atovaquone and qinghaosu derivatives . The results of the three assays were correlated for all the drugs tested except atovaquone. The two enzymatic assays are non-radioactive, rapid, reliable, inexpensive to perform and semi-automatic. However, they do require an initial parasitaemia of 2% with a haematocrit of 1.8%.


ketorolac

bupivacaine

Continuous bupivacaine infusion post-iliac crest bone graft harvesting in pediatric cleft surgery: role and comparison with ketorolac. To investigate the use of intravenous ketorolac and iliac crest bupivacaine infusion in the management of iliac crest donor-site pain in the pediatric cleft population. The null hypothesis was there is no difference with respect to pain scores between ketorolac and iliac crest bupivacaine infusion as analgesic adjuncts to intravenous opioids . ### methods A total of 54 children and adolescents (27 boys, 27 girls) undergoing alveolar cleft repair or Le Fort I osteotomy were assigned randomly in a prospective, single-blinded fashion to one of three groups: intravenous ketorolac plus iliac crest normal saline infusion, intravenous ketorolac plus iliac crest bupivacaine infusion, or iliac crest bupivacaine infusion alone. Iliac crest infusions and ketorolac were administered for 48 hours or until discharge, whichever occurred first. All patients received morphine via a patient-controlled analgesia device. ### Main Outcome Measure S Primary outcome was pain score, and secondary outcomes were morphine consumption and satisfaction scores. ### results Pain scores, morphine consumption, and satisfaction scores were not significantly different among groups. Estimated costs were significantly higher for bupivacaine infusion than intravenous ketorolac. ### conclusions Iliac crest donor-site pain is well managed in this patient population. Intravenous ketorolac and iliac crest bupivacaine infusion provide comparable analgesia for iliac crest bone graft donor-site pain in children and adolescents.


Etoposide

cytarabine

aclarubicin

G-CSF

Etoposide in combination with low-dose CAG ( cytarabine , aclarubicin , G-CSF ) for the treatment of relapsed or refractory acute myeloid leukemia : a multicenter , randomized control trial in southwest China . In a well-controlled multi-center randomized trial in southwestern China, 228 patients with refractory or relapsed AML were received a low-dose CAG regimen either with etoposide (E-CAG) or without etoposide (CAG). The complete remission (CR) rate, overall survival (OS) and toxicity were evaluated. Patients with E-CAG had a higher CR rate (71.1% vs. CAG 50.9%, P=0.0002). The tolerability appeared to be equivalent. Patients with CR who underwent allogenic hematopoietic stem cell transplantation (allo-HSCT) had a higher five-year OS over those without allo-HSCT (73.8% vs. 10.8%, P=0.000). The E-CAG regimen is expected to become a bridge between relapsed or refractory AML and allo-HSCT.


dolasetron

dolasetron

aprepitant

aprepitant

Lack of effect of aprepitant on hydrodolasetron pharmacokinetics in CYP2D6 extensive and poor metabolizers. To prevent chemotherapy-induced nausea and vomiting, aprepitant is given with a corticosteroid and a 5-hydroxytryptamine type 3 antagonist, such as dolasetron. dolasetron is converted to the active metabolite hydrodolasetron, which is cleared largely via CYP2D6. The authors determined whether aprepitant, a moderate CYP3A4 inhibitor, alters hydrodolasetron pharmacokinetics in CYP2D6 poor and extensive metabolizers. Six CYP2D6 poor and 6 extensive metabolizers were randomized in an open-label , crossover fashion to treatment A ( dolasetron 100 mg on day 1 ) and treatment B ( dolasetron 100 mg plus aprepitant 125 mg on day 1 , aprepitant 80 mg on days 2 - 3 ) . For hydrodolasetron area under the concentration-versus-time curve (AUC0-infinity) and peak plasma concentration (Cmax), geometric mean ratios (B/A) and 90% confidence intervals (CIs) fell below the predefined limit (2.0) for clinical significance (AUC0-infinity, 1.09 [90% CI, 1.01-1.18], Cmax, 1.08 [90% CI, 0.94-1.24]). aprepitant did not affect the pharmacokinetics of hydrodolasetron, regardless of CYP2D6 metabolizer type, and was generally well tolerated when coadministered with dolasetron in volunteers.


gemcitabine

ifosfamide

anthracycline

[Gemcitabine based combination chemotherapy, a new salvage regimen for recurrent platinum resistant epithelial ovarian cancer]. To evaluate the efficacy and toxicities of gemcitabine combined with ifosfamide and anthracycline chemotherapy for recurrent platinum resistant ovarian epithelial cancer. ### methods gemcitabine 800 mg/m(2) (day 1, 8), ifosfamide 1.5 g/m(2) (day 1 - 3), adriamycin 40 mg/m(2) or epirubicin 60 mg/m(2) (day 1) or mitoxantrone 10 mg/m(2) (day 1, 8) were used in recurrent platinum resistant/refractory ovarian cancer patients, the cycle was repeated at interval of 21 to 28 days. ### results A total of 60 patients received 172 cycles combined chemotherapy. There were no one cases complete response, while partial response 22 (37%, 22/60), stable 23 (38%, 23/60) and progression 15 (25%, 15/60) were observed, with clinical benefit rate 75% (45/60). The median time of progression-free survival was 7 months, and the median overall survival time was 20 months. The main side effect was hematologic toxicity with leukopenia rate of 82% (49/60), among which III-IV accounted for 31% (15/49). Digestive reaction was all in I-II, accounted for 42% (25/60). ### conclusion The regimen of gemcitabine combined with ifosfamide and anthracycline is feasible , tolerable and effective in patients with recurrent platinum resistant/refractory epithelial ovarian cancer .


cetuximab

irinotecan

oxaliplatin

capecitabine

Second-line cetuximab/irinotecan versus oxaliplatin/fluoropyrimidines for metastatic colorectal cancer with wild-type KRAS. The goal of the present study was to compare the efficacy of the combination of cetuximab and irinotecan to the combination of oxaliplatin and fluoropyrimidines as second-line chemotherapy in patients with irinotecan-refractory and oxaliplatin-naïve metastatic colorectal cancer (mCRC) harboring wild-type KRAS. The study included 120 patients with mCRC who had progressed after irinotecan-containing first-line chemotherapy and were never treated with oxaliplatin; 40 patients with wild-type KRAS were accrued prospectively in the experimental arm (arm A), and 80 patients accrued retrospectively were divided into control arms B (n = 46) and C (n = 34) according to KRAS genotype. Second-line treatments consisted of cetuximab plus irinotecan for arm A , and oxaliplatin plus either 5-fluorouracil ( FOLFOX ) or capecitabine ( CapeOX ) for the control arms . The median progression-free survival (PFS) was 8.3, 5.8 and 3.9 months, for arms A, B and C, respectively, with statistical significance favoring arm A (P = 0.007). Differences in overall survival did not reach statistical significance (18.3 vs 12.6 vs 12.9, P = 0.138), although there was a trend toward longer overall survival in arm A. In terms of benefit from oxaliplatin-containing regimens either as second-line or third-line therapy, the median PFS was 5.0 months in arms B and C as second-line therapy, and 4.0 months in arm A as third-line therapy, with no statistical significance (P = 0.385). Second-line cetuximab plus irinotecan is a valid treatment strategy for mCRC patients with irinotecan-refractory and oxaliplatin-naïve tumors harboring wild-type KRAS. oxaliplatin-containing chemotherapy resulted in equivalent PFS both as a second-line and a third-line therapy, enabling delay of the administration of FOLFOX and CapeOX until subsequent treatment cycles.


paclitaxel

carboplatin

Paclitaxel, Carboplatin and 1,25-D3 Inhibit Proliferation of Endometrial Cancer Cells  Endometrial cancer cells are known to be sensitive to carboplatin and paclitaxel. Furthermore, vitamin D (1,25-D3) has been reported to inhibit endometrial cancer cell growth both as a single agent and combined with carboplatin. However, there are no studies comparing the effect of paclitaxel and carboplatin as single agents vs. in combination in endometrial cancer cell lines. Neither has the effect of 1,25-D3 been studied with paclitaxel. The present study investigated the effect of paclitaxel, carboplatin and 1,25-D3 on the growth of endometrial cancer cells in vitro. ### Materials And Methods Two endometrial adenocarcinoma cell lines (UT-EC-1 and UT-EC-3) were cultured with different doses of paclitaxel, carboplatin and 1,25-D3. The cellular VDR (vitamin D receptor) mRNA levels were measured and the expression of estrogen (ER) and progesterone (PR) receptors by the cells was determined. ### results In the UT-EC-1 cell line the growth inhibition was 72 % with paclitaxel , 54 % with carboplatin and 73 % with the combination of these compounds . The corresponding numbers in UT-EC-3 were 70%, 33% and 65%, respectively. 1,25-D3 suppressed cell growth 88% with paclitaxel, 63% with carboplatin and 87% with their combination in the UT-EC-1 cell line. ### conclusion In both cell lines, single-agent paclitaxel was as effective as the combination of the compounds and more effective than single carboplatin. 1,25-D3 may further contribute to the cytotoxic effect of these agents.