cisplatin

adriamycin

etoposide

cyclophosphamide

Phase II study of an intensive combination chemotherapy with cisplatin , adriamycin , etoposide and cyclophosphamide ( CAVE ) in small cell lung cancer . One hundred and twelve patients with small cell lung cancer (SCLC) were treated with a combination (CAVE) of cisplatin (60 mg/m2 day 1), adriamycin (45 mg/m2 day 1), etoposide (80 mg/m2 days 1-2-3) and cyclophosphamide (1 g/m2 day 1) given every 4 weeks. A total of 10 courses were given. Response evaluation was initially evaluated after the first two courses of CAVE and repeated at least after treatment completion. This regimen was associated with severe hematological toxicity, mainly leucopenia; five toxic deaths related to sepsis were observed. One hundred and one patients were evaluable for response: 63 with limited disease and 49 with extensive disease. Overall complete and partial response rates after the first two courses of chemotherapy were 16% and 63% respectively but 14 late complete responses were documented, leading to a 30% total complete response rate; 38% in patients with limited disease and 19% in those with disseminated disease. Median overall survival was 46 weeks with a 17% 2 year survival. The only significant prognostic factor for survival was the type of response. There was no survival difference between 'early' and 'late' complete responders. Complete responders had a 75 week median survival time with a 34% 2 year survival. CAVE is thus an effective regimen for SCLC, but with a considerable toxicity.


amiodarone

sotalol

flecainide

propafenone

Dronedarone for the treatment of atrial fibrillation: a NICE single technology appraisal. The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of dronedarone (Multaq®, Sanofi-Aventis Limited, UK) to submit evidence on the clinical and cost effectiveness of the anti-arrhythmic drug (AAD) for the treatment of atrial fibrillation (AF) and atrial flutter, as part of the Institute's single technology appraisal (STA) process. The Centre for Reviews and Dissemination and the Centre for Health Economics, both at the University of York, were commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and NICE's subsequent decisions regarding the use of dronedarone within the UK NHS. The ERG review comprised a critique of the submitted evidence on the clinical effectiveness and cost effectiveness of dronedarone. The ERG examined the search strategy used to obtain relevant evidence, the selection of studies included in the assessment, outcome measures chosen and statistical methods employed. The ERG also validated the manufacturer's decision analytic model and used it to explore the robustness of the cost-effectiveness results to key assumptions. The main clinical effectiveness evidence supporting the use of dronedarone as a treatment for AF came from four randomized controlled trials. These trials were compared with a broader set of trials examining the effectiveness of other AADs for AF : amiodarone , sotalol and class 1c agents ( flecainide and propafenone ) . The evidence suggested that all AADs decreased the recurrence of AF but dronedarone had the smallest effect. A mixed treatment comparison analysis of the trials showed that dronedarone was associated with a lower risk of all-cause mortality than other AADs, but this was highly uncertain. There was limited evidence to assess the effect of dronedarone on stroke, and no statistically significant differences between dronedarone and other AADs were found for treatment discontinuation. From the evidence presented by the manufacturer, dronedarone appeared highly cost effective in each of the population groups examined compared with using standard baseline therapy alone as first-line treatment, or compared with sotalol or amiodarone as first-line AAD, with incremental cost-effectiveness ratios (ICERs) well below £20,000 per QALY gained. The ICER for dronedarone relative to class 1c agents was around £19,000 per QALY. Although the evidence presented by the manufacturer indicated that dronedarone was cost effective, the estimates of treatment effect relative to other AADs and safety in the longer term were highly uncertain. The NICE Appraisal Committee in its preliminary guidance did not recommend the use of dronedarone for AF. However, following the response from a large number of consultees and commentators, NICE revised its preliminary guidance to allow the use of the drug in a specific subgroup of AF patients with additional cardiovascular risk factors.


sorafenib

sunitinib

temsirolimus

everolimus

"Real world" treatment of metastatic renal cell carcinoma in a joint community-academic cohort: progression-free survival over three lines of therapy. New targeted therapeutics approved for metastatic renal cell carcinoma (mRCC) offer multiple options in each line of therapy; however, there are few prospective data beyond the first-line settings, and overall comparative effectiveness data are limited. In the targeted therapy era, progression-free survival (PFS) has been the most common regulatory end point for demonstrating the benefit of new therapies. ### Patients And Methods Drawing on a joint community-academic retrospective mRCC registry, we analyzed all patients who had undergone at least 1 line of systemic therapy (N = 325) for PFS. Patients were grouped according to treatment choice (sorafenib, sunitinib, temsirolimus, everolimus, and "other") for up to 3 lines of therapy. PFS by treatment choice and line of therapy was evaluated using Kaplan-Meier and Cox regression analyses. ### results PFS was longest in patients treated with sunitinib in the first and second lines of therapy. First-line PFS for sorafenib , sunitinib , temsirolimus , everolimus , and " other " was 6.9 , 8.9 , 4.2 , not analyzed ( too few patients ) , and 10.8 months , respectively . Second-line PFS was 4.6, 7.0, 3.2, 3.8, and 4.1 months, respectively. Third-line PFS was 4.5, 4.6, 9.9, 4.2, and 2.9, months, respectively. The risk of progression in patients treated with temsirolimus was about twice that of patients treated with sunitinib in the first and second lines of therapy. ### conclusion Patients treated with sunitinib had the longest PFS in the first and second lines of therapy. PFS from practice-based data appear consistent with trial-based expectations; however, practice variation was still evident.


gefitinib

pemetrexed

gefitinib

Combination of Gefitinib and Pemetrexed Prevents the Acquisition of TKI Resistance in NSCLC Cell Lines Carrying EGFR-Activating Mutation. Development of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors is a clinical issue in patients with epidermal growth factor receptor gene (EGFR)-mutated non-small cell lung cancer (NSCLC). The aim of this study was to investigate the potential of combining gefitinib and pemetrexed in preventing the acquisition of resistance to EGFR tyrosine kinase inhibitors in NSCLC cell lines harboring EGFR exon 19 deletion. ### methods The effect of different combinatorial schedules of gefitinib and pemetrexed on cell proliferation, cell cycle, apoptosis, and acquisition of gefitinib resistance in PC9 and HCC827 NSCLC cell lines and in PC9 xenograft models was investigated. ### results Simultaneous treatment with gefitinib and pemetrexed enhanced cell growth inhibition and cell death and prevented the appearance of gefitinib resistance mediated by T790 M mutation or epithelial-to-mesenchymal transition ( EMT ) in PC9 and HCC827 cells , respectively . In PC9 cells and in PC9 xenografts the combination of gefitinib and pemetrexed, with different schedules, prevented gefitinib resistance only when pemetrexed was the first treatment, given alone or together with gefitinib. Conversely, when gefitinib alone was administered first and pemetrexed sequentially alternated, a negative interaction was observed and no prevention of gefitinib resistance was documented. The mechanisms of resistance that developed in vivo included T790M mutation and EMT. The induction of EMT was a feature of tumors treated with gefitinib when given before pemetrexed, whereas T790M was recorded only in tumors treated with gefitinib alone. ### conclusions The combination of gefitinib and pemetrexed is effective in preventing gefitinib resistance; the application of intermittent treatments requires that gefitinib not be administered before pemetrexed.


etoposide

carboplatin

Standard-risk medulloblastoma treated by adjuvant chemotherapy followed by reduced-dose craniospinal radiation therapy: a French Society of Pediatric Oncology Study. The primary objective of this study was to decrease the late effects of prophylactic radiation without reducing survival in standard-risk childhood medulloblastoma. ### Patients And Methods Inclusion criteria were as follows: children between the ages of 3 and 18 years with total or subtotal tumor resection, no metastasis, and negative postoperative lumbar puncture CSF cytology. Two courses of eight drugs in 1 day followed by two courses of etoposide plus carboplatin ( 500 and 800 mg/m(2 ) per course , respectively ) were administered after surgery . Radiation therapy had to begin 90 days after surgery. Delivered doses were 55 Gy to the posterior fossa and 25 Gy to the brain and spinal canal. ### results Between November 1991 and June 1998, 136 patients (median age, 8 years; median follow-up, 6.5 years) were included. The overall survival rate and 5-year recurrence-free survival rate were 73.8% +/- 7.6% and 64.8% +/- 8.1%, respectively. Radiologic review showed that 4% of patients were wrongly included. Review of radiotherapy technical files demonstrated a correlation between the presence of a major protocol deviation and treatment failure. The 5-year recurrence-free survival rate of patients included in this study with all optimal quality controls of histology, radiology, and radiotherapy was 71.8% +/- 10.5%. In terms of sequelae, 31% of patients required growth hormone replacement therapy and 25% required special schooling. ### conclusion Reduced-dose craniospinal radiation therapy can be proposed in standard-risk medulloblastoma provided staging and radiation therapy are performed under optimal conditions.


Azithromycin

doxycycline

moxifloxacin

A case of human infection with a novel Babesia species in China. Babesiosis is an uncommon but emerging tick-borne disease caused by the genus Babesia. In this case study, we report a case of human infection with a novel Babesia sp. in China. ### findings The patient in question had been suffering from repetitive occurrences of mild fever of unknown origin and fatigue for 10 years. Ring forms, tetrads, and one or two dots of chromatin or trophozoite-like organisms were observed in the patient's thin blood smears and bone marrow smears. Using a confocal laser-scanning microscope, it was observed that the patient's serum had reactivity with the surface proteins of the B. microti strain. Electron microscopy revealed oval red blood cells with 1 ~ 2 μm of knob protrusions in the cellular membrane. The results of the Babesia-specific nested PCR assay for 18S rRNA confirmed the presence of Babesia infection. The construction of a phylogenetic relationship showed clustering with B. microti and B. duncani, which was identified as a novel Babesia species and named as Babesia sp. XXB/HangZhou. Azithromycin , doxycycline , and moxifloxacin hydrochloride were shown to relieve symptoms but were not as effective after continuous usage . After atovaquone (Mepron®) administration, the patient recovered from fever and tested negative for detection of Babesia-specific genes. ### conclusion Babesia sp. XXB/HangZhou is a novel Babesia species, which causes mild babesiosis in an immunocompetent patient.


doxycycline

azithromycin

Travel-associated multidrug-resistant organism acquisition and risk factors among US military personnel. International travel is a risk factor for incident colonization with extended spectrum beta-lactamase (ESBL)-producing organisms. These and other multidrug-resistant (MDR) bacteria are major pathogens in combat casualties. We evaluated risk factors for colonization with MDR bacteria in US military personnel travelling internationally for official duty. ### methods TravMil is a prospective observational study enrolling subjects presenting to military travel clinics. We analysed surveys, antimicrobial use data, and pre- and post-travel perirectal swabs in military travellers to regions outside the continental USA, Canada, Western or Northern Europe, or New Zealand, presenting to one clinic from 12/2015 to 12/2017. Recovered Gram-negative isolates underwent identification and susceptibility testing (BD Phoenix). Characteristics of trip and traveller were analysed to determine risk factors for MDR organism colonization. ### results 110 trips were planned by 99 travellers (74% male, median age 38 years [IQR 31, 47.25]); 72 trips with returned pre- and post-travel swabs were completed by 64 travellers. Median duration was 21 days (IQR 12.75, 79.5). 17% travelled to Mexico/Caribbean/Central America, 15% to Asia, 57% to Africa and 10% to South America; 56% stayed in hotels and 50% in dormitories/barracks. Travellers used doxycycline ( 15 % ) for malaria prophylaxis , 11 % took an antibiotic for travellers ' diarrhoea ( TD ) treatment ( fluoroquinolone 7 % , azithromycin 4 % ) . Incident MDR organism colonization occurred in 8 travellers (incidence density 3.5/1000 travel days; cumulative incidence 11% of trips [95% CI: 4-19%]), all ESBL-producing Escherichia coli. A higher incidence of ESBL-producing E. coli acquisition was associated with travel to Asia (36% vs 7%, P = 0.02) but not with travel to other regions, TD or use of antimicrobials. No relationship was seen between fluoroquinolone or doxycycline exposure and resistance to those antimicrobials. ### conclusions Incident colonization with MDR organisms occurs at a lower rate in this military population compared with civilian travellers, with no identified modifiable risk factors, with highest incidence of ESBL acquisition observed after South Asia travel.


timolol

hydrochlorothiazide

Enhancement of the antihypertensive effect of hydrochlorothiazide in dogs after suppression of renin release by beta-adrenergic blockade. 1. Renal hypertensive dogs were treated with hydrochlorothiazide (8-2 mumol/kg or 33 mumol/kg daily for 7 days), or timolol (4-6 mumol/kg daily for 4 days), a potent beta-adrenergic blocking agent, or combinations of these drugs). Changes in mean arterial blood pressure and plasma renin activity were measured over the treatment period. 2. Neither drug significantly lowered arterial blood pressure when administered alone. Plasma renin activity, which did not change during treatment with timolol, was substantially elevated during treatment with hydrochlorothiazide. 3 . When timolol was administered concomitantly with hydrochlorothiazide , plasma renin activity was suppressed and blood pressure was significantly lowered . 4. These observations suggest that compensatory activation of the renin-angiotensin system limits the antihypertensive activity of hydrochlorothiazide in renal hypertensive dogs and suppression of diuretic-induced renin release by timolol unmasks the antihypertensive effect of the diuretic.


temsirolimus

sunitinib

Phase I study combining treatment with temsirolimus and sunitinib malate in patients with advanced renal cell carcinoma . Concurrent inhibition of multiple oncogenic signaling pathways might improve the efficacy of anticancer agents and abrogate resistance mechanisms. This phase I study evaluated temsirolimus in combination with sunitinib in patients with advanced RCC. ### Patients And Methods Eligibility included advanced RCC and <or= 2 previous systemic regimens. At the starting dose, temsirolimus 15 mg was administered by intravenous (I.V.) infusion once weekly, and sunitinib 25 mg was administered orally once daily for 4 weeks, followed by a 2-week rest period. ### results In the first cohort, dose-limiting toxicities (grade 3 treatment-related toxicities that lasted >or= 7 days) were observed in 2 of 3 patients. One patient experienced grade 3 rash during week 3, which led to treatment discontinuation. A second patient had grade 3 thrombocytopenia (platelet count, 48,000/microL), cellulitis, and gout during week 3 and was hospitalized; platelets recovered to 109,000/microL 4 days after discontinuation of protocol therapy. A third patient experienced rash, asthenia, diarrhea, stomatitis, constipation, fever, and rectal hemorrhage, all of which were mild in severity. The study was terminated because of dose-limiting toxicity observed at low starting doses of both agents. ### conclusion Concomitant use of I.V. temsirolimus 15 mg weekly and oral sunitinib 25 mg daily (4 weeks on, 2 weeks off) is not recommended.


anastrozole

letrozole

tamoxifen

Emerging role of aromatase inhibitors in the treatment of breast cancer. The new generation of potent steroidal and nonsteroidal inhibitors of the enzyme aromatase act by decreasing estrogen production throughout the body in postmenopausal women. The most potent of these agents may also inhibit estrogen synthesis within metastatic breast cancer tissue. The newly developed, orally administered, nonsteroidal competitive inhibitors, such as anastrozole (Arimidex), letrozole (Femara), and vorozole (Rizivor), are a thousand times more potent inhibitors of aromatase than is aminoglutethimide. Furthermore, these agents are highly selective. In several large randomized trials, the new inhibitors produced similar response rates as megestrol acetate (160 mg/d) in postmenopausal women with hormone-dependent breast cancer, but showed a trend toward improved response duration and survival. They also produced less weight gain and fewer cardiovascular and thromboembolic side effects. In addition, letrozole proved superior to aminoglutethimide in another randomized trial. Both anastrozole ( 1.0 mg/d ) and letrozole ( 2.5 mg/d ) have now been approved as second-line treatment for hormone-dependent breast cancer in postmenopausal women in whom disease has progressed following tamoxifen treatment . Either drug should replace the routine use of megestrol acetate in this setting. Ongoing clinical studies are comparing anastrozole and letrozole to antiestrogens as first-line endocrine therapy for metastatic breast cancer. Other trials will study the possible roles of these compounds as adjuvant therapy and chemoprevention for breast cancer.


doxorubicin

etoposide

Therapeutic approach to drug resistant tumors. Drug resistance is a major problem in cancer chemotherapy. P-glycoprotein plays a major role in multidrug resistance in cancer cells. P-glycoprotein is expressed in some normal tissues and has physiological functions. These include protecting the brain against toxic substances at the blood-brain barrier site, excreting toxic substances from the liver, kidney, and gastrointestinal tracts, and transporting steroidal hormones in the adrenal grand. Once expressed in cancer cells. P-glycoprotein effluxes a variety of anticancer drugs , such as doxorubicin , vinca alkaloids , etoposide and taxol , and thereby allows cancer cells to show resistance to these drugs .


cimetidine

ranitidine

Omeprazole, cimetidine, and ranitidine: inhibition of acid production in isolated human parietal cells. The antisecretory properties of omeprazole, cimetidine, and ranitidine were studied in vitro, using human gastric mucosal cells, which were obtained by sequential pronase and collagenase incubation of small tissue specimens obtained by endoscopic biopsy. Acid production was measured as the accumulation of radioactive aminopyrine in the acid compartments of the parietal cells. Acid production was stimulated via H2-receptors by histamine (10(-4) M or 5 X 10(-6) M) and via intracellular mechanisms by db-cAMP (10(-3) M). omeprazole induced a dose-dependent inhibition of acid production for all stimulators (IC50 = 2 X 10(-7) M and 3 X 10(-8) M with high and low concentrations of histamine, respectively, and 5 X 10(-6) M with db-cAMP). The H2-receptor antagonists dose-dependently inhibited the histamine-stimulated acid production ( IC50 for cimetidine = 10(-5 ) M and 10(-6 ) M and for ranitidine = 10(-5 ) M and 2 X 10(-7 ) M for high and low concentrations of histamine , respectively ) . Neither cimetidine nor ranitidine inhibited acid production after intracellular stimulation with db-cAMP. omeprazole reduced the aminopyrine accumulation stimulated by histamine (10(-4) M) already within 5-10 min, whereas cimetidine (10(-3) M and ranitidine (10(-4) M) required 20-30 min. The unstimulated level of acid production was also inhibited by omeprazole but not by the H2-receptor antagonists.


aripiprazole

quetiapine

Cost-effectiveness of adjunctive therapy with atypical antipsychotics for acute treatment of major depressive disorder. While the clinical utility of atypical antipsychotics has been established in patients with major depressive disorder (MDD) who are refractory to antidepressant therapy, their cost-effectiveness is unknown. ### objective To examine the cost-effectiveness of aripiprazole , quetiapine , and olanzapine/fluoxetine in adults with MDD who are refractory to antidepressant therapy . ### methods Using techniques of decision analysis, we estimated expected outcomes and costs over 6 weeks in adults with MDD receiving (1) aripiprazole 2-20 mg/day and antidepressant therapy; (2) quetiapine 150 mg/day or 300 mg/day and antidepressant therapy; (3) the fixed-dose combination of olanzapine 6, 12, or 18 mg/day with fluoxetine 50 mg/day; or (4) antidepressant therapy alone. Cost-effectiveness was assessed in terms of the cost per additional responder at 6 weeks, defined as the ratio of the difference in the cost of MDD-related care over 6 weeks versus antidepressant therapy alone to the difference in the number of patients achieving clinical response by 6 weeks. We estimated the model using data from Phase 3 clinical trials of atypical antipsychotics along with other secondary data sources. ### results With antidepressant therapy alone, the estimated clinical response rate at 6 weeks was 30%. aripiprazole, quetiapine 150 mg/day, quetiapine 300 mg/day, and olanzapine/fluoxetine were estimated to increase clinical response at 6 weeks to 49%, 34%, 38%, and 45%, respectively. Costs of MDD-related care over 6 weeks were estimated to be $192 for antidepressant therapy, $847 for aripiprazole, $541 for quetiapine 150 mg/day, $672 for quetiapine 300 mg/day plus antidepressant therapy, and $791 for olanzapine/fluoxetine. Costs per additional responder (vs antidepressant therapy) over a 6-week period were estimated to be $3447 for aripiprazole, $8725 for quetiapine 150 mg/day, $6000 for quetiapine 300 mg/day, and $3993 for olanzapine/fluoxetine. ### conclusions Atypical antipsychotics substantially increase clinical response at 6 weeks. Cost per additional responder is lower for aripiprazole than for quetiapine or olanzapine/fluoxetine.


atenolol

nifedipine

nifedipine

Atenolol-nifedipine combinations compared to atenolol alone in hypertension: efficacy and tolerability. 1. In a double-blind, randomised, three-way-crossover study, 25 patients with sitting diastolic blood pressure between 95 and 120 mm Hg (Phase V) after 4 weeks' run-in on atenolol 50 mg twice daily, received atenolol 50 mg twice daily alone, atenolol 50 mg plus nifedipine 20 mg each twice daily and atenolol 50 mg plus nifedipine 40 mg each twice daily in three treatment periods each lasting 4 weeks. 'Washout' periods were not included. 2 . The two combination treatment regimes lowered the 12 h post-dose blood pressure more effectively than did atenolol alone , but the high dose nifedipine combination was no more effective than the low dose nifedipine combination . Sitting systolic BP (+/- s.e. mean) at the end of each period was 174 +/- 5 mm Hg after the atenolol run-in, 170 +/- 5 mm Hg with atenolol alone, 156 +/- 5 mm Hg with the low dose combination and 158 +/- 4 mm Hg with the high dose combination. Corresponding diastolic BP readings were 106 +/- 2 mm Hg, 106 +/- 2 mm Hg, 97 +/- 2 mm Hg and 99 +/- 2 mm Hg respectively. 3. Side-effects tended to occur less commonly with the low dose of the fixed combination than with atenolol alone. An increased number of side-effects occurred with the 40 mg twice daily doses of nifedipine, particularly flushing/erythema, oedema of the ankles/feet, and a hot feeling in the legs. These differences did not reach significance. 4. Overall compliance was good (98 +/- 0.7 s.e. mean %) and was similar within the different treatment regimes.(ABSTRACT TRUNCATED AT 250 WORDS)


doxorubicin

epirubicin

etoposide

cisplatin

mitoxantrone

tamoxifen

capecitabine

thalidomide

octreotide

Nonsurgical treatment of hepatocellular carcinoma. While surgical resection and tumor ablation are the preferred therapies for hepatocellular carcinoma (HCC), these are available or appropriate in only a minority of patients. This reflects the usual comorbidity of severe underlying liver disease that either precludes surgery or makes the surgical approach extremely dangerous. Nonetheless, regional control of HCC is highly relevant and many regional strategies have been explored, including hepatic intra-arterial chemotherapy transarterial chemoembolization, lipiodol chemoembolization, radiation therapy, cryosurgery, percutaneous ethanol injection, and radiofrequency ablation. In addition , a variety of systemic chemotherapeutic agents have been tested in HCC , including various combinations of 5-fluorouracil , doxorubicin , epirubicin , etoposide , cisplatin , and mitoxantrone , as well as interferon , tamoxifen , capecitabine , thalidomide , and octreotide . Published data regarding these regional and systemic therapies will be discussed in this review.


sertraline

paroxetine

Depression in Parkinson's Disease. Depression is very common in Parkinson's disease (PD), but its severity and particular symptoms vary. It can often be difficult to diagnose because many of the symptoms typically associated with depression (eg, sleep difficulties, fatigue) can be seen in nondepressed patients with PD, and signs thought to represent depression (eg, lack of facial expression, slowness) can be produced by PD itself. Apathy, although a possible feature of depression, can exist apart from depression and is often associated with cognitive impairment. Therefore, when evaluating patients with PD for possible depression, one should concentrate on the psychological or ideational aspects of the illness. One must determine whether the patient feels sad or hopeless or has a marked inability to enjoy life. Once it has been determined that the patient has clinically significant depressive symptoms, it is important to let him or her know that depression is an aspect of PD requiring treatment, just like the motor manifestations of the disease. The idea of adding antidepressant medications and the possibility of psychotherapy should be introduced. A very reasonable first-choice antidepressant is either sertraline or paroxetine . Because of isolated case reports of worsening motor function associated with institution of a selective serotonin reuptake inhibitor (SSRI), one should keep track of when the medication was started so that the patient can be seen again within a month. It is important from a psychological perspective to have regular follow-up visits when treating depression. If the SSRIs are ineffective or not tolerated, nortriptyline is a good next choice. It has fewer anticholinergic effects and is less likely to cause or worsen orthostatic hypotension than other tricyclic antidepressants. amitriptyline, although an old favorite of neurologists, is very sedating and has too much anticholinergic activity to be well tolerated in the higher doses needed to treat depression. If a patient could benefit from a dopamine agonist from a motor standpoint and his or her depressive symptoms are mild, consider using pramipexole, which may improve mood and motivation (although this has not yet been proven in a well-controlled trial). It is a good idea to keep patients on antidepressant therapy at least 6 months; many patients require long-term treatment. If a patient is severely depressed, he or she should be referred to a psychiatrist, who may consider admission to the hospital and possible electroconvulsive therapy.


fenofibrate

ciprofibrate

gemfibrozil

Gemfibrozil increases both apo A-I and apo E concentrations. Comparison to other lipid regulators in cholesterol-fed rats. HDL cholesterol (HDL-C) was increased by gemfibrozil (+3.6-fold), fenofibrate (+1.3-fold) and ciprofibrate (+1.2-fold) but not clofibrate or bezafibrate when dosed PO at 50 mg/kg for 2 weeks in cholesterol-fed rats. Cholesterol in apo B-containing lipoproteins decreased with gemfibrozil (-76%), clofibrate (-12%) and ciprofibrate (-12%). Plasma apo B decreased to the greatest extent with gemfibrozil (-86%) followed by ciprofibrate (-47%), fenofibrate (-40%), clofibrate (-24%) and bezafibrate (-20%). Only gemfibrozil increased plasma apo E levels which are characteristically low in this rat model. gemfibrozil, fenofibrate and ciprofibrate increased apo A-I concentrations. It is concluded that plasma lipid regulators which elevate HDL in this model might do so by altering the metabolism and hence plasma concentration of apoAI ( fenofibrate , ciprofibrate ) or both apo E and A-I ( gemfibrozil ) . It is hypothesized that drugs which alter the metabolism of both HDL peptides result in the greatest HDL-C elevation in the rat.


bevacizumab

ranibizumab

Bevacizumab and ranibizumab tachyphylaxis in the treatment of choroidal neovascularisation.  To evaluate the effect of switching to bevacizumab or ranibizumab after developing tachyphylaxis during anti-vascular endothelial growth factor ( VEGF ) therapy for choroidal neovascularisation ( CNV ) . ### methods The authors reviewed the records of all patients who received both ranibizumab and bevacizumab for treatment of CNV to identify those who developed tachyphylaxis, defined as optical coherence tomography evidence of initial decreased exudation followed by lack of further reduction or an increase in exudation. Signs of exudation included subretinal fluid (SRF), pigment epithelial detachment (PED) and/or cystoid macular oedema (CMO). ### results 26 eyes were included. 10 were initially treated with bevacizumab and then changed to ranibizumab for persistent SRF, PED and/or CMO. Of these, seven had occult CNV and three had predominantly classic CNV. One eye in the occult CNV group did not respond after being switched to ranibizumab. Six eyes had a positive therapeutic response, after one injection in four eyes, and after two or three injections in one eye each. In the classic group, two responded to ranibizumab and one did not. Sixteen eyes were initially treated with ranibizumab before changing to bevacizumab. Of these, 15 had occult CNV and 1 was predominantly classic. Three of the 16 eyes failed to respond to bevacizumab; 6 improved after one injection and 5 after two injections. ### conclusions Patients with CNV who develop tachyphylaxis to ranibizumab or bevacizumab may respond to another anti-VEGF drug. The majority of cases (81%) in this series demonstrated at least some response after switching therapies.


cyclophosphamide

doxorubicin

vincristine

methotrexate

cytarabine

methotrexate

adriamycin

Modified magrath regimens for adults with Burkitt and Burkitt-like lymphomas: preserved efficacy with decreased toxicity. Burkitt and Burkitt-like lymphomas are rapidly growing tumors which require specialized therapy. Although intensive, multi-agent regimens have been effective in children, results are more variable in adults. Magrath et al. previously described a regimen that was highly effective in children and young adults. This phase II study of a modified Magrath regimen was designed to assess its efficacy in older adults and reduce treatment-related toxicity. Fourteen patients with Burkitt/Burkitt-like lymphoma and median age of 47 years were stratified into two categories: low-risk (normal LDH and a single focus of disease measuring less than 10 cm, 3 patients) and high risk (all other, 11 patients). Low-risk patients received three cycles of modified CODOX-M ( cyclophosphamide , doxorubicin , adriamycin , vincristine with intrathecal methotrexate and cytarabine followed by high-dose systemic methotrexate , regimen A ) . High-risk patients received four alternating cycles of regimens A and B (A-B-A-B). Regimen B consisted of ifosfamide, cytarabine, etoposide and intrathecal methotrexate (IVAC). The modified treatment regimen was associated with no grade 3/4 neuropathy and only one episode of grade 3/4 mucositis. All patients completed protocol therapy and there were no treatment-related deaths. Twelve patients (86%, 90% CI: 61 97%) achieved a complete response; 1 patient achieved a PR and 1 patient died of progressive disease. Nine patients (64%) are alive and disease free at a median follow-up of 29 months. This modified Magrath regimen is effective and well-tolerated in a representative group of older adult patients.


vincristine

doxorubicin

dactinomycin

Outcome and Prognostic Factors in Stage III Favorable-Histology Wilms Tumor: A Report From the Children's Oncology Group Study AREN0532.  Background The National Wilms Tumor Study ( NWTS ) approach to treating stage III favorable-histology Wilms tumor ( FHWT ) is Regimen DD4A ( vincristine , dactinomycin , and doxorubicin ) and radiation therapy . Further risk stratification is required to improve outcomes and reduce late effects. We evaluated clinical and biologic variables for patients with stage III FHWT without combined loss of heterozygosity (LOH) at chromosomes 1p and 16q treated in the Children's Oncology Group protocol AREN0532. Methods From October 2006 to August 2013, 588 prospectively treated, centrally reviewed patients with stage III FHWT were treated with Regimen DD4A and radiation therapy. Tumor LOH at 1p and 16q was determined by microsatellite analysis. Ineligible patients (n = 5) and those with combined LOH 1p/16q (n = 40) were excluded. Results A total of 535 patients with stage III disease were studied. Median follow-up was 5.2 years (range, 0.2 to 9.5). Four-year event-free survival (EFS) and overall survival estimates were 88% (95% CI, 85% to 91%) and 97% (95% CI, 95% to 99%), respectively. A total of 58 of 66 relapses occurred in the first 2 years, predominantly pulmonary (n = 36). Eighteen patients died, 14 secondary to disease. A better EFS was associated with negative lymph node status ( P < .01) and absence of LOH 1p or 16q ( P < .01), but not with gross residual disease or peritoneal implants. In contrast, the 4-year EFS was only 74% in patients with combined positive lymph node status and LOH 1p or 16q. A total of 123 patients (23%) had delayed nephrectomy. Submitted delayed nephrectomy histology showed anaplasia (n = 8; excluded from survival analysis); low risk/completely necrotic (n = 7; zero relapses), intermediate risk (n = 63; six relapses), and high-risk/blastemal type (n=7; five relapses). Conclusion Most patients with stage III FHWT had good EFS/overall survival with DD4A and radiation therapy. Combined lymph node and LOH status was highly predictive of EFS and should be considered as a potential prognostic marker for future trials.


methamphetamine

clonidine

Serotonergic-catecholaminergic interactions and foot shock-induced jumping behavior in rats.  The role of serotonergic neurons in foot shock-induced jumping behavior was evaluated by studying the effects of serotonin agonists and depletors under conditions of increasing activity of catecholaminergic neurons by combining different shock intensities with methamphetamine or clonidine pretreatment . Low shock (40 V) jumping was suppressed by three different kinds of serotonergic agonists: 5-hydroxytryptophan (50 and 100 mg/kg), 5-methoxydimethyltryptamine (1 and 5 mg/kg) and clomipramine (5 mg/kg) but these drugs did not suppress high shock (60 V) jumping. A depletor of brain serotonin, p-chlorophenylalanine (200 mg/kg), failed to affect the jumping induced by both shock intensities. The inhibitory effect of serotonergic agonists on low shock jumping was abolished by pretreatment with methamphetamine (1 mg/kg) or clonidine (100 micrograms/kg). Furthermore, 5-methoxydimethyltryptamine (5 mg/kg), a serotonergic postsynaptic receptor stimulant, potentiated high shock jumping in rats pretreated with methamphetamine (3 and 5 mg/kg). The results indicated that activation of serotonergic neurons has a differential effect on jumping behavior ranging from inhibitory to facilitatory, depending upon the increasing activity of catecholaminergic neurons.


leuprolide

bicalutamide

A phase II trial of androgen deprivation therapy (ADT) plus chemotherapy as initial treatment for local failures or advanced prostate cancer. Long-term hormonal ablation in prostate cancer is associated with decreased overall health and quality of life. Few reports emphasized the role of chemotherapy in the management of early stage prostate cancer. This study analyzed the safety and efficacy of androgen deprivation therapy (ADT) plus chemotherapy as initial treatment for patients identified as local failures or not eligible for prostatectomy or radiation therapy due to advanced disease presentation. ### methods Enrolled patients received ADT in the form of leuprolide every 12 weeks for 24 months with bicalutamide initiating after the completion of chemotherapy . Chemotherapy consisted of ketoconazole and doxorubicin for weeks 1, 3, and 5 and estramustine and docetaxel and for weeks 2, 4 and 6. During weeks 7 and 8, no treatment was received. ### results Forty-six patients were enrolled, and forty-five patients were evaluable. Median progression-free survival (PFS) was 23.4 months. Median overall survival (OS) was 53.7 months. Out of 45 patients with measurable disease, 22 patients had an objective response: 9 patients achieved a complete response; 2 patients achieved a partial response; 10 patients achieved stable disease. Frequent grade 3 adverse events included elevated ALT (17 %), hypokalemia (13 %), and hypophosphatemia (13 %). Grade 4 adverse events were rare and included low bicarbonate (2 %), hypokalemia (2 %), leukocytopenia (2 %), and neutropenia (2 %). ### conclusions The treatment demonstrated clinical benefit in all patient subsets with minimal reversible treatment-related adverse events. Subgroup analysis suggests that having prior local therapy resulted in greater PFS and OS.


fluticasone

budesonide

beclomethasone

triamcinolone

Establishing a therapeutic index for the inhaled corticosteroids: part I. Pharmacokinetic/pharmacodynamic comparison of the inhaled corticosteroids. The inhaled corticosteroids contain physicochemical differences that alter both glucocorticoid receptor-binding characteristics and the pharmacokinetic variables of these drugs. Differences in receptor-binding affinity translate into differences in potency for different drugs. Differences in pharmacokinetics, however, determine the topical effect to systemic effect ratio, or the "pulmonary targeting" of the drug. Beneficial pharmacokinetic properties that may improve pulmonary targeting include low oral bioavailability, rapid systemic clearance, and slow absorption from the lung. Delivery devices can produce clinically significant differences in topical activity by altering the dose deposited in the lung and, for orally absorbed drugs, the amount deposited in the oropharynx and swallowed. Clinical trials have confirmed that differences in potency or drug delivery of 2-fold or more can be detected in patients with asthma. However, because of the relatively flat nature of the dose-response curve for morning peak expiratory flow and forced expiratory volume in 1 second, the trials must be adequately powered and well controlled. The use of bronchial provocation measures are problematic because of the prolonged lag time for response. Study design flaws can lead to misinterpretation of results. Clinical studies have indicated the following relative potency differences : fluticasone propionate > budesonide = beclomethasone dipropionate > triamcinolone acetonide = flunisolide . Current evidence suggests that potency differences can be overcome by giving larger doses of the less potent drug. However, because of these potency differences, studies of systemic effects should not be done in isolation of adequate topical activity studies to define the pulmonary targeting of the drugs.


lapatinib

trastuzumab

A retrospective, multicenter study of the efficacy of lapatinib plus trastuzumab in HER2-positive metastatic breast cancer patients previously treated with trastuzumab, lapatinib, or both: the Trastyvere study.  To evaluate the efficacy and safety of lapatinib ( L ) and trastuzumab ( T ) combination in HER2-positive metastatic breast cancer ( MBC ) patients previously treated with T and/or L. ### Materials And Methods We conducted a retrospective, post-authorized, multicenter study including patients with HER2-positive MBC or locally advanced breast cancer (ABC) treated with the combination of L-T. Concomitant endocrine therapy, as well as brain metastasis and/or prior exposure to L, were allowed. ### results One hundred and fifteen patients from 14 institutions were included. The median age was 59.8 years. The median number of prior T regimens in the advanced setting was 3 and 73 patients had received a prior L regimen. The clinical benefit rate (CBR) was 34.8% (95% CI 26.1-43.5). Among other efficacy endpoints, the overall response rate was 21.7%, and median progression-free survival (PFS) and overall survival were 3.9 and 21.6 months, respectively. Heavily pretreated and ≥ 3 metastatic organ patients showed lower CBR and PFS than patients with a low number of previous regimens and < 3 metastatic organs. Moreover, CBR did not significantly change in L-pretreated compared with L-naïve patients (31.5% versus 40.5% for L-pretreated versus L-naïve). Grade 3/4 adverse events were reported in 19 patients (16.5%). ### conclusion The combination of L-T is an effective and well-tolerated regimen in heavily pretreated patients and remains active among patients progressing on prior L-based therapy. Our study suggests that the L-T regimen is a safe and active chemotherapy-free option for MBC patients previously treated with T and/or L.


Meloxicam

sorafenib

Meloxicam combined with sorafenib synergistically inhibits tumor growth of human hepatocellular carcinoma cells via ER stress-related apoptosis . sorafenib (SOR) is a promising treatment for advanced hepatocellular carcinoma (HCC). However, the precise mechanisms of toxicity and drug resistance have not been fully explored and new strategies are urgently needed for HCC therapy. meloxicam (MEL) is a selective cyclooxygenase-2 (COX-2) inhibitor which elicits antitumor effects in human HCC cells. In the present study, we investigated the interaction between MEL and SOR in human SMMC‑7721 cells and the role endoplasmic reticulum (ER) stress exerts in the combination of SOR with MEL treatment-induced cytotoxicity. Our results revealed that the combination treatment synergistically inhibited cell proliferation and enhanced apoptosis. Furthermore, the combination treatment enhanced ER stress-related molecules which involved in SMMC-7721 cell apoptosis. GRP78 knockdown by siRNA or co-treatment with MG132 significantly increased this combination treatment-induced apoptosis. In addition, we found that the combination treatment suppressed tumor growth by way of activation of ER stress in in vivo models. We concluded that the combination of SOR with MEL treatment-induced ER stress, and eventually apoptosis in human SMMC-7721 cells. Knockdown of GRP78 using siRNA or proteosome inhibitor enhanced the cytotoxicity of the combination of SOR with MEL-treatment in SMMC-7721 cells. These findings provided a new potential treatment strategy against HCC.


fludarabine

cyclophosphamide

The long noncoding RNA, treRNA, decreases DNA damage and is associated with poor response to chemotherapy in chronic lymphocytic leukemia. The study of long noncoding RNAs (lncRNAs) is an emerging area of cancer research, in part due to their ability to serve as disease biomarkers. However, few studies have investigated lncRNAs in chronic lymphocytic leukemia (CLL). We have identified one particular lncRNA, treRNA, which is overexpressed in CLL B-cells. We measured transcript expression in 144 CLL patient samples and separated samples into high or low expression of treRNA relative to the overall median. We found that high expression of treRNA is significantly associated with shorter time to treatment. High treRNA also correlates with poor prognostic indicators such as unmutated IGHV and high ZAP70 protein expression. We validated these initial findings in samples collected in a clinical trial comparing the nucleoside analog fludarabine alone or in combination with the alkylating agent cyclophosphamide in untreated CLL samples collected prior to starting therapy ( E2997 ) . High expression of treRNA was independently prognostic for shorter progression free survival in patients receiving fludarabine plus cyclophosphamide. Given these results, in order to study the role of treRNA in DNA damage response we generated a model cell line system where treRNA was over-expressed in the human B-CLL cell line OSU-CLL. Relative to the vector control line, there was less cell death in OSU-CLL over-expressing treRNA after exposure to fludarabine and mafosfamide, due in part to a reduction in DNA damage. Therefore, we suggest that treRNA is a novel biomarker in CLL associated with aggressive disease and poor response to chemotherapy through enhanced protection against cytotoxic mediated DNA damage.


ganciclovir

foscarnet

Treatment and prophylaxis of cytomegalovirus disease. The diseases caused by cytomegalovirus (CMV) may threaten the life or sight of immunocompromised individuals such as patients undergoing transplantation and those with the acquired immunodeficiency syndrome. The management of CMV disease can be difficult. The antiviral agents ganciclovir and foscarnet are effective against CMV retinitis and gastrointestinal diseases , although dose-limiting adverse effects and the need for long-term maintenance therapy may hinder their use in many patients . When used to treat CMV pneumonitis in bone marrow transplant recipients, ganciclovir alone is not as effective as when it is combined with immune globulin. Since CMV disease can be fatal, several protocols have been developed for the transplant patient population, including administration of acyclovir, ganciclovir, screened blood products, and immune globulins.


metronidazole

clarithromycin

Where are We with current therapy? Despite intensive research and widely publicized recommendations from consensus meetings in different continents, the public and primary care physicians are relatively slow in picking up the impact of Helicobacter pylori infection and identifying optimal therapies. The treatment of H. pylori infection has evolved from bismuth-containing regimens, 2-week proton pump inhibitor (PPI)-dual therapies, and now, the widely accepted PPI/ranitidine bismuth citrate (RBC) single week triple therapies. There is a wealth of evidence showing that these regimens are highly efficacious and well tolerated by patients. The MACH-2 studies have confirmed that the addition of a PPI to two antimicrobials has significantly improved the cure rate of H. pylori infection and reduced the impact of antimicrobial resistance. Attempts to use shorter regimens ranging from 1 to 3 days should be resisted because of their unacceptably low therapeutic efficacy. In the United States, there are some indications that 10-14 days of treatment may be required. While the first-line therapies for H. pylori infection is well established, we are still struggling with the choice of optimal regimen in retreatment after the first attempt fails. Quadruple therapy combining PPI with bismuth, metronidazole and tetracycline has achieved a respectable success of around 85%. Switching between metronidazole and clarithromycin seems to be a sensible strategy as these two are the most effective anti-Helicobacter agents . Changing between PPI and RBC in the triple therapy would not make much difference without replacing some of the antimicrobials. rifabutin-containing regimens and high-dose PPI-amoxicillin dual therapy deserve more studies with large-scale studies. Data on anti-Helicobacter therapy for children are few. Most studies based on bismuth derivatives in combination with amoxicillin or tinidazole and were limited by the small number of cases. Recent studies showed 1-week bismuth-based triple therapy and 2-week PPI-based triple therapy are highly efficacious. Reinfection in children > 5 years of age after successful cure is rare. It is worthwhile to refine the optimal therapy for children as the treatment of this group would, theoretically, prevent the development gastric cancer in the long term.


etoposide

doxorubicin

Specific downregulation of bcl-2 and xIAP by RNAi enhances the effects of chemotherapeutic agents in MCF-7 human breast cancer cells. Antiapoptotic genes such as bcl-2 or xIAP may be responsible for resistance to apoptosis induced by cytotoxic drugs. The aim of this study was to investigate if downregulation of bcl-2 or xIAP by RNA interference (RNAi) would sensitize MCF-7 cells to etoposide and doxorubicin. FITC-siRNAs uptake was verified by fluorescence microscopy and downregulation of Bcl-2 or XIAP was confirmed by Western Blotting. Both siRNAs reduced the number of viable cells and increased cellular apoptosis. Treatment with siRNAs followed by treatment with etoposide or doxorubicin further reduced the number of viable cells, when compared to either of the treatments alone. Therefore , downregulation of bcl-2 or xIAP by RNAi enhances the effects of etoposide and doxorubicin .


Cetuximab

irinotecan

N0436 (Alliance): A Phase II Trial of Irinotecan With Cetuximab in Patients With Metastatic Breast Cancer Previously Exposed to Anthracycline and/or Taxane-Containing Therapy. irinotecan has a 20% to 25% response rate (RR) in patients with previously treated metastatic breast cancer (MBC). Epidermal growth factor receptor (EGFR) is overexpressed in some MBC, especially in triple-negative breast cancer (TNBC). Cetuximab is a monoclonal antibody against EGFR with additive preclinical activity with irinotecan . ### Patients And Methods We report a 1-stage phase II study on MBC, measurable disease, and previous anthracycline and/or taxane therapy. Patients received cetuximab 400 mg/m(2) on day 1 cycle 1 then 250 mg/m(2) weekly thereafter and irinotecan 80 mg/m(2) on days 1 and 8 of each 21-day cycle. The primary end point was overall RR (ORR) according to Response Evaluation Criteria in Solid Tumors criteria (version 1.1). ### results Of 19 eligible patients enrolled from February to September 2006, 14 patients (74%) had visceral disease, seven patients (37%) were hormone receptor-positive, two patients (11%) HER2-positive, and 11 patients (58%) were triple-negative. Patients received a median of 2 cycles (range, 1-37). Confirmed ORR was 11% (95% confidence interval [CI], 1%-33%), with 1 partial response and 1 complete response. One patient had stable disease for 8 months. RR for TNBC versus non-TNBC was 18% versus 0% (P = .49). Median time to progression was 1.4 months (95% CI, 1.0-2.2) and median overall survival was 9.4 months (95% CI, 2.8-16.1). Twelve patients had disease progression within 2 cycles during therapy. Because of a low RR and rapid disease progression, the study leadership decided to close the trial early. ### conclusion The tolerability of the combination of cetuximab and irinotecan is acceptable but demonstrated low overall activity. Potentially promising results were noted in patients with TNBC and further studies of these patients might be considered.


imipramine

fenfluramine

tranylcypromine

Manipulations of 5-HT activity and memory in the rat. The activity of 5-HT was manipulated by means of the peripheral injection of 5-HT reuptake inhibitors, fenfluramine and fluoxetine. These drug treatments, at doses higher than 1 mg/kg, produced retrograde amnesia in a one-trial appetitive learning task in rats. A non-specific inhibitor of 5-HT reuptake , imipramine , did not produce this amnesic effect , nor did the combination of fenfluramine with the MAOI tranylcypromine , although it produced , as expected , the " serotonergic syndrome . " Results for the metabolic precursor of 5-HT , 5-HTP , also administered peripherally , were inconsistent , with amnesic effects seen at 5 and 20 mg/kg but none at 10 mg/kg .


irinotecan

temozolomide

Activity of irinotecan and temozolomide in the presence of O6-methylguanine-DNA methyltransferase inhibition in neuroblastoma pre-clinical models . The combination of temozolomide (TMZ) and irinotecan is a regimen used in neuroblastoma patients with recurrent disease. O(6)-methylguanine-DNA methyltransferase (MGMT) may have a function in resistance to TMZ. Using neuroblastoma pre-clinical models, we determined whether the inhibition of MGMT by O(6)-benzylguanine (O6-BG) could enhance the anti-tumour activity of TMZ and irinotecan. ### methods The cytotoxicity of TMZ and irinotecan, either alone or in combination, was measured in five neuroblastoma cell lines in the presence or absence of O6-BG with a fluorescence-based cell viability assay (DIMSCAN). Anti-tumour activity was measured in three neuroblastoma xenograft models. ### results MGMT mRNA and protein were expressed in 9 out of 10 examined cell lines. Pretreatment of cells with 25 μM O6-BG decreased MGMT protein expression and enhanced The TMZ cytotoxicity by up to 0.3-1.4 logs in four out of five tested cell lines. TMZ (25 mg kg(-1) per day for 5 days every 3 weeks for four cycles) did not significantly improve mice survival, whereas the same schedule of irinotecan (7.5 mg kg(-1) per day) significantly improved survival (P<0.0001) in all three xenograft models. Combining O6-BG and/or TMZ with irinotecan further enhanced survival. ### conclusion Our in vitro and in vivo findings suggest that irinotecan drives the activity of irinotecan and TMZ in recurrent neuroblastoma. Inhibitors of MGMT warrant further investigation for enhancing the activity of regimens that include TMZ.


etoposide

vincristine

doxorubicin

cyclophosphamide

prednisone

EPOCH chemotherapy: toxicity and efficacy in relapsed and refractory non-Hodgkin's lymphoma. Based on in vitro evidence that tumor cells are less resistant to prolonged exposure to low concentrations of the natural product class, compared with brief higher concentration exposure, we developed a chemotherapy regimen (etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone [EPOCH]) in which the natural products are administered as a continuous infusion. ### Patients And Methods This is a phase II study of etoposide , vincristine , and doxorubicin , administered as a 96-hour continuous infusion , with intravenous ( IV ) bolus cyclophosphamide and oral prednisone ( EPOCH ) in 74 consecutive patients who relapsed from or failed to respond to most of the same drugs administered on a bolus schedule . Patients with aggressive lymphomas who achieved a good response after EPOCH were eligible to undergo bone marrow transplantation. ### results Patients with intermediate- or high-grade lymphoma comprised 76% of this series and 77% had stage IV disease. Seventy-one percent had previously received all of the drugs contained in the EPOCH regimen and 92% had received at least four of the drugs. Seventy patients were assessable for response, of whom 19 (27%) achieved a complete remission (CR) and 42 (60%) a partial remission (PR). Among 21 patients who had no response to prior chemotherapy, 15 (71%) responded, but only one achieved a CR. Patients who relapsed from an initial CR had a 100% response rate, with 76% CRs. With a median potential follow-up duration of 19 months, there was a 28% probability of being event-free at 1 year. Toxicity was primarily hematologic with neutropenia during 51% of cycles, but only a 17% incidence of febrile neutropenia. Gastrointestinal, neurologic, and cardiac toxicity were minimal. ### conclusion EPOCH chemotherapy was well tolerated and highly effective in patients who were resistant to or relapsed from the same drugs administered on a bolus schedule, suggesting that continuous infusion of the natural drug component of this regimen is capable of partially reversing drug resistance and reducing toxicity. Dose-intensity (DI) was > or = that achieved in primary treatment regimens for aggressive lymphomas.


mitotane

etoposide

doxorubicin

cisplatin

Update in adrenocortical carcinoma. Adrenocortical carcinoma (ACC) is an orphan malignancy that has attracted increasing attention during the last decade. Here we provide an update on advances in the field since our last review published in this journal in 2006. The Wnt/β-catenin pathway and IGF-2 signaling have been confirmed as frequently altered signaling pathways in ACC, but recent data suggest that they are probably not sufficient for malignant transformation. Thus, major players in the pathogenesis are still unknown. For diagnostic workup, comprehensive hormonal assessment and detailed imaging are required because in most ACCs, evidence for autonomous steroid secretion can be found and computed tomography or magnetic resonance imaging (if necessary, combined with functional imaging) can differentiate benign from malignant adrenocortical tumors. Surgery is potentially curative in localized tumors. Thus, we recommend a complete resection including lymphadenectomy by an expert surgeon. The pathology report should demonstrate the adrenocortical origin of the lesion (eg, by steroidogenic factor 1 staining) and provide Weiss score, resection status, and quantitation of the proliferation marker Ki67 to guide further treatment. Even after complete surgery, recurrence is frequent and adjuvant mitotane treatment improves outcome, but uncertainty exists as to whether all patients benefit from this therapy. In advanced ACC, mitotane is still the standard of care. Based on the FIRM-ACT trial , mitotane plus etoposide , doxorubicin , and cisplatin is now the established first-line cytotoxic therapy . However, most patients will experience progress and require salvage therapies. Thus, new treatment concepts are urgently needed. The ongoing international efforts including comprehensive "-omic approaches" and next-generation sequencing will improve our understanding of the pathogenesis and hopefully lead to better therapies.


dasatinib

nilotinib

Experience with dasatinib and nilotinib use in pregnancy. Pregnancy in a patient with chronic myeloid leukemia presents a therapeutic challenge. Both dasatinib and nilotinib are indicated for first-line treatment as well as for treatment-resistant chronic myeloid leukemia. Animal studies with dasatinib or nilotinib demonstrate fetal skeletal malformations as well as significant mortality during organogenesis. The goal of this article is to review the experience to date of dasatinib and nilotinib in human pregnancy, specifically dasatinib and nilotinib dose, length of exposure, trimester of use, as well as patient and fetal outcomes. Based on the limited data, both dasatinib and nilotinib may cause fetal harm. Additionally , thorough analysis of the available literature indicates no correlation between dasatinib nor nilotinib dose , length of exposure , trimester of use , and deleterious patient or fetal outcomes can be concluded . Therefore, health care professionals need to regularly counsel women of child bearing potential with chronic myeloid leukemia regarding the risks of taking dasatinib or nilotinib during pregnancy. The safest potential therapeutic options for the management of chronic myeloid leukemia in pregnancy include temporary discontinuation of the tyrosine kinase inhibitor followed by observation or intervention with interferon alfa and/or leukapheresis.


topotecan

paclitaxel

Clinical evidence for topotecan-paclitaxel non--cross-resistance in ovarian cancer. A large, randomized study comparing the efficacy and safety of topotecan versus paclitaxel in patients with relapsed epithelial ovarian cancer showed that these two compounds have similar activity. In this study, a number of patients crossed over to the alternative drug as third-line therapy, ie, from paclitaxel to topotecan and vice versa. We therefore were able to assess the degree of non-cross-resistance between these two compounds. ### Patients And Methods Patients who had progressed after one platinum-based regimen were randomized to either topotecan (1.5 mg/m(2)/d) x 5 every 21 days (n = 112) or paclitaxel (175 mg/m(2) over 3 hours) every 21 days (n = 114). A total of 110 patients received cross-over therapy with the alternative drug (61 topotecan, 49 paclitaxel) as third-line therapy. ### results Response rates to third-line cross-over therapy were 13.1% (8 of 61 topotecan) and 10.2% (5 of 49 paclitaxel; P =.638). Seven patients who responded to third-line topotecan and four patients who responded to paclitaxel had failed to respond to their second-line treatment. Median time to progression (from the start of third-line therapy) was 9 weeks in both groups, and median survival was 40 and 48 weeks for patients who were receiving topotecan or paclitaxel, respectively. The principal toxicity was myelosuppression ; grade 4 neutropenia was more frequent with topotecan ( 81.4 % of patients ) than with paclitaxel ( 22.9 % of patients ) . ### conclusion topotecan and paclitaxel have similar activity as second-line therapies with regard to response rates and progression-free and overall survival. We demonstrated that the two drugs have a degree of non-cross-resistance. Thus, there is a good rationale for incorporating these drugs into future first-line regimens.


genistein

doxorubicin

genistein

Synergistic cytotoxic effect of genistein and doxorubicin on drug-resistant human breast cancer MCF-7/Adr cells. The molecular mechanisms underlying genistein-mediated reversal of chemoresistance remains unknown. In the present study, we investigated the molecular mechanisms by which genistein overcomes chemoresistance and its effect on doxorubicin-induced cytotoxicity. Consistent with previous reports , genistein combined with doxorubicin had a synergistic effect on MCF-7/Adr cells , and genistein reduced the chemoresistance of these cells . genistein treatment increased the intracellular accumulation of doxorubicin but did not influence P-gp function. The combination of genistein and doxorubicin significantly induced cell cycle arrest and apoptosis. genistein treatment strongly inhibited HER2/neu but not MDR-1 expression at both the mRNA and protein levels. Therefore, our results demonstrated that genistein combined with doxorubicin had a synergistic effect on MCF-7/Adr cells, and the mechanisms likely involve an increase in the intracellular accumulation of doxorubicin and suppression of HER2/neu expression.


efavirenz

nevirapine

Risk of tuberculosis after antiretroviral treatment initiation: a comparison between efavirenz and nevirapine using inverse probability weighting. There is a high incidence of tuberculosis (TB) early after antiretroviral therapy (ART) initiation. This historical cohort study evaluated the association of efavirenz ( EFV ) compared to nevirapine ( NVP ) with post-ART TB among patients initiated on first-line ART from 2005 to 2009 in a large , urban HIV clinic in Uganda . ### methods Hazard ratios (HR) for developing TB were computed using multivariable Cox proportional hazards models with inverse weighting of the probability of being prescribed NVP or EFV (calculated by a multivariable logistic regression model), stratifying by baseline CD4+ T-cell count. Adjustment for time-updated CD4+ T-cell count, restriction of the analysis to patients remaining in follow-up and a TB-free survival analysis were performed as sensitivity analyses. ### results ART was initiated in 5,797 patients; 66% were women with a mean age of 37 years (SD 9) and a median baseline CD4+ T-cell count of 117 cells/mm3 (IQR 43-182). Overall, 60% (n = 3,484) were initiated on NVP and 40% (n = 2,313) on EFV. In the first 2 years of ART, 377 patients developed TB. The use of EFV compared to NVP was independently associated with higher TB incidence in patients with a baseline CD4+ T-cell count < 100 cells/mm3 (HR 2.05 [95% CI 1.29, 3.27]; P = 0.003), but not at higher CD4+ T-cell counts (HR 0.71 [95% CI 0.39, 1.31]; P = 0.428). These estimates were robust to all sensitivity analyses. ### conclusions There was a higher incidence of TB in patients with baseline CD4+ T-cell counts < 100 cells/mm3 initiated on EFV compared to those initiated on NVP. Further research in a trial setting or a larger multisite observational cohort is needed to confirm these findings.


ibrutinib

ublituximab

Efficacy of Ibrutinib-Based Regimen in Chronic Lymphocytic Leukemia: A Systematic Review. ibrutinib has shown to have better efficacy than standard chemoimmunotherapy in del17 positive chronic lymphocytic leukemia (CLL) patients; however its role in del17 negative patients is less clear. We aim to evaluate the efficacy of ibrutinib-based regimens in CLL. Seven databases were searched in accordance with PRISMA statement guidelines using the following keywords: chronic lymphocytic leukemia, CLL, Bruton tyrosine kinase inhibitor, BTK inhibitor, ibrutinib, and PCI-32765. Data from only prospective clinical trials was included. In a phase 3 trial (n = 136), the overall response rate (ORR) with ibrutinib was 92% whereas 18% patients had a complete response (CR). Progression free survival (PFS) and overall survival (OS) at 2 years were 89% and 95% respectively. Phase 3 trial (n = 195) with single agent ibrutinib showed ORR of 63%. PFS at 6 months and OS at 12 months were 88% and 90% respectively. In a phase 2 trial of relapsed and/or refractory (R/R) or high risk treatment naive (TN) patients, combination of ibrutinib and rituximab (n = 104) achieved an ORR of 100% (CR 28%) as compared to ORR 98% (CR 21%) with ibrutinib monotherapy (n = 102) with no significant difference in PFS. Combination of ibrutinib and ublituximab ( n = 64 ) had an ORR of 78 % ( CR 7 % ) in a phase 3 study . In del17p negative R/R patients, combination of bendamustine/rituximab (BR) and ibrutinib (n = 289) achieved an ORR of 83% (CR/CRi 10%) and the 18 month PFS was 79%. In a phase 2 trial treated with ibrutinib (n = 145), patients with del17p R/R disease achieved an ORR of 64% and the 24 month PFS and OS was 63% and 75% respectively. In TN del17p patients (n = 35), ORR was 97% (CR-0) and the 24 month PFS and OS were 82% and 84% respectively with single agent ibrutinib. ibrutinib is the treatment of choice for patients with del17p mutation and has good efficacy in RR/TN patients without del17p mutation. ibrutinib is being evaluated in combination with rituximab for del17p mutations. Future prospects include combination of ibrutinib with frontline chemotherapy and other novel agents for TN and RR del17p negative patients.


oxytetracycline

flumequine

Complex evaluation of ecotoxicity and genotoxicity of antimicrobials oxytetracycline and flumequine used in aquaculture. Ecotoxicity and genotoxicity of widely used veterinary antimicrobials oxytetracycline and flumequine was studied with six model organisms (Vibrio fischeri, Pseudomonas putida, Pseudokirchneriella subcapitata, Lemna minor, Daphnia magna, Escherichia coli). Overall median effective concentration ( EC50 ) values ranged from 0.22 mg/L to 86 mg/L. Pseudomonas putida was the most sensitive organism ( EC50 values for 16-h growth inhibition were 0.22 and 0.82 mg/L for oxytetracycline and flumequine , respectively ) , followed by duckweed Lemna minor ( 7-d growth inhibition , EC50 2.1 and 3.0 mg/L ) and green alga Pseudokirchneriella subcapitata ( 4-d growth inhibition , EC50 3.1 and 2.6 mg/L ) . The least sensitive organism was Daphnia magna (48-h immobilization, lowest-observed-effect concentration [LOEC] of oxytetracycline of 400 mg/L). oxytetracycline showed limited genotoxicity (SOS-chromotest with Escherichia coli, minimal genotoxic concentration of 500 mg/L), and flumequine was genotoxic at 0.25 mg/L. Based on the reported measured concentrations (MECs) and predicted no-effect concentrations (PNECs), oxytetracycline may be concluded to be of ecotoxicological concern (calculated risk quotient = 8), whereas flumequine seems to represent lower risk.


alemtuzumab

rituximab

Post-remission intervention with alemtuzumab or rituximab to eradicate minimal residual disease in chronic lymphocytic leukemia: where do we stand? The introduction of purine nucleoside analogs, later in combination with alkylating moieties and anti-CD20 immunotherapy, has profoundly improved the response rate and response duration in patients with chronic lymphocytic leukemia (CLL). The quality of clinical response following treatment may be improved to a level where residual leukemic cells become undetectable. As patients with this type of response appear to have extended survival rates, minimal residual disease (MRD) eradication is considered a new objective in CLL treatment with the aim of improving progression-free survival (PFS) and potentially overall survival (OS). This review therefore aims to overview the prognostic value of MRD eradication in CLL , the role of post-remission intervention with " passive " immunotherapy ( alemtuzumab or rituximab ) so as to eliminate persistent MRD or prevent MRD relapse , the impact of these strategies on disease-free survival and their possible adverse consequences . The data indicate a potential for post-remission alemtuzumab or rituximab to prolong PFS in CLL, although more investigations and longer follow-up are required before MRD-guided strategies can be recommended outside of clinical trials.


Paclitaxel

hydroxyurea

Paclitaxel , 5-fluorouracil , hydroxyurea , and concomitant radiation therapy for poor-prognosis head and neck cancer . A series of phase I and phase II studies investigating multiagent concomitant chemoradiotherapy in patients with poor-prognosis head and neck cancer have been conducted at the University of Chicago. Drug combinations initially included 5-fluorouracil (5-FU) and hydroxyurea, with the more recent addition of cisplatin; in the most recent trial, paclitaxel was substituted for cisplatin. The primary end point of these trials was definition of maximum tolerated doses in combination with radiation therapy. All radiation therapy was given concomitantly with chemotherapy on an every-other-week schedule (total dose, hydroxyurea and 5-FU were defined at 1 g given orally twice daily for a total of 11 doses and 800 mg/m2/d for 5 days (by continuous intravenous infusion), respectively. When cisplatin was added to this regimen, the observed myelosuppression necessitated the addition of granulocyte colony-stimulating factor. The recommended phase II doses for the three-drug combination were cisplatin 100 mg/m2 every 28 days, 5-FU 800 mg/m2/d for 5 days, and hydroxyurea 1 g orally twice daily for 11 doses. The feasibility of administering radiation at 1.5 Gy twice daily with chemotherapy was also established, which allowed the administration of 75 Gy over 5 cycles (10 weeks). The initial review of this trial suggested substantial toxicity, particularly mucositis and myelosuppression; however, local and regional control rates also were high. Most recently, paclitaxel has replaced cisplatin in this regimen. Recommended phase II doses were hydroxyurea 0.5 g orally twice daily for 11 doses, 5-FU 600 mg/m2/d for 5 days, and paclitaxel 20 mg/m2/d for 5 days, with radiation therapy administered twice daily in 1. 5-Gy fractions. A formal phase II study of this regimen in previously untreated patients with stage IV disease has recently completed accrual and is awaiting analysis. Evaluation of a simplified paclitaxel administration schedule (1-hour infusion on day 1 of chemoradiotherapy between the two radiation fractions) is under way. In addition, the feasibility of substituting gemcitabine for hydroxyurea is undergoing evaluation. Future trials in this disease should focus on developing new combinations that are less toxic and have similar efficacy.


nivolumab

ipilimumab

sunitinib

nivolumab

ipilimumab

Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting. ### methods In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment. ### findings Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32·4 months [IQR 13·4-36·3]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35·6-not estimable] vs 26·6 months [22·1-33·4]; hazard ratio [HR] 0·66 [95% CI 0·54-0·80], p<0·0001), progression-free survival (median 8·2 months [95% CI 6·9-10·0] vs 8·3 months [7·0-8·8]; HR 0·77 [95% CI 0·65-0·90], p=0·0014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0·0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37·9 months [32·2-not estimable]; HR 0·71 [95% CI 0·59-0·86], p=0·0003), progression-free survival (median 9·7 months [95% CI 8·1-11·1] vs 9·7 months [8·3-11·1]; HR 0·85 [95% CI 0·73-0·98], p=0·027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0·015). In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related. ### interpretation The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up , and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories . ### funding Bristol-Myers Squibb and ONO Pharmaceutical.


daunorubicin

doxorubicin

etoposide

mitoxantrone

Hypoxia-induced resistance to anticancer drugs is associated with decreased senescence and requires hypoxia-inducible factor-1 activity. Hypoxia in solid tumors is associated with the development of chemoresistance. Although many studies have focused on the effect of hypoxia on drug-induced apoptosis, the effect of nonapoptotic pathways on hypoxia-induced drug resistance has not been previously investigated. Here, we determined the effects of hypoxia on multiple forms of drug-induced death in human MDA-MB-231 breast carcinoma cells. Clonogenic assays showed that preexposure to hypoxia leads to resistance to various classes of chemotherapeutic agents , including anthracyclines ( daunorubicin and doxorubicin ) , epipodophyllotoxins ( etoposide ) , and anthracenediones ( mitoxantrone ) . Results revealed a high degree of heterogeneity in nuclear and cytoplasmic alterations in response to acute drug exposure; however, the majority of exposed cells displayed morphologic and biochemical changes consistent with drug-induced senescence. Hypoxia decreased only the proportion of cells in the senescent population, whereas the small proportion of cells exhibiting features of apoptosis or mitotic catastrophe were unaffected. Similar results were obtained with human HCT116 colon carcinoma cells, indicating that the protective effect of hypoxia on drug-induced senescence is not unique to MDA-MB-231 cells. Treatment of MDA-MB-231 cells with small interfering RNA targeting the alpha-subunit of hypoxia-inducible factor-1 (HIF-1), a key regulator of cellular adaptations to hypoxia, prevented hypoxia-induced resistance. HIF-1alpha small interfering RNA also selectively abolished the hypoxia-induced changes in the senescent population, indicating that the increased survival was due to protection against drug-induced senescence. These results support a requirement for HIF-1 in the adaptations leading to drug resistance and reveal that decreased drug-induced senescence is also an important contributor to the development of hypoxia-induced resistance.


anastrozole

tamoxifen

Economic Evaluation of Anastrozole Versus Tamoxifen for Early Stage Breast Cancer in Singapore. In Singapore, breast cancer is the leading female malignancy and its incidence has increased threefold over the past decades. For treatment of postmenopausal, hormone receptor positive early stage breast cancer, tamoxifen or aromatase inhibitors such as anastrozole are prescribed either as first-line therapy or sequentially. Currently, anastrozole is patented with a higher drug cost compared with tamoxifen. Hence , the aim of this study was to conduct an economic evaluation of anastrozole versus tamoxifen in early stage breast cancer . ### methods A Markov model with a lifetime horizon was developed by using results from the Arimidex, tamoxifen, Alone or in Combination trial. Direct medical costs were estimated by billing data obtained via financial electronic databases. Utility scores were elicited from 20 experienced oncology nurses using the visual analogue scale. Cost per quality-adjusted life-years was calculated by using the societal perspective. A discount rate of 3% for both charges (expressed in 2010 Singapore dollars) and benefits was used. ### results At an additional cost of S $17,597, anastrozole treatment resulted in a gain of 0.085 life-year survival and 0.154 quality-adjusted life-year. The incremental cost-effectiveness ratio of anastrozole was S $207,402 per life-year gained and S $114,061 per quality-adjusted life-year gained compared with tamoxifen. ### conclusion This is the first economic evaluation that used 10-year results from the Arimidex, tamoxifen, Alone or in Combination trial and utility elicited from the local population. If the World Health Organization's recommendation of 1 to 3 gross domestic product range is an acceptable threshold, anastrozole is deemed cost-effective compared with tamoxifen in the treatment of early stage breast cancer.


cyclophosphamide

etoposide

cisplatin

A randomized trial of mobilization of peripheral blood stem cells with cyclophosphamide , etoposide , and granulocyte colony-stimulating factor with or without cisplatin in patients with malignant lymphoma receiving high-dose chemotherapy . The purpose of this study was to evaluate the addition of cisplatin to cyclophosphamide, etoposide, and granulocyte colony-stimulating factor (G-CSF) for the mobilization of peripheral blood stem cells (PBSC). Eighty-one patients with malignant lymphoma were randomized to receive either cyclophosphamide 4 g/m2 and etoposide 600 mg/m2 (CE), and G-CSF 6 microg/kg/day (n = 41), or the same drugs with cisplatin 105 mg/m2 (CEP; n = 40) followed by collection of PBSC. Seventy-eight of 81 patients (96%) had apheresis performed and 70 (86%) received high-dose chemotherapy (HDC) with PBSC support. The median number of CD34+ cells collected after CE was 19.77 compared with 9.39 x 10(6)/kg after CEP (p = 0.09). More patients receiving CEP had grade 3-4 gastrointestinal (p = 0.03) and neurologic toxicities (p = 0.05), had significant delays in recovery of neutrophils (p = 0.0001) and platelets (p = 0.009), and received more red blood cell (p = 0.03) and platelet (p = 0.08) transfusions than patients receiving CE. There were no significant differences in treatment-related deaths, relapse, survival, or event-free survival between patients receiving CE or CEP when all 81 patients or the 70 patients receiving HDC were evaluated. It was concluded that the addition of cisplatin to CE did not improve CD34+ cell yields, was associated with more morbidity and resource utilization, and was not associated with improvement in outcomes.


docetaxel

gemcitabine

Treatment of pancreatic cancer with a combination of docetaxel , gemcitabine and granulocyte colony-stimulating factor : a phase II study of the Greek Cooperative Group for Pancreatic Cancer . To evaluate the tolerance and efficacy of front-line docetaxel plus gemcitabine treatment in patients with inoperable pancreatic cancer. ### Patients And Methods Fifty-four patients with locally advanced or metastatic pancreatic cancer were enrolled. gemcitabine (1000 mg/m2) was administered on days 1 and 8 and docetaxel (100 mg/m2) on day 8, every three weeks; rh-G-CSF (150 ig/m2 s.c.) was given prophylactically on days 9-15. ### results Seven (13%) patients achieved partial response and 18 (33%) stable disease (intent-to-treat). The median duration of response was 24 weeks, time to tumour progression 32 weeks, and overall survival 26 weeks. Performance status was improved in 33% of patients, pain in 43%, asthenia in 16%, weight gain in 28% and appetite in 27%. Grade 3-4 neutropenia occurred in 17 (31%) patients and grade 3-4 thrombocytopenia in four (4%). Six (11%) patients developed febrile neutropenia and one of them died from sepsis. ### conclusions This combination is a relatively well-tolerated out-patient regimen for patients with inoperable pancreatic cancer.


vancomycin

rifampicin

fosfomycin

[Vancomycin in meningitis caused by penicillin G resistant Streptococcus pneumoniae]. We report two cases of penicillin G-resistant pneumococcal meningitis in adults, with clinical and bacteriological failure of amoxicillin and negative or incomplete response to third generation cephalosporins. Meningitis occurred in a man treated for myeloma and in an elderly woman under prolonged intermittent amoxicillin therapy for chronic otitis. Such situations are known as exposing to pneumococcal meningitis and to resistance of the strain involved to penicillin G. Both patients were cured by vancomycin in continuous infusion associated with rifampicin or fosfomycin . Contrary to third generation cephalosporins, which have higher minimal inhibitory concentrations, vancomycin and rifampicin are still fully active against penicillin G-resistant pneumococcal strains. Thus, vancomycin administered in continuous infusion and associated with rifampicin and fosfomycin deserves to be tried as first-line treatment of pneumococcal meningitis in patients at risk of resistance to penicillin G.


etoposide

doxorubicin

DNA cleavage within the MLL breakpoint cluster region is a specific event which occurs as part of higher-order chromatin fragmentation during the initial stages of apoptosis. A distinct population of therapy-related acute myeloid leukemia (t-AML) is strongly associated with prior administration of topoisomerase II (topo II) inhibitors. These t-AMLs display distinct cytogenetic alterations, most often disrupting the MLL gene on chromosome 11q23 within a breakpoint cluster region (bcr) of 8.3 kb. We recently identified a unique site within the MLL bcr that is highly susceptible to DNA double-strand cleavage by classic topo II inhibitors ( e.g. , etoposide and doxorubicin ) . Here, we report that site-specific cleavage within the MLL bcr can be induced by either catalytic topo II inhibitors, genotoxic chemotherapeutic agents which do not target topo II, or nongenotoxic stimuli of apoptotic cell death, suggesting that this site-specific cleavage is part of a generalized cellular response to an apoptotic stimulus. We also show that site-specific cleavage within the MLL bcr can be linked to the higher-order chromatin fragmentation that occurs during the initial stages of apoptosis, possibly through cleavage of DNA loops at their anchorage sites to the nuclear matrix. In addition, we show that site-specific cleavage is conserved between species, as specific DNA cleavage can also be demonstrated within the murine MLL locus. Lastly, site-specific cleavage during apoptosis can also be identified at the AML1 locus, a locus which is also frequently involved in chromosomal rearrangements present in t-AML patients. In conclusion, these results suggest the potential involvement of higher-order chromatin fragmentation which occurs as a part of a generalized apoptotic response in a mechanism leading to chromosomal translocation of the MLL and AML1 genes and subsequent t-AML.


rituximab

bendamustine

Altered treatment of chronic lymphocytic leukemia in Germany during the last decade. Chronic lymphocytic leukemia (CLL) is the most common subtype of adult leukemia in the western world. We here report a nationwide survey monitoring the treatment decisions concerning CLL patients in Germany in 2011 and compare treatment trends to sequential surveys performed previously during the last decade. The rate of patients diagnosed in early stages (Binet A/B) notably increased (2006: 66 %, 2009: 71 %, 2011: 77 %) over the years. From 2006 to 2009, the most frequent applied regime switched from chlorambucil to fludarabine containing regimes (2006 chlorambucil: 32 %, 2009: 14 %, fludarabine 2006: 23 %, 2009: 37 %). In 2011 , the combination of rituximab with bendamustine ( 31 % ) was most frequent used followed by the rituximab-fludarabine-cyclophosphamide ( 22 % ) regime . Further, immune-chemotherapies were administered significantly more often over the observation period (2006: 15 %, 2011: 73 %). Taken together, this data reflects the change of treatment strategies over the last decade in clinical reality.


ofatumumab

bendamustine

Phase II Study of Bendamustine and Ofatumumab in Elderly Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma Who Are Poor Candidates for R-CHOP Chemotherapy.  The combination of ofatumumab and bendamustine in elderly patients with diffuse large B-cell lymphoma demonstrated modest efficacy compared with standard of care .The poor response may have been due to patient age and the high rate of treatment discontinuation. ### background This phase II trial evaluated the efficacy of bendamustine and ofatumumab in elderly patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) who were not candidates for rituximab cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). ### methods Patients received IV 90 mg/m ### results Twelve of 21 enrolled patients completed treatment; median age was 83 years. The most common reasons for treatment discontinuation were disease progression (three patients), intercurrent illness (two patients), and death (one patient due to drug-related sepsis and bowel necrosis and one patient due to unknown cause). Thrombocytopenia (14%), neutropenia (10%), diarrhea (10%), vomiting (10%), and dehydration (10%) were the most common grade ≥3 treatment-related adverse events. The overall response rate was 90.5% and the CRR was 33.3%. Median progression-free survival (PFS) and overall survival (OS) were 8.6 and 12.0 months, respectively. ### conclusion The combination of ofatumumab and bendamustine is feasible in elderly patients with DLBCL.


Imatinib

nilotinib

everolimus

Preclinical evaluation of KIT/PDGFRA and mTOR inhibitors in gastrointestinal stromal tumors using small animal FDG PET. Primary and secondary drug resistance to imatinib and sunitinib in patients with gastrointestinal stromal tumors (GISTs) has led to a pressing need for new therapeutic strategies such as drug combinations. Most GISTs are caused by mutations in the KIT receptor, leading to upregulated KIT tyrosine kinase activity. Imatinib and nilotinib directly inhibit the kinase activity of KIT , while RAD001 ( everolimus ) inhibits mTOR . We report a preclinical study on drug combinations in a xenograft model of GIST in which effects on tumor dimensions and metabolic activity were assessed by small animal PET imaging. ### methods Rag2-/-; γcommon -/- male mice were injected s.c. into the right leg with GIST 882. The animals were randomized into 6 groups of 6 animals each for different treatment regimens: No therapy (control), imatinib (150 mg/kg b.i.d.) by oral gavage for 6 days, then once/day for another 7 days, everolimus (10 mg/kg/d.) by oral gavage, everolimus (10 mg/kg/d.) + imatinib (150 mg/kg b.i.d.) by oral gavage for 6 days, then once/day for another 7 days, nilotinib (75 mg/kg/d.) by oral gavage, nilotinib (75 mg/kg/d.) + imatinib (150 mg/kg b.i.d) by oral gavage for 6 days, then once/day for another 7 days. Tumor growth control was evaluated by measuring tumor volume (cm3). Small animal PET (GE Explore tomography) was used to evaluate tumor metabolism and performed in one animal per group at base-line then after 4 and 13 days of treatment. ### results After a median latency time of 31 days, tumors grew in all animals (volume 0,06-0,15 cm3) and the treatments began at day 38 after cell injection. Tumor volume control (cm3) after 13 days of treatment was > 0.5 for imatinib alone and nilotinib alone, and < 0.5 for the 2 combinations of drugs and for everolimus alone. The baseline FDG uptake was positive in all animals. FDG/SUV/TBR was strongly reduced over time by everolimus both as a single agent and in combination with imatinib respectively: 3.1 vs. 2.3 vs. 1.9 and 2.5 vs 2.3 vs 0. ### conclusions As single agents, all drugs showed an anti-tumor effect in GIST xenografts but everolimus was superior. The everolimus plus imatinib combination appeared to be the most active regimen both in terms of inhibiting tumor growth and tumor metabolism. The integration of everolimus in GIST treatment merits further investigation.


Paclitaxel

Epirubicin

Tamoxifen

Evaluation of the effect of paclitaxel, epirubicin and tamoxifen by cell kinetics parameters in estrogen-receptor-positive ehrlich ascites tumor (eat) cells growing in vitro.  In this study the antiproliferative effects of Paclitaxel ( PAC ) , Epirubicin ( EPI ) and Tamoxifen ( TAM ) on growth kinetics of Ehrlich Ascites Tumor ( EAT ) cells were examined in culture . An estrogen-receptor-positive ER (+) hyperdiploid EAT cell line growing in vitro was also analysed in the present study. IC50 doses of PAC, EPI and TAM (12 microg/ml, 12 microg/ml and 2 microg/ml, respectively) were used. Cells were treated with the above doses for 0, 4, 8, 16, 24 and 32 hrs. At the end of these periods, living cell numbers were determined by collecting EAT cells in every group for growth study rate and for MTT assay. Therefore, the mitotic index was determined in the same experimental groups. The proliferation of EAT cells, inhibited by PAC, EPI and TAM concentrations was compared to control with increasing treatment time (4-32 hrs). Treatment of PAC, EPI and TAM alone for 24 hrs decreased the proliferation rate of EAT cells by 50% with respect to control. The inhibition of proliferation rate was higher in double drug treatment than that in single drug treatment with increased treatment time. In the treatment of three drugs applied for 32 hrs, this effect reached a maximum and proliferation rate decreased by 12% as compared to the (100%) control. In our studies, when the mitotic index parameter data were evaluated to determine which phase of the cell cycle was affected by PAC to cause the repression of cell reproduction, it was found that PAC exerted of its cytotoxic effect by causing cell accumulation at mitosis. The accumulation of the cells resulted in an increase in mitotic index values, which was an expected consequence of PAC treatment. It was observed that depending on the drug treatments, inhibition of proliferation rate and mitotic index in EAT cells were increased with respect to control, being with statistically significant occurrence (p < 0.01 - p < 0.001). As a result, concomitant treatment combined with hormonal therapy has given improved results compared with single treatment and PAC + EPI + TAM treatments had a maximum synergistic effect for 32 hrs (p < 0.001).


paclitaxel

carboplatin

Systemic therapy for non-serous ovarian carcinoma. Ovarian cancer is one of the top ten most common cancers in women around the world, with high-grade serous epithelial cancer being the most frequent type. However, around a quarter of cases consist of non-serous epithelial ovarian cancer (EOC), which is a heterogeneous group of malignancies that includes endometroid, mucinous, clear cell carcinoma (CCC), and carcinosarcoma. Another relevant group of nonepithelial tumors are those arising from germ cells or sex-cord stromal cells, which account for about 10% of all ovarian cancers. Although there are similarities in the presentation, evaluation, and management of these tumors, they have unique characteristics in terms of epidemiology, tumor biology, tumor marker expression, and response to treatment, warranting a different approach to each one of them. Collectively, the treatment of most of EOC include surgical cytoreduction followed by adjuvant systemic platinum-based chemotherapy. The most common chemotherapy and route of administration for systemic treatment is paclitaxel plus carboplatin given intravenously . However, the treatment of EOC has been rapidly evolving and emerging targeted therapies such as poly (adenosine diphosphate-ribose) polymerase inhibitors, immune checkpoint inhibitors, and antiangiogenic agents are also available. On the other hand, non-EOC responds well to combination chemotherapy used to treat testicular cancer (bleomycin, etoposide, cisplatin) and has a good prognosis. Frontline chemotherapeutic regimen selection differs according to histological subtype, molecular alterations, and patient characteristics. Here, we review specific characteristics of non-serous and non-EOC emphasizing the peculiarities of systemic therapy for each subtype.


belinostat

panobinostat

Comparison of HDAC inhibitors in clinical development: effect on HIV production in latently infected cells and T-cell activation. We aimed to compare the potential for inducing HIV production and the effect on T-cell activation of potent HDAC inhibitors undergoing clinical investigation. ### design In vitro study ### results The various HDAC inhibitors displayed significant potency differences in stimulating HIV-1 expression from the latently infected cell lines with panobinostat>givinostat ≈belinostat>vorinostat>valproic acid. panobinostat was significantly more potent than all other HDAC inhibitors and induced virus production even in the very low concentration range 8-31 nM. The proportion of primary T-cells expressing the early activation marker CD69 increased moderately in all HDAC inhibitor-treated cells compared with untreated cells. Finally, proof was obtained that panobinostat, givinostat and belinostat induce virus production in latently infected primary cells at therapeutic concentrations with panobinostat being the most potent stimulator. ### methods The latently infected cell lines ACH2 and U1 were treated with the HDAC inhibitors panobinostat, givinostat, belinostat, vorinostat and valproic acid. Viral induction was estimated by p24 production. Peripheral blood mononuclear cells from uninfected donors were treated with the HDAC inhibitors and the expression of activation markers on T-cell phenotypes was measured using flow cytometry. Finally , the ability of givinostat , belinostat and panobinostat to reactivate latent HIV-1 expression in primary T-cells was investigated employing a CCL19-induced latent primary CD4 + T cell infection model . ### conclusion At therapeutic concentrations panobinostat stimulate HIV-1 expression in latently infected cells with greater potency than other HDAC inhibitors undergoing clinical investigation. These findings warrant further investigation and panobinostat is now being advanced into clinical testing against latent HIV infection.