Observed Side Effects Research Articles

Combination of Mitoxantrone,Ara-C and Homoharringtonine In Treatment of Refractory and Relapsed Acute Myeloid Leukemia

Abstract 4294Advances in effective chemotherapy have improved clinical outcomes in acute leukemia in recent years. 5-year survival rate approaches 50–60% for acute myeloid leukemia (AML). However, the prognosis remains poor for patients who are relapsed or refractory to first-line therapy. Drug resistance and early disease recurrence are major contributing factors in the limited survival of patients with AML. The strategy for treating these patients is through reinduction chemotherapy followed by allogeneic stem cell transplantation. New combinations of different agents were employed in refractory patients to overcome drug resistance. The current study is to evaluate the efficacy of a MAH regimen comprising Mitoxantrone,Ara-C and Homoharringtonine in refractory or relapsed AML. 37 patients aged 14–65 years with refractory or relapsed AML (15 refractory AML patients, 22 relapsed AML patients) were treated with the MAH regimen(Mitoxantrone 10mg qd, iv.gtt, for 2□‘3 days;Ara-C 100mg bid, iv.gtt, for 5□‘7 days; Homoharringtonine 4mg qd iv.gtt, for 5□‘7 days). Chemotherapy duration lasted for 5 or 7days depended on bone marrow cellurarity. 15 (40.5%)and 1 (2.7%) patients achieved complete remission (CR) and partial remission (PR) respectively. The overall response rate was 43.2%. There was no relation between remission duration and previous chemotherapy. All patients who achieved CR received a consolidation and intensification therapy. The median overall survival (OS) for all patients was 97 days (range 18–487 d). For the patients who were in CR or PR,the median relapse-free survival(RFS) was 147 days(range 4 to 341 d). All patients experienced profound myelosuppression. The most common observed side effect of the regimen was infection because of grade ‡W neutropenia, which could be observed in 33 patients(89.1%). 4 patients died in aplasia due to severe infection and brain hemorrhage. In patients achieving remission, the median time to reach absolute neutrophil count (ANC) more than 0.5×109/l was (16.0±6.4)d. Platelet levels of more than 20×109/l were achieved in a median time of (12.7±6.2)d. Nonhematological side effects, consisting mainly of gastrointestinal toxicity(21/37,56.8%) and transient liver ALT and AST increase (4/37), were generally mild to moderate and tolerated. To a conclusion, MAH regimen can be employed in treatment of the refractory or relapsed AML patients who were not responded to other regimen. It is effective and is good tolerant.It could provide some refractory patients the chance to receive hematopoietic stem cell transplantation. Disclosures:No relevant conflicts of interest to declare.

The Effect of 670-nm Low Laser Therapy on Herpes Simplex Type 1

The purpose of this work was to study the effect of low-level laser therapy (LLLT) on the healing and relapse intervals in patients with recurrent labial herpes simplex infections. Several pharmaceuticals are available to reduce symptoms and improbé healing of labial herpes, but only LLLT has been reported to significantly influence the length of the recurrence period. In an initial study, 232 patients with herpes simplex type 1 virus symptoms were consecutively selected for either LLLT or conventional therapy, including acyclovir cream or tablets. One of the dentists was responsible for the diagnosis, a second dentist for the treatment, and and a third for the evaluation, to allow for a semi-blinded procedure. Patients in the laser group received 670-nm laser irradiation, 40 mW, 1.6 J, 2.04 J/cm(2), 51 mW/cm(2) per blister in the prodromal stage and 4.8 J in the crust and secondarily infected stages, plus 1.2 J at the C2-C3 vertebrae. Patients were monitored daily during the first week to control healing, and monthly for 1 year to check on recurrence. In a consecutive study, 322 patients receiving LLLT were followed during 5 years to observe the period of ocurrences. An obvious effect of LLLT was found for both initial healing and for the length of the recurrence periods. LLLTof herpes simples virus 1 (HSV-1) appears to be an effective treatment modality without any observed side effects.

Dipeptidyl Peptidase-4 Inhibition: Linking Chemical Properties to Clinical Safety

The new drug class of dipeptidyl peptidase-4 (DPP4) inhibitors has been widely accepted in the daily management of type 2 diabetes since its strategic advantages with regard to body weight, risk of hypoglycaemia, and beta cell survival. We have previously evaluated the theoretical implications of DPP4 inhibition given that the enzyme is involved in regulating biological activity of hormones, neuropeptides, and cytokines. We intend now 1) to provide a critical appraisal of safety and tolerability as they emerged from the available clinical studies, and 2) to establish, if possible, a relation between chemical properties, biological activity, and the observed side effects in vivo.

Weekly Taxotere and cisplatin with continuous-infusion 5-fluoruracil for the treatment of advanced gastric and esophageal cancer: a prospective, observational, single-institution experience

The combination of Taxotere (docetaxel), cisplatin, and prolonged-infusion 5-fluorouracil (5-FU) has emerged as an active treatment for advanced gastric cancer. However, the regimen proposed by van Cutsem et al. (J Clin Oncol 24:4991-7, 2006) is associated with significant toxicity and therefore alternative schedules are needed. In the present study, patients with advanced gastric or esophageal cancer received Taxotere 35mg/m(2) and cisplatin 25mg/m(2) on day 1, followed by 5-FU 180mg/m(2)/day as a 7-day prolonged infusion. Drugs were given weekly for 3 consecutive weeks followed by 1week's rest. Cycles were repeated every 4weeks. Overall, a total of 110 cycles were administered to 27 patients (median age 63years, range 40-78years). The median number of cycles per patient was 4 (range 2-6). Nine partial responses were obtained, resulting in an overall response rate of 33% [95% confidence interval (CI) 16-51], a median time to progression of 6.4months (95% CI 5.4-7.4), and a median overall survival of 10.7months (95% CI 6.6-14.8). Toxicity was mild; grade III-IV neutropenia was the most frequently observed side effect, in 9 administered cycles (8%); neutropenia was complicated by fever in 2 cycles. Other grade III-IV toxicities observed in >5% of patients were anemia and mucositis.

Serum C18-ceramide as a biomarker for response: Phase II trial of gemcitabine plus doxorubicin in patients with HNSCC.

5590 Background: Our previous studies showed the combination of gemcitabine (GEM) and doxorubicin (DOX) significantly inhibited the growth of human head and neck squamous cell carcinoma (HNSCC) both in culture and in pre-clinical studies via reconstitution of C18 ceramide, a tumor suppressor sphingolipid. A single-center, phase II clinical trial to determine the toxicity profile and treatment responses with GEM/DOX treatment was developed. Methods: Patients with HNSCC previously treated with platinum-based therapy received a combination of GEM 1000mg/m2 and DOX 25 mg/m2 on days 1 and 8 every 21 days. After every 2 cycles of treatment, patients were assessed radiographically, and serum samples were taken from patients for lipidomics analyses using high performance liquid chromatography/mass spectrometry to measure sphingolipid levels including C18 ceramide tumor suppressor signaling. With null and alternative response rates of 20% and 45%, power of 81% and alpha of 0.09, the Simon Optimal two-stage design enrolls 7 patients in stage 1 (continuing to stage 2 if >1 responses are observed) and 10 in stage 2. 6 or more responses in 17 patients allow the null to be rejected. Results: 17 patients were enrolled on this trial. Overall response rate was 29% (24% complete response (CR) 4/17) and 6% partial response (PR) 1/17). Stable disease (SD) was observed in the majority of patients (47%), while 29% of patients had progressive disease (PD). The median time-to-failure was 1.6 months and median survival was 5.6 months. Treatment was well tolerated with neutropenia being the most commonly observed side effect (9/17 patients). Sphingolipid analysis showed patients with CR+PR and SD had statistically significant increase in serum C18 ceramide levels in comparison to patients who had progressed (SD vs. PD p=0.05 and CR+PR vs. PD p=0.05). Conclusions: The GEM/DOX combination might be an effective treatment option for patients with recurrent or metastatic HNSCC. Additionally, Serum C18 ceramide elevations statistically significantly correlate with response. Serum C18 ceramide levels could serve as a predictive biomarker of response to chemotherapy in patients with HNSCC.

Sorafenib plus cisplatin and gemcitabine in the treatment of advanced hepatocellular carcinoma (HCC): A phase II study by the Gruppo Oncologico dell'Italia Meridionale (prot. GOIM 2705).

225 Background: Sorafenib is the standard treatment in advanced HCC. The combination of cisplatin and gemcitabine demonstrated to be active and well tolerated in tumors with a similar poor outcome such as pancreatic and biliary-tract cancers. Considering these data, the GOIM started a phase II trial aiming to evaluate the activity and safety of the combination of sorafenib, gemcitabine and cisplatin in advanced HCC. Methods: Patients affected by advanced HCC, not suitable for surgery or locoregional procedures, with measurable disease (Recist criteria), age ≥ 18 years, clip-score ≤3, ECOG performance status ≥ 60 (K.fsky), adequate bone marrow reserve and renal and hepatic function and who signed written informed consent, were enrolled and received cisplatin 40 mg/mq iv plus gemcitabine 800 mg/mq iv bi-weekly, while sorafenib was orally administrated at the dosage of 400 mg bid continuously. A maximum of 6 cycles of chemotherapy was planned; a maintenance with sorafenib was permitted for not progressing patients. The evaluation of activity was performed every three cycles. A Simon's two stage, two steps study design was applied: at the first step, at least 3 OR had to be observed among the first 28 patients to continue the enrollment. Up to now, 23 patients have been enrolled. Their main characteristics were: sex (male/female) 19/4, median age: 70 yrs, median PS 80,main sites of disease liver 22, lymph nodes 4, lung 2, others 3. Results: Up to now 18 patients are evaluable for activity while 5 are too early. One CR, 3 PR, 6 SD and 8 PRO for an ORR of 4/18 (22%) and a tumor control of 10/18 (55%). Twenty-one patients are evaluable for safety. The main observed side effects (%G1-2/G3-4) (NCI criteria) were: hand-foot skin reaction (HFSR) 9/14, mucositis 9/4, diarrhea 23/4, nausea/vomiting 23/0, leucopenia 23/0, anemia 9/0, thrombocytopenia 19/4, asthenia 14/14, cardiovascular 0/4, others 9/4. Conclusions: Our preliminary data seems to demonstrate that the combination of cisplatin, gemcitabine, and sorafenib is active and well tolerated in advanced HCC patients. The accrual is ongoing. No significant financial relationships to disclose.

High-dose tranexamic acid reduces blood loss in postpartum haemorrhage

IntroductionOur purpose in conducting this study was to determine whether administration of high-dose tranexamic acid (TA) at the time of diagnosis of postpartum haemorrhage (PPH) could reduce blood loss.MethodsThis was a randomised, controlled, multicentred, open-label trial. Women with PPH >800 mL following vaginal delivery were randomly assigned to receive TA (loading dose 4 g over 1 hour, then infusion of 1 g/hour over 6 hours) or not. In both groups, packed red blood cells (PRBCs) and colloids could be used according to French guidelines. The use of additional procoagulant treatments was permitted only in cases involving intractable bleeding. The primary objective was to assess the efficacy of TA in the reduction of blood loss in women with PPH, and the secondary objectives were the effect of TA on PPH duration, anaemia, transfusion and the need for invasive procedures.ResultsA total of 144 women fully completed the protocol (72 in each group). Blood loss between enrolment and 6 hours later was significantly lower in the TA group than in the control group (median, 173 mL; first to third quartiles, 59 to 377) than in controls (221 mL; first to third quartiles 105 to 564) (P = 0.041). In the TA group, bleeding duration was shorter and progression to severe PPH and PRBC transfusion was less frequent than in controls (P < 0.03). Invasive procedures were performed in four women in the TA group and in seven controls (P = NS). PPH stopped after only uterotonics and PRBC transfusion in 93% of women in the TA group versus 79% of controls (P = 0.016). Mild, transient adverse manifestations occurred more often in the TA group than in the control group (P = 0.03).ConclusionsThis study is the first to demonstrate that high-dose TA can reduce blood loss and maternal morbidity in women with PPH. Although the study was not adequately powered to address safety issues, the observed side effects were mild and transient. A larger international study is needed to investigate whether TA can decrease the need for invasive procedures and reduce maternal morbidity in women with PPH.Trial registrationControlled Trials ISRCTN09968140.

A parallel polynomial Jacobi–Davidson approach for dissipative acoustic eigenvalue problems

We consider a rational algebraic large sparse eigenvalue problem arising in the discretization of the finite element method for the dissipative acoustic model in the pressure formulation. The presence of nonlinearity due to the frequency-dependent impedance poses a challenge in developing an efficient numerical algorithm for solving such eigenvalue problems. In this article, we reformulate the rational eigenvalue problem as a cubic eigenvalue problem and then solve the resulting cubic eigenvalue problem by a parallel restricted additive Schwarz preconditioned Jacobi–Davidson algorithm (ASPJD). To validate the ASPJD-based eigensolver, we numerically demonstrate the optimal convergence rate of our discretization scheme and show that ASPJD converges successfully to all target eigenvalues. The extraneous root introduced by the problem reformulation does not cause any observed side effect that produces an undesirable oscillatory convergence behavior. By performing intensive numerical experiments, we identify an efficient correction-equation solver, an effective algorithmic parameter setting, and an optimal mesh partitioning. Furthermore, the numerical results suggest that the ASPJD-based eigensolver with an optimal mesh partitioning results in superlinear scalability on a distributed and parallel computing cluster scaling up to 192 processors.

Oxycodone in the Long-Term Treatment of Chronic Pain Related to Scleroderma Skin Ulcers

To demonstrate the efficacy and safety of long-term therapy with oxycodone in severe pain of scleroderma skin ulcers. Open study. Twenty-nine consecutive patients, referred to our Rheumatology Unit during 2006, affected by systemic sclerosis complicated by painful long-standing skin ulcers entered in the study. In all cases, pain was classified as severe according to World Health Organization guidelines, and oxycodone chloridrate (Oxycontin®; Mundipharma Pharmaceuticals, Milan, Italy) was administrated at the dosage of 10-20mg twice daily for a mean period of 7.9±3.2 standard deviation months. To evaluate the efficacy and safety of opioid therapy, the following parameters were recorded at standard time intervals: visual analog scale (VAS) pain, Pittsburgh sleep quality index (PSQI), hours of sleep per night, Health Assessment Questionnaire-Disability index, analgesics use (rescue therapy), side effects, vital signs, routine laboratory assessment. After 1 month of therapy, all patients experienced relief of pain (VAS decreased from 93.8±8.72 to 56.7±10.4, P<0.0001), and better quality of sleep (total hours of sleep increased from 3.68±1.28 to 5.27±0.75, P<0.0001; PSQI decreased from 9.72±3.95 to 3.37±1.04, P<0.0001). These parameters further improved after 3 months of therapy and remained stable during the follow-up; moreover, an increase of daily dosage of oxycodone was never required. The observed side effects were always transient and mild; only constipation, when present, was persistent. Oxycodone showed to be effective and safe in the treatment of pain due to severe scleroderma skin ulcers; contemporarily, it markedly improved the patient's compliance to local wound care procedures.

The effect of hexetidine mouthwash on the prevention of plaque and gingival inflammation: a systematic review

To review the literature concerning hexetidine-containing mouthwash as a monotherapy or as an adjunct to oral hygiene in the prevention of plaque accumulation and gingival inflammation. PubMed-MEDLINE and the Cochrane-CENTRAL were searched through January 2010 to identify appropriate studies. The primary outcome measurements were plaque accumulation and gingivitis parameters. Independent screening of titles and abstracts of 168 papers resulted in six publications that met the eligibility criteria. Mean values and standard deviations were obtained by data extraction. Descriptive comparisons are presented for hexetidine mouthwash and control mouthwashes (chlorhexidine and placebo). Considering the potential benefits in the light of the observed side effects, hexetidine appears to be a poor alternative to chlorhexidine.

Detection of centrosome aberrations in disease‐unrelated cells from patients with tumor treated with tyrosine kinase inhibitors

Tyrosine kinase inhibitors (TKIs) target various pathways associated with proliferation of aberrant clones in malignant diseases. Despite good response and acceptable tolerability, little is known concerning long-term toxicity. Furthermore, the influence of these inhibitors on disease-unrelated cells is not investigated yet. Centrosome aberrations are hallmarks of various cancers. We sought to evaluate the effect of TKIs on centrosomes of disease-unrelated cells. We examined cells of the oral mucosa (OM) and fibroblasts of patients with chronic myeloid leukemia (CML) treated with dasatinib and bosutinib. Results were compared with data from patients with CML treated with imatinib or nilotinib and with data from patients suffering from renal and hepatocellular carcinomas (RCC/HCC) treated with sorafenib or sunitinib. Cells of healthy donors served as controls. OM cells (n = 12) and fibroblasts (n = 7) of patients with CML treated with dasatinib and OM cells of three patients with CML treated with bosutinib showed centrosomal alterations (mean, 14%) compared with 16 (10 OM and 6 fibroblasts) controls (mean, 3%). OM cells of five patients with CML and one patient with systemic mastocytosis treated with imatinib or nilotinib and of eight patients with RCC or HCC treated with sorafenib or sunitinib showed centrosome defects in a mean of 15%. Our data have shown that TKI treatment of tumor patients may influence centrosomes in disease-unrelated cells or tissues. This may be important with regard to various observed side effects.

Weight change during adjuvant chemotherapy regimens for breast cancer.

599 Background: Weight gain and obesity are associated with increased risk for many health conditions threatening mortality, including recurrence of breast cancer. Weight gain is an observed side effect of adjuvant chemotherapy, however little is known about the amount of weight increase associated with specific regimens and risk factors. We sought to characterize weight change with commonly-administered adjuvant therapy regimens and to determine characteristics associated with weight change during treatment. Methods: Retrospective electronic medical record abstraction was performed on patients prescribed adjuvant chemotherapy from April 2008-December 2009, at the Rena Rowan Breast Center at the University of Pennsylvania. Women with previous cancer or gastric bypass surgery were excluded. Chemotherapy regimen (dose and schedule), demographics, height, weight at chemotherapy initiation and completion, and alterations in treatment were abstracted. Two sample t-tests compared the mean weight change of regimens by age (< 50 vs. ≥ 50). Results: 125 women with mean age 51 years (range 26-76) and BMI 26.2 (range 16.6-54.7) were analyzed. The most common regimens were docetaxel/cyclophosphamide (TC, 4 cycles, q3 weeks) and doxorubicin/cyclophosphamide × 4 followed by paclitaxel × 4 (dose-dense AC-T), (33.9% and 37.2%, respectively). Absolute and percent weight change observed during treatment differed significantly between regimens. Women receiving TC gained an average of 2.8 lbs (95% CI 1.2-4.3), those on dose dense AC-T lost 1.2 lbs (95% CI -3.6-1.1) (p = 0.007). Among younger women (<50), those on TC gained an average of 2.3% body weight (95% CI = 0.9-3.8); those on dose dense AC-T had no significant gain (0.004%; 95% CI = -1.7-1.7) (p = 0.04). Pretreatment BMI was not associated with a change in weight for either regimen when considered as a continuous or categorical variable (< 25, 25-29.9, ≥ 30; normal, overweight, and obese, respectively). Conclusions: Weight gain is not generalizable to all adjuvant chemotherapy regimens. There is a significant difference in the amount of weight change in women receiving TC vs. dose dense AC-T. Increased awareness of weight gain during treatment and interventions to minimize this effect are needed. No significant financial relationships to disclose.

Cetuximab monotherapy in advanced cervical cancer: a retrospective study with five patients

Effective cytotoxic treatment options for advanced cervical cancer are exceedingly limited. Therefore, interest has increased in targeted therapeutics for the treatment of cervical cancer. Cetuximab, a monoclonal antibody, binds specifically to the epidermal growth factor receptor (EGFR) and competitively inhibits the binding of epidermal growth factor and other ligands. In cervical cancer the expression of EGFR is reported in up to 85% of the tumour cells. Therefore, Cetuximab monotherapy could be a new option in the treatment of patients with advanced cervical cancer. Five patients with advanced cervical cancer were treated with Cetuximab monotherapy as third- to fifth-line therapy between 2005 and 2008 in our institution. The tumour stage at the time of diagnosis ranged between IIB and IVB. Cetuximab was applied with an initial loading dose of 400 mg/m(2) followed by a dose of 250 mg/m(2) weekly. Only one patient (20%) had a stable disease, and the other four a progressive disease during Cetuximab monotherapy, after the RECIST criteria. Four out of five patients (80%) developed an acneiform rash as a common observed side effect of Cetuximab therapy. The median survival time from the beginning of the Cetuximab therapy was 8.6 months. No advantage could be found in the treatment with Cetuximab monotherapy in patients with advanced cervical cancer in this study. Further studies are necessary to evaluate the significance of Cetuximab in the treatment of advanced cervical cancer.

Suitability of low-dosage oxytocin treatment to induce milk ejection in dairy cows

Chronic use of high oxytocin (OT) dosages can cause a reduced response to endogenous OT. In this study the OT dosages used in the milking practice of 82 dairy cow farms were recorded. The OT dosages per cow used were high, especially when injected i.m. (23±2 IU) compared with i.v. (7±1 IU). In addition, the minimum OT dosages needed to obtain normal milk removal in cows with disturbed milk ejection were investigated. Seventeen cows routinely treated with OT during milking (group T) and 17 cows without previous OT treatment were used (group C). After cessation of spontaneous milk flow, both T and C groups were injected i.v. with a low dosage of OT (0.2 or 0.5 IU/cow). The time from injection until cessation of the OT-induced milk flow was recorded (response phase). The response phase and the amounts of removed milk by effect of the OT injection increased with increasing OT dosage. Values for 0.2 and 0.5 IU/cow of OT injected i.v. were (response phase and amount of milk removed) 198±27 and 302±18s and 3.4±0.7kg and 6.5±1.3kg, respectively, for the C group, and 157±15 and 221±16s and 3.2±0.5 and 5.5±1.0kg, respectively, for the T group. Within 20min of the OT injection, plasma concentrations returned to basal levels. The threshold OT concentration at cessation of milk flow after injection of 0.2 or 0.5 IU/cow of OT was calculated based on the OT plasma half-life. The threshold increased with increasing dosages of OT and was higher in group T (8±1 and 14±1 pg/mL for 0.2 and 0.5 IU/cow, respectively) than in group C (7±1 and 11±1 pg/mL for 0.2 and 0.5 IU/cow, respectively). In conclusion, desensitization of the udder toward OT occurs when the udder is exposed to elevated OT plasma concentrations, both short-term during the actual milking and long-term due to chronic high-dosage OT treatment. However, low-dosage OT treatments to induce normal milk removal can minimize the observed side effects.

The Preparative Method and Clinical Application of Autologous memory T Lymphocyte.

Abstract 5123 BackgroundThe term autolymphocyte therapy refers to an adoptive cellular transfer strategy based on the ex vivo activation of memory T cells. The assumption is that because patients with metastatic cancer have been previously exposed to tumor antigens, memory T cells exist which can be collected and activated ex vivo. The result in autologous cytokines that can be used to activate other T cells. The method is simpler than it sounds and basically consisted of 2 cell collections using a cell separator and 2 cell cultures. The supernatant from the first culture, which contains the desired cytokines, is used to activate the second cohort of T cells. ObjectiveTo establish a preparative method of autologous memory T lymphocyte and use this T lymphocyte to treat hematologic malignancies and solid tumor. Method14 patients of hematologic malignancies and solid tumor had autolymphocyte therapy in 4 hospitals since 2002(Plasmacytoma1,NHL1, colon cancer3,HCC3,NSCLC1, nasopharyngeal carcinoma3, breast cancer1, Ovarian cancer1). These patients, including 11 male and 3 female, with a mean age of 55 (range, 25-71), were finally confirmed by pathology and histology autologouslymphokine, anti-CD3 antibody, IL-2. Cimetidine and Indomethacin induced peripheral blood mononuclear cell (PBMC) ex vivo to memory T lymphocyte by two steps. We tested memory T lymphocyte by flow cytometry before and after culture, we observed side effect during infusion. ResultAfter culturing peripheral blood lymphocyte for 9 days, the number of cell and CD4+/CD45RO+T cell increased. The data demonstrated: PBMC before culture was 1.07-67.2×109(median was 2.16×109),the cell after culture was 2.0-6.5×109(median was 3.2×109),CD4+/CD45RO+T cell rate was 27.59-86%(median was 77.76%) before culture and 82.09-99.55%(median was 89.49%) after culture. The absolute number of CD4+/CD45RO+T cell increased. Among 14 patients after infusion, one patient who had no medicine before infusion had fever of 39°C, 4 patients had low-grade fever and the rest 9 patients had no side effect. Follow-up: 5 patients abroad had no follow-up. In 1 to 10 months after therapy, all patients were alive. 4 patients were in partial remission and 5 patients in stable stage. ConclusionAutologous memory T lymphocyte is a safe and an effective way to treat advanced-stage hematologic malignancies and solid tumor. The mechanism and long-tem effect need more research and observe. DisclosuresNo relevant conflicts of interest to declare.

Gemifloxacin use in the treatment of acute bacterial exacerbation of chronic bronchitis.

The newest generation of fluoroquinolones have proven efficacy against bacterial organisms associated with acute exacerbation of chronic bronchitis (AECB). Gemifloxacin, as one of the quinolones in this class, exhibits many of the pharmacokinetic and pharmacodynamic characteristics of the class with a few notable differences. Against Streptococccus pneumoniae it has a lower minimal inhibitory concentration (MIC) than the other respiratory fluoroquinolones and it has activity against both bacterial DNA gyrase and topoisomerase IV. The increased activity of gemifloxacin against both enzymes may be associated with decreased rates of resistance. Clinically, gemifloxacin has been shown to have positive effects on length of hospitalization and increased success at long-term follow-up in AECB patients. These associations were observed in noninferiority comparison studies. Although an advantage with the use of gemifloxacin in AECB is suggested, there are no comparison data is available to conclude that gemifloxacin is superior to the other respiratory fluoroquinolones. Gemifloxacin is generally well tolerated, but is associated with a characteristic rash and gastrointestinal upset as its most common observed side effects.

EORTC 24051: Unexpected side effects of a phase I study of TPF induction chemotherapy (IC) followed by chemoradiation (CRT) with lapatinib (LAP), a dual EGFR/ErbB2 inhibitor, in patients with locally advanced larynx and hypopharynx squamous cell carcinoma (LA-LxHxSCC)

6017 Background: CRT is considered a standard approach for LA-LxHxSCC. TPF IC regimen seems to improve outcome in locally advanced head and neck SCC. The addition of LAP was investigated in combination with a sequential therapeutic approach (IC→ CRT). Methods: Eligible tumors were SCCHN: T3-T4 larynx (Lx), T2-T4 hypopharynx (Hx) N0–3 M0. The objective of this trial is to determine MTD, DLT and recommended dose of LAP when administered with TPF IC (docetaxel (T) 75mg/m2 (60 mg/m2 for the first cycle) d1, CDDP 75mg/m2 d1, 5FU 750mg/m2/d continuous infusion d1-d5 q3weeks) followed by CRT (weekly carboplatin AUC 1.5 and RT 70Gy in 7 weeks; 2Gy/fx). LAP is administered concomitantly with IC (escalating dose 500–1500mg po daily) and during CRT (1,500 mg daily). Results: Seven male patients were included; tumor sites: LX (n = 3) / Hx: (n = 4), median age 59 years (range: 47–79), WHO PS 0–1, no severe or uncontrolled comorbidity. Three pts were included in the first cohort, at dose level 1 (LAP 500 mg daily plus TPF IC). Renal toxicity was observed among these 3 pts (grade 4 [n = 1], grade 2 [n=1] and grade 1 [n=1]), with 1 DLT, leading to treatment interruption in this group. This nephrotoxicity was reversible after stopping lapatinib and hydration of the patients. As LAP plus cisplatinum plus RT was feasible in another study, a second cohort was conducted in 4 pts, receiving LAP at the same dosage, and docetaxel (T) was only introduced from cycle 2 of IC to see what is the role of T in the observed side effect. Two DLTs were observed among this second cohort of subjects: one pt presented a grade 2 renal toxicity, grade 3 diarrhea and dehydration and a second pt presented a grade 3 anorexia and grade 3 stomatitis. Based on the occurrence of 3 DLTs at the first dose level of LAP, patient recruitment was closed. Despite these safety issues, all patients recovered and were treated off-study. They will receive follow-up as foreseen by the protocol. Conclusions: These data suggest that LAP should not be combined with TPF IC regimen for LA-LxHxSCC due to prohibited toxicity. [Table: see text]

Bevacizumab-related hypertension: Search for underlying mechanisms

e14520 Background: Hypertension is a commonly observed side effect of inhibitors of VEGF/VEGFR-2 signaling such as bevacizumab. The mechanisms leading to this increase in blood pressure during anti-angiogenic therapy have not been elucidated. Recent studies suggest that functional rarefaction (a decrease in perfused microvessels) or anatomic rarefaction (a reduction in capillary density) may play an important role. The purpose of this study was to search for possible mechanisms that cause hypertension in patients treated with anti-angiogenic therapy and to confirm our hypothesis that systemic inhibition of VEGF inhibits vascular function and causes rarefaction. Methods: Patients treated with bevacizumab for any type of cancer were eligible. Measurements of blood pressure, flow-mediated dilatation (FMD), nitroglycerin-mediated dilatation (NMD), aortic pulse wave velocity (PWV), and capillary density and diameter with sidestream dark field (SDF) imaging of the mucosal microcirculation of the lip were performed at baseline, after 6 weeks of treatment, and 3 months after discontinuation of bevacizumab treatment. Results: Fourteen patients were included in this study. During bevacizumab treatment the mean systolic and diastolic blood pressure values increased, +3.4 mmHg (p=0.406), and +5.6 mmHg (p=0.023) resp. Mean FMD showed a statistically significant decrease of -3.1% (p=0.006). Mean NMD was unchanged. After 6 weeks treatment mean PWV increased significantly +0.7 m/s (p=0.0.027). A significant reduction in capillary density was seen from 18.0 capillary loops per image at baseline to 12.7 after 6 weeks (p=0.000007). Also a significant reduction in capillary diameter was seen, from 6.9 to 5.6 μm (p=0.002). Results after discontinuation of bevacizumab treatment were not yet available. Conclusions: Rarefaction (reduction in capillary density) and endothelial dysfunction observed in this study provide a plausible mechanism for the increase in blood pressure which results from treatment with bevacizumab. No significant financial relationships to disclose.

Prospective Clinical Trial Comparing Two Immunosuppressive Regimens, Tacrolimus and Mycophenolate Mofetil Versus Everolimus and Low-Dose Cyclosporine, in De Novo Renal Transplant Recipients: Results at 6 Months Follow-up

Objective The aim of this study in renal transplant recipients was to compare a tacrolimus plus mycophenolate mofetil (MMF) immunosuppressive regimen with a combination of low dose of cyclosporine and everolimus. Patients and Methods Sixty consecutive patients were prospectively assigned to receive tacrolimus and MMF (TAC; n = 30) or everolimus and low-dose cyclosporine (EVL; n = 30). Tacrolimus was dosed seeking a trough blood level of 8 to 10 ng/mL by month 3 and 5 to 8 ng/mL thereafter. Everolimus was dosed seeking a trough blood level of 3 to 8 ng/mL by day 7. Cyclosporine was dosed aiming at a C2 blood level of 350 to 700 ng/mL in the first week and 150 to 400 ng/mL thereafter. All patients received induction with basiliximab and maintenance treatment with corticosteroids. Results At 6-months follow-up, patient survival rates (TAC 100% vs EVL 100%) and graft survival rates (TAC 96.7% vs EVL 93.3%) were not significantly different between the groups. Patients in the EVL group showed more acute rejection episodes, but serum creatinine concentrations and creatinine clearances were not significantly different from the TAC group. Among the observed side effects, hypercholesterolemia was significantly higher in the EVL group (total cholesterol: TAC 206 ± 38 vs EVL 250 ± 55 mg/dL; P < .003). Conclusions This study showed that the immunosuppressive association of tacrolimus and MMF produced similar acute rejection episodes, graft survivals, and renal function at 6 months after renal transplantation compared with an immunosuppressive combination of everolimus and low-dose cyclosporine. Dyslipidemia was significantly greater among patients who received everolimus.

PR53P TREATMENT OF PROBLEMATIC PROLIFERATING HAEMANGIOMA WITH PROPRANOLOL

Aims: The mainstay treatment for problematic proliferating haemangioma is pharmacologic with high dose steroid being the first line treatment. A dramatic response occurs in 30% of cases, equivocal in 40% and continued growth is observed in the remainder cases. Steroid therapy is associated with significant side effects. We report our experience in treating proliferating haemangioma with Propranolol, discovered serendipitously by Léauté‐Labràze et al recently.Methodology: A 9‐week old boy was referred with a steroid‐resistant proliferating haemangioma involving the upper lip and nose causing feeding and breathing difficulties. The patient was commenced on Propranolol at 0.5 mg/kg twice daily for 24 hours increasing to 1 mg/kg twice daily. The treatment was administered as an inpatient with 4‐hourly heart rate and blood pressure and postprandial (30 minutes) blood glucose level monitoring, for the first 48 hours. The second patient was a 3‐month old boy with a similar rapidly proliferating lesion on the upper lip and nose. He was commenced on similar Propranolol regimen. Both patients were maintained on the original total daily dose of Propranolol.Results: In both cases rapid reduction of the size and softening of the lesion was noted within 48 hours of treatment with on going accelerated regression observed during the follow‐up period of 4 and 2 months respectively. No cardiovascular or metabolic side effects were observed in both patients.Conclusion: Accelerated regression is observed in 2 infants with problematic haemangioma following Propranolol therapy with no observed side effect. The possible mechanism of action of beta‐blocker on cell proliferation is discussed.