Efficacy and safety of azacitidine in pediatric patients with newly diagnosed advanced myelodysplastic syndromes before hematopoietic stem cell transplantation in the AZA-JMML-001 trial.

Here we report efficacy, pharmacokinetics, and safety data obtained in treatment-naive, pediatric patients with newly diagnosed advanced MDS receiving azacitidine in the AZA-JMML-001 study. The primary endpoint was response rate (proportion of patients with complete response [CR], partial response [PR], or marrow CR, sustained for ≥4 weeks). Of the 10 patients enrolled, one had an unconfirmed marrow CR and none had confirmed responses after three cycles; the study was therefore closed after stage 1. Azacitidine was well tolerated. The lack of efficacy of azacitidine in pediatric patients with newly diagnosed advanced MDS highlights the need for effective new treatments in these patients.

Results of a phase 2, multicenter, single-arm, open-label study of lenalidomide in pediatric patients with relapsed or refractory acute myeloid leukemia.

BACKGROUND: Outcomes after relapse remain poor in pediatric patients with acute myeloid leukemia (AML), and new therapeutic approaches are needed. Lenalidomide has demonstrated activity in adults with lower risk myelodysplastic syndromes and older adults with relapsed or refractory (R/R) AML. METHODS: In this phase 2 study (NCT02538965), pediatric patients with R/R AML who received two or more prior therapies were treated with lenalidomide (starting dose 2 mg/kg/day on days 1-21 of each 28-day cycle) for a maximum of 12 cycles. The primary endpoint was rate of complete response (CR) and CR with incomplete blood count recovery (CRi) within the first four cycles. RESULTS: Seventeen patients enrolled and received one or more dose of lenalidomide. Median age was 12 years (range 5-18 years), median white blood cell count was 3.7 × 109 /L, and median peripheral blood blast count was 1.0 × 109 /L. One patient (5.9%) with a complex karyotype including del(5q) achieved CRi after two cycles of lenalidomide. This responder proceeded to a second hematopoietic stem cell transplantation and has remained without evidence of disease for 3 years. All patients experienced one or more of grades 3-4 treatment-emergent adverse event (TEAE). The most common grades 3-4 TEAEs were thrombocytopenia (58.8%), febrile neutropenia (47.1%), anemia (41.2%), and hypokalemia (41.2%). CONCLUSIONS: In this population of pediatric patients with R/R AML, safety data were consistent with the known safety profile of lenalidomide. As only one patient responded, further evaluation of lenalidomide at the dose and schedule studied is not warranted in pediatric AML, with the possible exception of patients with del(5q).

Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010): a phase 3b study in refractory multiple myeloma.

Patients with relapsed and/or refractory multiple myeloma (RRMM) have poor prognosis. The STRATUS study assessed safety and efficacy of pomalidomide plus low-dose dexamethasone in the largest cohort to date of patients with RRMM. Patients who failed treatment with bortezomib and lenalidomide and had adequate prior alkylator therapy were eligible. Pomalidomide 4 mg was given on days 1-21 of 28-day cycles with low-dose dexamethasone 40 mg (20 mg for patients aged >75 years) on days 1, 8, 15, and 22 until progressive disease or unacceptable toxicity. Safety was the primary end point; secondary end points included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Among 682 patients enrolled, median age was 66 years, and median time since diagnosis was 5.3 years. Median number of prior regimens was 5. Most patients were refractory to both lenalidomide and bortezomib (80.2%). Median follow-up was 16.8 months; median duration of treatment was 4.9 months. Most frequent grade 3/4 treatment-emergent adverse events were hematologic (neutropenia [49.7%], anemia [33.0%], and thrombocytopenia [24.1%]). Most common grade 3/4 nonhematologic toxicities were pneumonia (10.9%) and fatigue (5.9%). Grade 3/4 venous thromboembolism and peripheral neuropathy were rare (1.6% each). The ORR was 32.6%, and the median DOR was 7.4 months. Median PFS and OS were 4.6 months and 11.9 months, respectively. We present the largest trial to date evaluating pomalidomide plus low-dose dexamethasone in patients with RRMM, further confirming that this regimen offers clinically meaningful benefit and is generally well tolerated. www.Clinicaltrials.gov identifier NCT01712789.

Phase 2 Study of Pomalidomide (CC-4047) Monotherapy for Children and Young Adults With Recurrent or Progressive Primary Brain Tumors.

INTRODUCTION: Treatment of recurrent primary pediatric brain tumors remains a major challenge, with most children succumbing to their disease. We conducted a prospective phase 2 study investigating the safety and efficacy of pomalidomide (POM) in children and young adults with recurrent and progressive primary brain tumors. METHODS: Patients with recurrent and progressive high-grade glioma (HGG), diffuse intrinsic pontine glioma (DIPG), ependymoma, or medulloblastoma received POM 2.6 mg/m2/day (the recommended phase 2 dose [RP2D]) on days 1-21 of a 28-day cycle. A Simon's Optimal 2-stage design was used to determine efficacy. Primary endpoints included objective response (OR) and long-term stable disease (LTSD) rates. Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), and safety. RESULTS: 46 patients were evaluable for response (HGG, n = 19; DIPG, ependymoma, and medulloblastoma, n = 9 each). Two patients with HGG achieved OR or LTSD (10.5% [95% CI, 1.3%-33.1%]; 1 partial response and 1 LTSD) and 1 patient with ependymoma had LTSD (11.1% [95% CI, 0.3%-48.2%]). There were no ORs or LTSD in the DIPG or medulloblastoma cohorts. The median PFS for patients with HGG, DIPG, ependymoma, and medulloblastoma was 7.86, 11.29, 8.43, and 8.43 weeks, respectively. Median OS was 5.06, 3.78, 12.02, and 11.60 months, respectively. Neutropenia was the most common grade 3/4 adverse event. CONCLUSIONS: Treatment with POM monotherapy did not meet the primary measure of success in any cohort. Future studies are needed to evaluate if POM would show efficacy in tumors with specific molecular signatures or in combination with other anticancer agents. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT03257631; EudraCT, identifier 2016-002903-25.

Response to upfront azacitidine in juvenile myelomonocytic leukemia in the AZA-JMML-001 trial.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for most children with juvenile myelomonocytic leukemia (JMML). Novel therapies controlling the disorder prior to HSCT are needed. We conducted a phase 2, multicenter, open-label study to evaluate the safety and antileukemic activity of azacitidine monotherapy prior to HSCT in newly diagnosed JMML patients. Eighteen patients enrolled from September 2015 to November 2017 were treated with azacitidine (75 mg/m2) administered IV once daily on days 1 to 7 of a 28-day cycle. The primary end point was the number of patients with clinical complete remission (cCR) or clinical partial remission (cPR) after 3 cycles of therapy. Pharmacokinetics, genome-wide DNA-methylation levels, and variant allele frequencies of leukemia-specific index mutations were also analyzed. Sixteen patients completed 3 cycles and 5 patients completed 6 cycles. After 3 cycles, 11 patients (61%) were in cPR and 7 (39%) had progressive disease. Six of 16 patients (38%) who needed platelet transfusions were transfusion-free after 3 cycles. All 7 patients with intermediate- or low-methylation signatures in genome-wide DNA-methylation studies achieved cPR. Seventeen patients received HSCT; 14 (82%) were leukemia-free at a median follow-up of 23.8 months (range, 7.0-39.3 months) after HSCT. Azacitidine was well tolerated and plasma concentration--time profiles were similar to observed profiles in adults. In conclusion, azacitidine monotherapy is a suitable option for children with newly diagnosed JMML. Although long-term safety and efficacy remain to be fully elucidated in this population, these data demonstrate that azacitidine provides valuable clinical benefit to JMML patients prior to HSCT. This trial was registered at www.clinicaltrials.gov as #NCT02447666.

Continuous Sunitinib treatment in patients with advanced hepatocellular carcinoma: a Swiss Group for Clinical Cancer Research (SAKK) and Swiss Association for the Study of the Liver (SASL) multicenter phase II trial (SAKK 77/06).

BACKGROUND: Sunitinib (SU) is a multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activity. The objective of this trial was to demonstrate antitumor activity of continuous SU treatment in patients with hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Key eligibility criteria included unresectable or metastatic HCC, no prior systemic anticancer treatment, measurable disease, and Child-Pugh class A or mild Child-Pugh class B liver dysfunction. Patients received 37.5 mg SU daily until progression or unacceptable toxicity. The primary endpoint was progression-free survival at 12 weeks (PFS12). RESULTS: Forty-five patients were enrolled. The median age was 63 years; 89% had Child-Pugh class A disease and 47% had distant metastases. PFS12 was rated successful in 15 patients (33%; 95% confidence interval, 20%-47%). Over the whole trial period, one complete response and a 40% rate of stable disease as the best response were achieved. The median PFS duration, disease stabilization duration, time to progression, and overall survival time were 1.5, 2.9, 1.5, and 9.3 months, respectively. Grade 3 and 4 adverse events were infrequent. None of the 33 deaths were considered drug related. CONCLUSION: Continuous SU treatment with 37.5 mg daily is feasible and has moderate activity in patients with advanced HCC and mild to moderately impaired liver dysfunction. Under this trial design (>13 PFS12 successes), the therapy is considered promising. This is the first trial describing the clinical effects of continuous dosing of SU in HCC patients on a schedule that is used in an ongoing, randomized, phase III trial in comparison with the current treatment standard, sorafenib (ClinicalTrials.gov identifier, NCT00699374).

Oxaliplatin, irinotecan and capecitabine (OCX) for first-line treatment of advanced/metastatic colorectal cancer: a phase I trial (SAKK 41/03).

BACKGROUND: A phase I multicentre trial was conducted to define the recommended dose of capecitabine in combination with oxaliplatin and irinotecan (OCX) in metastatic colorectal cancer. PATIENTS AND METHODS: Patients with performance status (PS) < 2 and adequate haematological, renal and liver function received oxaliplatin 70 mg/m(2) on days 1 and 15, irinotecan 100 mg/m(2) on days 8 and 22 and one of five dose levels (DL 1-5, between 800 and 1,600 mg/ m(2)) of capecitabine on days 1-29 every 5 weeks. RESULTS: 23 patients received a median of 3 cycles. 3 dose-limiting toxicities occurred (DL 1: grade 3 (G3) elevated alkaline phosphatase; DL 5: 1 patient G4 hyperglycaemia/G3 diarrhoea and 1 sudden death). The most common severe adverse event was G3 diarrhoea (13%). Severe haematotoxicity was rare. Therapy was stopped mainly due to metastasectomy or tumour progression (7 patients each). 8 patients reached a partial response. Median time to progression and overall survival (OS) were 8.0 and 21.9 months, respectively. CONCLUSIONS: The recommended capecitabine dose in this schedule is 1,400 mg/m(2) daily. The OCX regimen is well tolerated. The response rate was surprisingly low with progression-free survival (PFS) and OS within the range of a triple combination. Further studies in combination with targeted agents are warranted.

Phase II results from a phase I/II study to assess the safety and efficacy of weekly nab-paclitaxel in paediatric patients with recurrent or refractory solid tumours: A collaboration with the European Innovative Therapies for Children with Cancer Network.

BACKGROUND: The phase I component of a phase I/II study defined the recommended phase II dose and established the tolerability of nab-paclitaxel monotherapy in paediatric patients with recurrent or refractory solid tumours. The activity and safety of nab-paclitaxel monotherapy was further investigated in this phase II study. PATIENTS AND METHODS: Paediatric patients with recurrent or refractory Ewing sarcoma, neuroblastoma or rhabdomyosarcoma received 240 mg/m2 of nab-paclitaxel on days 1, 8 and 15 of each 28-day cycle. The primary end-point was the overall response rate (ORR; complete response [CR] + partial response [PR]). Secondary end-points included duration of response, disease control rate (DCR; CR + PR + stable disease [SD]), progression-free survival, 1-year overall survival, safety and pharmacokinetics. RESULTS: Forty-two patients were enrolled, 14 each with Ewing sarcoma, neuroblastoma and rhabdomyosarcoma. The ORRs were 0%, 0% and 7.1% (1 confirmed PR), respectively. The DCRs were 30.8% (4 SD), 7.1% (1 SD) and 7.1% (1 confirmed PR and 0 SD) in the Ewing sarcoma, neuroblastoma and rhabdomyosarcoma groups, respectively. The median progression-free survival was 13.0, 7.4 and 5.1 weeks, respectively, and the 1-year overall survival rates were 48%, 25% and 15%, respectively. The most common grade III/4IVadverse events were haematologic (neutropenia [50%] and anaemia [48%]), and grade III/IV peripheral neuropathy occurred in 2 patients (14%) in the rhabdomyosarcoma group. Pharmacokinetics analyses revealed that paclitaxel tissue distribution was both rapid and extensive. CONCLUSIONS: In this phase II study, limited activity was observed; however, the safety of nab-paclitaxel in paediatric patients was confirmed. TRIAL REGISTRATION: NCT01962103 and EudraCT 2013-000144-26.

Tenofovir use is associated with an increase in serum alkaline phosphatase in the Swiss HIV Cohort Study.

BACKGROUND: Tenofovir (TDF) use has been associated with proximal renal tubulopathy, reduced calculated glomerular filtration rates (cGFR) and losses in bone mineral density. Bone resorption could result in a compensatory osteoblast activation indicated by an increase in serum alkaline phosphatase (sAP). A few small studies have reported a positive correlation between renal phosphate losses, increased bone turnover and sAP. METHODS: We analysed sAP dynamics in patients initiating (n = 657), reinitiating (n = 361) and discontinuing (n = 73) combined antiretroviral therapy with and without TDF and assessed correlations with clinical and epidemiological parameters. RESULTS: TDF use was associated with a significant increase of sAP from a median of 74 U/I (interquartile range 60-98) to a plateau of 99 U/I (82-123) after 6 months (P < 0.0001), with a prompt return to baseline upon TDF discontinuation. No change occurred in TDF-sparing regimes. Univariable and multivariable linear regression analyses revealed a positive correlation between sAP and TDF use (P < or = 0.003), but no correlation with baseline cGFR, TDF-related cGFR reduction, changes in serum alanine aminotransferase (sALT) or active hepatitis C. CONCLUSIONS: We document a highly significant association between TDF use and increased sAP in a large observational cohort. The lack of correlation between TDF use and sALT suggests that the increase in sAP is because of the bone isoenzyme and indicates stimulated bone turnover. This finding, together with published data on TDF-related renal phosphate losses, this finding raises concerns that TDF use could result in osteomalacia with a loss in bone mineral density at least in a subset of patients. This potentially severe long-term toxicity should be addressed in future studies.

Phase I results of a phase I/II study of weekly nab-paclitaxel in paediatric patients with recurrent/refractory solid tumours: A collaboration with innovative therapies for children with cancer.

BACKGROUND: nab-Paclitaxel has demonstrated efficacy in adults with solid tumours and preclinical activity in paediatric solid tumour models. Results from phase I of a phase I/II study in paediatric patients with recurrent/refractory solid tumours treated with nab-paclitaxel are reported. PATIENTS AND METHODS: Patients with recurrent/refractory extracranial solid tumours received nab-paclitaxel on days 1, 8 and 15 every 4 weeks at 120, 150, 180, 210, 240, or 270 mg/m2 (rolling-6 dose-escalation) to establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). RESULTS: Sixty-four patients were treated. Dose-limiting toxicities were grade 3 dizziness at 120 mg/m2 and grade 4 neutropenia >7 days at 270 mg/m2. The most frequent grade 3/4 adverse events were haematologic, including neutropenia (36%), leukopenia (36%) and lymphopenia (25%). Although the MTD was not reached, 270 mg/m2 was declared non-tolerable due to grade 3/4 toxicities during cycles 1-2 (neutropenia, n = 5/7; skin toxicity, n = 2/7; peripheral neuropathy, n = 1/7). Of 58 efficacy-evaluable patients, complete response occurred in one patient (2%; Ewing sarcoma) and partial responses in four patients (7%; rhabdomyosarcoma, Ewing sarcoma, renal tumour with pulmonary metastases [high-grade, malignant] and sarcoma not otherwise specified); all responses occurred at ≥210 mg/m2. Thirteen patients (22%) had stable disease (5 lasting ≥16 weeks) per RECIST. CONCLUSIONS: nab-Paclitaxel 240 mg/m2 qw3/4 (nearly double the adult recommended monotherapy dose for this schedule in metastatic breast cancer) was selected as the RP2D based on the tolerability profile, pharmacokinetics and antitumour activity. Phase II is currently enrolling patients with recurrent/refractory neuroblastoma, rhabdomyosarcoma and Ewing sarcoma. CLINICALTRIALS.GOV: NCT01962103. EUDRACT: 2013-000144-26.

Tenofovir use is associated with a reduction in calculated glomerular filtration rates in the Swiss HIV Cohort Study.

BACKGROUND: A growing number of case reports have described tenofovir (TDF)-related proximal renal tubulopathy and impaired calculated glomerular filtration rates (cGFR). We assessed TDF-associated changes in cGFR in a large observational HIV cohort. METHODS: We compared treatment-naive patients or patients with treatment interruptions > or = 12 months starting either a TDF-based combination antiretroviral therapy (cART) (n = 363) or a TDF-sparing regime (n = 715). The predefined primary endpoint was the time to a 10 ml/min reduction in cGFR, based on the Cockcroft-Gault equation, confirmed by a follow-up measurement at least 1 month later. In sensitivity analyses, secondary endpoints including calculations based on the modified diet in renal disease (MDRD) formula were considered. Endpoints were modelled using pre-specified covariates in a multiple Cox proportional hazards model. RESULTS: Two-year event-free probabilities were 0.65 (95% confidence interval [CI] 0.58-0.72) and 0.80 (95% CI 0.76-0.83) for patients starting TDF-containing or TDF-sparing cART, respectively. In the multiple Cox model, diabetes mellitus (hazard ratio [HR] = 2.34 [95% CI 1.24-4.42]), higher baseline cGFR (HR = 1.03 [95% CI 1.02-1.04] by 10 ml/min), TDF use (HR = 1.84 [95% CI 1.35-2.51]) and boosted protease inhibitor use (HR = 1.71 [95% CI 1.30-2.24]) significantly increased the risk for reaching the primary endpoint. Sensitivity analyses showed high consistency. CONCLUSION: There is consistent evidence for a significant reduction in cGFR associated with TDF use in HIV-infected patients. Our findings call for a strict monitoring of renal function in long-term TDF users with tests that distinguish between glomerular dysfunction and proximal renal tubulopathy, a known adverse effect of TDF.

Treatment and prognosis of AIDS-related lymphoma in the era of highly active antiretroviral therapy: findings from the Swiss HIV Cohort Study.

OBJECTIVE: To assess the characteristics of combination antiretroviral therapy (cART) administered concomitantly with chemotherapy and to establish prognostic determinants of patients with AIDS-related non-Hodgkin's lymphoma. METHODS: The study included 91 patients with AIDS-related non-Hodgkin's lymphoma from the Swiss HIV Cohort Study enrolled between January 1997 and October 2003, excluding lymphomas of the brain. We extracted AIDS-related non-Hodgkin's lymphoma- and HIV-specific variables at the time of lymphoma diagnosis as well as treatment changes over time from charts and from the Swiss HIV Cohort Study database. Cox regression analyses were performed to study predictors of overall and progression-free survival. RESULTS: During a median follow up of 1.6 years, 57 patients died or progressed. Thirty-five patients stopped chemotherapy prematurely (before the sixth cycle) usually due to disease progression; these patients had a shorter median survival than those who completed six or more cycles (14 versus 28 months). Interruptions of cART decreased from 35% before chemotherapy to 5% during chemotherapy. Factors associated with overall survival were CD4+ T-cell count (<100 cells/microl) (hazard ratio [HR] 2.95 [95% confidence interval (CI) 1.53-5.67], hepatitis C seropositivity (HR 2.39 [95% CI 1.01-5.67]), the international prognostic index score (HR 1.98-3.62 across categories) and Burkitt histological subtypes (HR 2.56 [95% CI 1.13-5.78]). CONCLUSIONS: Interruptions of cART were usually not induced by chemotherapy. The effect of cART interruptions on AIDS-related non-Hodgkin's lymphoma prognosis remains unclear, however, hepatitis C seropositivity emerged-as a predictor of death beyond the well-known international prognostic index score and CD4+ T-cell count.

Empirical use of antibiotics and adjustment of empirical antibiotic therapies in a university hospital: a prospective observational study.

BACKGROUND: Several strategies to optimise the use of antibiotics have been developed. Most of these interventions can be classified as educational or restrictive. Restrictive measures are considered to be more effective, but the enforcement of these measures may be difficult and lead to conflicts with prescribers. Any intervention should be aimed at targets with the highest impact on antibiotic prescribing. The aim of the present study was to assess the adequacy of empirical and adjusted antibiotic therapies in a Swiss university hospital where no antibiotic use restrictions are enforced, and to identify risk factors for inadequate treatment and targets for intervention. METHODS: A prospective observational study was performed during 9 months. All patients admitted through the emergency department who received an antibiotic therapy within 24 hours of admission were included. Data on demographic characteristics, diagnoses, comorbidities, systemic inflammatory response syndrome (SIRS) parameters, microbiological tests, and administered antibiotics were collected prospectively. Antibiotic therapy was considered adequate if spectrum, dose, application modus, and duration of therapy were appropriate according to local recommendations or published guidelines. RESULTS: 2943 admitted patients were evaluated. Of these, 572 (19.4%) received antibiotics within 24 hours and 539 (94%) were analysed in detail. Empirical antibiotic therapy was inadequate in 121 patients (22%). Initial therapy was adjusted in 168 patients (31%). This adjusted antibiotic therapy was inadequate in 46 patients (27%). The main reason for inadequacy was the use of antibiotics with unnecessarily broad spectrum (24% of inadequate empirical, and 52% of inadequate adjusted therapies). In 26% of patients with inadequate adjusted therapy, antibiotics used were either ineffective against isolated pathogenic bacteria or antibiotic therapy was continued despite negative results of microbiological investigations. CONCLUSION: The rate of inadequate antibiotic therapies was similar to the rates reported from other institutions despite the absence of a restrictive antibiotic policy. Surprisingly, adjusted antibiotic therapies were more frequently inappropriate than empirical therapies. Interventions aiming at improving antibiotic prescribing should focus on both initial empirical therapy and streamlining and adjustment of therapy once microbiological results become available.

A smoking cessation programme in HIV-infected individuals: a pilot study.

BACKGROUND: Antiretroviral therapy (ART) is a risk factor for cardiovascular disease (CVD) and smoking the most important modifiable cardiovascular risk factor. METHODS: We prospectively evaluated a smoking cessation programme (SCP) in HIV-infected individuals (intervention: counselling and nicotine replacement therapy). Primary endpoint was the smoking cessation rate at 12 months; secondary endpoints were CVD morbidity and mortality. Controls were a not randomized control group of smokers not participating in the SCP. RESULTS: Four-hundred and seventeen of 680 (61%) patients were smokers, and 34 of these participated in the SCP. Of these 34 individuals, 82% were male, the median age was 43 years, prior AIDS was recorded in 29%, and depressive disorder was recorded in 18/%. Twenty-five (74%) patients were receiving ART. Additional risk factors were dyslipidaemia (68%), a prior cardiovascular event (24%), hypertension (1 5%), and a family history of CVD in 2/34 (6%) individuals. According to the Framingham equation, the 10-year risk of CVD was higher in SCP participants than in controls (11.2% versus 8.5%, P=0.06). At termination of the SCP, 17/34 (50%) individuals had stopped smoking compared with 57/383 (15%) controls. Self-reported smoking abstinence for a12 months was 13/34 (38%) in the intervention group and 27/383 (7%) in the control group (odds ration 6.2, 95% confidence interval 2.8-14.3). During the follow-up, two SCP participants and 4 controls experienced a myocardial infarction. One patient in the control group died of CVD. CONCLUSIONS: SCP in HIV-infected individuals is feasible and should be encouraged. The long-term impact of smoking cessation on CVD morbidity and mortality should be evaluated in comparative trials.

A longitudinal analysis of healthcare costs after treatment optimization following genotypic antiretroviral resistance testing: does resistance testing pay off?

OBJECTIVE: To assess the impact of antiretroviral therapy optimized by genotypic antiretroviral resistance testing (GRT) on healthcare costs over a 2-year period in patients after antiretroviral treatment failure. STUDY DESIGN: Non-randomized, prospective, tertiary care, clinic-based study. PATIENTS: One-hundred and forty-two HIV patients enrolled in the 'ZIEL' study and the Swiss HIV Cohort Study who experienced virological treatment failure. METHODS: For all patients GRT was used to optimize the antiretroviral treatment regimen. All healthcare costs during 2 years following GRT were assessed using microcosting. Costs were separated into ART medication costs and healthcare costs other than ART medication (that is, non-ART medication costs, in-patient costs and ambulatory [out-patient] costs). These cost estimates were then split into four consecutive 6-month periods (period 1-4) and the accumulated cost for each period was calculated. Univariate and multivariate regression modelling techniques for repeated measurements were applied to assess the changes of healthcare costs over time and factors associated with healthcare costs following GRT. RESULTS: Overall healthcare costs after GRT decreased over time and were significantly higher in period 1 (32%; 95% confidence interval [Cl]: 18-47) compared with period 4. ART medication costs significantly increased by 1,017 (95% Cl: 22-2,014) Swiss francs (CHF) from period 1-4, whereas healthcare costs other than ART medication costs decreased substantially by a factor of 3.1 (95% Cl: 2.6-3.7) from period 1 to period 4. Factors mostly influencing healthcare costs following GRT were AIDS status, costs being 15% (95% Cl: 6-24) higher in patients with AIDS compared with patients without AIDS, and baseline viral load, costs being 12% (95% Cl: 6-17) higher in patients with each log increase in plasma RNA. CONCLUSIONS: Optimized antiretroviral treatment regimens following GRT lead to a reduction of healthcare costs in patients with treatment failure over 2 years. Patients in a worse health state (that is, a positive AIDS status and high baseline viral load) will experience higher overall costs.

Clinical implications of distinct metastasizing preferences of different melanoma subtypes.

BACKGROUND: The incidence and mortality of malignant melanoma have been rising during the past decades, the latter being due to the high invasion capacity and the metastatic potential of melanoma cells to distant organs. OBJECTIVE: We investigated the distribution pattern of melanoma metastases taking into account different clinicopathological subtypes of melanoma. METHODS: We studied 310 stage IV (AJCC 2009) melanoma patients retrospectively with regard to potential correlations between frequency and occurrence of metastasis and the genetic background and pathological/clinical melanoma subtypes. For all patients, the time to distant metastasis (TTDM) and the distribution patterns of metastases were analyzed and correlated to the median survival time. RESULTS: Superficially Spreading (SSM) and Nodular melanomas (NMM) spread to the brain more frequently than Acrolentiginous (ALM) and Mucosal (MM) melanomas (p = 0.0012). The preference to affect the skeleton was significantly higher for ALM and MM in comparison to SSM and NMM (p = 0.0049). Lentigo maligna (LMM) tumors showed a significantly lower metastatic spread to distant lymph nodes (p = 0.0159). BRAF mutant versus wildtype tumors showed no significant differences concerning localization of metastasis but patients with BRAF mutant tumors were significantly younger at primary diagnosis and had a significantly shorter stage IV survival (p = 0.0106). CONCLUSION: This study shows a clear distinction of melanoma subtypes with regard to metastasizing preferences. Further knowledge about melanoma subtype specific characteristics, including molecular markers predictive of homing preferences, may help to understand and manage this heterogeneous disease in terms of prognosis and follow-up procedures.

Carboplatin and paclitaxel plus ASA404 as first-line chemotherapy for extensive-stage small-cell lung cancer: a multicenter single arm phase II trial (SAKK 15/08).

INTRODUCTION: Small-cell lung cancer (SCLC) is a highly vascularized tumor. ASA404 is a tumor vascular disrupting agent. This is the first trial to report the effects of combining chemotherapy with ASA404 in SCLC. METHODS: Patients with untreated metastatic SCLC were treated with carboplatin (area under curve, 6) plus paclitaxel (175 mg/m(2)) plus ASA404 (1800 mg/m(2)) on day 1 every 21 days for up to 6 cycles. The primary endpoint was the progression-free survival (PFS) rate at 24 weeks. RESULTS: Median age was 61 years; 53% were women, 41% had weight loss; and 96% had a performance status of 0-1. Twelve patients completed all 6 cycles, and most adverse events were related to chemotherapy. Median PFS and time to progression were 7.0 months (95% CI, 5.7-9.4 months) and 7.5 months (95% CI, 5.7-9.4 months), respectively. The progression-free survival (PFS) rate at 24 weeks was 41% (95% CI, 18%-65%). The overall response rate was 94%. The median overall survival time was 14.2 months (95% CI, 8.2-16.0 months) and 1-year survival was 57%. The median follow-up time was 17.7 months. Due to negative results with ASA404 in non-small-cell lung cancer trials, the trial was stopped prematurely after 17 of 56 planned patients were being accrued. CONCLUSIONS: This is the first report of a clinical trial with a vascular disrupting agent in SCLC. No unexpected toxicity was observed. PFS was not prolonged with carboplatin and paclitaxel plus ASA404.

Detecting BRAF Mutations in Formalin-Fixed Melanoma: Experiences with Two State-of-the-Art Techniques.

BACKGROUND: Melanoma is characterized by a high frequency of BRAF mutations. It is unknown if the BRAF mutation status has any predictive value for therapeutic approaches such as angiogenesis inhibition. PATIENTS AND METHODS: We used 2 methods to analyze the BRAF mutation status in 52 of 62 melanoma patients. Method 1 (mutation-specific real-time PCR) specifically detects the most frequent BRAF mutations, V600E and V600K. Method 2 (denaturing gel gradient electrophoresis and direct sequencing) identifies any mutations affecting exons 11 and 15. RESULTS: Eighteen BRAF mutations and 15 wild-type mutations were identified with both methods. One tumor had a double mutation (GAA) in codon 600. Results of 3 samples were discrepant. Additional mutations (V600M, K601E) were detected using method 2. Sixteen DNA samples were analyzable with either method 1 or method 2. There was a significant association between BRAF V600E mutation and survival. CONCLUSION: Standardized tissue fixation protocols are needed to optimize BRAF mutation analysis in melanoma. For melanoma treatment decisions, the availability of a fast and reliable BRAF V600E screening method may be sufficient. If other BRAF mutations in exons 11 and 15 are found to be of predictive value, a combination of the 2 methods would be useful.