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In Florida, where syphilis is a reportable disease, the number of primary and secondary (P&S) syphilis cases has increased from 3,266 in 2008–2010 to 5,340 in 2013–2015, a 63% increase. The objective of this study was to compare the performance and sensitivity of the syphilis reverse algorithm with the traditional algorithm for detecting P&S (infectious) syphilis cases. Clinical specimens from individuals who self-referred for syphilis testing at public health clinics were processed using the traditional algorithm (non-treponemal rapid plasma reagin (RPR) test followed by a confirmatory treponemal (EIA) test) and then further tested with the Architect Syphilis TP (ASTP) immunoassay (Abbott Diagnostics, Chicago, IL, USA) or by RPR confirmation, if needed (reverse algorithm). Of 1,079 specimens, 59 were positive for syphilis. The sensitivity of the reverse algorithm was 98.3% (58/59) and of the traditional algorithm was 72.9% (43/59). Based on clinical evidence, of the 16 traditional algorithm-negative but reverse algorithm-positive cases, 68.8% (11/16) were classified as missed P&S infections (treatment naïve) and 31.2% (5/16) were classified as missed past syphilis (latent or infections with documented linkage to care). The reverse algorithm enables the detection of additional P&S syphilis cases missed by our current traditional algorithm.

Background Despite the proven benefits of iron chelation therapy (ICT) in the management of chronic iron overload and related complications, compliance to long-term ICT is challenging. Results from the ECLIPSE study, an open-label, randomized, multicenter, 2-arm, phase 2 study evaluated the safety of deferasirox dispersible tablet and film-coated tablet (FCT) formulations in patients with transfusion-dependent thalassemia (TDT) or very low, low, or intermediate risk myelodysplastic syndrome (MDS) treated over 24 weeks. Methods The aim of the current study (a 2-year, open-label, multicenter, single-arm, phase 3 study) is to evaluate the long-term safety and efficacy of deferasirox FCT in a subset of patients with TDT or lower/intermediate-risk MDS treated for 2 years after the completion of 24 weeks of treatment with deferasirox in the ECLIPSE phase 2 study. Results Of 53 patients enrolled, 34 (64.2%) completed treatment and study. Adverse events (AEs) reported in most patients (~ 70%) were of mild to moderate severity. Headache and diarrhea were the most frequently (> 25%) reported AEs. None of the serious AEs (including 1 death) were considered treatment related. No new safety signal was identified, and long-term safety of deferasirox FCT was consistent with the known safety profile of deferasirox. No major concerns associated with gastrointestinal tolerability, renal safety, or hematological abnormalities (thrombocytopenia/neutropenia) were reported during the 2 years. Patients receiving deferasirox FCT had a treatment compliance (by pill count) of ~ 90% and persistence (continuous use for ≥ 30 days) of > 95%. Reduction in serum ferritin level was almost consistent starting from week 2 across all post-baseline time points (relative reduction: month 6, 19%; month 12, 29%). Conclusions The results from this 2-year interventional study suggest that the recommended dosing of deferasirox FCT, with better tolerability, palatability, and compliance, offers a favorable option of ICT for long-term management of iron overload and associated complications in TDT. Trial registration ClinicalTrials.gov, NCT02720536. Registered 28 March 2016, https://www.clinicaltrials.gov/ct2/show/NCT02720536

Background and aimsWe aimed to determine if patient baseline characteristics affect responses to linagliptin and identify relevant predictors of glycated hemoglobin (HbA1c) reduction in patients with type 2 diabetes mellitus (T2DM).Methods and resultsData were pooled from three 24-week, placebo-controlled trials of similar design (linagliptin, n = 1651; placebo, n = 607). Patients were categorized according to baseline characteristics: age, T2DM duration, gender, body mass index (BMI), Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), and metabolic syndrome (MetS). Changes from baseline in HbA1c after 24 weeks were assessed with analysis of covariance (ANCOVA). The proportion of patients with baseline HbA1c >7% achieving HbA1c of ≤7% at week 24 were evaluated. Independent predictors of HbA1c response with linagliptin were analyzed in a multivariate analysis with ANCOVA. Linagliptin treatment led to significant mean (SE) placebo-corrected reductions from baseline in HbA1c across all subgroups (−0.42% [±0.11] to −0.79% [0.08]; all p 7% achieving a target HbA1c ≤7% was greater with linagliptin versus placebo (30.2% vs 11.5%; odds ratio 3.82; 95% CI 2.82 to 5.17; p

Aims: To determine the effects of empagliflozin on adiposity indices among patients with type 2 diabetes mellitus. Methods: Changes in weight, waist circumference, estimated total body fat, index of central obesity and visceral adiposity index were assessed using analysis of covariance and testing of treatment by strata for age, sex and baseline waist circumference in patients with type 2 diabetes mellitus randomized to blinded treatment with empagliflozin versus placebo in clinical trials of 12 weeks (cohort 1) or 24 weeks (cohort 2) duration. Results: This study comprised 3300 patients (cohort 1, N = 823; cohort 2, N = 2477). Empagliflozin reduced weight, waist circumference and adiposity indices versus placebo in both cohorts. Adjusted mean (95% confidence interval) change from baseline in empagliflozin versus placebo was −1.7 kg (−2.1 to −1.4 kg) and −1.9 kg (−2.1 to −1.7 kg) for body weight ( p Conclusion: Empagliflozin significantly reduced weight and adiposity indices with the potential to improve cardiometabolic risk among patients with type 2 diabetes mellitus.

Glucose-lowering treatment options for type 2 diabetes mellitus patients with chronic kidney disease are limited. We evaluated the potential for linagliptin in combination with insulin in type 2 diabetes mellitus patients with mild-to-severe renal impairment. Data for participants in two phase 3 trials with linagliptin who were receiving insulin were analysed separately ( n = 811). Placebo-adjusted mean HbA1c changes from baseline were −0.59% (mild renal impairment) and −0.69% (moderate renal impairment) after 24 weeks and −0.43% (severe renal impairment) after 12 weeks. Drug-related adverse events with linagliptin were similar to placebo (mild renal impairment: 19.9% vs 26.5%; moderate renal impairment: 22.0% vs 25.0%; severe renal impairment: 46.3% vs 43.6%, respectively). Frequencies of hypoglycaemia in patients with mild, moderate and severe renal impairment were 34.9%, 35.6% and 66.7% with linagliptin and 37.5%, 39.7% and 49.1% with placebo, respectively. Episodes of severe hypoglycaemia were low (⩽5.6%). Adding linagliptin to insulin in type 2 diabetes mellitus patients with chronic kidney disease improved glucose control and was well tolerated.

The prevalence of type 2 diabetes in black/African Americans from North and South America is high; yet data evaluating antidiabetic agents in this population is scarce. To address this gap, we pooled data from the clinical development program for linagliptin.A retrospective pooled analysis of eight completed randomized, placebo-controlled Phase III trials of linagliptin identified 336 patients with type 2 diabetes who self-identified their ethnicity as black or African American. Participants received linagliptin (n = 173, 5 mg/day) or placebo (n = 163) as monotherapy, or as add-on to other antidiabetic agents, including insulin. The primary end point was the change in glycated hemoglobin (HbA1c) from baseline to week 18 or 24.The placebo-adjusted mean change (95% confidence interval [CI]) in HbA1c from baseline was -0.69% (-0.92 to -0.46; p0.0001) at week 18 (eight trials), and -0.64% (-0.90 to -0.39; p0.0001) at week 24 (six trials). The placebo-adjusted mean change (95% CI) in fasting plasma glucose from baseline was -11.7 mg/dL (-23.1 to -0.3; p = 0.0446) at week 18 and -14.7 mg/dL (-25.7 to -3.8; p = 0.0087) at week 24. Incidence of investigator-defined hypoglycemia was similar between the two groups (linagliptin, 12.1%; placebo, 11.7%). Overall, the safety profile of linagliptin in this patient group was comparable to that of placebo, with comparable incidence of adverse events; linagliptin was weight-neutral in this patient population.Linagliptin provided clinically significant improvements in glycemic control without increased risk of hypoglycemia and without weight gain, representing a useful type 2 diabetes therapy option for the black/African American population.

Aims Renal disease is a frequent comorbidity of type 2 diabetes mellitus (T2DM) and an important factor complicating the choice of glucose-lowering drugs. The aim of this analysis was to evaluate the efficacy and safety of the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin (5 mg/day) in mono, dual or triple oral glucose-lowering regimens in subjects with T2DM and mild or moderate renal impairment (RI). Methods In this pooled analysis of three 24-week, placebo-controlled, phase 3 trials, subjects with mild (estimated glomerular filtration rate (eGFR) 60–

Purpose This phase II trial aimed to evaluate feasibility and efficacy of a first-line combination of targeted therapies for advanced non-squamous NSCLC: bevacizumab (B) and erlotinib (E), followed by platinum-based CT at disease progression (PD). Methods 103 patients with advanced non-squamous NSCLC were treated with B (15 mg/kg day 1 of each 21-day cycle) and E (150 mg daily) until PD or unacceptable toxicity. Upon PD patients received 6 cycles of CT (cisplatin/carboplatin and gemcitabine). The primary endpoint was disease stabilization rate (DSR) after 12 weeks of BE treatment. Results 101 patients were evaluable. Under BE, DSR at week 12 was 54.5%. 73 patients had at least stable disease (SD), including 1 complete remission and 17 partial responses (PR). No unexpected toxicities were observed. Median time to progression (TTP) under BE was 4.1 months. 62 patients started CT; 35 received at least 4 cycles (6 PR, 32 SD). At a median follow-up of 36 months, median overall survival (OS) was 14.1 months. Conclusions First-line BE treatment followed by a fixed CT regimen at PD is feasible with acceptable toxicity and activity. In a non-squamous NSCLC population unselected for EGFR status, we found OS rates similar to standard CT.

Aims: This analysis aimed to evaluate efficacy and safety of empagliflozin in combination therapy in < 65 y.o.patients, overweight/obese, and with uncontrolled T2DM. Methods: Pooled analysis from three phase-III trials, in < 65 y.o. patients, with BMI 25–35 kg/m2, and HbA1c ≥8% at baseline. Patients (N = 439) were randomized to placebo (n = 138), empagliflozin 10 mg (n = 160), or empagliflozin 25 mg (n = 141) once daily (24 weeks) as add-on to metformin, to metformin plus sulfonylurea, or to pioglitazone ± metformin. Results:At week 24, adjusted mean (SE) changes from baseline in HbA1c were −0.19% (0.07) for placebo vs.−1.10% (0.07) and −1.10% (0.07) for empagliflozin 10 and 25 mg, respectively (both p b 0.001). Adjusted mean (SE) changes from baseline in weight were −0.33 kg (0.21) for placebo vs. -1.94 kg (0.19) and −2.14 kg (0.20) for empagliflozin 10 and 25 mg, respectively (both p b 0.001). Adverse events were reported in 57.2% on placebo, 64.4% on empagliflozin 10 mg and 59.6% on empagliflozin 25 mg. Genital infection AEs were reported in 1.4% on placebo, 3.8% on empagliflozin 10 mg, and 5.0% on empagliflozin 25 mg. Conclusions: In this specific population, empagliflozin in combination with other oral agents, significantly reduced HbA1c and body weight and was well tolerated.

We investigated the efficacy and safety of empagliflozin over 24 weeks in Asian patients with type 2 diabetes (T2DM) using pooled data from four phase III trials. In these trials, patients were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg or placebo as monotherapy or add-on to metformin, metformin plus sulphonylurea or pioglitazone ± metformin. In total, 1326 patients from Asia received ≥1 dose of study drug. At week 24, adjusted mean differences versus placebo in change from baseline in glycated haemoglobin (HbA1c) were -0.66% [95% confidence interval (CI) -0.76, -0.56] and -0.73% (95% CI -0.83, -0.64) and in weight were -1.6 kg (95% CI -1.9, -1.3) and -1.8 kg (95% CI -2.1, -1.5) with empagliflozin 10 and 25 mg, respectively (all p < 0.001). Empagliflozin significantly reduced systolic and diastolic blood pressure. The proportion of patients reporting ≥1 adverse event was similar across treatment groups, but events consistent with genital infection were more common in patients treated with empagliflozin 10 mg (3.4%) or 25 mg (2.3%) than placebo (0.9%). Thus in Asian patients with T2DM, empagliflozin reduced HbA1c, weight and blood pressure, and was well tolerated.

Liver disease is highly prevalent among people with type 2 diabetes mellitus (T2DM). We evaluated the dipeptidyl peptidase-4 inhibitor linagliptin in subjects with T2DM and hepatic disorders.Data were pooled from 17 randomized, double-blind, placebo-controlled clinical trials of linagliptin in T2DM subjects that included individuals with self-reported history of hepatic disorders at baseline. The primary endpoint was change in HbA1c from baseline to week 24.Of the 7009 participants (56% white, 39% Asian), 574 had hepatic disorders, most commonly hepatic steatosis (60%). At week 24, adjusted mean±standard error (SE) change in HbA1c from baseline in those with hepatic disorders was -0.75%±0.05 with linagliptin and -0.20%±0.08 with placebo [treatment difference: -0.54% (95% confidence interval-0.72 to -0.36); P.0001]. There was no significant difference in HbA1c reduction between subjects with or without baseline hepatic disorders (P=.4042). Among subjects with hepatic disorders, 13.5% and 14.8% of the linagliptin and placebo groups, respectively, reported drug-related adverse events while 10.4% and 15.9%, respectively, reported hypoglycemia. Overall, adverse event rates were similar in individuals with or without hepatic disorders.This large pooled analysis suggests that linagliptin is effective and well tolerated in people with T2DM and liver disease.

Background: The anti-angiogenic drug, bevacizumab (Bv), is currently used in the treatment of different malignancies including breast cancer. Many angiogenesis-associated molecules are found in the circulation of cancer patients. Until now, there are no prognostic or predictive factors identified in breast cancer patients treated with Bv. We present here the first results of the prospective monitoring of 6 angiogenesis-related molecules in the peripheral blood of breast cancer patients treated with a combination of Bv and PLD in the phase II trial, SAKK 24/06. Methods: Patients were treated with PLD (20 mg/m2) and Bv (10 mg/kg) on days 1 and 15 of each 4-week cycle for a maximum of 6 cycles, followed by Bv monotherapy maintenance (10 mg/m2 q2 weeks) until progression or severe toxicity. Plasma and serum samples were collected at baseline, after 2 months of therapy, then every 3 months and at treatment discontinuation. Enzyme-linked immunosorbent assays (Quantikine, R&D Systems and Reliatech) were used to measure the expression levels of human vascular endothelial growth factor (hVEGF), placental growth factor (hPlGF), matrix metalloproteinase 9 (hMMP9) and soluble VEGF receptors hsVEGFR-1, hsVEGFR-2 and hsVEGFR-3. The log-transformed data (to reduce the skewness) for each marker was analyzed using an analysis of variance (ANOVA) model to determine if there was a difference between the mean of the subgroups of interest (where α = 0.05). The untransformed data was also analyzed in the same manner as a “sensitivity” check. Results: 132 blood samples were collected in 41 out of 43 enrolled patients. Baseline levels of the molecules were compared to disease status according to RECIST. There was a statistically significant difference in the mean of the log-transformed levels of hMMP9 between responders [CR+PR] versus the mean in patients with PD (p-value=0.0004, log fold change=0.7536), and between patients with disease control [CR+PR+SD] and those with PD (p-value= Conclusions: Our results suggest that baseline plasma level of the matrix metalloproteinase, hMMP9, could predict tumor response and PFS in patients treated with a combination of Bv and PLD. These data justify further investigation in breast cancer patients treated with anti-angiogenic therapy. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-16-07.

Aims/Introduction The efficacy and safety of drugs can vary between different races or ethnic populations because of differences in the relationship of dose to exposure, pharmacodynamic response or clinical efficacy and safety. In the present post-hoc analysis, we assessed the influence of race on the pharmacokinetics, pharmacodynamics, efficacy and safety of monotherapy with the dipeptidyl peptidase-4 inhibitor, linagliptin, in patients with type 2 diabetes enrolled in two comparable, previously reported randomized phase III trials. Materials and Methods Study 1 (with a 12-week placebo-controlled phase) recruited Japanese patients only (linagliptin, n = 159; placebo, n = 80); study 2 (24-week trial) enrolled Asian (non-Japanese; linagliptin, n = 156; placebo, n = 76) and white patients (linagliptin, n = 180; placebo, n = 90). Results Linagliptin trough concentrations were equivalent across study and race groups, and were higher than half-maximal inhibitory concentration, resulting in dipeptidyl peptidase-4 inhibition >80% at trough. Linagliptin inhibited plasma dipeptidyl peptidase-4 activity to a similar degree in study 1 and study 2. Linagliptin reduced fasting plasma glucose concentrations by a similar magnitude across groups, leading to clinically relevant reductions in glycated hemoglobin in all groups. Glycated hemoglobin levels decreased to a slightly greater extent in study 1 (Japanese) and in Asian (non-Japanese) patients from study 2. Linagliptin had a favorable safety profile in each race group. Conclusions Trough exposure, pharmacodynamic response, and efficacy and safety of linagliptin monotherapy were comparable among Japanese, Asian (non-Japanese) and white patients, confirming that the recommended 5-mg once-daily dose of linagliptin is appropriate for use among different race groups.

OBJECTIVE Sodium–glucose cotransporter 2 (SGLT2) inhibitors cause substantially less weight loss than expected from the energy excreted via glycosuria. Our aim was to analyze this phenomenon quantitatively. RESEARCH DESIGN AND METHODS Eighty-six patients with type 2 diabetes (HbA1c 7.8 ± 0.8% [62 ± 9 mmol/mol], estimated glomerular filtration rate [eGFR] 89 ± 19 mL ⋅ min−1 ⋅ 1.73 m−2) received empagliflozin (25 mg/day) for 90 weeks with frequent (n = 11) assessments of body weight, eGFR, and fasting plasma glucose (FPG). Time-dependent glucose filtration was calculated as the product of eGFR and FPG; time-dependent glycosuria was estimated from previous direct measurements. The relation of calorie-to-weight changes was estimated using a mathematical model of human energy metabolism that simulates the time course of weight change for a given change in calorie balance and calculates the corresponding energy intake changes. RESULTS At week 90, weight loss averaged −3.2 ± 4.2 kg (corresponding to a median calorie deficit of 51 kcal/day [interquartile range (IQR) 112]). However, the observed calorie loss through glycosuria (206 kcal/day [IQR 90]) was predicted to result in a weight loss of –11.3 ± 3.1 kg, assuming no compensatory changes in energy intake. Thus, patients lost only 29 ± 41% of the weight loss predicted by their glycosuria; the model indicated that this difference was accounted for by a 13% (IQR 12) increase in calorie intake (269 kcal/day [IQR 258]) coupled with a 2% (IQR 5) increase in daily energy expenditure (due to diet-induced thermogenesis). This increased calorie intake was inversely related to baseline BMI (partial r = −0.34, P < 0.01) and positively to baseline eGFR (partial r = 0.29, P < 0.01). CONCLUSIONS Chronic glycosuria elicits an adaptive increase in energy intake. Combining SGLT2 inhibition with caloric restriction is expected to be associated with major weight loss.

In a Phase III randomized trial (EMPA-REG BP™), patients with type 2 diabetes (T2DM) and hypertension (defined as mean seated office systolic blood pressure [SBP] 130-159 mmHg and diastolic BP [DBP] 80-99 mmHg at screening) received empagliflozin (EMPA) 10 mg (n=276), EMPA 25 mg (n=276) or placebo (PBO; n=271) once daily in the morning for 12 weeks (mean [SD] age 60.2 [9.0] yrs, HbA1c 7.90 [0.74] %, 24-h SBP 131.4 [12.3] mmHg, 24-h DBP 75.0 [7.8] mmHg). We assessed changes from baseline in SBP (mean 24-h, awake-time, sleep-time) via ambulatory BP monitoring at week 12 in patients categorized as dippers (sleep-time mean SBP ≤90% of awake-time mean; n=417) or non-dippers (sleep-time mean SBP >90% of awake-time mean; n=350). Baseline mean (SD) 24-h SBP (mmHg) was 129.9 (11.6) in dippers and 133.1 (12.4) in non-dippers. Adjusted mean (SE) changes from baseline in mean 24-h SBP (mmHg) in dippers were -0.2 (0.7) with PBO vs -3.8 (0.6) and -3.9 (0.7) with EMPA 10 and 25 mg, respectively (both p In patients with T2DM and hypertension, EMPA 10 mg and 25 mg significantly reduced SBP vs PBO in dippers and non-dippers.

The sodium glucose cotransporter 2 inhibitor empagliflozin (EMPA) reduces HbA1c, weight and blood pressure (BP) in patients with type 2 diabetes (T2D). While glucose lowering with EMPA is dependent on renal function, the impact of chronic kidney disease (CKD) on BP reduction with EMPA is less well understood. Our aim was to determine if impaired renal function attenuates antihypertensive effects of EMPA. A Phase III randomized placebo (PBO)-controlled trial (EMPA-REG BP™) investigated the efficacy and safety of EMPA in patients with T2D and hypertension (defined as mean seated office systolic BP [SBP] 130-159 mmHg and diastolic BP [DBP] 80-99 mmHg at screening). Patients (mean [SD] age 60.2 [9.0] years, HbA1c 7.90 [0.74] %, 24-hour SBP 131.4 [12.3] and 24-hour DBP 75.0 [7.8] mmHg) received EMPA 10 mg (n=276), EMPA 25 mg (n=276) or PBO (n=271) once daily for 12 weeks. We assessed changes from baseline in mean ambulatory 24-hour SBP and HbA1c in subgroups by baseline eGFR (MDRD equation), adjusting for differences in baseline mean 24-hour SBP (for SBP analyses only), HbA1c, region, number of antihypertensive medications, treatment, eGFR and treatment by eGFR interaction between groups. In patients with normal renal function, or stage 2 or 3 CKD, EMPA significantly reduced HbA1c and mean 24-hour SBP vs PBO (Table). As expected, PBO-corrected HbA1c reductions with EMPA appeared to decrease with decreasing eGFR (Table). In contrast, PBO-corrected reductions in mean 24-hour SBP with EMPA mostly appeared to increase with decreasing eGFR (Table). Unlike HbA1c, mean 24-hour SBP reductions with EMPA in patients with T2D and hypertension appear to be greater in patients with lower eGFR, indicating that SBP modulation with EMPA may involve pathways other than urinary glucose excretion such as diuretic effects, weight loss, improved glycemic control, reduced arterial stiffness or direct vascular effects.

Background VeriStrat® is a serum proteomic test used to determine whether patients with advanced non-small cell lung cancer (NSCLC) who have already received chemotherapy are likely to have good or poor outcomes from treatment with gefitinib or erlotinib. The main objective of our retrospective study was to evaluate the role of VS as a marker of overall survival (OS) in patients treated with erlotinib and bevacizumab in the first line. Patients and methods Patients were pooled from two phase II trials (SAKK19/05 and NTR528). For survival analyses, a log-rank test was used to determine if there was a statistically significant difference between groups. The hazard ratio (HR) of any separation was assessed using Cox proportional hazards models. Results 117 patients were analyzed. VeriStrat classified patients into two groups which had a statistically significant difference in duration of OS (p = 0.0027, HR = 0.480, 95% confidence interval: 0.294–0.784). Conclusion VeriStrat has a prognostic role in patients with advanced, nonsquamous NSCLC treated with erlotinib and bevacizumab in the first line. Further work is needed to study the predictive role of VeriStrat for erlotinib and bevacizumab in chemotherapy-untreated patients.

Background To determine the outcome and patterns of failure in oral cavity cancer (OCC) patients after postoperative intensity modulated radiotherapy (IMRT) with concomitant systemic therapy. Methods All patients with locally advanced (AJCC stage III/IV) or high-risk OCC (AJCC stage II) who underwent postoperative IMRT at our institution between December 2006 and July 2010 were retrospectively analyzed. The primary endpoint was locoregional recurrence-free survival (LRRFS). Secondary endpoints included distant metastasis-free survival (DMFS), overall survival (OS), acute and late toxicities. Results Overall 53 patients were analyzed. Twenty-three patients (43%) underwent concomitant chemotherapy with cisplatin, two patients with carboplatin (4%) and four patients were treated with the monoclonal antibody cetuximab (8%). At a median follow-up of 2.3 (range, 1.1–4.6) years the 3-year LRRFS, DMFS and OS estimates were 79%, 90%, and 73% respectively. Twelve patients experienced a locoregional recurrence. Eight patients, 5 of which had both a flap reconstruction and extracapsular extension (ECE), showed an unusual multifocal pattern of recurrence. Ten locoregional recurrences occurred marginally or outside of the high-risk target volumes. Acute toxicity grades of 2 (27%) and 3 (66%) and late toxicity grades of 2 (34%) and 3 (11%) were observed. Conclusion LRRFS after postoperative IMRT is satisfying and toxicity is acceptable. The majority of locoregional recurrences occurred marginally or outside of the high-risk target volumes. Improvement of high-risk target volume definition especially in patients with flap reconstruction and ECE might transfer into better locoregional control.

A sequential treatment design was chosen in this trial to ensure complete resistance to single-agent non-steroidal aromatase inhibitor (AI) and trastuzumab both given as monotherapy before receiving the combination of a non-steroidal AI and trastuzumab. Key eligibility criteria included postmenopausal patients with advanced, measurable, human epidermal growth factor receptor-2 (HER-2)-positive disease (assessed by FISH, ratio (≥2)), hormone receptor (HR)-positive disease, and progression on prior treatment with a non-steroidal AI, e.g. letrozole or anastrozole, either in the adjuvant or in the advanced setting. Patients received standard dose trastuzumab monotherapy in step 1 and upon disease progression continued trastuzumab in combination with letrozole in step 2. The primary endpoint was clinical benefit rate (CBR) in step 2. Totally, 13 patients were enrolled. In step 1, six patients (46%) achieved CBR. Median time to progression (TTP) was 161 days (95% confidence interval (CI): 82-281). In step 2, CBR was observed in eight out of the 11 evaluable patients (73%), including one patient with partial response. Median TTP for all the 11 patients was 188 days (95% CI: 77-not reached). Results of this proof-of-concept trial suggest that complete resistance to both AI and trastuzumab can be overcome in a proportion of patients by combined treatment of AI and trastuzumab, as all patients served as their own control. Our results appear promising for a new treatment strategy that offers a chemotherapy-free option for at least a subset of patients with HR-positive, HER-2-positive breast cancer over a clinically relevant time period.

Activating epidermal growth factor receptor (EGFR) mutations are recognized biomarkers for patients with metastatic non-small cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitors (TKIs). EGFR TKIs can also have activity against NSCLC without EGFR mutations, requiring the identification of additional relevant biomarkers. Previous studies on tumor EGFR protein levels and EGFR gene copy number revealed inconsistent results. The aim of the study was to identify novel biomarkers of the response to TKIs in NSCLC by investigating whole genome expression at the exon-level. We used exon arrays and clinical samples from a previous trial (SAKK19/05) to investigate the expression variations at the exon-level of 3 genes potentially playing a key role in modulating treatment response: EGFR, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and vascular endothelial growth factor (VEGFA). We identified the expression of EGFR exon 18 as a new predictive marker for patients with untreated metastatic NSCLC treated with bevacizumab and erlotinib in the first line setting. The overexpression of EGFR exon 18 in tumor was significantly associated with tumor shrinkage, independently of EGFR mutation status. A similar significant association could be found in blood samples. In conclusion, exonic EGFR expression particularly in exon 18 was found to be a relevant predictive biomarker for response to bevacizumab and erlotinib. Based on these results, we propose a new model of EGFR testing in tumor and blood.

Background FcγRIIB promotes rituximab internalisation on various B-cell targets, including in follicular lymphoma, which may lead to reduced efficacy. We analysed diagnostic tumour samples from the SAKK 35/98 trial, which has follow-up data of nearly 10 years to determine the relation of FcγRIIB expression with responses and clinical outcomes after rituximab monotherapy in follicular lymphoma. Methods Available archived tissue samples were stained with an anti-human FcγRIIB antibody. Positive samples were graded into negative/low intensity staining (n=116) or medium/high staining (n=13) by a histopathologist masked to clinical outcomes. Failure-free survival (FFS) was defined as time from first rituximab infusion until failure to achieve complete/partial response at week 12, progression, relapse, a second cancer, or death from any cause. Objective response rate (ORR) was associated with intensity staining levels with Fisher's exact test. All time-to-event endpoints were evaluated with the Kaplan-Meier method; groups were compared with the log-rank test. Hazard ratio (HR) was assessed with Cox proportional hazards models. Findings Patients expressing medium/high levels of FcγRIIB were less likely to respond to rituximab than were those with negative/low levels (ORR 23·1% [95% CI 7·5–50·9] vs 58·6% [49·5–67·2], p=0·02). FFS was higher in the negative/low staining group than in the medium/high staining group (median 8·3 months [95% CI 2·8–13·4, IQR 2·76–28·5] vs 2·8 [not calculable, 2·76–2·76], p=0·002; HR 0·43 [95% CI 0·23–0·78]). There was a non-significant trend towards better overall survival in the low/negative group compared with the medium/high group (median 140·0 months vs 50·0, p=0·13; HR 0·56 [95% CI 0·26–1·20]). Interpretation Elevated FcγRIIB expression level is associated with poor response to rituximab in patients with follicular lymphoma. This group may show better results with non-internalising type II antibodies, a hypothesis for validation in future prospective clinical trials. Funding Cancer Research UK.

Abstract 2956 Introduction: The HIV protease inhibitor nelfinavir has anti-myeloma activity in mice; it is approved at the 1250 mg bid dose for oral treatment of HIV. We performed a phase I dose escalation trial of nelfinavir in combination with bortezomib in patients with advanced hematologic malignancies. Methods: During cycle 1 (28 days), trial treatment consisted of 1 week nelfinavir monotherapy, followed by nelfinavir in combination with standard dose bortezomib (1.3 mg/m2i.v. day 8, 11, 15, 18), while cycles 2 and 3 (21 days each) consisted of 2 weeks nelfinavir in combination with bortezomib (day 1, 4, 8, 11). Non-progressing patients could continue therapy for up to 4 additional cycles with the same regimen as cycles 2 and 3. Nelfinavir dose was escalated in a 3+3 design over 3 dose levels (1250, 1875, 2500 mg bid). Dose limiting toxicity (DLT), the primary endpoint, was grade 3–4 non-hematological toxicity (excluding grade 3 bilirubin/alanine aminotransferase (ALT) or hyperlipidemia reversible within 2 weeks) or severe hematologic toxicity unrelated to the underlying disease during cycle 1. Secondary endpoints included pharmacodynamic and pharmacokinetic assessments during cycle 1 at baseline, nelfinavir monotherapy and after application of nelfinavir and bortezomib in combination, as well as signals for activity. Results: Twelve evaluable patients were registered (median age 58 years; 8 male; performance status 0–1 in 10/12 patients); 8 had multiple myeloma, 2 leukemia (1 acute myeloid, 1 acute lymphoblastic) and 2 lymphoma (1 diffuse large B-cell lymphoma, 1 mantle-cell (MCL)). All myeloma patients failed both prior bortezomib and lenalidomide-containing therapy; 7/8 had progressed under prior bortezomib. One patient (2500 mg bid dose) experienced a transient grade 4 elevated ALT, categorized as DLT, which resolved within 2 weeks. The patient continued the same regimen off study without recurrent hepatic toxicity. No further DLTs occurred, thus nelfinavir 2500 mg bid was established to be safe in combination with standard dose bortezomib. One patient with highly aggressive lymphoma died from cerebral vein thrombosis; a myeloma patient experienced a non-fatal pulmonary embolism. Elevated ALT (2 patients) was the only additional non-hematological toxicity grade 3/4 observed in >1 patient. Grade 3 febrile neutropenia and grade 4 thrombocytopenia were seen in 1 and 4 patients, respectively. Best treatment response was evaluated for 11 patients (1 not evaluable). Partial response was achieved in 3 patients (2 myeloma, 1 MCL) and stable disease for at least 2 cycles of therapy in 5 patients. Overall, 4/12 patients completed >=3 cycles of treatment. Assessment of proteasome activity in peripheral blood mononuclear cells (PBMC) from treated patients after 1 week nelfinavir monotherapy revealed inhibition of total proteasome activity in vivo by nelfinavir compared to baseline (mean inhibition, as determined by specific, quantitative intracellular affinity labeling of active proteasome subunits: 14.9 %, 95% confidence interval (CI): 8.8–23.5%, p= Conclusion: This is the first trial to report on the use of nelfinavir as an anti-neoplastic agent in patients with hematologic malignancies. It identifies nelfinavir as FDA approved, orally available drug with pan-proteasome inhibiting activity in vivo. Nelfinavir treament up to 2500 mg bid is safe as monotherapy and in combination with standard dose bortezomib. Bortezomib in combination with nelfinavir shows signals for clinical activity in individual myeloma patients that have failed bortezomib and lenalidomide-containing therapies. Nelfinavir warrants further clinical investigation in multiple myeloma, in particular in combination with proteasome inhibitors. Disclosures: No relevant conflicts of interest to declare.

Abstract 2747 Background: Single-agent immunotherapy with rituximab is a viable treatment option for low risk FL, with limited toxicity and a long duration of response in some patient subsets. We have previously shown that high expression of FcγRIIB promotes rituximab internalisation on various B cell targets, including FL (Blood 2011 118:2530–2540), something not seen with type II anti-CD20 antibodies. The SAKK 35/98 trial examined rituximab monotherapy in FL and now has long-term follow-up data of almost 10 years (JCO 2010 28:4480–4484). We analysed diagnostic tumour samples from this trial to determine the relationship of FcγRIIB expression to responses and clinical outcomes after rituximab treatment in FL. Methods: 202 patients (pts) with newly diagnosed or relapsed FL received induction treatment with rituximab 375 mg/m2 weekly for 4 weeks. Pts with stable or responding disease at week 12 were randomized into 2 groups: no further treatment or prolonged treatment with single infusions of rituximab 375 mg/m2 at weeks 12, 20, 28 and 36. Archived tissue samples from 135 evaluable pts were stained using an anti-human FcγRIIB antibody (clone EP888Y, Abcam) at a dilution of 1:3000 on a Dako autostainer. The samples were pretreated with the Dako EnVisionFLEX target retrieval solution high pH and detection using the Dako AS-Link 48 with Dako EnVision flex plus detection kit. Positive samples were graded into negative/low intensity staining (n=120) versus medium/high (n=13) by an expert lymphoma histopathologist blinded to the clinical outcomes. Data from 2 slides and response at week 12 data for 4 pts were unavailable (1 of whom also has missing slide data), resulting in 130 pts available for analysis. Failure-free survival (FFS) was defined as time from registration until failure to achieve complete/partial response at week 12, progression, relapse, a second cancer or death from any cause. Objective response rate (ORR) was associated with intensity staining levels using Fisher's exact test. All time-to-event endpoints were evaluated using the Kaplan-Meier method; groups were compared using the log-rank test. The hazard ratio (HR) was assessed using Cox proportional hazards models. Results: Registered and randomised pts had very similar baseline characteristics; previously untreated pts had slightly more favourable characteristics but were balanced between the 2 treatment arms. Pts expressing medium/high levels of FcγRIIB were less likely to respond to rituximab by week 12 (ORR 58.1% vs 23.1%, Fisher's exact test, p=0. 02), a finding independent of prior therapy. For FFS, there was a statistically significant difference (p=0.001; HR=0.42; 95% confidence interval (C.I.): 0.23–0.77) between the negative/low staining group (median: 21.4 months; 95% C.I.: 7.0–34.2) and the medium/high staining group (median: 7.0 months; 95% C.I.: Not calculable). The interaction between staining levels and randomised treatment groups for FFS was not statistically significant. There was a non-significant trend towards better overall survival in the low/negative group (median: 140.0 vs 50.0 months; p=0.15; HR=0.57; 95% C.I.: 0.27–1.23); however the event rate was lower (36.8% vs 61.5%). Conclusion: Elevated FcγRIIB expression level is associated with poor response to rituximab in pts with FL. This group may show better results with non-internalising type II antibodies, a hypothesis for validation in future prospective clinical trials. Disclosures: Ghielmini: Roche: Honoraria, Speakers Bureau. Johnson:Roche: Honoraria.

10570 Background: The Swiss Group for Clinical Cancer Research (SAKK) investigated the activity of bevacizumab/erlotinib (BE) in 101 treatment-naive non-squamous stage IIIB and IV non-small cell lu...

e21069 Background: It is essential to understand the mechanisms of action of new therapies in advanced lung cancer. The SAKK investigated the response to bevacizumab/erlotinib (BE) on disease stabi...

7561 Background: Standard CT is toxic and yields unsatisfactory results in advanced NSCLC. The aim of this trial was to evaluate feasibility and efficacy of BE first-line combination, followed by C...

PurposeDipeptidyl peptidase (DPP)-4 inhibitors are an increasingly used antihyperglycemic therapy for patients with type 2 diabetes mellitus (T2DM). Linagliptin, an orally administered DPP-4 inhibitor, has demonstrated favorable efficacy/safety in clinical trials. The aim of this post hoc pooled analysis was to expand current knowledge of the safety of linagliptin.MethodsSafety data for once-daily linagliptin 5 mg (1 study of linagliptin 2.5 mg twice daily) were analyzed from 22 randomized, double-blind, Phase I–III, placebo-controlled clinical trials of ≤102 weeks’ duration. Assessments of pooled data included incidence of patient-reported adverse events (AEs).FindingsData from 7400 patients (linagliptin, 4810; placebo, 2590) were pooled. Most patients (58.4%) had T2DM diagnosis for >5 years; approximately 75% were receiving ≥1 type of background therapy in addition to linagliptin/placebo. Overall exposure to the study drug was 2412.8 years for linagliptin and 1481.4 years for placebo (mean [SD], 183 [120] days and 209 [150] days, respectively). Overall frequencies of AEs were similar for linagliptin- and placebo-treated patients (57.3% and 61.8%, respectively). The incidence of neoplastic AEs was low (0.6% and 0.9%, respectively); there were no reports of pancreatic neoplasia. Pancreatitis was observed in 2 linagliptin-treated patients (

The Xpert® MTB/RIF (Xpert) assay is a rapid PCR-based assay for the detection of Mycobacterium tuberculosis complex DNA (MTBc) and mutations associated with rifampin resistance (RIF). An updated version introduced in 2011, the G4 Xpert, included modifications to probe B and updated analytic software. An analytical study was performed to assess Xpert detection of mutations associated with rifampin resistance in rifampin-susceptible and -resistant isolates. A clinical study was performed in which specimens from US and non-US persons suspected of tuberculosis (TB) were tested to determine Xpert performance characteristics. All specimens underwent smear microscopy, mycobacterial culture, conventional drug-susceptibility testing and Xpert testing; DNA from isolates with discordant rifampin resistance results was sequenced. Among 191 laboratory-prepared isolates in the analytical study, Xpert sensitivity for detection of rifampin resistance associated mutations was 97.7% and specificity was 90.8%, which increased to 99.0% after DNA sequencing analysis of the discordant samples. Of the 1,096 subjects in the four clinical studies, 49% were from the US. Overall, Xpert detected MTBc in 439 of 468 culture-positive specimens for a sensitivity of 93.8% (95% confidence interval [CI]: 91.2%–95.7%) and did not detect MTBc in 620 of 628 culture-negative specimens for a specificity of 98.7% (95% CI: 97.5%–99.4%). Sensitivity was 99.7% among smear-positive cases, and 76.1% among smear-negative cases. Non-determinate MTBc detection and false-positive RIF resistance results were low (1.2 and 0.9%, respectively). The updated Xpert assay retained the high sensitivity and specificity of the previous assay versions and demonstrated low rates of non-determinate and RIF resistance false positive results.