Number Of Additional Patients Research Articles

P164 Fracture risk in axial spondyloarthritis: a retrospective analysis of the use of the Fracture Risk Assessment Tool in a cohort of affected patients

Abstract Background/Aims Fractures are common in axial spondyloarthritis (axSpA) patients. The FRAX (Fracture Risk Assessment Tool) score is a validated tool for the assessment of fracture risk. Unlike axSpA, rheumatoid arthritis (RA) is counted as a risk factor in FRAX. The primary aim was to calculate a FRAX score in a cohort of axSpA patients. In addition, a second FRAX score was determined by ticking the “RA risk” as positive on the second assessment. Methods Data were examined on a cohort of axSpA patients attending the St James’s Hospital Spondylitis service. Bone mineral density was assessed at the neck of femur on the patient’s dual x-ray absorptiometry (DXA). This, plus the individual patient’s risk factors, were added to the FRAX score calculator. The analysis was then repeated with the RA risk box ticked as positive. The effect of such an adjustment (taking account of their diagnosis of axSpA) on the fracture risk status of these patients was made to assess if this resulted in an additional number of patients within the cohort being at risk of fracture. A patient with a 10-year hip fracture risk of > 3% or 10-year major osteoporotic fracture risk of > 20% is high risk. Results Table 1 summarises the characteristics of the cohort. All (100%) of the patients met ASAS axSpA criteria and 85% met Modified New York (mNY) criteria for ankylosing spondylitis. Five patients had known osteoporosis and an additional 9 patients were classified as being at increased fracture risk using the FRAX Tool. A further 7 patients could be classified as being at increased fracture risk when the FRAX was adjusted for the axSpA diagnosis, by ticking the RA risk box as positive. Conclusion Fracture risk is a significant issue in patients with axSpA; however, this risk is frequently under-recognised. The use of the FRAX score improves the detection of those at fracture risk, and its use should be strongly encouraged in all rheumatology clinics managing axSpA patients. When the same weighting is given to axSpA as RA, there is a further increase in the identification of patients at risk of fractures. Disclosure P. Mulkerrin: None. F. O'Shea: None. G. Fitzgerald: None.

P794 Effectiveness of administering zinc acetate hydrate to patients with inflammatory bowel disease and zinc deficiency: a retrospective observational two-center study

Abstract Background Inflammatory bowel disease (IBD) patients frequently have zinc deficiency and that IBD patients with zinc deficiency are at higher risk for IBD-related complications and surgery. We reported the efficacy of zinc replacement therapy for IBD patients with zinc deficiency at ECCO2020, and now we report the results of our analysis with an extended observation period and an additional number of patients. Methods IBD patients with zinc deficiency who received zinc acetate hydrate (ZAH) from March 2017 to November 2021 were registered in this 2-center（Hokkaido University Hospital and Sapporo Higashi Tokushukai Hospital）, retrospective, observational study. Results One hundred twenty patients with Crohn’s disease (CD, n=82) or ulcerative colitis (UC, n=38) were registered. Median serum zinc level and CDAI in CD patients significantly improved (59.0-92.3 μg/dL, P<0.001; 118-86, P<0.001, respectively) 4 weeks after ZAH administration. Similarly, median serum zinc levels and CDAI significantly improved (58.5-82.0 μg/dL, P<0.001; 96-78, P<0.001, respectively) 20 weeks after ZAH administration. In the 18 patients who underwent endoscopy both within 4 weeks before and within 60 weeks after ZAH administration, median SES-CD improved from 11.5 to 5.5 (P<0.001). Logistic regression analysis identified “serum zinc level ≥52 μg/dl before ZAH administration” as a factor contributing to normalization of serum zinc concentration and “CDAI ≥96 before ZAH administration” as a factor contributing to improvement of disease activity. Median serum zinc level and partial Mayo scores (PMS) in UC patients significantly improved (63.0-94.0μg/dL, P<0.001; 2-0, P=0.002, respectively) 4 weeks after ZAH administration. Median serum zinc levels significantly improved (62.0-100.0μg/dL, P<0.001) 20 weeks after ZAH administration, but no significant changes in PMS were observed. In the 12 patients who underwent endoscopy both within 4 weeks before and within 60 weeks after ZAH administration, median UCEIS improved from 5 to 3 (P=0.004). Logistic regression analysis identified “dose of ZAH ≥75 mg/day” as a factor contributing to normalization of serum zinc concentration and “serum zinc level ≥65 μg/dl before ZAH administration” as a factor contributing to improvement of disease activity. In both CD and UC, there was a significant correlation between serum zinc level and CDAI, CRP, and serum albumin level before ZAH administration. Conclusion ZAH administration to IBD patients with zinc deficiency is effective in improving zinc deficiency and may contribute to improving disease activity in IBD.

Clinically significant prostate cancer (csPCa) detection with various prostate sampling schemes based on different csPCa definitions

BackgroundCombining targeted biopsy (TB) with systematic biopsy (SB) is currently recommended as the first-line biopsy method by the European Association of Urology (EAU) guidelines in patients diagnosed with prostate cancer (PCa) with an abnormal magnetic resonance imaging (MRI). The combined SB and TB indeed detected an additional number of patients with clinically significant prostate cancer (csPCa); however, it did so at the expense of a concomitant increase in biopsy cores. Our study aimed to evaluate if ipsilateral SB (ipsi-SB) + TB or contralateral SB (contra-SB) + TB could achieve almost equal csPCa detection rates as SB + TB using fewer cores based on a different csPCa definition.MethodsPatients with at least one positive prostate lesion were prospectively diagnosed by MRI. The combination of TB and SB was conducted in all patients. We compared the csPCa detection rates of the following four hypothetical biopsy sampling schemes with those of SB + TB: SB, TB, ipsi-SB + TB, and contra-SB + TB.ResultsThe study enrolled 279 men. The median core of SB, TB, ipsi-SB + TB, and contra-SB + TB was 10, 2, 7 and 7, respectively (P < 0.001). ipsi-SB + TB detected significantly more patients with csPCa than contra-SB + TB based on the EAU guidelines (P = 0.042). They were almost equal on the basis of the Epstein criteria (P = 1.000). Compared with SB + TB, each remaining method detected significantly fewer patients with csPCa regardless of the definition (P < 0.001) except ipsi-SB + TB on the grounds of D1 (P = 0.066). Ten additional subjects were identified with a higher Gleason score (GS) on contra-SB + TB, and only one was considered as significantly upgraded (GS = 6 on ipsi-SB + TB to a GS of 8 on contra-SB + TB).ConclusionsIpsi-SB + TB could acquire an almost equivalent csPCa detection value to SB + TB using significantly fewer cores when csPCa was defined according to the EAU guidelines. Given that there was only one significantly upgrading patient on contra-SB, our results suggested that contra-SB could be avoided.

Abstract 11337: Sensitivity Analysis of an Electronic Health Record-Based Algorithm to Facilitate Detection of Familial Hypercholesterolemia: Results in Genetically Confirmed Familial Hypercholesterolemia

Introduction: Familial hypercholesterolemia (FH) is a genetic disorder resulting in elevated LDL-C levels and increased risk of cardiovascular disease. Algorithms have been developed to facilitate FH detection. We previously developed a continuous, electronic health record (EHR)-based algorithm using the Dutch Lipid Clinical Network (DLCN) criteria, with automated correction of LDL-C levels for use of lipid-lowering-therapy (LLT). In this study, we performed a sensitivity analysis of the algorithm in patients with previously genetically confirmed FH. Methods: We selected all patients with genetically confirmed FH, seen during 2018 and 2019. DLCN scores were calculated before and after correction for LLT at the most recent visit. The primary outcome was the number of FH patients with DLCN criteria ≥6 points for LDL-C (which would have been an indication for genetic testing) before and after correction for LLT. Secondary endpoint was the additional number of patients with ≥6 points after also adding data on patient- and family history. Results: We included 222 patients with genetically confirmed FH; mean (SD) age: 50 (17) years; female: n=134 (60,4%). In total, 210 patients (94,6%) used some type of LLT. Mean (SD) LDL-C was 3,0 (1,4) mmol/L before correction for LLT and 7,5 (3,7) mmol/L after correction for LLT. Before correction for LLT, the algorithm identified 3 patients (1,4%) with ≥6 DLCN points, increasing to 59 patients (26,6%) after correction for LLT and to 76 patients (34,2%) after adding data on patient-, and family history. Conclusion: We conclude that, even after correction for LLT and addition of data on patient-, and family history, the sensitivity of a DLCN-based algorithm appeared relatively low in a population with genetically confirmed FH. Correction for LLT is important to increase sensitivity of the algorithm. Interestingly, FH detection algorithms inevitably rely on phenotypical characteristics of patients, whereas the present data show that genotypical FH does not necessarily express as phenotypical FH recognized by the DLCN-based algorithm. These data highlight the need for improvement of the DLCN-based algorithm and the importance of cascade testing for FH.

Pharmacoeconomic aspects of the therapy for moderate and severe psoriatic arthritis

Objective: to perform cost-effectiveness analysis of the treatment for adult patients with psoriatic arthritis (PsA) with a Russian interleukin- 17А inhibitor netakimab in comparison with other biologic disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) and to evaluate the influence of the inclusion of netakimab in the therapy for PsA on the budget of the Russian healthcare system.Material and methods. The evaluation of cost-effectiveness was performed from the position of the Russian healthcare system for patients with moderate and severe PsA. The evaluation was performed based on the results of the network meta-analysis of the randomized clinical studies. The criterion of clinical effectiveness included the changes in the condition of the joints by the criteria of the American College of Rheumatology (ACR20, ACR50, and ACR70) and changes in skin symptoms by the index of the prevalence and severity of psoriasis (PASI 75 and PASI 90) with a recalculation into quality-adjusted life-year (QALY). The time horizon of the cost-effectiveness analysis was 2 years. The calculation was based on the registered prices and VAT. If there was an original drug and a biosimilar registered on the pharmaceutical market, the calculation was based on the median of the registered prices. The budget impact analysis of the influence of netakimab inclusion in the therapy for patients with PsA was performed considering the structure of the prescription of bDMARDs and tsDMARDs that was determined in the pharmaco-epidemiological study conducted in the Russian Federation in 2020. The analysis was performed for patients that received medication by the scheme of reimbursement. The time horizon of the study was 3 years old.Results. In the base-case analysis, the cost-effectiveness ratio for netakimab was 1.210 mln rub/QALY (by 66.2–88.5% lower than in cases when comparison drugs were used). The budget impact analysis showed that the inclusion of netakimab in the therapy for PsA could reduce the costs by 376.60 mln rub (21.1%). Considering budget saving, the number of additional patients that can be treated will increase by 26.7% within 3 years.Conclusion. Netakimab is characterized by higher cost-effectiveness in comparison with other bDMARDs (adalimumab, golimumab, guselkumab, ixekizumab, infliximab, secukinumab, ustekinumab, certolizumab pegol, etanercept) and tsDMARDs (apremilast, tofacitinib) prescribed in the Russian Federation for patients with PsA. The inclusion of netakimab in the therapy for PsA will reduce the financial burden on the healthcare system.

Predicting Significant Iliac Vein Compression Using a Probability Scoring System Derived From Minimal Luminal Area on Computed Tomography Angiography in Patients 65 Years of Age or Younger.

The presence of 50% or more stenosis on intravascular ultrasound (IVUS) is considered diagnostic of iliac vein compression (ILVC) by most operators. We have previously developed a scoring system combining minimal luminal area (MLA) at the compression site and age to predict ILVC as seen on IVUS. We present a revised and improved scoring system following an additional number of patients and limited to patients 65 years of age and younger. Patients were included from retrospective (n = 52) and prospective (n = 18) registries of consecutive patients who underwent computed tomography angiography (CTA) of the pelvis with venous filling and IVUS within a few weeks apart to evaluate for symptomatic ILVC at a single cardiovascular practice. Quantitative vascular analysis was performed on all images obtained. MLA and age were used to calculate a score derived from a previously published logistic regression formula. Patients >65 years in age were excluded. The predicted findings from the score were compared with the actual presence of compression on IVUS. The revised scoring system is based on a score of < or ≥ 0.533824 and MLA (mm²) of <140, ≥140 to <200, and ≥200. The negative predictive value (NPV) and positive predictive value (NPV and PPV) of each cut-off in predicting ILVC on IVUS were calculated. A total of 70 symptomatic patients were included (mean age, 52.6 ± 12.3 years). The model offered the following: accuracy = 54/70 (77.1%); sensitivity = 51/52 (98.1%); specificity = 3/18 (16.7%); PPV = 51/66 (77.3%); and NPV = 3/4 (75.0%). A scoring system using MLA on CTA and age provides a fairly accurate diagnostic test to predict the presence of significant ILVC as seen on IVUS.

Budget Impact Analysis of Switching to Rituximab's Biosimilar in Rheumatology and Cancer in 13 Countries Within the Middle East and North Africa.

IntroductionBiosimilars of monoclonal antibodies are being rapidly developed and approved by public health regulatory authorities worldwide. These biosimilars are expected to bring significant budgetary savings to national governments and consequently increase patients’ accessibility to biological therapy. Rituximab has been used extensively for the treatment of cancer and rheumatoid disorders over the past two decades. New biosimilars of Rituximab have been developed and introduced into clinical practice. We have analyzed the budgetary impact and savings outcome of introducing Rituximab’s biosimilar into 13 countries within the Middle East and North Africa through the implementation of a budget impact analysis model.MethodsOur model was based on a 1-year full uptake and switch scenario of the Rituximab’s biosimilar CT-P10. The model calculated the total number of patients based on the total national consumption of Rituximab per country. Accordingly, the model produced savings per each indication which were translated into the additional number of patients that would be permitted access to Rituximab’s therapy as a result of these savings.ResultsIn our modeling scenario, the total projected savings that will result from the uptake of Rituximab’s biosimilar within the MENA region were estimated to be 46.59 million dollars. The cumulative savings in all 13 countries would allow access of Rituximab’s therapy for a total of 6589 patients which is equivalent to a 14% increase in the number of patients benefiting from Rituximab’s therapy.ConclusionThe introduction of Rituximab’s biosimilar within the Middle East and North Africa region is associated with significant budgetary savings that will allow public national health authorities to reinvest such economic gains either in expanding access to Rituximab therapy or other costly lifesaving biologicals.

Electronic health records to facilitate continuous detection of familial hypercholesterolemia

Background and aimsFamilial hypercholesterolemia (FH) is an inherited disorder associated with increased risk of coronary heart disease as a result of high LDL-cholesterol (LDL-C). The clinical diagnosis can be made with the Dutch Lipid Clinic Network criteria (DLCN criteria). FH is an underdiagnosed disorder, possibly due to false negative LDL-C interpretation during lipid lowering therapy (LLT). We hypothesized that automated health record-based integration of data can provide a signal to facilitate identification of FH patients. MethodsWe included patients with LDL-C ≥6.5 mmol/l after correction for LLT in all patients testing LDL-C in Northwest Clinics, The Netherlands. Patients previously diagnosed with FH were excluded. The primary endpoint was the additional number of patients with DLCN criteria ≥6 points after correction for LLT. Secondary endpoints were the additional number of patients with DLCN criteria ≥6 points after also adding data on patient- and family history, and LDL-C before and after correction for LLT. Analysis was performed in a daily automated routine (HiX ChipSoft). ResultsIn a total of 41,937 individual LDL-C measurements during 26 weeks, we found 351 patients with LDL-C ≥6.5 mmol/l after automated correction for LLT. FH had previously been diagnosed in 42 patients. In the remaining 309 patients (58.3% female; age: 66 ± 11 yrs (mean ± SD); 85.8% on LLT), the number of patients with DLCN criteria ≥6 points increased from 9 to 95 after correction for LLT, and to 127 after also adding patient and family history. The mean LDL-C before and after correction for LLT was 4.69 ± 1.42 mmol/l and 8.16 ± 1.68 mmol/l, respectively (mean ± SD; p < 0.001). ConclusionsWe conclude that automated medical record-based integration of LDL-C, LLT and patient- and family history can provide a crucial signal to facilitate identification of FH. Whether this signal results in subsequent genetic identification of FH patients and their relatives requires further study.

P011 A number needed to harm analysis of safety outcomes from randomized controlled trials of biologics and tofacitinib in ulcerative colitis

BACKGROUND: Emerging evidence on vedolizumab supports its safety profile given its unique gut-specific mechanism of action. Long-term safety is an important outcome when choosing between treatment options for moderately to severely active ulcerative colitis (UC). A systematic literature review and indirect treatment comparison examined published evidence on safety outcomes reported from randomized controlled trials (RCTs) of approved biologics and tofacitinib in UC. METHODS: MEDLINE, Embase, and Cochrane Library databases were searched from 1997 to July 2018 to identify RCTs reporting safety outcomes with biologic agents (vedolizumab, adalimumab, infliximab, golimumab, ustekinumab, certolizumab, natalizumab) and tofacitinib approved to treat moderately to severely active UC. All maintenance treatment studies (follow-up, 44–60 weeks) were included. A network meta-analysis estimated odds ratios (ORs) using vedolizumab as reference treatment for the following safety measures assessed at approximately 52 weeks: overall adverse events (AEs), serious AEs (SAEs), AEs leading to discontinuation, overall infections, serious infections, and arthralgia. Number needed to harm (NNH), defined as the additional number of patients that would have to be treated with vedolizumab for one person to experience a safety outcome, was also calculated. A positive NNH denotes better safety with vedolizumab compared with other agents, with higher NNH values representing a correspondingly better safety profile for vedolizumab vs the given comparator treatment option. RESULTS: Of 3,102 publications identified, 6 RCTs (2 golimumab; 1 each vedolizumab, adalimumab, infliximab, and tofacitinib) were eligible for inclusion. Compared with vedolizumab, all ORs for SAEs trended higher for other treatment options (adalimumab: 1.99 [95% credible interval (CI) 0.84–4.70]; infliximab: 1.73 [0.76–3.97]; and tofacitinib: 1.66 [0.62–4.39]) or achieved statistical significance (golimumab: 2.55 [1.10–5.70]). The NNH values for SAEs were adalimumab: 18; infliximab: 24; golimumab: 12; and tofacitinib: 27. For AEs leading to discontinuation, ORs trended higher for other treatment options relative to vedolizumab (adalimumab: 2.32 [0.48–12.68]; infliximab: 3.48 [0.68–21.70]; golimumab: 3.43 [0.74–20.90]; tofacitinib: 1.61 [0.34–8.95]). The NNH values for AEs leading to discontinuation were adalimumab: 29; infliximab: 16; golimumab: 16; and tofacitinib: 63. For serious infections, ORs again trended higher for other treatment options (adalimumab: 1.23 [0.16–8.76]; infliximab: 1.78 [0.29–10.67]; golimumab: 4.09 [0.66–25.99]; tofacitinib: 1.28 [0.12–16.05]). The NNH values for serious infections were adalimumab: 333; infliximab: 100; golimumab: 25; and tofacitinib: 250. Similar numerical trends were observed with vedolizumab for the safety outcomes of overall AEs, overall infections, and arthralgia. CONCLUSION(S): In a network meta-analysis of RCTs, vedolizumab consistently demonstrated better safety profile trends relative to other approved treatment options for moderately to severely active UC. Vedolizumab had the highest NNH values for all safety outcomes, especially serious infections. These indirect comparison results were limited to RCT patient populations, and real-world studies in larger patient populations are needed to confirm these findings.

Sample size adjustment designs with time-to-event outcomes: A caution.

Sample size adjustment designs, which allow increasing the study sample size based on interim analysis of outcome data from a randomized clinical trial, have been increasingly promoted in the biostatistical literature. Although it is recognized that group sequential designs can be at least as efficient as sample size adjustment designs, many authors argue that a key advantage of these designs is their flexibility; interim sample size adjustment decisions can incorporate information and business interests external to the trial. Recently, Chen et al. (Clinical Trials 2015) considered sample size adjustment applications in the time-to-event setting using a design (CDL) that limits adjustments to situations where the interim results are promising. The authors demonstrated that while CDL provides little gain in unconditional power (versus fixed-sample-size designs), there is a considerable increase in conditional power for trials in which the sample size is adjusted. In time-to-event settings, sample size adjustment allows an increase in the number of events required for the final analysis. This can be achieved by either (a) following the original study population until the additional events are observed thus focusing on the tail of the survival curves or (b) enrolling a potentially large number of additional patients thus focusing on the early differences in survival curves. We use the CDL approach to investigate performance of sample size adjustment designs in time-to-event trials. Through simulations, we demonstrate that when the magnitude of the true treatment effect changes over time, interim information on the shape of the survival curves can be used to enrich the final analysis with events from the time period with the strongest treatment effect. In particular, interested parties have the ability to make the end-of-trial treatment effect larger (on average) based on decisions using interim outcome data. Furthermore, in "clinical null" cases where there is no benefit due to crossing survival curves, the sample size adjustment design is shown to increase the probability of recommending an ineffective therapy. Access to interim information on the shape of the survival curves may jeopardize the perceived integrity of trials using sample size adjustment designs. Therefore, given the lack of efficiency advantage over group sequential designs, sample size adjustment designs in time-to-event settings remain unjustified.

Non-persistence and non-adherence to MTX therapy in patients with rheumatoid arthritis: a retrospective cohort study based on German RA patients.

ObjectiveThis study aimed to assess the level of nonpersistence (NP) and nonadherence (NA) to methotrexate (MTX) therapy in German patients with rheumatoid arthritis (RA).Materials and methodsBased on German claims data, RA patients who received a MTX therapy (subgroup: treatment-naive patients) were analyzed. NP was defined as treatment gap >12 weeks. Regarding NA, it is the overall medication possession ratio (MPR) during an observational period of 12 or 24 months after therapy, and the MPR is calculated only for the periods of therapy continuation; NA was defined as MPR <80%.ResultsA total of 7,146 RA patients who received at least one MTX prescription (subgroup: 1,211 treatment-naive patients) could be observed (mean age: 64.4 years, 73.6% female). Percentage of NP patients among MTX-naive patients after 6, 12 and 18 months was 16.7%, 34.0% and 36.7%, respectively. After MTX therapy discontinuation, 39.9% had restarted their MTX therapy, 13.8% had received another non-MTX synthetic disease-modifying antirheumatic drug (sDMARD), 8.1% had biological DMARD (bDMARD) and 49.2% had not received any DMARD prescription at all. Overall, 12- and 24-month MPRs for MTX therapy were 83.0% and 76.5% with a percentage of NA patients of 25.8% and 33.8%, respectively. During periods of general treatment continuation, the percentage of patients with an MPR <80% was 6.5%.ConclusionNP to MTX treatment seems to be common in one-fourth of German patients with RA. An additional number of patients, at least 6.5%, are also affected by NA. A considerable percentage of RA patients who discontinued MTX therapy do not receive any follow-up DMARD therapy.

The potential health and economic impact of improving stroke care standards for Australia.

Background Evidence of the burden of suboptimal stroke care should expedite quality improvement. We aimed to estimate the health and economic impact of improving acute stroke management to best practice standards using Australia as a case study. Methods Hospital performance in Australia was estimated using data from the National Stroke Audit of Acute Services 2013. The percentage of patients provided evidence-based therapies in all hospitals was compared to that achieved in the aggregate of top performing benchmark hospitals (that included between them, a minimum contribution of 15% of all cases audited). The number of additional patients who would receive therapies if this performance gap was rectified was applied to a standardized economic simulation model that comprised stroke rates and resource-use estimates from the North East Melbourne Stroke Incidence Study applied to the 2013 Australian population. Results In 2013, 41,398 patients were estimated to have been hospitalized with stroke. If acute care was improved to that of Australian benchmarks, there would be an additional 15,317 patients accessing stroke units; 1960 receiving thrombolysis; and 4007 being treated with antihypertensive medication, 3082 with antiplatelet medication, 2179 with anticoagulant medication, and 3514 with lipid-lowering therapy. Approximately 9329 disability-adjusted life years could be avoided. This additional care provided would be cost effective at AUD 3304 per disability adjusted life year avoided. Conclusion The benefits of reducing evidence-practice gaps in Australia are considerable. Further investment in initiatives to optimize hospital care is justified.

Phase I dose escalation study of pemetrexed and carboplatin in chemotherapy-naive elderly patients with advanced nonsquamous non-small cell lung cancer.

e19137 Background: The subgroup analyses in several phase III trials have suggested that overall survival after platinum-doublet chemotherapy in elderly patients with non-small cell lung cancer (NSCLC) can be similar to those in younger patients. The combination of carboplatin (CBDCA) with pemetrexed (PEM) is expected as a suitable treatment for carefully selected elderly patients with advanced non-squamous (non-Sq) NSCLC. Methods: Patients with ≥75 years, PS of 0-1, chemotherapy-naïve advanced non-Sq NSCLC were enrolled in this study. They received escalated doses of CBDCA at AUC 4 (cohort 1) or AUC 5 (cohort 2) and PEM 500 mg/m2 every 3 weeks for six cycles. Dose escalation was decided by dose-limiting toxicity (DLT) occurred in the first cycle of chemotherapy. Study protocol stipulated that additional number of patients, up to maximum of 20 patients, was enrolled to receive the recommended dose of study treatment. The primary objectives were to evaluate feasibility and determine the recommended dose of this combination. Results: A total of 20 patients (6 patients in cohort 1, 14 patients in cohort 2) were enrolled in this study. Median age was 77 (range 75-83). No DLTs were observed in the patients with cohort 1 and the first 6 patients of cohort 2 during the first cycle of chemotherapy, thus the combination of PEM 500 mg/m2 plus CBDCA at AUC 5 was determined as the recommended dose. Median number of cycles was 4 (range 1-6). The major toxicities were neutropenia, thrombocytopenia, anemia. During the entire period of study, 2 and 5 patients needed to have platelet transfusion and RBC transfusion, respectively. Liver dysfunction, fatigue and anorexia were also common, but these were generally manageable. Six partial responses and 9 stable diseases were observed, giving an overall response rate of 30% and a disease control rate of 75%. Median progression-free survival time was 4.8 months (95% CI, 4.1 – 5.4 months). Conclusions: The combination of PEM 500 mg/m2 plus CBDCA at AUC 5 was determined as the recommended dose. This combination therapy is generally tolerable, and may have encouraging antitumor activity in chemotherapy-naïve elderly patients with advanced non-Sq NSCLC. Clinical trial information: UMIN000003231.

ER, PR, and HER2 assessment in Hispanic women with breast cancer: A comparison between IHC and AQUA technology.

e11568 Background: Estrogen (ER), progesterone (PR) receptors and HER2 are important markers for breast cancer (BC) treatment planning. These markers are often measured by immunochemistry (IHC) but IHC is subject to limitations of operator subjectivity and equivocal results making selection of appropriate therapy difficult and ultimately affecting patient outcome. Methods: 135 females with BC were recruited in Puerto Rico between Sept and Dec 2012. Median patient age was 57 and 95 % had invasive ductal carcinoma. Our aim was to compare discordance rates of ER, PR and HER2 between IHC and AQUA, an automated fluorescent technology that quantifies antigen expression, in a population of Hispanic women and to investigate whether specimen type or tumor grade influence discordance rate between the two technologies. Results: 103 of 135 patient samples were found to be ER+ by both technologies and 28 samples were ER- by both IHC and AQUA. 4 samples (3%) were discordant; 2 each were AQUA+/IHC- and AQUA-/IHC+. 73 of 135 samples expressed PR by both technologies and 55 samples were PR- by both IHC and AQUA. 14 samples (10%) were discordant; 7 each were AQUA+/IHC- and AQUA-/IHC+. 87 of 135 samples were HER2- and 13 patients were found to be HER2+ by both technologies. However 35 samples (26%) were discordant for HER2 status; 31 were AQUA+/IHC- while 4 AQUA-/IHC+. 100 of the HER2 results were scored 0-1 (negative) by IHC and 25 % of these cases were overturned by AQUA to HER2 +. 19 of the HER2 results were scored 2 (borderline) by IHC. 32 % of these cases were positive by AQUA. Conclusions: Discordance rate were 3% for ER, 10 % for PR but 26% for HER2 between IHC and AQUA. The Cohen’s Kappa coefficient for ER and PR were 0.914 and 0.785 respectively but only 0.299 for HER2 (p values &lt; 0.00001 for all 3 values). Needle/core biopsy yielded more HER2 discordance than lumpectomy/mastectomy (31% vs. 16%). HER2 discordance between IHC and AQUA was more common in higher grade tumors. The large number of HER2 negative IHC cases scored positive by AQUA, and considering the data demonstrating that HER2 by AQUA better predicts benefit from trastuzumab (Slamon D, SABCS 2012) suggests that a significant additional number of patients could benefit from such targeted therapy.

Cost‐effectiveness of atazanavir+ritonavir (ATV+RTV) vs. lopinavir/ritonavir (LPV/r) in women of childbearing age in the United Kingdom

Purpose of the studyIn the UK, an increasing proportion of individuals with HIV are women of childbearing age (WOCBA). Literature on the potential effects of antiretroviral therapy (ART) on certain risk factors for coronary heart disease (CHD), such as total cholesterol (TC), has not differentiated the reported ART‐associated risk by other risk factors for CHD (e.g. age and gender). Given the different age‐specific CHD risk estimates for men and women, particularly the low risk of CHD in WOCBA, the cost‐effectiveness of LPV/r vs ATV+RTV specifically among WOCBA warrants examination. Therefore, the objective of this study was to perform a cost‐effectiveness and budget impact analysis of two first‐line protease inhibitor‐based regimens, LPV/r versus ATV+RTV, among HIV‐infected, ARV‐naïve WOCBA in the UK.MethodsA modified version of a previously published Markov model was utilized [1]. CHD risk estimates were based on the Framingham risk score. Baseline assumptions were that 33% of women were smokers with a mean age of 25 years. Guidelines regarding therapeutic drug monitoring among pregnant women in the 3rd trimester who receive ATV+RTV were incorporated [2]. Age‐specific pregnancy rates were estimated in order to determine ARV utilization during gestation. The model employed a lifetime horizon under a NHS perspective and a discount rate of 3.5%. Costs were presented in 2011 GBP.Summary of resultsThe model predicted no appreciable difference in quality‐adjusted survival (in terms of QALYs) between the two regimens over a lifetime (0.2 days in favor of ATV+RTV) and an increased cost of £3,003 per patient on the ATV+RTV regimen. Cost savings of £1,977 over 5 years and £2,916 over 10 years were predicted for patients who initiated LPV/r. Furthermore, for every 100 patients started on LPV/r, the savings accrued after one year allow for the treatment of 6 additional patients. After 10 years, the number of additional patients that can be treated accumulated to 42. The model predicted a mean of 1.4 pregnancies per woman, and an overall difference between the regimens of 0.3% in CHD events after 10 years.ConclusionsInitiating HIV infected, ARV‐naïve WOCBA on a LPV/r‐based regimen compared to an ATV+RTV‐based regimen produces substantial short‐ and long‐term cost savings with similar life expectancy. These results warrant consideration, as selecting LPV/r over ATV+RTV may provide an opportunity for improving access to ART for WOCBA living with HIV in the UK.

Oscillating Field Stimulation in the Treatment of Spinal Cord Injury

Abstract The application of electrical current to injured tissue is known to promote healing. The use of this modality in healing the injured spinal cord to promote neurologic recovery has been introduced as a potential treatment for patients who previously had minimal hope of recovery. In in vitro and in vivo experiments, neural regeneration has been seen to occur, especially when an oscillating field is used. With this modality, an electrical current is applied in which the polarity changes direction on a periodic basis, preventing the “die-back” phenomenon of severed neural pathways. This mechanism of recovery has been demonstrated in several species in which sacrifice has been undertaken and spinal cords examined. In a study of humans, a small number of patients participated in a single phase Ia trial in which the safety of an implantable device was demonstrated, with indications of probable benefit, consistent with laboratory and animal studies. In addition, a number of additional patients were treated, and their results were examined along with the original cohort and were compared with historical control subjects. The device used in this mode of treatment has not been approved for use in the general spinal cord–injured population, pending further study. A larger multi-institutional trial needs to be done to further demonstrate efficacy and effectiveness, and outcomes will need to be agreed upon by spinal cord injury researchers, patients, and regulators before widespread use will be permitted. Unfortunately, some subtle changes experienced and valued by patients are not recognized as important or desirable by regulators or by all researchers.

Implications of full compliance with the computed tomography scanning recommendations of the National Institute for Clinical Excellence and Scottish Intercollegiate Guidelines Network guidelines for the management of head injury

A prospective study was conducted to examine clinical practices in the management of head-injured patients preinception and postinception of the Scottish Intercollegiate Guidelines Network guidelines. Comparison was made between the Scottish Intercollegiate Guidelines Network and National Institute for Clinical Excellence guidelines on their indications for computed tomography scanning. Information was available on 2827 adult patients. Two hundred and thirty-two patients satisfied one or more Scottish Intercollegiate Guidelines Network criteria for computed tomography scanning. Four hundred and seventy-eight patients fulfilled one or more National Institute for Clinical Excellence criteria for scanning. No patient with Scottish Intercollegiate Guidelines Network or National Institute for Clinical Excellence indications for computed tomography scanning and who was not scanned, subsequently required neurosurgical treatment for a complication related to their injury. Full compliance with the scanning recommendations in the Scottish Intercollegiate Guidelines Network and National Institute for Clinical Excellence guidelines will require a significant increase in scanning resource and is unlikely to lead to the identification of a significant additional number of patients with intracranial lesions requiring neurosurgical intervention.

Screening for occult cancer in patients with acute venous thromboembolism

One in every five episodes, venous thromboembolism (VTE) occurs in patients with known cancer [1], but VTE may also be the first manifestation of an underlying (previously not known) malignancy [2,3]. This association is greatest within the first few months, thus suggesting these cancers are present at the time of diagnosis. A number of studies have been published on this issue, but there still exists controversy over the adequacy of performing some screening workup in patients with acute VTE in order to detect cancer in earlier phases. What a number of studies have already demonstrated is: (i) that a diagnosis of cancer is more likely to arise in patients without identified risk factors for thrombosis and apparently idiopathic VTE than in those in whom VTE occurs postoperatively or after immobilization [4,5]; (ii) that the variation in reported incidence reflects the different definitions for idiopathic and secondary cases, and variation in the intensity of cancer surveillance in each study; and (iii) that these cancers are more often in early stages of the disease [6,7]. However, there still remain some important unresolved questions: (i) is there any specific subgroup of patients with idiopathic VTE who may benefit more from an aggressive workup?; (ii) what is the most cost-effective workup to perform in these patients?; (iii) do early detection of cancer influence the survival of these patients? Firstly, as one in every two patients with VTE has idiopathic VTE, it would be interesting to know if hidden cancer is more frequent in any specific subgroup of patients. There is some evidence that patients with recurrent idiopathic VTE [5], bilateral DVT [8], upper-extremity DVT [9] or increased D-dimer levels at presentation [10] have an increased risk for hidden cancer. Besides, there is some controversy over the role of patient’s age, with some reports finding occult cancer most commonly in the younger, others in the elderly. A large study is warranted in which all these findings might be validated. Secondly, although intuitively a search for occult malignancy is attractive, there is no evidence that such an approach identifies all occult malignancies and ultimately affects the course of the disease. The mere knowledge of the presence of a substantial risk for occult cancer has led to the common practice of performing at least some extra tests in the attempt to identify occult malignancies in addition to the standard clinical evaluation. In a prospective observational study, we demonstrated that in patients with acute VTE a routine clinical evaluation results in the identification of approximately half of the patients who harbor an undiagnosed malignancy at the time of the thrombotic event [6]. A further limited diagnostic work-up, including abdominopelvic ultrasound and tumor markers, identified a malignancy in an additional number of patients. However, follow-up revealed that approximately half of the remaining patients with occult malignancies were missed. Up to now, the only randomized trial comparing extensive screening vs. no screening in patients with idiopathic VTE has demonstrated that most cancers are potentially diagnosable at presentation [7]. However, a study including ultrasound and computed tomography of the abdomen and pelvis, stool guaiac examination, gastroscopy, colonoscopy, sputum cytology, mammography, and measurement of tumor markers is unlikely to be cost-effective. In this issue of the Journal, Di Nisio et al. [11] provide some evidence that some screening strategies may be cost-effective, comparing the total costs of a number of screening strategies, and the expected Live Years Gained with each of them. This is a useful study that has the limits of the original study (mainly, the small number of patients and the unknown life expectancy in patients with concurrent cancer and VTE), as acknowledged by the authors. Finally, there is no evidence to date that routine cancer screening would improve the prognosis of these patients. Any benefit associated with an extensive strategy of investigation should be considered in conjunction with the potential for

Increased bone resorption and failure to respond to antiresorptive therapy in progressive dystrophic calcification.

The aim of this study was to evaluate strategies to halt the progression of severe dystrophic calcification in a patient with progressive systemic sclerosis (PSS) and to monitor serial changes in biochemical markers of bone resorption and indices of calcium (Ca) metabolism in response to therapy. The relationship of bone turnover to the extent of dystrophic calcification was also investigated in a number of additional patients with varying degrees of calcinosis. Serial markers of bone turnover and indices of Ca metabolism were measured over a 3-year period in one patient with PSS and severe dystrophic calcification. Bone mineral density (BMD) was assessed by dual-energy x-ray absorptiometry (DXA). Bone turnover in this patient and two additional patients with PSS or dermatomyositis (DM) and severe dystrophic calcification (Group A, n = 3) was compared with that in patients with connective tissue disease with little or no evidence of dystrophic calcification (Group B, n = 13). Serial data on one patient with severe progressive calcinosis showed increased bone resorption markers, which remained high over a 3-year period despite antiresorptive therapy. BMD was low. Patients with PSS/DM with severe dystrophic calcification had higher bone resorption than those with minimal or no evidence of calcification. Mean serum ionized Ca and urinary Ca excretion were both lower in those with severe calcinosis. Bone resorption was increased in patients with connective tissue disease and severe dystrophic calcification. Several antiresorptive agents were shown to be ineffective in limiting either bone turnover or clinical progression in one patient.

Late Thrombosis After Radiation

Five years after Condado et al1 first treated human coronary arteries with brachytherapy, there is ongoing clinical investigation into its safety and efficacy in preventing restenosis. As with any novel technique, unexpected complications may dampen early high expectations and result in pessimism and skepticism. However, time, experience, and complete data analysis will determine the reality. Costa and coworkers2 may be reacting prematurely by reporting a new phenomenon in interventional cardiology entitled “late, sudden thrombosis after PTCA plus radiotherapy.” They report 6 (6.6%) of 91 patients who presented with late total occlusion/thrombosis at angiographic follow-up; these patients were enrolled into different radiation protocols using different β-emitters at different prescribed doses. Late total occlusion or late thrombosis is a valid concern, especially when associated with acute myocardial infarction (MI). However, can we really draw any conclusion from 6 heterogeneous case reports taken from a small cohort of patients in the absence of a control group? Is this announcement based on too few data, and is it premature? An editorial based on a Brief Rapid Communication mandates the editorialist to gather additional information, disclose his own insights, and provide the readers (the jury in this case) with as much information as possible. Acute thrombosis occurs during or early after intervention, and subacute thrombosis occurs within the subsequent 30 days. Both usually present with unstable symptoms and angiographic evidence of thrombus. However, the definition of late thrombosis may be problematic. It may not present with symptoms. It may be detected only when follow-up angiography shows a late total occlusion, which could also be the result of progressive intimal hyperplasia. Late total occlusion/thrombosis should be defined as any angiographically documented total occlusion >30 days after the procedure. For patients who have a patent treatment site at 6 months and subsequently develop a total …