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Controversy exists regarding the use of dose capping of weight-based unfractionated heparin (UFH) infusions in obese and morbidly obese patients. The primary objective of this study was to compare time to first therapeutic activated partial thromboplastin time (aPTT) in hospitalized patients receiving UFH for acute venous thromboembolism (VTE) among three body mass index (BMI) cohorts: non-obese (< 30 kg/m2), obese (30–39.9 kg/m2), and morbidly obese (⩾ 40 kg/m2). In this single-center, retrospective cohort study, patients were included if they ⩾ 18 years of age, had a documented VTE, and were on an infusion of UFH for at least 24 hours. Weight-based UFH doses were calculated using actual body weight. A total of 423 patients met the inclusion criteria, with 230 (54.4%), 146 (34.5%), and 47 (11.1%) patients in the non-obese, obese, and morbidly obese cohorts, respectively. Median times to therapeutic aPTT were 16.4, 16.6, and 17.1 hours in each cohort. Within 24 hours, the cumulative incidence rates for therapeutic aPTT were 70.7% for the non-obese group, 69.9% for the obese group, and 61.7% for the morbidly obese group (obese vs non-obese: HR = 1.02, 95% CI: 0.82–1.26, p = 0.88; morbidly obese vs non-obese: HR = 0.87, 95% CI: 0.62–1.21, p = 0.41). There was no significant difference in major bleeding events between BMI groups (obese vs non-obese, p = 0.91; morbidly obese vs non-obese, p = 0.98). Based on our study, heparin dosing based on actual body weight without a dose cap is safe and effective.

Excessive perioperative fluid administration likely increases postoperative cardiovascular, infectious, and GI complications. Early administration of diuretics after elective surgery facilitates rapid mobilization of excess fluid, potentially leading to decreased bowel edema, more rapid return of bowel function, and reduced length of hospital stay.This study aimed to evaluate the benefit of early diuresis after elective colon and rectal surgery in the setting of an enhanced recovery after surgery practice.This was a prospective study.The study was conducted at a quaternary referral center.A randomized, open-label, parallel-group trial was conducted in patients undergoing elective colon and rectal surgery at a single quaternary referral center.The primary intervention was administration of intravenous furosemide plus enhanced recovery after surgery on postoperative day 1 and 2 versus enhanced recovery after surgery alone.The primary outcome was length of hospital stay. Secondary outcomes included 30-day readmission rate, time to stool output during hospitalization after surgery, and incidence of various complications within the first 48 hours of hospital stay.In total, 123 patients were randomly assigned to receive either furosemide plus enhanced recovery after surgery (n = 62) or enhanced recovery after surgery alone (n = 61). Groups were evenly matched at baseline. At interim analysis, length of hospital stay was not superior in the intervention group (80.6 vs 99.6 hours, p = 0.564). No significant difference was identified in the rates of nasogastric tube replacement (1.6% vs 9.7%, p = 0.125). Time to return of bowel function was significantly longer in the intervention group (45.4 vs 48.8 hours, p = 0.048). The decision was made to end the study early because the conditional power of the study favored futility.This was a single-center study.Early administration of furosemide does not significantly reduce the length of hospital stay after elective colon and rectal surgery in the setting of enhanced recovery after surgery practice. See Video Abstract at http://links.lww.com/DCR/A714.

Potent platelet inhibition is one of the most important medical interventions to prevent ischemic complications during and after percutaneous coronary intervention (PCI). Practice has evolved with the introduction of potent oral P2Y12 inhibitors that provide quick, effective platelet inhibition, and the need for routine glycoprotein IIb/IIIa inhibitors (GPIs) has decreased. Additionally, a shorter duration of GPI infusion has been shown to be safe with adequate oral antiplatelet loading, but clinical outcome data are limited to eptifibatide. This single-center, retrospective cohort study analyzed in-hospital outcomes for patients who received adjunctive GPI therapy for PCI before and after an institution-wide switch to high-dose bolus tirofiban with shortened infusion from short-duration eptifibatide. The primary end point was a composite in-hospital outcome of major and minor bleeding and cardiovascular events (death, myocardial infarction, coronary artery bypass grafting, ischemic stroke, and target vessel revascularization). Secondary end points included bleeding and cardiovascular event types. A total of 357 and 446 patients received eptifibatide and tirofiban, respectively, from February 1, 2014 through September 30, 2017. Thirty five eptifibatide and 46 tirofiban patients experienced an in-hospital composite event (9.8% vs 10.3%, p = 0.81). There was no difference found between in-hospital bleeding (6.4% vs 5.4%, p = 0.52) or cardiovascular events (5.6% vs 6.5%, p = 0.60) with the use of eptifibatide or tirofiban, respectively. Multivariable analysis showed that patients with transradial access or an indication of unstable angina were less likely to experience an in-hospital composite event (OR 0.30 and 0.19, respectively, p

This paper describes a rapid, high-throughput flow-through membrane immunoassay (FMIA) platform. A nitrocellulose membrane was spotted in an array format with multiple capture and control reagents for each sample detection area, and assay steps were carried out by sequential aspiration of sample and reagents through each detection area using a 96-well vacuum manifold. The FMIA provides an alternate assay format with several advantages over ELISA. The high surface area of the membrane permits high label concentration using gold labels, and the small pores and vacuum control provide rapid diffusion to reduce total assay time to ~30 min. All reagents used in the FMIA are compatible with dry storage without refrigeration. The results appear as colored spots on the membrane that can be quantified using a flatbed scanner. We demonstrate the platform for detection of IgM specific to lipopolysaccharides (LPS) derived from Salmonella Typhi. The FMIA format provides analytical results comparable to ELISA in less time, provides integrated assay controls, and allows compensation for specimen-to-specimen variability in background, which is a particular challenge for IgM assays.

Purpose: Radioimmunotherapy has been approved for relapsed follicular lymphoma (FL), including rituximab-refractory FL. This study was designed to determine the CR rate with short-course chemoimmunotherapy with cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (CHOP-R) followed by 90-Y ibritumomab tiuxetan (RIT) with extended rituximab as first-line treatment. Experimental Design: Between March 2004 and February 2007, 60 patients with stage II to IV symptomatic or bulky FL from a single institution supported by a large community network entered this phase II trial. Patients received CHOP-R for three treatment cycles before RIT followed by four additional weekly treatments with rituximab. Response was determined using fusion [18 F] fluorodeoxyglucose-positron emission tomography (PET)-computed tomography (CT) imaging. Results: Of the 60 patients entering this trial, 55 patients completed all protocol therapy. The median follow up was 19.7 months (range, 0.26-35.9 months). For intent-to-treat analysis, the complete response (CR) rate after CHOP-R, as assessed by CT and PET imaging, was 40% and 46%, respectively. After RIT, the CR rate improved, as assessed by CT and PET imaging, to 82% and 89%, respectively. Ten patients have progressed, including eight from best response of CR. Seven of 18 patients who were PET positive after CHOP-R progressed compared with 3 of 37 patients who were PET negative (P = 0.010). Conclusions: In patients with previously untreated, symptomatic or bulky FL, short-course chemoimmunotherapy and consolidation RIT and extended rituximab resulted in a high CR rate. Failure to achieve an early PET CR after CHOP-R indicated high risk of relapse.

In resource-limited settings, the lack of decentralized molecular diagnostic testing and sparse access to centralized medical facilities can present a critical barrier to timely diagnosis, treatment, and subsequent control and elimination of infectious diseases. Isothermal nucleic acid amplification methods, including reverse transcription loop-mediated isothermal amplification (RT-LAMP), are well-suited for decentralized point-of-care molecular testing in minimal infrastructure laboratories since they significantly reduce the complexity of equipment and power requirements. Despite reduced complexity, however, there is still a need for a constant heat source to enable isothermal nucleic acid amplification. This requirement poses significant challenges for laboratories in developing countries where electricity is often unreliable or unavailable. To address this need, we previously developed a low-cost, electricity-free heater using an exothermic reaction thermally coupled with a phase change material. This heater achieved acceptable performance, but exhibited considerable variability. Furthermore, as an enabling technology, the heater was an incomplete diagnostic solution. Here we describe a more precise, affordable, and robust heater design with thermal standard deviation

Epidemiologic and experimental data support a role for 1,25-dihydroxyvitamin D(3) in the growth regulation of prostate cancer. We conducted a phase II clinical trial evaluating calcitriol (1,25(OH)(2)D(3)) in patients with hormone refractory prostate cancer. We enrolled 14 patients in this study. 1,25(OH)(2)D(3) was initiated at a daily oral dose of 0.5 μg and escalated to 1.5 μg daily. No objective responses were observed. However, in two patients decreases of 25% and 45% in prostate specific antigen levels were seen. Hypercalcemia was the predominant toxicity. We conclude that 1,25(OH)(2)D(3) given in this manner is inactive in advanced prostate cancer. Dose escalation of oral 1,25(OH)(2)D(3) is limited by hypercalcemia.

In many low resource settings multiple diseases are endemic. There is a need for appropriate multi-analyte diagnostics capable of differentiating between diseases that cause similar clinical symptoms. The work presented here was part of a larger effort to develop a microfluidic point-of-care system, the DxBox, for sample-to-result differential diagnosis of infections that present with high rapid-onset fever. Here we describe a platform that detects disease-specific antigens and IgM antibodies. The disposable microfluidic cards are based on a flow-through membrane immunoassay carried out on porous nitrocellulose, which provides rapid diffusion for short assay times and a high surface area for visual detection of colored assay spots. Fluid motion and on-card valves were driven by a pneumatic system and we present designs for using pneumatic control to carry out assay functions. Pneumatic actuation, while having the potential advantage of inexpensive and robust hardware, introduced bubbles that interfered with fluidic control and affected assay results. The cards performed all sample preparation steps including plasma filtration from whole blood, sample and reagent aliquoting for the two parallel assays, sample dilution, and IgG removal for the IgM assays. We demonstrated the system for detection of the malarial pfHRPII antigen (spiked) and IgM antibodies to Salmonella Typhi LPS (patient plasma samples). All reagents were stored on card in dry form; only the sample and buffer were required to run the tests. Here we detail the development of this platform and discuss its strengths and weaknesses.

We describe a technology, the NanoString nCounter gene expression system, which captures and counts individual mRNA transcripts. Advantages over existing platforms include direct measurement of mRNA expression levels without enzymatic reactions or bias, sensitivity coupled with high multiplex capability, and digital readout. Experiments performed on 509 human genes yielded a replicate correlation coefficient of 0.999, a detection limit between 0.1 fM and 0.5 fM, and a linear dynamic range of over 500-fold. Comparison of the NanoString nCounter gene expression system with microarrays and TaqMan PCR demonstrated that the nCounter system is more sensitive than microarrays and similar in sensitivity to real-time PCR. Finally, a comparison of transcript levels for 21 genes across seven samples measured by the nCounter system and SYBR Green real-time PCR demonstrated similar patterns of gene expression at all transcript levels.

This retrospective study evaluates the efficacy of megestrol acetate in patients with hormone refractory metastatic adenocarcinoma of the prostate. Data are presented from 14 patients with advanced prostatic adenocarcinoma who were treated with 160-320 mg of megestrol acetate daily. Each patient was either asymptomatic or had minimal cancer-related symptoms. Disease response was monitored by prostate-specific antigen levels. The response rate was 14%, with two patients having a partial response. No complete responses were observed. The median time to disease progression was 2 months. Our findings when considered together with results from previously published data demonstrate little activity of megestrol acetate in patients with hormone refractory prostate cancer. Therefore, we cannot recommend megestrol acetate as an effective second-line therapy.

Approximately 200,000 men will be diagnosed with prostate cancer in 1994. While localized disease is potentially curable with surgery or radiation therapy, metastatic disease is incurable. The most frequent site of metastasis is bone. Spinal cord compression occurs in approximately 7% of men with prostate cancer. Back pain often heralds the diagnosis of spinal cord compression. In prostate cancer patients with back pain or signs of myelopathy or radiculopathy, plain radiographs of the spine and magnetic resonance imaging should be performed. Early diagnosis is of utmost importance. The neurologic status prior to treatment is the major determinant influencing outcome. Following diagnosis, corticosteroid therapy should begin immediately. Hormonal therapy should be instituted in those patients who have not previously undergone hormonal manipulation. The standard approach to definitive therapy is radiation. Surgical decompression plays a role in patients with severe myelopathy, spinal instability, and in those patients whose neurologic status deteriorates during or after radiation therapy.

Abstract 4142 Introduction: High dose chemotherapy combined with autologous stem cell transplantation (ASCT) as opposed to conventional chemotherapy improved progression free survival (PFS) and overall survival (OS) in multiple myeloma (MM) and is currently the standard of care for newly diagnosed MM patients less than 65 years old. Over the last decade, novel agents such as lenalidomide or bortezomib have dramatically improved MM outcomes with similar response rates as ASCT and the role of upfront ASCT has become more controversial. Therefore the goal of this randomized clinical trial is to determine the role of upfront ASCT in newly diagnosed myeloma patients receiving novel agent lenalidomide and low-dose dexamethasone induction. Methods: Patients aged ≥18 years with newly confirmed, measurable MM in stage 2 and 3 (Salmon Durie) and meeting CRAB criteria were enrolled. Patients were randomized to transplant (Arm A) or to non-transplant (Arm B). Patients in Arm A received 4 cycles of lenalidomide (25mg days 1 – 21) plus low-dose dexamethasone (40mg days 1,8,15,22) followed by ASCT conditioned with 200 mg/m2 melphalan (LD+ASCT); Arm B patients received 8 cycles of lenalidomide plus low-dose dexamethasone (LD alone). Both arms received stem cell collection after 4 cycles of therapy if patients achieved at least a partial remission (PR). Patients with stable disease (SD) or progressive disease (PD) went off study. The primary objective was to compare best response. The secondary endpoints included duration of response (DOR), progression free survival (PFS), overall survival (OS) and evaluation of secondary malignancies in both arms. Results: From February 2008 to May 2011, 44 patients with newly diagnosed MM were randomized. The patient characteristics were as follow: median age of the patients was 61.7 years (range 48∼75), 45.5% female and 55.5% male patients, ISS stage I 31%, II 51% and III 18%. 40 patients were eligible for evaluation and 20 patients were randomized to Arm A or Arm B, respectively. The data were analyzed according to latest IMWG response criteria (Blood. 2011 May 5;117(18):4691–5). In an intention to treat analysis, patients in Arm A (LD + ASCT), achieved a 100% Overall Response Rate (ORR) with 40% PR (n=8) and 60% Very Good Partial Response (VGPR) (n=12). In Arm B (LD only) the ORR was 75% (n=15), including 15% CR (n=3), 35% VGPR (n=7), 25% PR (n=5), 20% SD (n=4) and 5% PD (n=1). The ORR was significantly superior in the LD+ASCT group compared to LD alone (p=0.047). After a median follow-up of 25.3 months, 17 patients have PD (8 in LD+ASCT and 9 in LD alone), 6 have died (1 in LD+ASCT and 5 in LD alone). DOR, PFS and OS were not significantly different in both groups. OS showed a trend to be superior in patients treated with LD+ASCT (p=0.08). (Table 1). One patient in the LD+ASCT arm developed MDS 13 months after start of therapy. Conclusion: Our interim analysis of an ongoing clinical study suggests that treatment of newly diagnosed MM patients with lenalidomide plus low-dose dexamethasone induction followed by upfront ASCT resulted in significantly improved ORR. There was no difference in terms of DOR or PFS with a trend of superior OS in the LD+ASCT group. The study requires careful interpretation based on the low patient number and relatively short follow up, but supports the continued role of upfront consolidative ASCT in newly diagnosed MM patients. The incidence of secondary malignancy was low with the development of 1 MDS. Updated data on response and overall survival will be available at the time of presentation. Disclosures: Roodman: Amgen: Consultancy; Millennium Pharmaceuticals: Consultancy. Raptis:Millennium: Speakers Bureau; Celgene Corp: Speakers Bureau; Eisai: Speakers Bureau. Lentzsch:Celgene Corp: Consultancy, Research Funding; Onyx: Consultancy; Genzyme: Consultancy; prIME Oncology: Honoraria; Imedex: Honoraria; Clinical Care Options: Honoraria.

Nat. Biotechnol. 26, 317–325 (2008); published online 17 February 2008, corrected after print 16 May 2008 In the version of this article initially published, the list of authors omitted the final author, Krassen Dimitrov, and should have read as follows: Gary K Geiss1, Roger E Bumgarner2, Brian Birditt1, Timothy Dahl1, Naeem Dowidar1, Dwayne L Dunaway1, H Perry Fell1, Sean Ferree1, Renee D George1,5, Tammy Grogan1, Jeffrey J James1, Malini Maysuria1, Jeffrey D Mitton1, Paola Oliveri3,5, Jennifer L Osborn1,5, Tao Peng2, Amber L Ratcliffe1, Philippa J Webster1, Eric H Davidson3, Leroy Hood4 & Krassen Dimitrov4,5

8005 Background: Therapy with CHOP-R and radioimmunotherapy (RIT) is a promising treatment for untreated FL. Press reports complete responses (CR) of 69% in FL patients (pts.) with 6 cycles of CHOP followed by I-131 tositumomab. We report efficacy and safety using 3 cycles of CHOP-R followed by IT and extended R. Methods: Eligibility criteria include symptomatic or grade 3 untreated FL. 60 pts. have been accrued and 47 evaluated. The treatment consists of two phases: CHOP-R for 3 cycles followed by IT. One week after IT, pts receive R weekly × 4. Bone marrow (BM) biopsies and fusion PET-CT scans are obtained at baseline, after CHOP-R, and 12 weeks post RIT. The primary endpoint is CR rate. CR requires a neg. PET scan and conventional Working Group criteria. Results: Toxicity data are available for 47 pts of median age 56 (range, 39–78), 44 of whom completed both phases of therapy and are evaluated for response. Characteristics and CR rates after IT are shown: 3 pts. did not receive RIT (1 second malignancy, 1 non-compliance, 1 septic death). Of the 44, CR after CHOP-R is 41%. After IT, CR improved to 89%. Of the 5 pts who did not achieve CR, 3 had neg. PET scans (2 with PR, 1 with SD by CT), and 2 had residual disease by PET with PR by CT. At a mean follow-up of 16 months (range, 6–33 months), there are 4 relapses: 3 who achieved CR by PET-CT, 1 with PR by PET-CT. Toxicity was predominantly myelosuppression. There was 1 episode of febrile neutropenia after RIT. Conclusions: 3 cycles of CHOP-R followed by IT and R achieve a high CR in previously-untreated pts. with FL. Addition of RIT increased CR from 41% to 89%. Data will be presented on the affect of bulky disease, positive BM, grade 2 or 3 histology, and high FLIPI score on CR. Further follow-up is necessary to evaluate response duration and determine whether there is a correlation with early or late CR. [Table: see text] [Table: see text]

7589 Background: There has been some question regarding the predictive value of 111In scans in FL. We report imaging results with fusion PET-CT scans and 111In scans in a single-institution, non-randomized, phase II trial in patients with FL treated with CHOP-R followed by 90Y ibritumomab tiuxetan (Zevalin (Z)) and R. Methods: Eligible patients have CD20 positive FL, Grade 1–3 or transformed, Stage II-IV, no prior treatment with monoclonal antibody or chemotherapy, and symptomatic disease (if grade 1–2). CHOP-R is given every 21 days for 3 cycles. Four weeks after the last dose of CHOP-R, patients receive the Zevalin regimen, which includes 111In imaging and 90Y therapy. One week after Z, patients receive R 375 mg/m2 IV weekly for 4 doses. Bone marrow examination and fusion PET-CT scans are performed at baseline, after CHOP-R, and 12 weeks after Z. The primary endpoint is CR, and responses are reported using the International Working Group (IWG) criteria with the additional requirement of a negative PET scan for CR/CRu. Results: Thirty-six FL patients have been accrued, and 16 patients have completed therapy and follow-up studies. One patient did not have a positive PET scan at baseline. Following therapy, the proportion with a negative PET scan improved from 8 of 15 (53.3%) after CHOP-R to 15 of 15 (100%) after Z. Using IWG criteria in combination with PET scan results, the CR rate increased from 4 of 15 (26.7%) after CHOP-R to 12 of 15 (80%) after Z. Five of 6 patients (83%) with tumor uptake by 111In scan and 7 of 9 (78%) with a 111In scan negative for tumor achieved a CR. Conclusions: There was no significant difference in CR between those patients with 111In tumor uptake versus patients with a negative 111In scan. Functional imaging with PET-CT may be a more sensitive method than CT alone in determining residual disease in FL. This trial continues to accrue patients, and more time is needed to determine the duration of response and time to next therapy. No significant financial relationships to disclose.

Background: CHOP-rituximab (CHOP-R) and radioimmunotherapy (RIT) have demonstrated efficacy in the treatment of follicular NHL. The combination of these agents as initial therapy is a novel strategy which has been previously reported with promising results (Hainsworth et al. Proc ASCO.2005;23,Abstract 6577). We report the safety and efficacy of this approach in a single-institution, non-randomized, phase II trial with abbreviated CHOP-R followed by Zevalin and rituximab. The rationale for following Zevalin with additional rituximab includes the potential beneficial effect of extended therapy and the possible vaccinal effect (Cartron et al. Blood.2004;104,2635). Methods: Eligible patients have CD20 positive follicular NHL, Grade 1–3, Stage II-IV, no prior treatment with monoclonal antibody or chemotherapy, and symptomatic disease. CHOP-R is first given in standard doses every 21 days for 3 cycles. Four weeks after the last dose of CHOP-R, patients receive the Zevalin regimen. One week after the therapeutic Zevalin dose, patients receive rituximab 375 mg/m2 IV weekly for 4 doses. Bone marrow examination and fusion PET-CT scans were performed at baseline, after CHOP-R, and 12 weeks after RIT. For this study, a complete remission required both functional imaging with positron emission tomography (PET) scanning showing no areas of FDG-avidity and the International Working Group criteria including CT scanning. Results: At the planned interim analysis after accrual of 19 patients, 8 patients have completed therapy and follow-up studies and are fully evaluable. For these 8 patients with follicular NHL, two were Grade 1, three were Grade 2, and three were Grade 3. Half had Stage III disease and half had Stage IV. The median age was 59 (range 45–77). Two patients had a FLIPI score of 1 (low risk), four patients had a score of 2 (intermediate risk), and two patients had a score of 3 (poor risk). The overall response rate after 3 cycles of CHOP-R was 75% with a CR in 2 of these 8 patients (25%). After treatment with Zevalin and rituximab, 7 of 8 (87.5%) achieved a CR (CR/CRu with negative PET scan). During treatment with CHOP-R, 2 patients had Grade 3/4 neutropenia, and 1 patient had Grade 4 hyperglycemia. After treatment with Zevalin, 4 patients developed Grade 3/4 thrombocytopenia, and 4 patients developed Grade 3/4 neutropenia. During the Zevalin phase, there were no episodes of neutropenic fever. Conclusions: Three cycles of CHOP-R followed by Zevalin and rituximab is effective in inducing a CR (CR/CRu) in previously-untreated patients with follicular NHL, decreases exposure to anthracyclines, and is a promising regimen for initial therapy. In this trial, the CR rate of 25% after CHOP-R increased to 87.5% after treatment with Zevalin and rituximab. Functional imaging with fusion PET-CT may be a more sensitive technique than CT scanning in determining residual tumor. This trial continues to accrue patients, and additional time is needed to determine the duration of response and time to next therapy.

Background: Measurement of serum prostate-specific antigen (PSA) and digital rectal examination (DRE) are commonly used for prostate cancer screening. Clinicians have been advised to avoid measuring serum PSA after DRE because of the possibility of spurious elevation. However, studies in healthy volunteers have found no change. We sought to determine whether DRE performed by internists affects PSA levels in a primary care clinic population. Methods: Men older than 49 years enrolled in a Veterans Affairs internal medicine clinic were eligible for the study. For all patients, prostate size and nodularity were assessed by DRE. Blood for determination of PSA levels was drawn immediately before DRE and 30 minutes after DRE. All patients completed a questionnaire regarding voiding. Results: Two hundred two men aged 50 to 85 years (mean, 67 years) were enrolled and had complete data. The mean PSA level increased by 0.26 μg/L after DRE (P Conclusions: We conclude, in an elderly veteran population, that DRE causes a statistically significant but clinically insignificant increase in serum PSA level. Additionally, we found that symptoms and physical examination results cannot be used to select a population for whom PSA screening would likely be useful. (Arch Intern Med. 1995;155:389-392)