Primary Response Criteria Research Articles

Double reading performance and the impact of adjudication on progression-free survival estimations: Findings from a lung clinical trial.

e23010 Background: The FDA recommends Blinded Independent Central Review (BICR) with double read for clinical trials with imaging. However, inter-reader variability is a concern in these trials. While studies have investigated the variability of RECIST, the primary response criteria, little attention has been given to the optimal association of readers. The evaluation of therapeutic response in phase III trials relies on the Date of first Progressive Disease (DoPD), with the Discrepancy Rate (DR) as the preferred index for measuring inter-reader variability in DoPD evaluation. Another important index measures readers' bias, assessing their tendency to over or under-estimate diagnoses. In cases of discrepancies, a third reader is brought in for adjudication. However, the impact of adjudication on trials' Progression-Free Survival (PFS) is not well-documented. Our study examines the variability in a lung clinical trial using RECIST, analyzing double reading performance, reader association prediction, and the impact of adjudication on PFS estimations. Methods: We retrospectively analyzed five phase III lung clinical trials using the RECIST 1.1 criteria in BICR with double reads. The trials involved 7 readers organized into 11 teams, each reader having participated in multiple trials and performed over 50 reads, resulting in 1017 patients' reviews. Our analysis included: Calculation of DR and bias for each team, and testing the correlation between DR and bias. Computation of the signed bias for each individual reader. Evaluation of a probabilistic model to predict the DR for each team and the bias for each reader. Comparison of PFS between single and double reads after adjudication and endorsement of one of the readings. Results: A multiple comparisons test did not reveal any difference between teams’ DR (Marascuilo test; q > 0.05). The average DR across all teams was 39.9% [95%CI; 37.8; 41.9]. However, we did find significant differences in bias when comparing 9/55 pairs of teams (Marascuilo test; q < 0.05). The range of absolute bias values was 20% to 100%. We did not find a correlation between bias and DR (p = 0.64). Additionally, when comparing the average bias value per reader, no differences were observed (Marascuilo test; q < 0.05). We failed to predict teams DR and readers' bias. The endorsement rate of readers ranged [18%; 82%]. After adjudication, we found that 27% of the PFS were lower than the minimum value obtained from the single readers, in one case 20.6% shorter. Conclusions: Significant readers' bias has a notable impact on double readings, independent of the DR values. The performance of one reader cannot be generalized based on others. Additionally, adjudication significantly affects the PFS of clinical trials. These findings emphasize the importance of considering readers' bias and the potential consequences of adjudication in clinical trial assessments.

Roux-en-Y Gastric Bypass in Patients with Super Obesity: Primary Response Criteria and Their Relationship with Comorbidities Remission.

The prevalence of super obesity has increased considerably in recent years, representing up to the 0.5% of the population. Even though bariatric surgery induces significant weight loss in these patients, it has been reported that up to 50% of the patients with super obesity will fail according to the current primary response criteria. To evaluate and compare different primary response criteria and their impact regarding comorbidities remission. A total of 104 patients with super obesity who underwent Roux-en-Y gastric bypass (RYGB) were identified in our institution from March 2004 to February 2019. An evaluation of the primary response at a 2-year follow-up was made using different criteria. A multivariate analysis was made to evaluate related variables to comorbidities remission. Two years later, the rate of patients who achieved an EWL > 50%, %EWL > 70%, and BMI < 35kg/m2 were 84.5%, 52.1%, and 62%, respectively. Regarding the comorbidities, 85%, 84.8%, and 81.1% of the patients improved or remitted T2D, HBP, and hyperlipidemia, respectively. An EWL > 50% 2years later was related to complete remission of hyperlipidemia (p = 0.047), whereas weight regain above 10% is a risk factor for failure of complete remission of HBP in 3years. More than 75% of patients with super obesity yield an EWL > 50% 2years later. In terms of hyperlipidemia, it is desirable to achieve an EWL of at least 50%. Whereas for T2D and HBP, a minimum of 25% TWL yields 72% and 60.5% of complete remission.

Relative bioavailability of guanidinoacetic acid delivered ruminally or abomasally to cattle.

This study assessed the relative bioavailability of guanidinoacetic acid (GAA) in cattle. Seven ruminally cannulated Holstein steers (initial body weight of 280 kg) were used in an experiment with a 5 × 5 Latin square design; the two additional steers received a treatment sequence identical to two steers in the Latin square. Treatments were: control (no GAA, water infusion), ruminal infusion of 10 or 20 g/d GAA, and abomasal infusion of 10 or 20 g/d GAA, with all infusions delivered continuously. Periods were 7 d in length, and on day 7, blood and urine samples were collected to determine the concentrations of GAA and its associated metabolites. Plasma creatine concentrations increased linearly (P < 0.01) with GAA infusion to the abomasum and tended to increase linearly (P = 0.06) when GAA was infused ruminally. Urinary creatine concentrations increased linearly with increasing amounts of GAA infused in the abomasum (P < 0.01) and the rumen (P < 0.05). There were no significant effects of GAA infusion to either the abomasum or rumen on plasma or urinary concentrations of GAA. Plasma creatinine concentrations were not affected by GAA infusion to the abomasum or rumen. Urinary creatinine concentrations decreased when GAA was infused abomasally (P < 0.05). Because plasma and urinary creatine concentrations yielded the statistically strongest linear responses, they were selected as the primary response criteria for quantifying ruminal escape of GAA. Calculated by slope-ratio methodology, estimates for the ruminal escape of GAA based on plasma creatine and urinary creatine concentrations were 47% and 49%, respectively. Ruminally infused GAA was about half as effective as abomasally infused GAA in elevating plasma and urinary concentrations of creatine.

Whole Tumor Histogram Analysis Using DW MRI in Primary Central Nervous System Lymphoma Correlates with Tumor Biomarkers and Outcome.

The ability to non-invasively predict outcomes and monitor treatment response in primary central nervous system lymphoma (PCNSL) is important as treatment regimens are constantly being trialed. The aim of this study was to assess the validity of using apparent diffusion coefficient (ADC) histogram values to predict Ki-67 expression, a tumor proliferation marker, and patient outcomes in PCNSL in both immunocompetent patients and patients living with HIV (PLWH). Qualitative PCNSL magnetic resonance imaging (MRI) characteristics from 93 patients (23 PLWH and 70 immunocompetent) were analyzed, and whole tumor segmentation was performed on the ADC maps. Quantitative histogram analyses of the segmentations were calculated. These measures were compared to PCNSL Ki-67 expression. Progression-free survival (PFS) and overall survival (OS) were analyzed via comparison to the International Primary Central Nervous System Lymphoma Collaboration Group Response Criteria. Associations between ADC measures and clinical outcomes were assessed using univariate and multivariate Cox proportional hazards models. Normalized ADC (nADC)Min, nADCMean, nADC1, nADC5, and nADC15 values were significantly associated with a poorer OS. nADCMax, nADCMean, nADC5, nADC15, nADC75, nADC95, nADC99 inversely correlated with Ki-67 expression. OS was also significantly associated with lesion hemorrhage. PFS was not significantly associated with ADC values but with lesion hemorrhage. ADC histogram values and related parameters can predict the degree of tumor proliferation and patient outcomes for primary central nervous system lymphoma patients and in both immunocompetent patients and patients living with HIV.

Can Body Mass Index Predict the Outcome of Diffuse Large B-Cell Lymphoma? - a Single-Center Retrospective Study in China

Body mass index (BMI), as a rough indicator of obesity, has been increasing over the years, along with a high incidence of cardiovascular disease and many malignancies, including diffuse large B-cell lymphoma (DLBCL). However, the predictive prognostic value of BMI at diagnosis for the outcome of DLBCL is controversial. So far, the reported study population has rarely been Chinese. We aimed to assess whether BMI can predict the outcome of Chinese DLBCL patients.We carried out a single-center retrospective study to assess the predictive value of BMI in the outcome of Chinese patients with DLBCL. Among a total of 207 patients who were newly diagnosed with DLBCL in our center between January 2008 and May 2015, 143 eligible patients were enrolled. These patients were stratified into two groups, 74 patients in the low BMI group (BMI<23.0kg/m2)and 69 patients in the high BMI group (BMI≥23.0kg/m2). We compared the baseline characteristics in the low and high BMI groups, and complete remission (CR), partial remission (PR) and progressive disease (PD) as primary response criteria in the two groups. Univariate and multivariate analyses were used to evaluate whether low or high BMI had an impact on progression-free survival (PFS) and overall survival (OS).Well-known influence factors including age, Ca125, B2-microglobulin, international prognostic index, B symptoms, Ann Arbor stage and the use of rituximab were similar between the two groups, while gender was not (P<0.023) but did not act as a risk factor. Besides, drug dose did not vary by BMI. No association between BMI and primary response was observed. Patients in the higher BMI group were inclined to have better OS (p=0.008), but we did not find an association between BMI and PFS (p=0.069).Higher BMI at diagnosis may predict a longer OS, especially for female patients but may not affect the outcome of primary response and PFS. Multi-center and prospective studies are warranted to see if this holds true for the general Chinese DLBCL population, and mechanistic investigations may lead to new treatment options. DisclosuresNo relevant conflicts of interest to declare.

Effects of dietary vitamin E concentration and source on sow, milk, and pig concentrations of α-tocopherol1,2

A total of 126 gilts and sows (PIC 1050) and their litters were used to determine the effects of dietary vitamin E concentration and source on sow plasma, milk, and pig concentrations of α-tocopherol. Additionally, we estimated the bioavailability of D-α-tocopheryl acetate (D-α-TAc) relative to DL-α-tocopheryl acetate (DL-α-TAc) when fed in diets containing dried distillers grains with solubles (DDGS). The 6 dietary treatments included DL-α-TAc at 44 and 66 mg/kg and D-α-TAc at 11, 22, 33, and 44 mg/kg. From breeding to d 69 of gestation, sows were fed 2.0 kg/d of a diet containing 40% DDGS, 0.30 mg/kg added Se, and no added vitamin E. Vitamin E treatments were fed from d 70 of gestation through weaning. Plasma was collected from sows on d 69 and 100 of gestation, at farrowing, and at weaning. Colostrum and milk samples were also collected. Plasma from 3 pigs per litter and heart and liver samples from 1 pig per litter were collected at weaning. Plasma, milk, and tissues from 6 litters per treatment were analyzed for α-tocopherol. Although tissue, plasma, and milk concentrations of α-tocopherol were the primary response criteria of interest, sow and litter performance were measured. As expected, treatment effects were not observed for lactation feed intake, sow BW, or backfat measurements. A trend (P = 0.085) for a treatment effect on average pig BW at weaning was detected, with pigs nursing sows fed 44 mg/kg DL-α-TAc weighing less because of a younger weaning age. No other differences in litter performance were observed. As D-α-TAc increased in the diet, sow plasma, colostrum, and milk, pig plasma, and pig heart concentrations of α-tocopherol increased (linear, P < 0.03). Sows fed diets with 44 mg/kg D-α-TAc had increased (P < 0.03) plasma and colostrum and pig plasma concentrations of α-tocopherol compared with sows fed 44 mg/kg of DL-α-TAc. Sows fed 66 mg/kg DL-α-TAc also had greater (P = 0.022) plasma α-tocopherol at weaning than sows fed 44 mg/kg DL-α-TAc. Bioavailability coefficients for D-α-TAc relative to DL-α-TAc ranged from 1.9 to 4.2 for sow and pig plasma α-tocopherol, 2.9 to 3.6 for colostrum α-tocopherol, 1.6 for milk α-tocopherol, and 1.7 to 2.0 for pig heart and liver α-tocopherol. Overall, this study indicates the bioavailability for D-α-TAc relative to DL-α-TAc varies depending on the response criteria but is greater than the standard potency value of 1.36.

Dextranomer in Stabilized Sodium Hyaluronate (Solesta®)

Dextranomer in stabilized sodium hyaluronate, hereafter referred to as dextranomer/hyaluronic acid, is a biocompatible bulking agent administered by submucosal injection. It is hypothesized to expand the submucosal layer of the proximal anal canal, thereby augmenting bowel control. Treatment with dextranomer/hyaluronic acid was associated with symptomatic improvements in adult patients with faecal incontinence participating in a randomized, double-blind, sham-controlled, multinational study and a noncomparative, multinational study. In the double-blind study, patients in the dextranomer/hyaluronic acid group met the primary efficacy objective in that a significantly higher proportion of patients responded to treatment (≥50% reduction from baseline in the number of incontinence episodes) at the 6-month post-treatment timepoint than in the sham group (two of three primary response criteria), with the durability of the treatment response (≥25% reduction from baseline in the number of incontinence episodes) confirmed at the 12-month post-treatment timepoint (third primary response criterion). For the most part, dextranomer/hyaluronic acid did not significantly differ from the sham treatment in terms of quality of life and various other symptomatic endpoints at 6 months post-treatment in the double-blind study, although there were significant improvements from baseline in various parameters, such as the mean number of incontinence-free days, the median number of incontinence episodes and mean Faecal Incontinence Quality of Life domain scores, at 12 months post-treatment. In general, dextranomer/hyaluronic acid was well tolerated for up to 18 months post-treatment, with the majority of treatment-related adverse events considered mild or moderate in intensity.

Soluble Tumor Necrosis Factor Receptor: Enbrel (Etanercept) for Subacute Pulmonary Dysfunction Following Allogeneic Stem Cell Transplantation

Subacute lung disease, manifested as either obstructive (OLD) or restrictive (RLD) lung dysfunction, is a common complication following allogeneic stem cell transplantation. In each case, therapeutic options are limited, morbidity remains high, and long-term survival is poor. Between 2001 and 2008, 34 patients with noninfectious, obstructive (25) or RLD restrictive lung dysfunction (nine) received etanercept (Enbrel®, Amgen Inc.) 0.4 mg/kg/dose, subcutaneously, twice weekly, for 4 (group A) or 12 weeks (group B). Corticosteroids (if present at study entry) were kept constant for the initial 4 weeks of therapy and then tapered as tolerated. Thirty-one of 34 (91%) subjects were evaluable for response, and 10 (32%) met primary response criteria. There was no difference in response based on the duration of treatment (29% group A versus 35% group B; P = .99), the presence of RLD or OLD (33% versus 32%; P = .73), or the severity of pulmonary disease at study onset. Estimated 5-year overall survival rates following therapy were 61% (95% confidence interval, 46%-80%) for all subjects and 90% (95% confidence level, 73%-100%) for the 10 who met the primary response criteria. Five-year survival estimates for subjects treated with RLD was 44%, compared with 67% for those treated for OLD (P = .19). Etanercept was well tolerated, with no bacteremia or viremia observed. Pathogens were noted on posttherapy bronchoalveolar lavage in two cases. These data support the development of expanded clinical trials to study etanercept as a therapeutic agent for subacute lung injury after allogeneic stem cell transplantation.

Agreement Is Poor Among Current Criteria Used to Define Response to Cardiac Resynchronization Therapy

Numerous criteria believed to define a positive response to cardiac resynchronization therapy have been used in the literature. No study has investigated agreement among these response criteria. We hypothesized that the agreement among the various response criteria would be poor. A literature search was conducted with the keywords "cardiac resynchronization" and "response." The 50 publications with the most citations were reviewed. After the exclusion of editorials and reviews, 17 different primary response criteria were identified from 26 relevant articles. The agreement among 15 of these 17 response criteria was assessed in 426 patients from the Predictors of Response to Cardiac Resynchronization Therapy (PROSPECT) study with Cohen's kappa-coefficient (2 response criteria were not calculable from PROSPECT data). The overall response rate ranged from 32% to 91% for the 15 response criteria. Ninety-nine percent of patients showed a positive response according to at least 1 of the 15 criteria, whereas 94% were classified as a nonresponder by at least 1 criterion. kappa-Values were calculated for all 105 possible comparisons among the 15 response criteria and classified into standard ranges: Poor agreement (kappa< or =0.4), moderate agreement (0.4<kappa<0.75), and strong agreement (kappa> or =0.75). Seventy-five percent of the comparisons showed poor agreement, 21% showed moderate agreement, and only 4% showed strong agreement. The 26 most-cited publications on predicting response to cardiac resynchronization therapy define response using 17 different criteria. Agreement between different methods to define response to cardiac resynchronization therapy is poor 75% of the time and strong only 4% of the time, which severely limits the ability to generalize results over multiple studies.

An Open-Label, Phase II Study Evaluating the Safety and Efficacy of PTK787/ZK222584 in Patients With Metastatic Neuroendocrine Tumors That Have Evidence of Progressive Disease or an Increase in Disease Related Syndrome Symptoms

Background: Vatalanib inhibits endothelial growth factor receptor (VEGFR) by binding to the intracellular kinase domain of all 3 VEGFRs. Neuroendocrine tumors (NETs) express VEGF receptors. Inhibiting VEGF with bevacizumab, sorafenib, and sunitinib reduced time to progression or tumor size in some NET patients (pts). To determine vatalanib's tolerability and efficacy in NET pts, a trial was performed. Methods: Eligibility criteria included NET pts with biopsy-proven metastatic disease and rising biomarkers on somatostatin analog therapy. Eligible pts had measurable lesions, a KPS > 60%, and normal hematologic, renal, and hepatic functions. A stable octreotide LAR dose, not exceeding 30 mg monthly, was required. Initial total daily dosing of vatalanib was 1,250 mg. Biochemical responses within a 90 day interval were the primary response criteria. Secondary endpoints included radiographic/scintigraphic scan changes and safety. Results: Twenty-four pts (12 males) were enrolled between 5/20/05 to 5/28/09. The median age (range) was 60.4 (25-74). Eighteen pts were evaluable for efficacy and safety. Four pts continue on therapy. One pt withdrew consent; 2 pts died of disease prior to first cycle initiation; 1 pt was allergic to vatalanib. Six pts required a 10-28 day discontinuation for rising SGOT/SGPT, alkaline phosphatase, G2 proteinuria, G2 headache, and G3 nausea/vomiting. Resumption of vatalanib at 1,000 mg daily was well tolerated in 2 pts and 750 mg in another. One pt developed carcinoid crisis with fever, flushing, and rising 5HIAA. Grade 1 nausea occurred in 15 pts with antiemetics required for 4 pts. A partial (> 50% decrease) biochemical response occurred in 4 pts. The observed radiographic and scintigraphic responses in 16 pts have shown progressive disease in 6 and stable/minimal response in 10 pts. Accrual continues. Conclusions: Vatalanib is well tolerated in most pts and results in a 24% biochemical partial response rate in NET pts with rising biochemical markers on somatostatin analog therapy.

Preclinical and clinical studies with the multi-kinase inhibitor CEP-701 as treatment for prostate cancer demonstrate the inadequacy of PSA response as a primary endpoint

PURPOSE: CEP-701 is a potent inhibitor of trk receptors that causes cell death in prostate cancer (PC) models. CEP-701 binds to serum proteins and a preprostatectomy study was performed to assess prostate tissue penetration and clinical response to CEP-701.METHODS: Growth assays and western blot analyses were performed to evaluate CEP-701 kinase inhibition. In a preprostatectomy study, patients received CEP-701 for five days prior to prostatectomy and prostate tissue analyzed for CEP-701 levels. A phase II dose escalation study was performed in patients with hormone refractory PC with rising PSA and no metastases. Endpoints included PSA response and safety.RESULTS: CEP-701 binds to serum proteins limiting tissue penetration. An oral dose of 40 mg bid of CEP-701 for five days produced levels of 219 ± 38 nM in prostate at time of prostatectomy. No patients in the Phase II study met the primary response criteria of > 50% PSA decline. 7/9 patients had increase in PSA slope on CEP-701 compared to PSA slope prestudy. 5/9 patients had a decrease in PSA levels after stopping CEP-701. Laboratory studies showed increased PSA production by CEP-701 growth arrested human PC cells in vitro and in vivo.CONCLUSIONS: Evaluation of PSA response is an inadequate indicator of response in CEP-701 treated PC patients. Therefore, the effectiveness of CEP-701 as treatment for prostate cancer has not been adequately tested. Based on a strong preclinical rationale, further clinical studies with CEP-701 using alternative endpoints are indicated.

Prospective, randomized, multicentre clinical trial on the use of interferon a 2a plus PUVA versus PUVA monotherapy in patients with cutaneous T-cell lymphoma, stages I and II

7541 To further define the role of IFN in combination with PUVA we conducted this prospective, randomized, multicentre clinical trial, in cooperation with 26 departments of dermatology in Germany and Switzerland, comparing the efficacy and tolerability of the combination of IFN alfa plus PUVA versus PUVA alone. IFN alfa 2a was administered at 9 Mill units three times a week s.c. in the combination arm, photochemotherapy was applied after oral intake of 8-methoxypsoralen (0.6 mg/kg body weight) five times a week during the first weeks, three times a week from weeks 5 to 23, and twice a week from weeks 24 to 48, with escalating doses, beginning with 0.25J/cm2. Of 124 patients randomized in this trial stages I and II, 50 were evaluable in the PUVA arm and 43 in the IFN plus PUVA arm in total 93 patients. Overall 75% of all patients showed a complete remission, 79% in the combination arm and 72% in the PUVA arm. The primary response criteria of this randomized trial protocol as a rate of complete remissions was therefore statistically non significant. However, the total dose of meladinine to reach best response was significantly lower in the combination arm, in the IFN arm only 74% of the meladinine dose and 57% of the UVA dose was necessary to reach a complete remission in comparison to the PUVA arm. The follow-up period was defined was defined on time to progression and documentation maximal 12 months after best response. The medium follow-up duration is 101 weeks, the medium value 123.7 weeks. The Kaplan-Meyer graph analysis showed a significant difference towards the progression-free interval of the IFN PUVA arm (log-rank test; p = 0.0398, 2-sided, Wilcoxen test p = 0.0465). The results are based on 55 documented progressions of 93 patients. The medium progression-free time for the whole group is 63 weeks, for the PUVA arm 53 weeks, and in the combination arm 113 weeks. Based on these findings, we conclude that IFN alfa 2a plus oral photochemotherapy induces a high remission rate with less UVA dose compared to PUVA alone and doubles the progression-free time of CTCL, stages I and II. IFN and PUVA will be the first-line treatment in early CTCL of the EORTC treatment guidelines. No significant financial relationships to disclose.

An Open-Label Study of Lamotrigine Adjunct or Monotherapy for the Treatment of Adolescents With Bipolar Depression

The treatment of pediatric bipolar depression has not been well studied. The authors wished to prospectively study the efficacy of lamotrigine as adjunctive or monotherapy in adolescents with bipolar disorder who were experiencing a depressive episode. This was an 8-week open-label trial of lamotrigine with 20 adolescents ages 12-17 years (mean age 15.8; 7 boys, 13 girls) with diagnoses of bipolar disorder I, II, or not otherwise specified, who were experiencing a depressive episode. Lamotrigine was begun at 12.5 to 25 mg/day. Primary response criteria was a 1 or a 2 on the Clinical Global Impression-Improvement at week 8. A secondary criterion was at least a 50% decrease in Children's Depression Rating Scale-Revised scores. Nineteen subjects completed the trial. The mean final dose was 131.6 mg/day. Seven subjects were taking other psychotropic medications. Sixteen subjects (84%) responded by primary criteria, and 12 (63%) responded to our secondary criteria. Eleven subjects (58%) were considered in remission at week 8. Young Mania Rating Scale and Overt Aggression Scale-Modified scores also decreased significantly during the trial. There was no significant weight change, rash, or other adverse effects during the trial. Adolescents with bipolar depression appeared to respond to lamotrigine treatment, whether as adjunctive therapy or monotherapy, with decreases in depression, mania, and aggression. Larger, placebo-controlled studies of lamotrigine are needed in this population.

Predictors of response to cardiac resynchronization therapy (PROSPECT)—study design

Cardiac resynchronization therapy (CRT) is currently indicated in patients with moderate to severe heart failure, a wide QRS complex and significant left ventricular dysfunction despite optimal medical therapy. Adoption of these criteria for CRT results in a favorable response in only two thirds of candidates. "Predictors of response to cardiac resynchronization therapy (PROSPECT)," a prospective, multicenter, nonrandomized study, aims to identify echocardiographic measures of dyssynchrony and evaluate their ability to predict response to CRT. PROSPECT will enroll approximately 300 patients in up to 75 centers in the United States, Asia, and Europe with clinical follow-up for 6 months. We will prospectively and individually test a variety of conventional echocardiographic and tissue Doppler imaging parameters against measures of clinical response. The primary response criteria are improvement in the heart failure Clinical Composite Score and left ventricular reverse remodeling. Enrollment began in March 2004 and is expected to conclude early 2005.

Effects of increasing lysine:calorie ratio in pigs grown in a commercial finishing environment (2002)

Seven experiments using 7,801 pigs (75 to 265 lb) were conducted to determine the biologic and economic effects of increasing dietary lysine in commercially reared grow-finish pigs. Each study was generally 28 d long and evaluated a different weight range of the grow-finish period for barrows (3 trials) and gilts (4 trials), respectively. All studies contained six dietary treatments of incrementally increasing lysine:calorie ratio. The primary response criteria measured were growth, carcass, and economic performance. Pigs fed high-energy diets in early finishing ( 150 lb) has more quantitatively significant effects on growth and carcass performance. Due the magnitude of the biological responses observed, economic penalties for feeding below the lysine requirement were modest early and severe later in the grow-finish period. These studies indicate that income over marginal feed cost (IOMFC) is consistently optimized near the biological requirement for optimal growth and feed conversion. However, feed cost per pound of gain is consistently minimized below these biological requirements. Therefore, diet costs alone provide little value in developing cost effective feeding strategies. In addition, prediction equations to calculate the optimum lysine:calorie ratio based on body weight (BW, lb) were developed. The lysine:calorie ratio prediction equation is: lysine:calorie ratio, g total lysine/Mcal ME = -.006045 × BW + 3.694 for barrows and lysine:calorie ratio = -.00744 × BW + 4.004 for gilts.

Amino Acid Limitation and Flow to Duodenum at Four Stages of Lactation. 1. Sequence of Lysine and Methionine Limitation1,2

Four Holstein cows with ruminal and duodenal cannulas were assigned to a 4 × 4 Latin square at each of four stages of lactation (peak, wk 4; early, wk 8 to 12; mid, wk 17 to 21; and late, wk 27 to 31). Treatments were duodenal infusions of 1) Met, 2) Lys, 3) Met plus Lys, and 4) casein; periods were 7 to 10 d. Quantities of DL-Met, L-Lys, and casein infused at the four stages of lactation were 12, 30, and 400; 12, 30, and 400; 10, 25, and 333; and 8, 20, and 266 g/d, respectively. Rations were composed of corn and grass-legume silages, corn meal, wheat middlings, soybean meal, and distillers dried grains with solubles. Intake of CP (percentage of NRC) and percentage of total CP from corn sources were (peak) 87, 56; (early) 90, 71; (mid) 98, 73; and (late) 114, 77. Using content and yield of milk protein as primary response criteria, Lys appeared to be first-limiting and Met second-limiting at peak lactation; their infusion together resulted in the same production of milk (40 kg/d) and milk protein (1135 g/d) as did casein. Lysine was first-limiting in early lactation, but whether Met was second-limiting was questionable. The two AA were colimiting in midlactation. There appeared to be no AA deficiencies in late lactation. Amounts of Lys and Met (percentage of total essential AA) in duodenal digesta during peak (12.4, 3.7), early (12.6, 3.5), and midlactation (14.9, 3.9) were not adequate for optimal AA utilization.