Long-term outcomes to neoadjuvant pembrolizumab based on pathological response for patients with resectable stage III/IV cutaneous melanoma.

BACKGROUND: While neoadjuvant immunotherapy for melanoma has shown promising results, the data have been limited by a relatively short follow-up time, with most studies reporting 2-year outcomes. The goal of this study was to determine long-term outcomes for stage III/IV melanoma patients treated with neoadjuvant and adjuvant programmed cell death receptor 1 (PD-1) inhibition. PATIENTS AND METHODS: This is a follow-up study of a previously published phase Ib clinical trial of 30 patients with resectable stage III/IV cutaneous melanoma who received one dose of 200 mg IV neoadjuvant pembrolizumab 3 weeks before surgical resection, followed by 1 year of adjuvant pembrolizumab. The primary outcomes were 5-year overall survival (OS), 5-year recurrence-free survival (RFS), and recurrence patterns. RESULTS: We report updated results at 5 years of follow-up with a median follow-up of 61.9 months. No deaths occurred in patients with a major pathological response (MPR, <10% viable tumor) or complete pathological response (pCR, no viable tumor) (n = 8), compared to a 5-year OS of 72.8% for the remainder of the cohort (P = 0.12). Two of eight patients with a pCR or MPR had a recurrence. Of the patients with >10% viable tumor remaining, 8 of 22 patients (36%) had a recurrence. Additionally, the median time to recurrence was 3.9 years for patients with ≤10% viable tumor and 0.6 years for patients with >10% viable tumor (P = 0.044). CONCLUSIONS: The 5-year results from this trial represent the longest follow-up of a single-agent neoadjuvant PD-1 trial to date. Response to neoadjuvant therapy continues to be an important prognosticator with regard to OS and RFS. Additionally, recurrences in patients with pCR occur later and are salvageable, with a 5-year OS of 100%. These results demonstrate the long-term efficacy of single-agent neoadjuvant/adjuvant PD-1 blockade in patients with a pCR and the importance of long-term follow-up for these patients. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02434354.

A comparison of the optical intrascope, the Hennessy & Chong Fat Depth Indicator and the Danish MFA probe to predict pig carcass backfat thickness.

Two automatic backfat measurement devices (the New Zealand Hennessy & Chong Fat Depth Indicator (FDI) and the Danish Meat Fat Automatic (MFA) probe) were compared with the Optical Intrascope (OI) as alternative devices to predict P(2) backfat thickness (65 mm from the dorsal mid-line at the level of the posterior edge of the head of the last rib) in pig carcass classification schemes. Prediction equations of P(2) backfat thickness (mm) taken on the cold carcass (cold P(2)) were developed for two operators who made independent hot carcass P(2) measurements (hot P(2)) with the O1, FDI and MFA on each of 114 carcasses. The OI and FDI were found to be of equivalent precision in predicting cold P(2) with the same operator (residual standard deviation, RSD = 1·29 and 1·30, respectively). The MFA was significantly (P < 0·05) less precise (RSD = 1·81). Between operator measurements of hot P(2) with the FDI (RSD = 1·17) had significantly (P < 0·05) less variation compared with the OI and MFA (RSD = 1·27).

Comparison of ultrasonic measurement of backfat depth on live pigs and carcases with a digital recording instrument.

A hand-held, digital recording ultrasonic backfat tester (Sonalyser) was used on 200 live pigs and their carcases to predict carcase P2 backfat depth measured with the Introscope optical probe. Readings were taken on live pigs at a position which approximated to the P2 site on the carcase. This site was tattooed. Sonalyser and Introscope readings were taken on the carcase at the P2 site and at the tattooed site. Regression equations of Introscope readings as a function of Sonalyser live pig and carcase measurements were developed. Calculation of partial F values showed the Sonalyser was more precise in measuring backfat on the live pig than the carcase. With R(2) = 0·77 and residual standard deviation (rsd) = 1·35 mm was judged to be acceptable for predicting carcase Introscope backfat from live pig measurement. Due to the lower precision, and other practical limitations to its use in abattoirs, the Sonalyser was not suitable for measuring backfat on the carcase. The limiting factors may have contributed to the lower R(2) (0·69) and higher rsd (1·55 mm) of the regression between Sonalyser and Introscope carcase fat depth.

Prediction of the weight of lean and fat yield in bacon weight carcasses. A comparison of predictors used in commercial pig carcass classification.

Alternative methods of pig carcass description were compared as predictors of the weight (kg) of commercial lean yield and fat yield in 209 bacon weight carcasses. The predictors used included hot carcass weight and carcass sex in association with: the backfat measurements used in the Danish grading scheme (minimum loin, 3rd-4th lumbar and 3rd-4th last rib fat thickness); the proposed Australian system (P(2) fat thickness); fat classes published by the South Australian Livestock Marketing Study Group (1980); mid-line carcass measurements (backfat at minimum loin, mid back, maximum shoulder as well as carcass length) and visual carcass grade. There was no difference in precision between the carcass classification systems as predictors of lean yield. (R(2) = 69·0 % and residual standard deviation = 1·5.) Precision varied between the predictors of fat yield. The predictors were ranked as follows with R(2)(%) and residual standard deviation in parentheses. Danish (80·0, 0·50); Australian (70·5, 0·60); fat class (67·8, 0·64); mid-line (64·9, 0·67) and grade (58·1, 0·72).

Chemical composition of growing pigs and its relationship with body tissue composition assessed by X-ray-computed tomography.

Ninety hybrid (mainly Large White × Landrace) pigs from 2 experimental replicates were used to study the potential use of computed tomography (CT) as a nondestructive technology for estimating the chemical body composition of growing pigs. Body tissue components (lean, fat, and bone) of 6 live pigs from each sex (boars, gilts, and barrows) were assessed by CT imaging before slaughter at approximately 30, 60, 90, 120, and 150 kg of BW. After slaughter, the empty body components were ground and frozen until analyzed for protein, lipid, ash, and moisture content. Several growth functions were evaluated and the allometric function (Y = aBW(b)), which was evaluated as log(10)chemical component weight = b(0) + b(1)log(10)BW, provided the best fit to the data. For each sex, the allometric coefficient (b(1)) for protein (0.92 to 0.99) was close to but less than 1; for ash (1.03 to 1.12), it was close to but greater than 1; for moisture (0.82 to 0.86), it was less than 1, and for lipid (1.61 to 1.71), it was greater than 1. Deposition rates (change in component weight per unit change in BW) for each chemical component were predicted using derivatives of the function. The mean deposition rates for protein and lipid were 0.141 and 0.286 kg/kg of BW gain, respectively. The deposition rate for protein was generally stable across different BW, whereas that for lipid increased as BW increased. In addition, linear, quadratic, exponential, and logistic functions were fitted to the data to study the relationship between the CT data and chemical components. The linear function was assessed to be the best equation, based on the Bayesian information criterion. The prediction equation for protein (kg) = -1.64 + 0.28 × CT lean (kg), and for lipid (kg) = -0.69 + 1.09 × CT fat (kg), had R(2) values of 0.924 and 0.987, respectively. Sex had no effect (P > 0.05) on the prediction of protein and lipid. The effect of BW was not significant (P > 0.05) for the prediction of lipid, but it was significant (P > 0 0.05) for the prediction of protein. However, the addition of BW to the base prediction equation for protein resulted in an increase of only 0.013 in the R(2) value. It was concluded from this study that CT scanning has great potential as a nondestructive technology for estimating the physical and chemical body composition of pigs. Additional research is required to validate the utility and accuracy of the prediction equations.

Differential growth and development of pigs as assessed by X-ray computed tomography.

Data from 54 hybrid (mainly Large White x Landrace) pigs (18 boars, 18 gilts, and 18 barrows) were used to quantify and mathematically describe the differential growth and development of body components of live pigs. The pigs were 32.4 +/- 3.2 kg of BW and 70 +/- 1 d of age (mean +/- SD) at the beginning of the study, were individually penned and fed ad libitum, and were weighed weekly. Computed tomography (CT) imaging was used to determine the weights of lean, fat, bone, and skin tissue in the live pig at 30, 60, 90, 120, and 150 kg of BW. For each target BW, the sum of all the weights of the body components, as assessed by CT, was referred to as CT BW. Linear and nonlinear models were developed to evaluate the patterns of growth and development of each body component relative to CT BW. The correlation between the actual BW and CT BW was close to unity (r = 0.99), indicating that CT scanning could accurately predict the BW of pigs. Across sex and castrate status, percentage of fat (fat weight/CT BW) in the pig was least (11.2%) at the 30-kg target BW and continued to increase to 22.6% by the 150-kg target BW. Percentage of lean, however, was greatest (67.2%) at the 30-kg target BW and continued to decrease to 53.4% by the 150-kg target BW. The sex or castrate status x target BW interaction was significant (P < 0.05) for all the body components, indicating that the developmental patterns were different among sex or castrate status. Barrows were fatter relative to gilts, which in turn were fatter than boars. For lean, the observed pattern for sex or castrate status differences was opposite that for fat. To predict responses to management strategies on growth and development in pigs, accurate mathematical models are required, and the results of this study indicate that the nonlinear (e.g., augmented allometric and generalized nonlinear) functions provided better descriptions of the growth and development of most body components of the live pig than did the simpler (e.g., linear and allometric) models.

Optimum duration of performance tests for evaluating growing pigs for growth and feed efficiency traits.

The optimum duration of test for the measurement of ADG, ADFI, feed:gain ratio [which is the reciprocal of the efficiency of gain (G:F) and therefore increases as the efficiency of gain decrease and vice versa], and residual feed intake was examined in growing pigs. Data from 144 hybrid (mainly Large White x Landrace) pigs involved in a longitudinal (n = 54) and serial slaughter (n = 90) experiment were used. The pigs were housed in individual pens from 70 +/- 1 d of age (mean +/- SD) and fed ad libitum a pelleted commercial diet. Feed intake and BW data on pigs that had a minimum of 10-wk records were partitioned into a 14-d adjustment and a 56-d test period. Phenotypic correlations among weekly measurements were used to examine the repeatability of each trait. Changes in phenotypic residual variance and correlation using shortened (7-, 14-, 21-, 28-, 35-, 42-, and 49-d) tests compared with the full-length 56-d test were used as criteria to assess the optimum test duration. The results of the phenotypic correlations among weekly measurements indicated that ADFI, which was characterized by moderate to high correlations (0.41 to 0.81), was more repeatable than ADG, which was characterized by low correlations (0.00 to 0.43). Mean gut fill (n = 107) was 4.2% of BW but was characterized by large variation among the pigs (SD = 1.8; CV = 42.2%). This variation in gut fill was a major contributor to the low repeatability of the measurement of ADG. These repeatability results indicated that ADG, rather than ADFI, will determine the optimum duration of test for the feed efficiency traits. The results of the shortened relative to the full-length test indicate that for growing pigs under good nutrition and ad libitum feeding, a 28-d test was adequate for the measurement of feed intake, whereas a 35-d test was required to measure ADG, feed:gain ratio, and residual feed intake without compromising the accuracy of measurement.

Ghrelin secretion is more closely aligned to energy balance than with feeding behaviour in the grower pig.

Secretory characteristics of the ghrelin profile for the pig are still unknown. Our objective was to clarify the mechanisms that influence ghrelin secretion during differing feeding patterns. Pigs were initially fed a commercial pelleted diet offered ad libitum and blood samples collected for 24 h at intervals of 1 h. The pigs were then entrained for 17 days to a twice daily interval feeding regimen (0900-1000 and 1600-1700 h) and blood samples were collected for 12 h (0800-2000 h). This was followed by a similar interval feeding and blood sampling regimen with the 0900-1000 h feeding period being replaced by a sham feed where pigs were shown their usual feed but none offered. During the ad libitum feeding regimen, there was no preprandial rise or postprandial fall in circulating plasma total ghrelin concentration, which remained constant throughout the sampling period. In addition, no preprandial rise or postprandial fall in ghrelin concentrations was observed when pigs were fed either twice or once daily; however, plasma ghrelin concentration rose gradually over the 12-h sampling period during the twice daily feeding regimen and increased further when pigs were fed once per day. This increase in ghrelin levels coincided with an increase in plasma GH and non-esterified fatty acid concentrations and was not associated with either plasma glucose or insulin concentrations. These results suggest that circulating total plasma ghrelin concentrations in the pig appear to be influenced by chronic changes in energy balance rather than the feeding pattern per se.

Effects of grouping unfamiliar cohorts, high ambient temperature and stocking density on live performance of growing pigs.

Ninety-six crossbred intact male pigs (34.5 +/- 3.5 kg BW) were allocated by weight and vocalization score to a 2 x 2 x 2 dynamic experimental design including two stocking densities (1 or 2 m(2)/pig), two temperatures (22 degrees C and 30 degrees C), and two short groupings of unfamiliar cohorts (six pigs as one pig per group, and six pigs per group). The study was conducted over 8 wk, and live weight gain (WTG) and feed intake (FI; as-fed basis) were measured weekly. During the first week, pigs were housed in individual pens from four independent rooms. To group pigs, pen partitions were removed. Pigs were grouped in Rooms 2 and 3 from wk 2 to 4, and in Rooms 1 and 4 during wk 7. Temperature was increased from 22 degrees C to 30 degrees C in Rooms 1 and 2 during wk 4 and 7. Pen partitions were replaced in Rooms 2 and 3 at the end of wk 4 and in Rooms 1 and 4 at the end of wk 7 to return pigs to their individual pens. Grouping pigs decreased FI during wk 3 (15.08 +/- 0.43 vs. 14.03 +/- 0.41 kg P < 0.10), and during wk 7 (17.42 +/- 0.46 vs. 14.24 +/- 0.41 kg; P < 0.01). In addition, grouping had a negative effect (P < 0.001) on WTG at wk 3 (7.38 +/- 0.28 vs. 5.71 +/- 0.28 kg) and at wk 7 (6.70 +/- 0.26 vs. 2.99 +/- 0.26 kg). For grouped pigs, raising the temperature decreased (P < 0.01) WTG (7.49 +/- 0.29 vs. 6.41 +/- 0.29 kg during wk 4, and 3.37 +/- 0.38 vs. 2.62 +/- 0.38 kg during wk 7). Mean FI was decreased (P < 0.01) with the 30 degrees C treatment during wk 7 only (15.49 +/- 0.33 kg at 22 degrees C compared with 12.99 +/- 0.33 kg at 30 degrees C). Compensatory feed intake was evident after the treatments had ceased at wk 6, whereby previously heat-treated grouped pigs had a higher FI (17.97 +/- 0.45 kg) than the animals individually housed at 22 degrees C (12.99 +/- 0.33 kg). Stocking density effects were noted after the grouping and high temperature treatments had ceased. For instance, during wk 5, low-density-housed pigs grew faster (P < 0.001) than their high-density counterparts (9.04 +/- 0.38 vs. 7.49 +/- 0.29 kg). In conclusion, under the conditions of this study, the grouping of unfamiliar cohorts and high ambient temperature treatments had a detrimental effect on pig performance, and these effects were reversible.

The effect of active immunization against adrenocorticotropic hormone on cortisol, beta-endorphin, vocalization, and growth in pigs.

Because the poor growth performance of intensively housed pigs is associated with increased circulating glucocorticoid concentrations, we investigated the effects of glucocorticoid suppression by inducing a humoral immune response to ACTH on physiological and production variables in growing pigs. Grower pigs (28.6 +/- 0.9 kg) were immunized with amino acids 1 through 24 of ACTH conjugated to ovalbumin and suspended in diethylaminoethyl (DEAE) dextran-adjuvant or adjuvant alone (control) on d 1, 28, and 56. The ACTH-specific antibody titers generated suppressed increases in cortisol concentrations on d 63 in response to an acute stressor (P = 0.002; control = 71 +/- 8.2 ng/mL; ACTH-immune = 43 +/- 4.9 ng/mL) without altering basal concentrations. Plasma beta-endorphin concentrations were also increased (P < 0.001) on d 63 (control = 18 +/- 2.1 ng/mL; ACTH-immune = 63 +/- 7.3 ng/mL), presumably because of a release from negative feedback on the expression of proopiomelanocortin in pituitary corticotropes. Immunization against ACTH did not alter ADG (P = 0.120; control = 1,077 +/- 25; ACTH-immune = 1,143 +/- 25 g) or ADFI (P = 0.64; control = 2,719 +/- 42; ACTH-immune = 2,749 +/- 42 g) and did not modify behavior (P = 0.681) assessed by measuring vocalization in response to acute restraint. In summary, suppression of stress-induced cortisol responses through ACTH immunization increased beta-endorphin concentrations, but it did not modify ADG, ADFI, or restraint vocalization score in growing pigs.

The optimum dietary amino acid pattern for growing pigs. 2. Requirements for maintenance and for tissue protein accretion.

Experiments were made to estimate separately the amino acid requirements of growing pigs for maintenance and for protein accretion. The relationship between nitrogen retention and amino acid intake was estimated for each essential amino acid (except histidine) by giving, at rates of N intake of 0.25 and 2.0 g/kg body-weight (W)0.75 per d, diets in which one amino acid was made specifically deficient. From the regression coefficients it was calculated that, for the accretion of 1 g body protein, the dietary amino acid requirements were (mg) threonine 47, valine 53, methionine + cystine 36, methionine 19, isoleucine 43, leucine 78, phenylalanine + tyrosine 84, phenylalanine 41, lysine 68 and tryptophan 12. The daily amino acid requirements for N equilibrium were also estimated. From the relationship between N retention and amino acid intake the daily amino acid requirements for N equilibrium were estimated to be (mg/kg W0.75 per d) threonine 53, valine 20, methionine + cystine 49, methionine 9, isoleucine 16, leucine 23, phenylalanine + tyrosine 37, phenylalanine 18, lysine 36 and tryptophan 11. It was estimated that both for maintenance and for protein accretion tyrosine could provide close to half the total phenylalanine + tyrosine needs. Cystine could supply close to half the total sulphur amino acid needs for protein accretion but 0.8 of the needs for maintenance.