Restoring adiponectin via rosiglitazone ameliorates tissue wasting in mice with lung cancer.

AIM: To investigate systemic regulators of the cancer-associated cachexia syndrome (CACS) in a pre-clinical model for lung cancer with the goal to identify therapeutic targets for tissue wasting. METHODS: Using the Kras/Lkb1 (KL) mouse model, we found that CACS is associated with white adipose tissue (WAT) dysfunction that directly affects skeletal muscle homeostasis. WAT transcriptomes showed evidence of reduced adipogenesis, and, in agreement, we found low levels of circulating adiponectin. To preserve adipogenesis and restore adiponectin levels, we treated mice with the PPAR-γ agonist, rosiglitazone. RESULTS: Rosiglitazone treatment increased serum adiponectin levels, delayed weight loss, and preserved skeletal muscle and adipose tissue mass, as compared to vehicle-treated mice. The preservation of muscle mass with rosiglitazone was associated with increases in AMPK and AKT activity. Similarly, activation of the adiponectin receptors in muscle cells increased AMPK activity, anabolic signaling, and protein synthesis. CONCLUSION: Our data suggest that PPAR-γ agonists may be a useful adjuvant therapy to preserve tissue mass in lung cancer.

Switching from natalizumab to an anti-CD20 monoclonal antibody in relapsing remitting multiple sclerosis: A systematic review.

BACKGROUND: Use of natalizumab (NTZ) is precluded in many Multiple Sclerosis (MS) patients by the risk of progressive multifocal leukoencephalopathy (PML). Regardless, some patients may commence natalizumab for short term disease control in spite of being seropositive, and others may seroconvert whilst on treatment. In these circumstances, discontinuation of NTZ should not occur until a clear exit strategy is established to prevent post-NTZ disease reactivation, which often exceeds the severity of disease activity prior to NTZ treatment. The objective of this systematic review was to summarise the available evidence for CD20-monoclonal antibodies (CD20mAb) as a suitable NTZ exit strategy, and to identify whether a superior switch protocol can be established. METHODS: In accordance with PRISMA guidelines, a total of 2393 references were extracted from a search of three online databases (PubMed, Scopus, MEDLINE). Following the application of inclusion/exclusion criteria, a total of 5 studies representing 331 patients were included. RESULTS: The overall incidence of clinical relapse during washout periods ranging from 4.4-10.7 weeks was 0 %. The incidence of clinical relapse during two-year follow-up ranged from 1.8 % to 10 % for switches to all types of CD20 monoclonal antibody. The weighted mean for clinical relapse at 12 months was 8.8 %. Three studies reported an annualised relapse rate (ARR) ranging from 0.02-0.12 with a weighted mean ARR of 0.07. The overall incidence of PML during washout was 0 % and the overall incidence of PML within 6 months follow-up was 0.6 %. CONCLUSIONS: This systematic review provides the first attempt at identifying a superior switch protocol in patients at risk of PML transitioning from NTZ to a CD20mAb. Our results indicate that CD20mAb's are a suitable transitional option for patients who discontinue NTZ, with our cohort demonstrating very low rates of carryover PML and low rates of clinical relapse. The most appropriate washout period is unclear due to confounding factors but is likely between 4 and 12 weeks.

Postoperative chemotherapy relative dose intensity and overall survival in patients with colon cancer.

PURPOSE: Quantifying the association of chemotherapy relative dose intensity (RDI) with overall survival may enable supportive care interventions that improve chemotherapy RDI to estimate their magnitude of potential clinical benefit. METHODS: This cohort study included 533 patients with stage II-III colon cancer who initiated a planned regimen of 12 cycles of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy. The primary exposure was chemotherapy RDI. The primary outcome was overall survival. Restricted cubic splines estimated hazard ratios (HR). RESULTS: Chemotherapy regimen RDI was associated with overall survival in an L-shaped pattern (linear P = 0.006; nonlinear P = 0.057); the risk of death was flat above 85% but increased linearly below 85%. For example, a decrease in RDI from 85 to 75% was associated with an increased risk of death [HR: 1.20 (95% CI: 1.08, 1.52)], whereas an increase in RDI from 85 to 95% was not associated with the risk of death [HR: 1.06 (95% CI: 0.82, 1.38)]. CONCLUSION: If chemotherapy RDI is considered a potential surrogate of overall survival, supportive care interventions that improve chemotherapy RDI might confer a potential clinical benefit in this population.

Nerve transfer for restoration of lower motor neuron-lesioned bladder, urethral and anal sphincter function. Part 4: Effectiveness of the motor reinnervation.

In pilot work, we showed that somatic nerve transfers can restore motor function in long-term decentralized dogs. We continue to explore the effectiveness of motor reinnervation in 30 female dogs. After anesthesia, 12 underwent bilateral transection of coccygeal and sacral (S) spinal roots, dorsal roots of lumbar (L)7, and hypogastric nerves. Twelve months postdecentralization, eight underwent transfer of obturator nerve branches to pelvic nerve vesical branches, and sciatic nerve branches to pudendal nerves, followed by 10 mo recovery (ObNT-ScNT Reinn). The remaining four were euthanized 18 mo postdecentralization (Decentralized). Results were compared with 18 Controls. Squat-and-void postures were tracked during awake cystometry. None showed squat-and-void postures during the decentralization phase. Seven of eight ObNT-ScNT Reinn began showing such postures by 6 mo postreinnervation; one showed a return of defecation postures. Retrograde dyes were injected into the bladder and urethra 3 wk before euthanasia, at which point, roots and transferred nerves were electrically stimulated to evaluate motor function. Upon L2-L6 root stimulation, five of eight ObNT-ScNT Reinn showed elevated detrusor pressure and four showed elevated urethral pressure, compared with L7-S3 root stimulation. After stimulation of sciatic-to-pudendal transferred nerves, three of eight ObNT-ScNT Reinn showed elevated urethral pressure; all showed elevated anal sphincter pressure. Retrogradely labeled neurons were observed in L2-L6 ventral horns (in laminae VI, VIII, and IX) of ObNT-ScNT Reinn versus Controls in which labeled neurons were observed in L7-S3 ventral horns (in lamina VII). This data supports the use of nerve transfer techniques for the restoration of bladder function.NEW & NOTEWORTHY This data supports the use of nerve transfer techniques for the restoration of bladder function.

Biomechanical Comparison Between Double-Row Repair and Soft Tissue Tenodesis for Treatment of Proximal Rectus Femoris Avulsions.

Background: Some patients with proximal rectus femoris (PRF) avulsions require surgical treatment after failed nonoperative treatment. There is no consensus on the superiority of suture anchor repair with the suture-bridge repair (SBR) technique versus tenodesis repair (TR) for PRF avulsions. Purpose: To compare the failure load and elongation at failure between SBR and TR and to compare the stiffness of these 2 repair techniques versus the native state. Study Design: Controlled laboratory study. Methods: Seven pairs of human cadaveric hemipelvises were dissected to the PRF and sartorius origins. Each specimen underwent preconditioning followed by a distraction test to determine the stiffness of the native specimen. One specimen of each pair received one of the repair methods (SBR or TR), while the other specimen in the pair received the other repair technique. After repair, each specimen underwent preconditioning followed by a pull to failure. The failure load, elongation at failure, stiffness, mode of failure, and stiffness as a percentage of the native state were determined for each repair. Results: The SBR group exhibited a stronger failure load (223 ± 51 N vs 153 ± 32 N for the TR group; P = .0116) and significantly higher stiffness as a percentage from the native state (70.4% ± 19% vs 33.8% ± 15.5% for the TR group; P = .0085). While the stiffness of the repair state in the SBR group (41.5 ± 9.4 N/mm) was not significantly different from that of the native state (66.2 ± 36 N/mm), the stiffness of the repair state in the TR group (20.3 ± 7.5 N/mm) was significantly lower compared with that of the native state (65.4 ± 22.1 N/mm; P < .001) and repair state in the SBR group (41.5 ± 9.4 N/mm; P = .02). The SBR group primarily failed at the repair site (71%), and the TR group primarily failed at the suture-sartorius interface (43%) and at the muscle (29%). Conclusion: SBR and TR specimens were significantly weaker than the native tendon. The stiffness of the SBR was equivalent to that of the native tendon, while TR was significantly less stiff than the native tendon. The SBR was superior to TR in terms of failure load, stiffness, and percentage stiffness from the native state. Clinical Relevance: SBR may be a better surgical option than TR to optimize failure load and stiffness for PRF avulsions.

Supinator to Posterior Interosseous Nerve Transfer for Recovery of Hand Opening in the Tetraplegic Patient: A Case Series.

BACKGROUND AND OBJECTIVES: Cervical spinal cord injury results in devastating loss of function. Nerve transfers can restore functional use of the hand, the highest priority function in this population to gain independence. Transfer of radial nerve branches innervating the supinator to the posterior interosseous nerve (SUP-PIN) has become a primary intervention for the recovery of hand opening, but few outcome reports exist to date. We report single-surgeon outcomes for this procedure. METHODS: The SUP-PIN transfer was performed on adults with traumatic spinal cord injury resulting in hand paralysis. Outcome measures include Medical Research Council strength grade for extension of each digit, and angles representing critical apertures: the first web space opening of the thumb, and metacarpophalangeal angle of the remaining fingers. Factors affecting these measurements, including preserved tone and spasticity of related muscles, were also assessed. RESULTS: Twenty-three adult patients with a C5-7 motor level underwent SUP-PIN transfers on 36 limbs (median age 31 years, interquartile range [21.5, 41]). The median interval from injury to surgery was 10.5 (8.2, 6.5) months, with 9 (7.5, 11) months for the acute injuries and 50 (32, 66) months for the chronic (>18 months) injuries. Outcomes were observed at a mean follow-up of 22 (14, 32.5) months. 30 (83.3%) hands recovered at least antigravity extension of the thumb and 34 (94.4%) demonstrated successful antigravity strength for the finger extensors, providing adequate opening for a functional grasp. Chronic patients (>18 months after injury) showed similar outcomes to those who had earlier surgery. Supination remained strong (at least M4) in all but a single patient and no complications were observed. CONCLUSION: SUP-PIN is a reliable procedure for recovery of finger extension. Chronic patients remain good candidates, provided innervation of target muscles is preserved. Higher C5 injuries were more likely to have poor outcomes.

Advances in Adherence Reporting of Resistance Training in a Clinical Trial during Adjuvant Chemotherapy for Colon Cancer.

PURPOSE: Detailed reporting of individually tailored exercise prescriptions (ExR x ) used in clinical trials is essential to describe feasibility, tolerability, and efficacy of the intervention and to inform translation to clinical care. This article outlines the methodology used to develop a resistance training (RT) ExR x for people with colon cancer receiving chemotherapy and reports adherence to the randomized controlled trial testing the impact of RT on relative dose intensity of chemotherapy and patient-reported toxicities. METHODS: Participants randomized to the exercise arm ( n = 90) were included. To promote muscle hypertrophy, the ExR x was twice-weekly, moderate to heavy loads (65%-85% one-repetition maximum), high sets (3-5), and intermediate repetitions (6-10) of five large multijoint movements with adjustable dumbbells. Attendance (achieved frequency) and adherence (achieved volume) were calculated. Group-based trajectory modeling was used to identify clusters of individuals with similar adherence patterns and compared baseline characteristics across adherence groups. RESULTS: The median attendance was 69.1%. Adherence was 60.6% but higher for those receiving 3 versus 6 months of chemotherapy (80.4 vs 47.4%; P < 0.05 ). Participants engaged in a median of 1.4 d of RT each week, lifting 62% of the one-repetition maximum load, for 3.0 sets and 7.5 repetitions per set. Three distinct adherence groups were identified: 13% "nonstarter," 37% "tapered off," and 50% "consistent exercisers." Females were more likely to be in the nonstarter and tapered-off groups. CONCLUSIONS: This article outlines suggested methods for reporting ExR x of RT in oncology clinical trials and provides insight into the tolerance of ExR x of RT during chemotherapy treatment for colon cancer. These findings aim to foster constructive dialogue and offer a premise for designing future research to elucidate the benefits of exercise during chemotherapy.

Effect of home-based resistance training on chemotherapy relative dose intensity and tolerability in colon cancer: The FORCE randomized control trial.

BACKGROUND: Many patients with colon cancer cannot fully adhere to postoperative chemotherapy due to dose-limiting toxicities, resulting in lower relative dose intensity (RDI) and potentially compromising overall survival. This study examined whether home-based resistance training (RT) during adjuvant chemotherapy improves RDI and patient-reported toxicities versus usual care (UC) in colon cancer patients. METHODS: Multicenter, randomized control trial (RCT) conducted at community and academic practices. Enrollment of patients receiving postoperative chemotherapy for colon cancer occurred between February 23, 2018, and September 29, 2021; final follow-up was March 21, 2022. Participants were randomized to RT (n = 90) or UC (n = 91) for the duration of chemotherapy. Participants in the RT group engaged in twice weekly home-based progressive RT. At the end of the study, UC was given an online exercise program. RESULTS: Among 181 randomized patients (mean age, 55.2 [SD, 12.8] years, 95 [52.5%] were men), there were no differences in the mean RDI among those in RT (79% [SD, 19%]) and those in UC (82% [SD, 19%]); (mean difference -0.04 [95% confidence interval (CI), -0.09 to 0.02]). Assignment to RT did not significantly reduce the number of moderate/severe symptoms per week across follow-up (relative rate: 0.94 [95% CI, 0.72-1.22]). Additionally, time since randomization did not significantly modify the effect of RT on the overall number of symptoms (p = .06). CONCLUSIONS: Among patients with colon cancer, these results do not support home-based RT as an adjunct to chemotherapy specifically to improve planned treatment intensity.

Design of a randomized, placebo-controlled study evaluating efficacy and safety of a cancer preventative vaccine in dogs.

Preventative anti-cancer vaccination strategies have long been hampered by the challenge of targeting the diverse array of potential tumor antigens, with successes to date limited to cancers with viral etiologies. Identification and vaccination against frameshift neoantigens conserved across multiple species and tumor histologies is a potential cancer preventative strategy currently being investigated. Companion dogs spontaneously develop cancers at a similar incidence to those in people and are a complementary comparative patient population for the development of novel anti-cancer therapeutics. In addition to an intact immune system with tumors that arise in an autochthonous tumor microenvironment, dogs also have a shorter lifespan and temporally compressed tumor natural history as compared to humans, which allows for more rapid evaluation of safety, immunogenicity, and efficacy of cancer vaccination strategies. Here we describe the study protocol for the Vaccination Against Canine Cancer Study (VACCS), the largest interventional cancer clinical trial conducted in companion dogs to date. In addition to safety and immunogenicity, the primary endpoint of VACCS is the cumulative incidence (CI) of dogs developing malignant neoplasia of any type at the end of the study period. Secondary endpoints include changes in incidence of specific tumor types, survival times following neoplasia diagnosis, and all-cause mortality.

The dose-response effect of aerobic exercise on inflammation in colon cancer survivors.

Background: Physical activity after surgical resection for colon cancer is associated with significantly longer disease-free survival. Inflammation is hypothesized to mediate the association between physical activity and disease-free survival in colon cancer. Methods: In this exploratory analysis of a randomized dose-response trial, 39 colon cancer survivors who completed standard therapy were stratified by cancer stage and randomized in a 1:1:1 ratio to one of three treatment groups for 24 weeks of usual-care control, 150 min/wk of moderate-intensity aerobic exercise (low-dose), or 300 min/wk of moderate-intensity aerobic exercise (high-dose). Inflammation outcomes included high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL6), and soluble tumor necrosis factor-alpha receptor 2 (sTNFαR2). Mixed models for repeated measures were used to test the hypothesis that exercise was associated with dose-response reductions in inflammation; exploratory analyses examined treatment effects by cancer stage. Results: In the overall population, aerobic exercise was not associated with dose-response reductions in hs-CRP, IL6, or sTNFαR2. Cancer stage modified the association between randomized group and hs-CRP (P=0.022) and IL6 (P<0.001) but not sTNFαR2 (P=0.39). In stage I-II disease, compared to control, exercise was not associated with inflammation outcomes. In stage III disease, compared to control, low-dose exercise reduced hs-CRP: -35.4% (95% CI: -70.1, -0.7) and IL6: -29.6% (95% CI: -58.4, -0.8) but not sTNFαR2: 2.7% (95% CI: sTNFαR2: -15.7, 21.1); high-dose exercise was not associated with inflammation outcomes in stage III disease. Conclusion: This exploratory analysis offers preliminary data to support the hypothesis that inflammation may mediate the association between physical activity and disease-free survival in colon cancer. Clinical trial registration: clinicaltrials.gov, identifier NCT02250053.

Biomechanical Comparison of Proximal Hamstring Reconstruction Using Distal Hamstring Graft Versus Fascia Lata Graft for Treatment of Chronic Hamstring Injury.

BACKGROUND: Surgical reconstruction using autografts is often required in treating chronic proximal hamstring injuries where the hamstring has retracted >5 cm. There is a paucity of evidence that evaluates reconstructive procedures using the 2 most popular autografts, distal hamstring and fascia lata. PURPOSE: To (1) compare failure load and elongation at failure between the proximal hamstring tendon reconstruction with distal hamstring and fascia lata grafts and (2) compare the stiffness between these reconstructions and the native state. STUDY DESIGN: Controlled laboratory study. METHODS: Seven pairs of human cadaveric hemipelvises (mean age, 60.4 ± 5.0 years; 6 male, 1 female) with no evidence of previous injury or abnormality were dissected to the proximal hamstring origin. Through use of a dynamic tensile testing system, each specimen underwent preconditioning followed by a distraction test to determine the native specimen stiffness. Each pair of specimens was assigned to undergo proximal hamstring reconstruction with distal hamstring and reconstruction with fascia lata. Each specimen then underwent preconditioning followed by pull to failure. The failure load, elongation at failure, mode of failure, and stiffness were determined for each repair. RESULTS: The distal hamstring group exhibited a greater failure load (mean, 334 ± 108 N; P = .031) and higher stiffness (mean, 47.6 ± 16.0 N/mm; P = .009) compared with the fascia lata group (mean, 179 ± 78 N and 23.0 ± 11.2 N/mm, respectively). Although the stiffness of the repair state in the distal hamstring group (mean, 61.4 ± 13.4 N/mm) was not significantly different from that of the native state (mean, 47.6 ± 16.0 N/mm), the stiffness of the repair state in the fascia lata group (mean, 23.0 ± 11.2 N/mm) was significantly lower than that of the native state (mean, 60.1 ± 17.7 N/mm) (P < .0001). The elongation at failure of the distal hamstring graft group (mean, 33.0 ± 6.6 mm) was not significantly different from that of the fascia lata graft group (mean, 29.2 ± 14.9 mm) (P = .58). The most common modes of failure for the distal hamstring group (29% each) were at the repair site, at the graft-muscle interface, and at the muscle, while the most common modes of failure for the fascia lata graft were at the tendon-graft interface. CONCLUSION: The distal hamstring group achieved higher failure load and stiffness than the fascia lata group, and stiffness of the distal hamstring group was not significantly different from that of the native tendon. Elongation at failure was not different between repair techniques. Although distal hamstring graft failure predominantly occurred in 3 distinct locations, failure of the fascia lata repair occurred predominantly at the tendon-graft interface. These cadaveric results suggest that it may be more clinically appropriate to use distal hamstring versus fascia lata for proximal hamstring reconstruction. CLINICAL RELEVANCE: Our time-zero study suggests that the proximal hamstring reconstruction with distal hamstring could be the preferred surgical treatment for chronic hamstring injury over reconstruction with fascia lata. The failure load of reconstruction with distal hamstring was inferior to that of primary suture anchor, suggesting that rehabilitation after reconstruction should not be more aggressive than the standard postoperative rehabilitation protocol for acute repair.

Physical activity and cognitive function: moment-to-moment and day-to-day associations.

BACKGROUND: The beneficial effect of acute physical exercise on cognitive performance has been studied in laboratory settings and in long-term longitudinal studies. Less is known about these associations in everyday environment and on a momentary timeframe. This study investigated momentary and daily associations between physical activity and cognitive functioning in the context of everyday life. METHODS: Middle-aged adults (n = 291, aged 40-70) were asked to wear accelerometers and complete ecological momentary assessments for eight consecutive days. Processing speed and visual memory were assessed three times per day and self-rated evaluations of daily cognition (memory, thinking, and sharpness of mind) were collected each night. The number of minutes spent above the active threshold (active time) and the maximum vector magnitude counts (the highest intensity obtained) before each cognitive test and at a daily level were used as predictors of momentary cognitive performance and nightly subjective cognition. Analyses were done with multilevel linear models. The models were adjusted for temporal and contextual factors, age, sex, education, and race/ethnicity. RESULTS: When participants had a more active time or higher intensity than their average level within the 20 or 60 minutes prior to the cognitive test, they performed better on the processing speed task. On days when participants had more active time than their average day, they rated their memory in the evening better. Physical activity was not associated with visual memory or self-rated thinking and sharpness of mind. CONCLUSIONS: This study provides novel evidence that outside of laboratory settings, even small increases in physical activity boost daily processing speed abilities and self-rated memory. The finding of temporary beneficial effects is consistent with long-term longitudinal research on the cognitive benefits of physical activity.

Hepatozoon spp. infection in wild canids in the eastern United States.

BACKGROUND: Hepatozoon spp. are apicomplexan parasites known to cause musculoskeletal disease in a variety of animals. Two species are known to infect wild and domestic canids in the US: Hepatozoon canis and H. americanum. METHODS: In this study, blood, heart, and/or spleen samples were collected from 278 wild canids (180 coyotes, 93 red foxes, and 5 gray foxes) in the eastern US and tested via PCR for Hepatozoon. Histology slides of heart and skeletal muscle were assessed for Hepatozoon cysts and associated inflammation when fresh tissue was available (n = 96). RESULTS: Hepatozoon spp. were found in 24.2% (59/278) of individuals, with Hepatozoon canis in 14.0% (34/278) and H. americanum in 10.7% (26/278). One coyote was positive for both H. canis and H. americanum. Foxes were more likely to be positive for H. canis than coyotes (23% and 7% respectively, P = 0.0008), while only coyotes were positive for H. americanum. Of the eight sampled states, H. canis was present in six (Louisiana, North Carolina, Pennsylvania, South Carolina, Tennessee, and Virginia) while H. americanum was found in two southern states (South Carolina and Louisiana). Infection status was positively correlated with myositis and myocarditis, and heart or muscle cysts were found in 83% (5/6) of H. americanum-positive coyotes. CONCLUSION: This survey showed a moderate prevalence of H. canis and H. americanum in states where the parasite was previously unrecorded including South Carolina and Pennsylvania.

The risk index as a basis for risk/benefit analyses and protocol optimization in diagnostic nuclear imaging.

BACKGROUND: Potential risk associated with low-dose radiation exposures is often expressed using the effective dose (E) quantity. Other risk-related quantities have been proposed as alternatives. The recently introduced risk index (RI) shares similarities with E but expands the metric to incorporate medical imaging-appropriate risks factors including patient-specific size, age, and sex. PURPOSE: The aim of this work is to examine the RI metric for quantifying stochastic radiation risk and demonstrate its applications in nuclear imaging. The advantages in this improved metric may help the field progress toward stratified risk consideration in the course of patient management, improve efforts for procedure optimization, and support an evolution in the science of radiation risk assessment. METHODS: In this study we describe, implement, and calculate RI for various diagnostic nuclear imaging scenarios using reference biokinetics published in ICRP Publication 128 for commonly utilized radiopharmaceuticals. All absorbed dose, E and RI calculations were performed using the freely available MIRDcalc nuclear medicine dosimetry software; the organ specific risk parameters used in the software are also benchmarked in this text. The resulting RI and E values are compared and various trends in RI values identified. RESULTS: E and RI coefficients were calculated for 3016 use cases. Notably RI values vary depending on patient characteristics. Overall, across the population, global trends in RI values can be identified. In general, RI values were 2.15 times higher for females than males, due to higher risk coefficients and activities being distributed in smaller reference masses. The pediatric patients showed higher RIs than adults, as younger patients generally receive higher absorbed doses per administered activity, and are more radiosensitive, and have a longer projected lifespan at risk. A compendium of E and RI values is also provided in table format to serve as a reference for the community. CONCLUSIONS: RI is a rational quantity that could be used for justification, risk communication and protocol optimization in medical imaging. It has some advantages when compared to the long-utilized E value with respect to personalization, since accounts for patient size, age, sex, and natural incidence of cancer risk.

Humeral Head Reconstruction With Osteochondral Allograft: Bone Plug Optimization for Hill-Sachs Lesions Using CT-Based Computer Modeling Analysis.

Background: Engaging Hill-Sachs lesions (HSLs) pose a significant risk for failure of surgical repair of recurrent anterior shoulder instability. Reconstruction with fresh osteochondral allograft (OCA) has been proposed as a treatment for large HSLs. Purpose: To determine the optimal characteristics of talus OCA bone plugs in a computer-simulated HSL model. Study Design: Descriptive laboratory study; Level of evidence, 6. Methods: Included were 132 patients with recurrent anterior instability with visible HSLs; patients who had multidirectional instability or previous shoulder surgery were excluded. Three-dimensional computed tomography models were constructed, and a custom computer optimization algorithm was generated to maximize bone plug surface area at the most superior apex (superiorization) and minimize its position relative to the most medial margin of the HSL defect (medialization). The optimal number, diameter, medialization, and superiorization of the bone plug(s) were reported. Percentages of restored glenoid track width and conversion from off- to on-track HSLs after bone plug optimization were calculated. Results: A total of 86 patients were included in the final analysis. Off-track lesions made up 19.7% of HSLs and, of these, the mean bone plug size was 9.9 ± 1.4 mm, with 2.2 mm ± 1.7 mm of medialization and 3.3 mm ± 2.9 mm of superiorization. The optimization identified 21% of HSLs requiring 1 bone plug, 65% requiring 2 plugs, and 14% requiring 3 plugs, with a mean overall coverage of 60%. The mean width of the restored HSLs was 68%, and all off-track HSLs (n = 17) were restored to on-track. A Jenks natural-breaks analysis calculated 3 ideal bone plug diameters of 8 mm (small), 10.4 mm (medium), and 12 mm (large) in order to convert this group of HSLs to on-track. Conclusion: Using a custom computer algorithm, we have demonstrated the optimal talus OCA bone plug diameters for reconstructing HSLs to successfully restore the HSL track and, on average, 60% of the HSL surface area and 68% of the HSL width. Clinical Relevance: Reconstructing HSLs with talus OCA is a promising treatment option with excellent fit and restoration of HSLs. This study will help guide surgeons to optimize OCA bone plugs from the humeral head, femoral head, and talus for varying sizes of HSLs.

Physical activity in recurrent colon cancer: Cancer and Leukemia Group B/SWOG 80702 (Alliance).

BACKGROUND: One in three patients with stage III colon cancer will experience tumor recurrence. It is uncertain whether physical activity during and after postoperative chemotherapy for stage III colon cancer improves overall survival after tumor recurrence. METHODS: A prospective cohort study nested within a randomized multicenter trial of patients initially diagnosed with stage III colon cancer who experienced tumor recurrence (N = 399) was conducted. Postoperative physical activity before tumor recurrence was measured. Physical activity energy expenditure was quantified via metabolic equivalent task hours per week (MET-h/week). The primary end point was overall survival after tumor recurrence. Multivariable flexible parametric survival models estimated relative and absolute effects with two-sided hypothesis tests. RESULTS: Compared with patients expending <3.0 MET-h/week of physical activity (comparable to <1.0 h/week of brisk walking), patients with ≥18.0 MET-h/week of physical activity (comparable to 6 h/week of brisk walking) had a 33% relative improvement in overall survival time after tumor recurrence (hazard ratio, 0.67; 95% CI, 0.42-0.96). The overall survival rate at 3 years after tumor recurrence was 61.3% (95% CI, 51.8%-69.2%) with <3.0 MET-h/week of physical activity and 72.2% (95% CI, 63.1%-79.6%) with ≥18 MET-h/week of physical activity (risk difference, 10.9 percentage points; 95% CI, 1.2-20.8 percentage points). CONCLUSIONS: Higher postoperative physical activity is associated with improved overall survival after tumor recurrence in patients initially diagnosed with stage III colon cancer. These data may be relevant to patients who, despite optimal postoperative medical therapy, have a high risk of tumor recurrence.

WISER Survivor Trial: Combined Effect of Exercise and Weight Loss Interventions on Adiponectin and Leptin Levels in Breast Cancer Survivors with Overweight or Obesity.

Adipocyte dysregulation is one mechanism linking overweight and breast cancer recurrence. Exercise and weight loss are associated with a decreased risk of breast cancer recurrence in breast cancer survivors with overweight or obesity, which may be mediated through reduced leptin levels, increased adiponectin levels, and an elevated adiponectin to leptin (A:L) ratio. The four-arm randomized controlled WISER Survivor trial examined the 12-month intervention effects of exercise, weight loss, and the combination of exercise and weight loss on adipokine levels among breast cancer survivors (n = 339) with overweight or obesity. Compared with Control, the Combination of Exercise and Weight Loss decreased leptin levels (-35.9%; 95% CI: -46.8%, -25.0%) and increased A:L ratio (11.6%; 95% CI: 5.6%, 17.6%) but did not change adiponectin levels (4.1%; 95% CI: -3.1%, 11.2%). Compared with Control, Weight Loss Alone decreased leptin levels (-35.6%; 95% CI: -46.6%, -24.5%) and increased A:L ratio (10.6%; 95% CI: 4.7%, 16.5%) but did not change adiponectin levels (0.9%; 95% CI: -6.0%, 7.9%). Compared with Control, Exercise Alone did not change leptin levels, adiponectin levels, or A:L ratio. In analyses that consolidated intervention groups, compared with Control, weight loss of ≥5% decreased leptin levels (p trend < 0.01) and increased A:L ratio (p trend < 0.01) but did not alter adiponectin levels (p trend = 0.53). Weight loss, with or without exercise, was associated with decreased leptin levels in breast cancer survivors with overweight or obesity. Improvements in the adipokine secretion profile (A:L ratio) were primarily driven by a weight loss-induced change in leptin levels.

The effects of dietary essential fatty acid ratios and linoleic acid level in grow-finish pigs.

The objective of this study was to investigate the effects of dietary linoleic acid level and the ratio of linoleic acid:linolenic acid (LA:ALA) on the growth performance, expression of genes associated with lipid metabolism, and inflammatory status of grow-finish pigs. A total of 300 growing pigs (body weight [BW] = 41.1 ±â€…6.3 kg) were randomly assigned to either a high (30 g/kg; HLA) or low (15 g/kg; LLA) dietary linoleic acid level with a high (23:1; HR), moderate (13:1; MR) or low (4:1; LR) dietary LA:ALA in a 2 × 3 factorial design. Diets were fed across three 28-d phases and were balanced for dietary metabolizable energy. Pigs were housed five pigs per pen in single-sex pens. Blood samples were collected on days 0, 21, 42, and 84, and synovial fluid was collected from the hock joint on days 0 and 84 for inflammatory marker analysis. Data were analyzed as repeated measures using PROC MIXED (SAS 9.4) with initial BW as a covariate, pen as the experimental unit, and LA level, LA:ALA, sex, phases, and their interactions as fixed effects. Compared to HLA, LLA pigs tended to have increased BW at days 56 and 84 (P = 0.088). There was no effect of LA × LA:ALA for growth performance. For the overall days 0 to 84 growth period, pigs fed HR had increased ADG compared to MR, with pigs receiving LR performing intermediate of MR and HR. Gilts receiving HR diets had increased day 84 BW compared to gilts receiving the low and moderate LA:ALA (P = 0.006), which was a result of improved overall days 0 to 84 ADG compared to gilts receiving the MR diets (P = 0.023). Barrows fed LR had improved BW on day 56 compared to MR and HR and higher final BW compared to HR, with MR performing intermediately (P = 0.006). This was a result of greater days 0 to 84 ADG (P = 0.023). Overall, C-reactive protein (CRP), tumor necrosis factor-α (TNFα), and interleukin-6 were reduced in the plasma of pigs over time (P ≤ 0.037). Across all treatments, CRP and TNFα were reduced in the hock and carpus synovial fluid on day 84 vs. day 0 (P ≤ 0.049). In conclusion, LA:ALA ratios utilized in this study can be fed at varying linoleic acid levels without impacting growth or inflammation. Additionally, LA:ALA ratios can differentially impact the growth of gilts and barrows.

Previous research in lactating sows has reported that dietary inclusion of the essential fatty acids linoleic acid and linolenic acid is important for performance. Research in grow­finish pigs has shown an improvement in gilt growth performance when fed differing linoleic:linolenic acid ratios (LA:ALA); however, further research evaluating LA:ALA in diets with similar metabolizable energy is needed in growing pigs. In the present research, a 23:1 dietary essential fatty acid ratio increased the final body weight of gilts compared to a 13:1 or 4:1 LA:ALA, while barrows fed a 4:1 dietary essential fatty acid ratio had increased gain and final body weight compared to a 23:1 LA:ALA. Plasma and synovial fluid inflammatory markers were also reduced with time and were unaffected by dietary LA:ALA or linoleic acid inclusion. Dietary essential fatty acid ratio can differentially impact the growth of barrows and gilts, with no impact on systemic or joint inflammation.

Restoring adiponectin via rosiglitazone ameliorates tissue wasting in mice with lung cancer.

The cancer associated cachexia syndrome (CACS) is a systemic metabolic disorder resulting in loss of body weight due to skeletal muscle and adipose tissues atrophy. CACS is particularly prominent in lung cancer patients, where it contributes to poor quality of life and excess mortality. Using the Kras/Lkb1 (KL) mouse model, we found that CACS is associated with white adipose tissue (WAT) dysfunction that directly affects skeletal muscle homeostasis. WAT transcriptomes showed evidence of reduced adipogenesis, and, in agreement, we found low levels of circulating adiponectin. To preserve adipogenesis and restore adiponectin levels, we treated mice with the PPAR-γ agonist, rosiglitazone. Rosiglitazone treatment increased serum adiponectin levels, delayed weight loss, and preserved skeletal muscle and adipose tissue mass, as compared to vehicle-treated mice. The preservation of muscle mass with rosiglitazone was associated with increases in AMPK and AKT activity. Similarly, activation of the adiponectin receptors in muscle cells increased AMPK activity, anabolic signaling, and protein synthesis. Our data suggest that PPAR-γ agonists may be a useful adjuvant therapy to preserve tissue mass in lung cancer.