Role of prehabilitation following major uro-oncologic surgery: a narrative review.

PURPOSE: Functional status and physical independence play a key role in terms of quality of life, access to treatment, and continuity of care. Surgery, a central component of cancer treatments, leads to detrimental effects on functional capacity, which can be peculiarly relevant in vulnerable patients undergoing major procedures. Prehabilitation is a multidisciplinary intervention that uses the preoperative period to prevent or attenuate treatment-related functional decline and its subsequent consequences. This paper narratively reviews the rationale and the evidence of prehabilitation for uro-oncologic surgery. METHODS: A narrative review was conducted in August 2020, aiming to: (1) identify and discuss the impact of modifiable determinants of postoperative outcomes in urology and (2) review randomized controlled trials (RCT) exploring the role of preoperative exercise, nutrition, and psychological interventions in uro-oncologic surgery. RESULTS: Eight RCTs on preoperative conditioning interventions met the inclusion criteria, focusing on radical cystectomy for bladder cancer (RC) and radical prostatectomy for prostate cancer (RP). There is strong evidence that poor physical, nutritional and psychosocial status negatively impacts on surgical outcomes. Single modality interventions, such as preoperative exercise or nutrition alone, had no effect on 'traditional' surgical outcomes as length of stay or complication. However, multimodal approaches targeting postoperative functional status have shown to be effective and safe. CONCLUSION: There is initial evidence on the effectiveness and safety of multimodal prehabilitation in preserving functional capacity following RC and RP. However, to date, outcomes such as complications and length of stay seem to be not affected by prehabilitation.

Strategies for optimal perioperative outcomes in gastric cancer.

Cancer and surgery represent a major stress on the human body. Any condition that prevents patients from tolerating the physiological stress is a risk factor for poor outcome. There is a need to identify these impairments early in the process with a simple screening, followed by assessments that provide a holistic picture of the patient. The proposed path of multimodal prehabilitation acts synergistically with enhanced recovery after surgery care to achieve optimal patient outcomes.

Functional capacity of prediabetic patients: effect of multimodal prehabilitation in patients undergoing colorectal cancer resection.

BACKGROUND: Prehabilitation is the process of increasing functional capacity (FC) before surgery. Poor glycemic control is associated with worse outcomes in patients undergoing surgery. Therefore, prediabetic patients could particularly benefit from prehabilitation. METHODS: This is a pooled analysis of individual patient data from three multimodal prehabilitation trials in colorectal cancer surgery. Following a baseline assessment using the 6-minute walking test (6MWT), subjects were randomized to multimodal prehabilitation or to a control group. Participants were reassessed 24 h before surgery and 4 weeks after surgery. Prediabetes (PreDM) was defined as HbA1c 5.7%-6.4%. Multivariable logistic regression was used to adjust for potentially confounding variables. RESULTS: Participation in a prehabilitation program was the most important predictive factor of clinical improvement in FC prior to surgery (Adjusted OR 2.42, 95% CI 1.18, 4.94); prediabetes was not a statistically significant predictor of improvement in FC after adjustments for covariates. Prehabilitation attenuated the loss of FC in unadjusted analyses after surgery in prediabetic patients (PreDM Control: median change -6 m [IQR -50-20] vs PreDM Prehab: median change +25 m [IQR -20-53], p = 0.045). Adjusted analyses also suggested the protective effect against loss of FC after surgery was stronger in prediabetic patients (PreDM Prehab vs PreDM Control: OR 5.5, 95% CI: 1.2-25.8; Normo Prehab vs Normo Control: OR 1.5, 95% CI: 0.53-4.52). CONCLUSIONS: Multimodal prehabilitation favored clinical recovery of FC after surgery in CRC patients, especially prediabetic patients.

Prehabilitation in Thoracic Cancer Surgery: From Research to Standard of Care.

OBJECTIVE: To determine whether personalized, stepped prehabilitation care is a feasible, safe, and effective implementation strategy. DESIGN: Quality improvement project. Data collected prospectively from August 2018 to December 2019 were analyzed retrospectively to describe the clinical implementation of a prehabilitation care program for elective lung cancer surgery. SETTING: Single center, tertiary university hospital. PARTICIPANTS: Eighty-one consecutive adult patients living in the metropolitan area of Montreal were included if an elective resection of suspected or confirmed lung cancer was planned. INTERVENTIONS: At the earliest contemplation of surgery, the whole cohort was screened for impaired physical, nutritional, and/or psychological status. Patients screened at higher risk received dedicated assessment and personalized prehabilitation care upon specific needs. MEASUREMENTS AND MAIN RESULTS: Patients' specific needs and their access and flow through the different services were described. Prehabilitation effectiveness was evaluated using walking and exercise tests, and adverse events were monitored. Eighty-one patients were screened for functional impairments. Forty patients showed reduction of physical function, seven of them refused the specific assessment, one refused in-hospital exercise; 48 patients showed nutritional risk, eight of them refused or did not comply with nutritional therapy. Overall, 45 high-risk patients received a one-month personalized prehabilitation program: 16 partook in a trimodal program (exercise, nutrition, and psychological), and 22 received a program with both nutrition and exercise. No adverse events occurred during the study period. After prehabilitation, six-minute waking distance improved by 29.9 meters (standard deviation 47.3 m) (n = 35; p = 0.001) and the oxygen uptake at the anaerobic threshold improved by 1.6 (1.7) mL/kg/min (n = 13; p = 0.004). Length of hospital stay was two (interquartile range one-four) days in prehabilitated patients versus three (two-seven) days in the usual care group (p = 0.101). CONCLUSIONS: A personalized, stepped prehabilitation program targeting high-risk patients undergoing elective lung cancer surgery was feasible, safe, and effective.

Effect of two different pre-operative exercise training regimens before colorectal surgery on functional capacity: A randomised controlled trial.

BACKGROUND: Multimodal prehabilitation, including exercise training, nutritional therapy and anxiety reduction, has been shown to attenuate functional decline associated with surgery. Due to the growing interest in functional status as a targeted surgical outcome, a better understanding of the optimal prescription of exercise is critical. OBJECTIVE: The objective is to compare peri-operative functional trajectory in response to two different exercise training protocols within a 4-week, supervised, multimodal prehabilitation programme. DESIGN: This was a single blinded, single centre, randomised controlled study. Participants performed four assessments: at baseline, after prehabilitation (just before surgery), and at 1 and 2 months after surgery. PATIENTS: Adult patients scheduled for elective resection of nonmetastatic colorectal cancer were included provided there were no absolute contraindications to exercise nor poor language comprehension. INTERVENTION: Patients followed either high-intensity interval training (HIIT), or moderate intensity continuous training (MICT), as part of a 4-week multimodal prehabilitation programme. Both groups followed the same supervised resistance training, nutritional therapy and anxiety reduction interventions. All patients followed standardised peri-operative management. MAIN OUTCOME MEASURE: Changes in oxygen consumption at anaerobic threshold, measured with sequential cardio-pulmonary exercise testing, were assessed and compared between groups. RESULTS: Forty two patients were included in the primary analysis (HIIT n = 21 vs. MICT n = 21), with mean ±â€ŠSD age 64.5 ±â€Š11.2 years and 62% were men. At 2 months after surgery, 13/21 (62%) in HIIT and 11/21 (52%) in MICT attended the study visits. Both protocols significantly enhanced pre-operative functional capacity, with no difference between groups: mean (95% confidence interval) oxygen consumption at anaerobic threshold 1.97 (0.75 to 3.19) ml kg min in HIIT vs. 1.71 (0.56 to 2.85) in MICT, P = 0.753. At 2 months after surgery, the HIIT group showed a higher improvement in physical fitness: 2.36 (0.378 to 4.34) ml kg min, P = 0.021. No adverse events occurred during the intervention. CONCLUSION: Both MICT and HIIT enhanced pre-operative functional capacity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03361150.

Prehabilitation: the anesthesiologist's role and what is the evidence?

PURPOSE OF REVIEW: Surgery poses major threats to functional independence. Prehabilitation is a preoperative conditioning intervention that aims to prevent or attenuate surgery-related functional decline and its consequences. The present review is to summarize most recent evidence on the effectiveness of prehabilitation on key topics in cancer care, such as perioperative functional capacity, surgical and oncologic outcomes. RECENT FINDINGS: Recent studies predominantly focus on functional outcomes, demonstrating a positive effect of prehabilitation on perioperative physical fitness. SUMMARY: Prehabilitation prevents functional decline associated with major cancer surgery. Evidence is still needed to support its effectiveness in relation to postoperative complication, length of hospital stay, tumor progression, response to medical treatment, and survival. Ongoing and future research is essential to prompt the role of perioperative medicine in cancer care.

Improved Disease-free Survival After Prehabilitation for Colorectal Cancer Surgery.

OBJECTIVE: The objective of this study was to investigate the effect of prehabilitation on survival after colorectal cancer surgery. SUMMARY OF BACKGROUND DATA: Preoperative multimodal exercise and nutritional programs (prehabilitation) improve functional capacity and recovery following colorectal surgery. Exercise may also affect cancer outcomes by mediating the systemic inflammatory response. The effect of prehabilitation on cancer outcomes is unknown. METHODS: Pooled data from 3 prehabilitation trials (2 randomized controlled trials, 1 cohort) in patients undergoing elective, biopsy-proven, primary non-metastatic colorectal cancer surgery from 2009 to 2014 within an enhanced recovery program were analyzed. Patients were grouped into +prehab or-prehab. The primary outcomes were 5-year disease-free (DFS) and overall survival (OS). DFS and OS were analyzed using Kaplan-Meier curves and multiple Cox regression. RESULTS: A total of 202 patients were included (+prehab 104, -prehab 98). Median prehabilitation duration was 29 days (interquartile range 20-40). Patient and tumor characteristics were well-balanced (33% stage III). Postoperative complications and time to adjuvant chemotherapy were similar. Mean duration of follow-up was 60.3 months (standard deviation 26.2). DFS was similar for the combined group of stage I-III patients (P = 0.244). For stage III patients, prehabilitation was associated with improved DFS (73.4% vs 50.9%, P = 0.044). There were no differences in OS (P = 0.226). Prehabilitation independently predicted improved DFS (hazard ratio 0.45; 95% confidence interval, 0.21-0.93), adjusting for stage and other confounders. Prehabilitation did not independently predict OS. CONCLUSION: In this report, prehabilitation is associated with improved 5-year DFS in stage III colorectal cancer. This finding should be confirmed in future trials.

Multimodal prehabilitation in colorectal cancer patients to improve functional capacity and reduce postoperative complications: the first international randomized controlled trial for multimodal prehabilitation.

BACKGROUND: Colorectal cancer (CRC) is the second most prevalent type of cancer in the world. Surgery is the only curative option. However, postoperative complications occur in up to 50% of patients and are associated with higher morbidity and mortality rates, lower health related quality of life (HRQoL) and increased expenditure in health care. The number and severity of complications are closely related to preoperative functional capacity, nutritional state, psychological state, and smoking behavior. Traditional approaches have targeted the postoperative period for rehabilitation and lifestyle changes. However, recent evidence shows that the preoperative period might be the optimal moment for intervention. This study will determine the impact of multimodal prehabilitation on patients' functional capacity and postoperative complications. METHODS/DESIGN: This international multicenter, prospective, randomized controlled trial will include 714 patients undergoing colorectal surgery for cancer. Patients will be allocated to the intervention group, which will receive 4 weeks of prehabilitation (group 1, prehab), or the control group, which will receive no prehabilitation (group 2, no prehab). Both groups will receive perioperative care in accordance with the enhanced recovery after surgery (ERAS) guidelines. The primary outcomes for measurement will be functional capacity (as assessed using the six-minute walk test (6MWT)) and postoperative status determined with the Comprehensive Complication Index (CCI). Secondary outcomes will include HRQoL, length of hospital stay (LOS) and a cost-effectiveness analysis. DISCUSSION: Multimodal prehabilitation is expected to enhance patients' functional capacity and to reduce postoperative complications. It may therefore result in increased survival and improved HRQoL. This is the first international multicenter study investigating multimodal prehabilitation for patients undergoing colorectal surgery for cancer. TRIAL REGISTRATION: Trial Registry: NTR5947 - date of registration: 1 August 2016.

The impact of improved functional capacity before surgery on postoperative complications: a study in colorectal cancer.

Background: Poor functional capacity (FC) is an independent predictor of postoperative morbidity. However, there is still a lack of evidence as to whether enhancing FC before surgery has a protective effect on postoperative complications. The purpose of this study was to determine whether an improvement in preoperative FC impacted positively on surgical morbidity. Methods: This was a secondary analysis of a cohort of patients who underwent colorectal resection for cancer under Enhanced Recovery After Surgery care. FC was assessed with the 6-min walk test, which measures the distance walked in 6 min (6MWD), at 4 weeks before surgery and again the day before. The study population was classified into two groups depending on whether participants achieved a significant improvement in FC preoperatively (defined as a preoperative 6MWD change ≥19 meters) or not (6MWD change <19 meters). The primary outcome measure was 30-d postoperative complications, assessed with the Comprehensive Complication Index (CCI). The association between improved preoperative FC and severe postoperative complication was evaluated using multivariable logistic regression. Results: A total of 179 eligible adults were studied: 80 (44.7%) improved in 6MWD by ≥19 m preoperatively, and 99 (55.3%) did not. Subjects whose FC increased had lower CCI (0 [0-8.7] versus 8.7 [0-22.6], p = .022). Furthermore, they were less likely to have a severe complication (adjusted OR 0.28 (95% CI 0.11-0.74), p = .010), and to have an ED visit. Conclusion: Improved preoperative FC was independently associated with a lower risk of severe postoperative complications. Further investigation is required to establish a causative relationship conclusively.

Supervised exercise training with multimodal pre-habilitation leads to earlier functional recovery following colorectal cancer resection.

BACKGROUND: Exercise training is a component of the pre-habilitation program. While in one previous study the training was home-based, in a subsequent investigation it was supervised in hospital. The hypothesis of this secondary analysis of the two studies was to determine whether supervised exercise further accelerates the return to baseline walking ability. METHODS: Data from two consecutive randomized control trials (RCT) comparing pre-habilitation to the rehabilitation of cancer patients scheduled for colorectal surgery were pooled for analysis. The interventions were similar and included home-based exercise training, nutritional counseling and protein supplementation, and relaxation techniques administered either before surgery (pre-habilitation) or after surgery (rehabilitation). Patients in the second RCT received additional supervised exercise sessions. Functional capacity was assessed with the 6-minute walk test (6 MWT) at baseline, before surgery, and at 4 and 8 weeks after surgery. Adjusted logistic regression was used to determine the improvement of the 6-minute walk distance (6MWD). RESULTS: Baseline mean 6MWD of 63 patients in the supervised group was 465.1 m (SD, 115), and that of 77 patients in the nonsupervised group was 407.8 m (SD, 109) (P < 0.01). Perioperative supervised exercise training enhanced further functional capacity and muscle strength when compared with the nonsupervised group (P < 0.01). Those receiving exercise supervision had over two times higher chances to return to baseline after surgery. Supervised pre-habilitation was the best combination (4 weeks OR = 7.71, and at 8 weeks OR = 8.62). CONCLUSION: Supervised exercise training leads to meaningful changes in functional capacity thus accelerating the postoperative return to baseline activities.

Evaluation of supervised multimodal prehabilitation programme in cancer patients undergoing colorectal resection: a randomized control trial.

BACKGROUND: Prehabilitation has been previously shown to be more effective in enhancing postoperative functional capacity than rehabilitation alone. The purpose of this study was to determine whether a weekly supervised exercise session could provide further benefit to our current prehabilition program, when comparing to standard post-surgical rehabilitation. METHODS: A parallel-arm single-blind randomized control trial was conducted in patients scheduled for non-metastatic colorectal cancer resection. Patients were assigned to either a once weekly supervised prehabilitation (PREHAB+, n = 41) or standard rehabilitation (REHAB, n = 39) program. Both multimodal programs were home-based program and consisted of moderate intensity aerobic and resistance exercise, nutrition counseling with daily whey protein supplementation and anxiety-reduction strategies. Perioperative care was standardized for both groups as per enhanced recovery after surgery (ERAS®) guidelines. Functional exercise capacity, as determined by the 6-minute walk test distance (6MWD), was the primary outcome. Exercise quantity, intensity and energy expenditure was determined by the CHAMPS questionnaire. RESULTS: Both groups were comparable for baseline walking capacity (PREHAB+: 448 m [IQR 375-525] vs. REHAB: 461 m [419-556], p=.775) and included a similar proportion of patients who improved walking capacity (>20 m) during the preoperative period (PREHAB+: 54% vs. REHAB: 38%, p = .222). After surgery, changes in 6MWD were also similar in both groups. In PREHAB+, however, there was a significant association between physical activity energy expenditure and 6MWD (p < .01). Previously inactive patients were more likely to improve functional capacity due to PREHAB+ (OR 7.07 [95% CI 1.10-45.51]). CONCLUSIONS: The addition of a weekly supervised exercise session to our current prehabilitation program did not further enhance postoperative walking capacity when compared to standard REHAB care. Sedentary patients, however, seemed more likely to benefit from PREHAB+. An association was found between energy spent in physical activity and 6MWD. This information is important to consider when designing cost-effective prehabilitation programs.

Multimodal prehabilitation improves functional capacity before and after colorectal surgery for cancer: a five-year research experience.

BACKGROUND: Multimodal prehabilitation is a preoperative conditioning intervention in form of exercise, nutritional assessment, whey protein supplementation, and anxiety-coping technique. Despite recent evidence suggesting that prehabilitation could improve functional capacity in patients undergoing colorectal surgery for cancer, all studies were characterized by a relatively small sample size. The aim of this study was to confirm what was previously found in three small population trials. MATERIAL AND METHODS: Data of 185 participants enrolled in a pilot single group study and two randomized control trials conducted at the McGill University Health Center from 2010 to 2015 were reanalyzed. Subjects performing trimodal prehabilitation (exercise, nutrition, and coping strategies for anxiety) were compared to the patients who underwent the trimodal program only after surgery (rehabilitation/control group). Functional capacity was assessed with the six-minute walk test (6MWT), a measure of the distance walked over six minutes (6MWD). A significant functional improvement was defined as an increase in 6MWD from baseline by at least 19 m. Changes in 6MWD before surgery, at four and eight weeks were compared between groups. RESULTS: Of the total study population, 113 subjects (61%) underwent prehabilitation. Changes in 6MWD in the prehabilitation group were higher compared to the rehabilitation/control group during the preoperative period {30.0 [standard deviation (SD) 46.7] m vs. -5.8 (SD 40.1) m, p < 0.001}, at four weeks [-11.2 (SD 72) m vs. -72.5 (SD 129) m, p < 0.01], and at eight weeks [17.0 (SD 84.0) m vs. -8.8 (SD 74.0) m, p = 0.047]. The proportion of subjects experiencing a significant preoperative improvement in physical fitness was higher in those patients who underwent prehabilitation [68 (60%) vs. 15 (21%), p < 0.001]. CONCLUSION: In large secondary analysis, multimodal prehabilitation resulted in greater improvement in walking capacity throughout the whole perioperative period when compared to rehabilitation started after surgery.

Four-week prehabilitation program is sufficient to modify exercise behaviors and improve preoperative functional walking capacity in patients with colorectal cancer.

PURPOSE: High complication rates following colorectal surgery render many patients unable to fully regain functional capacity, thus seriously compromising quality of life. The aim of this study was to assess whether a 4-week trimodal prehabilitation program (exercise, nutritional supplementation, and counseling on relaxation techniques), implemented during the preoperative period, is sufficient to modify exercise behaviors and improve functional capacity of elderly patients scheduled for colorectal cancer surgery. METHODS: Patients were assigned to either a prehabilitation (PREHAB; n = 57) or matched time control group (CTRL; n = 59). Over the 4-week period prior to surgery, patients in PREHAB participated in a trimodal prehabilitation program. Patients in CTRL received the same program but only postoperatively. The Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire was used to measure physical activity levels, while the 6-min walk test (6MWT) was used for assessment of functional walking capacity. Measurements were collected at baseline and at the time of surgery. RESULTS: Over the preoperative period, patients in PREHAB significantly increased the amount of moderate- and vigorous-intensity physical activities that they performed. PREHAB patients also demonstrated a greater improvement in 6MWT compared to CTRL. At the time of surgery, a greater proportion of patients in PREHAB met current physical activity guidelines, as compared to CTRL. CONCLUSIONS: These findings highlight the positive effects of a trimodal prehabilitation program on patients' physical activity levels and functional walking capacity and demonstrate that modifying exercise behaviors and improving physical function within the 4-week preoperative period are an achievable goal.

A narrative review of chemokine receptors CXCR1 and CXCR2 and their role in acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a severe form of acute respiratory failure characterised by extensive inflammatory injury to the alveolocapillary barrier leading to alveolar oedema, impaired gas exchange and, ultimately, hypoxaemia necessitating the use of supplemental oxygen combined with some degree of positive airway pressure. Although much heterogeneity exists regarding the aetiology, localisation and endotypic characterisation of ARDS, what remains largely undisputed is the role of the innate immune system, and in particular of neutrophils, in precipitating and propagating lung injury. Activated neutrophils, recruited to the lung through chemokine gradients, promote injury by releasing oxidants, proteases and neutrophil extracellular traps, which ultimately cause platelet aggregation, microvascular thrombosis and cellular death. Among various neutrophilic chemoattractants, interleukin-8/C-X-C motif ligand 8 and related chemokines, collectively called ELR+ chemokines, acting on neutrophils through the G protein-coupled receptors CXCR1 and CXCR2, are pivotal in orchestrating the neutrophil activation status and chemotaxis in the inflamed lung. This allows efficient elimination of infectious agents while at the same time minimising collateral damage to host tissue. Therefore, understanding how CXCR1 and CXCR2 receptors are regulated is important if we hope to effectively target them for therapeutic use in ARDS. In the following narrative review, we provide an overview of the role of ELR+ chemokines in acute lung injury (ALI) and ARDS, we summarise the relevant regulatory pathways of their cognisant receptors CXCR1/2 and highlight current preclinical and clinical evidence on the therapeutic role of CXCR1 and CXCR2 inhibition in animal models of ALI, as well as in ARDS patients.

Combination Drug Therapy for the Management of Chronic Neuropathic Pain.

Chronic neuropathic pain (NP) is an increasingly prevalent disease and leading cause of disability which is challenging to treat. Several distinct classes of drugs are currently used for the treatment of chronic NP, but each drug targets only narrow components of the underlying pathophysiological mechanisms, bears limited efficacy, and comes with dose-limiting side effects. Multimodal therapies have been increasingly proposed as potential therapeutic approaches to target the multiple mechanisms underlying nociceptive transmission and modulation. However, while preclinical studies with combination therapies showed promise to improve efficacy over monotherapy, clinical trial data on their efficacy in specific populations are lacking and increased risk for adverse effects should be carefully considered. Drug-drug co-crystallization has emerged as an innovative pharmacological approach which can combine two or more different active pharmaceutical ingredients in a single crystal, optimizing pharmacokinetic and physicochemical characteristics of the native molecules, thus potentially capitalizing on the synergistic efficacy between classes of drugs while simplifying adherence and minimizing the risk of side effects by reducing the doses. In this work, we review the current pharmacological options for the treatment of chronic NP, focusing on combination therapies and their ongoing developing programs and highlighting the potential of co-crystals as novel approaches to chronic NP management.

Effect of Multimodal Prehabilitation on Reducing Postoperative Complications and Enhancing Functional Capacity Following Colorectal Cancer Surgery: The PREHAB Randomized Clinical Trial.

Importance: Colorectal surgery is associated with substantial morbidity rates and a lowered functional capacity. Optimization of the patient's condition in the weeks prior to surgery may attenuate these unfavorable sequelae. Objective: To determine whether multimodal prehabilitation before colorectal cancer surgery can reduce postoperative complications and enhance functional recovery. Design, Setting, and Participants: The PREHAB randomized clinical trial was an international, multicenter trial conducted in teaching hospitals with implemented enhanced recovery after surgery programs. Adult patients with nonmetastasized colorectal cancer were assessed for eligibility and randomized to either prehabilitation or standard care. Both arms received standard perioperative care. Patients were enrolled from June 2017 to December 2020, and follow-up was completed in December 2021. However, this trial was prematurely stopped due to the COVID-19 pandemic. Interventions: The 4-week in-hospital supervised multimodal prehabilitation program consisted of a high-intensity exercise program 3 times per week, a nutritional intervention, psychological support, and a smoking cessation program when needed. Main Outcomes and Measures: Comprehensive Complication Index (CCI) score, number of patients with CCI score more than 20, and improved walking capacity expressed as the 6-minute walking distance 4 weeks postoperatively. Results: In the intention-to-treat population of 251 participants (median [IQR] age, 69 [60-76] years; 138 [55%] male), 206 (82%) had tumors located in the colon and 234 (93%) underwent laparoscopic- or robotic-assisted surgery. The number of severe complications (CCI score >20) was significantly lower favoring prehabilitation compared with standard care (21 of 123 [17.1%] vs 38 of 128 [29.7%]; odds ratio, 0.47 [95% CI, 0.26-0.87]; P = .02). Participants in prehabilitation encountered fewer medical complications (eg, respiratory) compared with participants receiving standard care (19 of 123 [15.4%] vs 35 of 128 [27.3%]; odds ratio, 0.48 [95% CI, 0.26-0.89]; P = .02). Four weeks after surgery, 6-minute walking distance did not differ significantly between groups when compared with baseline (mean difference prehabilitation vs standard care 15.6 m [95% CI, -1.4 to 32.6]; P = .07). Secondary parameters of functional capacity in the postoperative period generally favored prehabilitation compared with standard care. Conclusions and Relevance: This PREHAB trial demonstrates the benefit of a multimodal prehabilitation program before colorectal cancer surgery as reflected by fewer severe and medical complications postoperatively and an optimized postoperative recovery compared with standard care. Trial Registration: trialregister.nl Identifier: NTR5947.

Efficacy and Safety of Reparixin in Patients with Severe COVID-19 Pneumonia: A Phase 3, Randomized, Double-Blind Placebo-Controlled Study.

INTRODUCTION: Polymorphonuclear cell influx into the interstitial and bronchoalveolar spaces is a cardinal feature of severe coronavirus disease 2019 (COVID-19), principally mediated by interleukin-8 (IL-8). We sought to determine whether reparixin, a novel IL-8 pathway inhibitor, could reduce disease progression in patients hospitalized with severe COVID-19 pneumonia. METHODS: In this Phase 3, randomized, double-blind, placebo-controlled, multicenter study, hospitalized adult patients with severe COVID-19 pneumonia were randomized 2:1 to receive oral reparixin 1200 mg three times daily or placebo for up to 21 days or until hospital discharge. The primary endpoint was the proportion of patients alive and free of respiratory failure at Day 28, with key secondary endpoints being the proportion of patients free of respiratory failure at Day 60, incidence of intensive care unit (ICU) admission by Day 28 and time to recovery by Day 28. RESULTS: Of 279 patients randomized, 182 received at least one dose of reparixin and 88 received placebo. The proportion of patients alive and free of respiratory failure at Day 28 was similar in the two groups {83.5% versus 80.7%; odds ratio 1.63 [95% confidence interval (CI) 0.75, 3.51]; p = 0.216}. There were no statistically significant differences in the key secondary endpoints, but a numerically higher proportion of patients in the reparixin group were alive and free of respiratory failure at Day 60 (88.7% versus 84.6%; p = 0.195), fewer required ICU admissions by Day 28 (15.8% versus 21.7%; p = 0.168), and a higher proportion recovered by Day 28 compared with placebo (81.6% versus 74.9%; p = 0.167). Fewer patients experienced adverse events with reparixin than placebo (45.6% versus 54.5%), most mild or moderate intensity and not related to study treatment. CONCLUSIONS: This trial did not meet the primary efficacy endpoints, yet reparixin showed a trend toward limiting disease progression as an add-on therapy in COVID-19 severe pneumonia and was well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04878055, EudraCT: 2020-005919-51.

Ketoprofen lysine salt has a better gastrointestinal and renal tolerability than ketoprofen acid: A comparative tolerability study in the Beagle dog.

Due to the widespread use of non-steroidal anti-inflammatory drugs (NSAIDs), the incidence of NSAID-associated adverse events has increased exponentially over the past decades. Ketoprofen (ketoprofen acid, KA) is a widely used NSAID and, like with other NSAIDs, its use can be associated with adverse effects that especially involve the gastrointestinal tract and the kidney. The salification of KA with L-lysine has led to the synthesis of ketoprofen lysine salt (KLS), which is characterized by higher solubility and a more rapid gastrointestinal absorption compared to KA. Previous studies have reported that KLS has also an increased gastric tolerance in vitro, and this is due to the inhibition of lipid peroxidation and reactive oxygen species scavenging effects of L-lysine. Here, we report in vivo tolerability/toxicity studies that were conducted prior seeking KLS marketing authorization, in which we compared KLS and KA safety profile, focusing in particular on the evaluation of the gastrointestinal and renal tolerability of the drugs administered orally to dogs. Our results demonstrate that KLS has an increased in vivo gastrointestinal tolerability compared to KA and show, for the first time, that KLS has also increased in vivo renal tolerability compared to KA, thus supporting the concept that L-lysine may counteract NSAID-induced oxidative stress-mediated gastrointestinal and renal injury.

Neoadjuvant Prehabilitation Therapy for Locally Advanced Non-Small-Cell Lung Cancer: Optimizing Outcomes Throughout the Trajectory of Care.

BACKGROUND: Prehabilitation is well established for improving outcomes in cancer surgery. Combining prehabilitation with neoadjuvant treatments may provide an opportunity to rapidly initiate cancer-directed therapy while improving functional status in preparation for local consolidation. In this proof-of-concept study, we analyzed non-small-cell lung cancer patients who underwent simultaneous prehabilitation and neoadjuvant therapy. PATIENTS AND METHODS: We retrospectively analyzed all patients who underwent neoadjuvant treatment for non-small-cell lung cancer followed by curative intent surgery between 2015 and 2021. Patients who were screened for the prehabilitation program were identified. The screening included assessment of physical performance, nutritional status, and signs of anxiety and depression. RESULTS: We identified a total of 141 patients who underwent neoadjuvant therapy. Twenty patients were screened to undergo a prehabilitation program. Four patients did not complete the exercise program (1 surgical intervention too soon, 1 drop-out after the first session, and 2 patients were deemed fit without intervention). The postoperative median length of stay was 2 days (range 1-18). Patients improved their 6-minute-walk test despite undergoing neoadjuvant treatment by a mean of 33 meters (± 50, P = .1). Self-reported functional status (DASI) showed significant improvement by a mean of 10 points (± 11, P = .03), and HADS-anxiety-score was significantly reduced after the prehabilitation program by a mean of 1.5 points (± 1, P = .005). CONCLUSION: Neoadjuvant prehabilitation therapy is feasible and associated with encouraging results. The performance of all measures remains a logistic challenge. With multimodal strategies for lung cancer treatment becoming key to optimal outcomes, neoadjuvant prehabilitation therapy is a concept worthy of prospective multi-center evaluation.