The association of postoperative morbidity and age on 5-year survival after colorectal surgery in the elderly population: a nationwide cohort study.

AIM: This study aimed to evaluate the association of age and postoperative morbidity on 5-year overall survival (OS) after elective surgery for colorectal cancer. METHOD: Patients undergoing elective, curatively intended surgery for colorectal cancer Union for International Cancer Control Stages I-III between January 2014 and December 2019 were selected from four Danish nationwide healthcare databases. Patients were divided into four groups: group I 65-69 years old; group II 70-74 years old; group III 75-79 years old; and group IV ≥80 years old. Propensity score matching was used to reduce potential confounding bias. The primary outcome was the association of age and postoperative morbidity with 5-year OS. The secondary outcome was conditional survival, given that the patient had already survived the first 90 days after surgery. RESULTS: After propensity score matching with a 1:1 ratio, group II contained 2221 patients; group III 952 patients; and group IV 320 patients. There was no significant difference in 5-year OS between group I (reference) and groups II and III (P = 0.4 and P = 0.9, respectively). Patients with severe postoperative complications within 30 days after surgery had a significantly decreased OS (P < 0.01); however, when patients who died within the first 90 days were excluded from the analysis, the differences in 5-year OS were less pronounced across all age groups. CONCLUSION: Postoperative morbidity, and not patient age, was associated with a lower 5-year OS. Long-term survival for patients who experience a complication is similar to patients who did not have a complication when conditioning on 90 days of survival.

Multimodal prehabilitation in elective oncological colorectal surgery enhances postoperative functional recovery: A secondary analysis of the PREHAB randomized clinical trial.

INTRODUCTION: Colorectal cancer (CRC) ranks as the second leading cause of cancer-related deaths. The PREHAB trial revealed that prehabilitation in colorectal surgery leads to a reduction of severe complications and enhanced functional capacity. Nevertheless, risk selection for prehabilitation and the potential benefits for patients without postoperative complications remains unclear. This study aims to assess postoperative functional capacity, also in patients without postoperative complications. MATERIALS & METHODS: This study was a secondary analysis of the PREHAB trial. Functional capacity tests, including cardiopulmonary exercise testing (CPET), steep ramp test (SRT), 6-min walking test (6MWT), stair climb test (SCT), 30" sit-to-stand test (STS), timed-up-and-go test (TUG), and muscle strength assessments, were conducted at baseline (T0) and 4 weeks postoperatively (T3). The primary outcome was the relative change in functional capacity from baseline to postoperative (ΔT0-T3) per group (i.e., prehabilitation vs control). Secondary, identical analysis were performed for patients without postoperative complications in each group. RESULTS: Intention-to-treat analysis included 251 patients. For postoperative functional capacity, prehabilitation patients showed improvements in VO2peak (p = 0.024), VO2AT (p = 0.017), SRT (p = 0.001), 6MWT (p = 0.049), SCT (p = 0.012), and STS (p = 0.001) compared to the control group. Regarding muscle strength, prehabilitation patients showed improvements in estimated 1RM lateral pull down (p = 0.016), 1RM chest press (p = 0.001), 1RM leg press (p = 0.001) and HGS (p = 0.005) compared to controls. Additionally, prehabilitation patients more often reached baseline levels at T3 in VO2AT (p = 0.037), SRT (p = 0.008), 6MWT (p = 0.013), STS (p = 0.012), estimated 1RM lateral pull down (p = 0.002), 1RM chest press (p = 0.001) and 1RM leg press (p = 0.001) compared to controls. Moreover, even patients without postoperative complications in the prehabilitation group showed better postoperative functional capacity and more often reached baseline levels at T3, compared to controls. CONCLUSION: Multimodal prehabilitation in CRC surgery is associated with improved postoperative functional capacity, even in patients without postoperative complications.

Preoperative multimodal prehabilitation before elective colorectal cancer surgery in patients with WHO performance status I or II: randomized clinical trial.

BACKGROUND: Multimodal prehabilitation is a promising adjunct to the current surgical treatment pathway for colorectal cancer patients to further improve postoperative outcomes, especially for high-risk patients with low functional capacity. The aim of the present study was to test the effect of prehabilitation on immediate postoperative recovery. METHOD: The study was designed as a RCT with two arms (intervention and control). The intervention consisted of 4 weeks of multimodal prehabilitation, with supervised physical training, nutritional support and medical optimization. The control group received standard of care. A total of 40 patients with colorectal cancer (WHO performance status I or II) undergoing elective surgery with curative intent were included. The primary outcome was postoperative recovery within the first 3 postoperative days, measured by Quality of Recovery-15, a validated questionnaire with a scoring range between 0 and 150 and a minimal clinically relevant difference of 8. RESULTS: In total, 36 patients were analysed with 16 in the intervention group and 20 in the control group. The mean age of the included patients was 79 years. The overall treatment effect associated with the intervention was a 21.9 (95% c.i. 4.5-39.3) higher quality of recovery-15 score during the first 3 postoperative days compared to control, well above the minimal clinically relevant difference. CONCLUSION: Four weeks of multimodal prehabilitation prior to elective curative intended colorectal cancer surgery in patients with WHO performance status I or II was associated with a clinically relevant improvement in postoperative recovery.Registration number: NCT04167436 (http://www.clinicaltrials.gov).

Combined endoscopic and laparoscopic surgery (CELS) for early colon cancer in high-risk patients.

BACKGROUND: Local excision of early colon cancers could be an option in selected patients with high risk of complications and no sign of lymph node metastasis (LNM). The primary aim was to assess feasibility in high-risk patients with early colon cancer treated with Combined Endoscopic and Laparoscopic Surgery (CELS). METHODS: A non-randomized prospective feasibility study including 25 patients with Performance Status score ≥ 1 and/or American Society of Anesthesiologists score ≥ 3, and clinical Union of International Cancer Control stage-1 colon cancer suitable for CELS resection. The primary outcome was failure of CELS resection, defined as either: Incomplete resection (R1/R2), local recurrence within 3 months, complication related to CELS within 30 days (Clavien-Dindo grade ≥ 3), death within 30 days or death within 90 days due to complications to surgery. RESULTS: Fifteen patients with clinical T1 (cT1) and ten with clinical T2 (cT2) colon cancer and without suspicion of metastases were included. Failure occurred in two patients due to incomplete resections. Histopathological examination classified seven patients as having pT1, nine as pT2, six as pT3 adenocarcinomas, and three as non-invasive tumors. In three patients, the surgical strategy was changed intraoperatively to conventional colectomy due to tumor location or size. Median length of stay was 1 day. Seven patients had completion colectomy performed due to histological high-risk factors. None had LNM. CONCLUSIONS: In selected patients, CELS resection was feasible, and could spare some patients large bowel resection.

Neo-train: study protocol and feasibility results for a two-arm randomized controlled trial investigating the effect of supervised exercise during neoadjuvant chemotherapy on tumour response in patients with breast cancer.

BACKGROUND: Prehabilitation with exercise interventions during neoadjuvant chemotherapy (NACT) is effective in reducing physical and psychosocial chemotherapy-related adverse events in patients with cancer. In preclinical studies, data also support a growth inhibitory effect of aerobic exercise on the tumour microenvironment with possible improved chemotherapy delivery but evidence in human patients is limited. The aim of the study here described is to investigate if supervised exercise with high-intensity aerobic and resistance training during NACT can improve tumour reduction in patients with breast cancer. METHODS: This parallel two-armed randomized controlled trial is planned to include 120 women aged ≥ 18 years with newly diagnosed breast cancer starting standard NACT at a university hospital in Denmark (a total of 90 participants needed according to the power calculation and allowing 25% (n = 30) dropout). The participants will be randomized to usual care or supervised exercise consisting of high-intensity interval training on a stationary exercise bike and machine-based progressive resistance training offered three times a week for 24 weeks during NACT, and screening-based advice to seek counselling in case of moderate-severe psychological distress (Neo-Train program). The primary outcome is tumour size change (maximum diameter of the largest lesion in millimetre) measured by magnetic resonance imaging prior to surgery. Secondary outcomes include clinical/pathological, physical and patient-reported measures such as relative dose intensity of NACT, hospital admissions, body composition, physical fitness, muscle strength, health-related quality of life, general anxiety, depression, and biological measures such as intratumoural vascularity, tumour infiltrating lymphocytes, circulating tumour DNA and blood chemistry. Outcomes will be measured at baseline (one week before to 1-2 weeks after starting NACT), during NACT (approximately week 7, 13 and 19), pre-surgery (approximately week 21-29), at surgery (approximately week 21-30) and 3 months post-surgery (approximately 33-42 weeks from baseline). DISCUSSION: This study will provide novel and important data on the potential benefits of supervised aerobic and resistance exercise concomitant to NACT on tumour response and the tumour microenvironment in patients with breast cancer, with potential importance for survival and risk of recurrence. If effective, our study may help increase focus of exercise as an active part of the neoadjuvant treatment strategy. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov (NCT04623554) on November 10, 2020.

Paralytic Ileus as an Extra-Pulmonary Manifestation of COVID-19.

Extra-pulmonary manifestations of COVID-19 (SARS-CoV-2) are of increasing interest as a consequence of the increase in cases worldwide and a better understanding of the pathophysiology of the disease. However, gastrointestinal symptoms are rarely described but are a common occurrence. We report a case of a 62-year-old male with severe pulmonary infection with COVID-19, who presented with abdominal pain, hematemesis, bloody diarrhea, and abdominal distention, which led to the diagnosis of paralytic ileus after diagnostic laparoscopy. Further, we discuss the potential pathophysiological mechanisms behind this manifestation of COVID-19.

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.

Effect of modifying high-risk factors and prehabilitation on the outcomes of colorectal cancer surgery: controlled before and after study.

BACKGROUND: Low functional capacity, malnutrition, and anaemia are associated with an increased risk of complications after surgery. These high-risk indicators can be improved through preoperative interventions. The aim of the study was to examine the effect of screening for modifiable high-risk factors combined with targeted interventions on postoperative complications in patients undergoing colorectal cancer surgery. METHODS: A controlled before-and-after study was conducted including patients with colorectal cancer undergoing elective curative surgery between August 2015 and October 2018, in two institutions (intervention and control hospital). The intervention consisted of a screening for anaemia, low functional capacity, and nutritional status and their implementation (iron supplementation, prehabilitation, nutritional supplements, and consultation with a dietician), for a minimum of 4 weeks before surgery. The primary outcome was a composite measure consisting of unplanned admission to the intensive care unit, complications with Clavien-Dindo score of 3a or above, length of hospital stay less than 10 days, readmission, or death within 30 days during the postoperative course. RESULTS: A total of 1591 patients were included for analysis with 839 at the intervention hospital and 752 at the control hospital. In a difference-in-difference analysis, adjusted for age, sex, smoking, stage of disease, ASA score, surgical approach, and surgical procedure, the intervention was associated with a 10.9 per cent (95 per cent c.i. 2.1 to 19.7 per cent) absolute risk reduction of a complicated postoperative course, primarily due to a reduction in severe complications. CONCLUSION: The combined intervention of screening and prehabilitation was associated with a decreased risk of a complicated course, primarily in a reduction of severe complications.

Azithromycin and hydroxychloroquine in hospitalised patients with confirmed COVID-19: a randomised double-blinded placebo-controlled trial.

BACKGROUND: Combining the antibiotic azithromycin and hydroxychloroquine induces airway immunomodulatory effects, with the latter also having in vitro antiviral properties. This may improve outcomes in patients hospitalised for coronavirus disease 2019 (COVID-19). METHODS: Placebo-controlled double-blind randomised multicentre trial. Patients aged ≥18 years, admitted to hospital for ≤48 h (not intensive care) with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription PCR test were recruited. The intervention was 500 mg daily azithromycin for 3 days followed by 250 mg daily azithromycin for 12 days combined with 200 mg twice-daily hydroxychloroquine for all 15 days. The control group received placebo/placebo. The primary outcome was days alive and discharged from hospital within 14 days (DAOH14). RESULTS: After randomisation of 117 patients, at the first planned interim analysis, the data and safety monitoring board recommended stopping enrolment due to futility, based on pre-specified criteria. Consequently, the trial was terminated on 1 February 2021. 61 patients received the combined intervention and 56 patients received placebo. In the intervention group, patients had a median (interquartile range) 9.0 (3-11) DAOH14 versus 9.0 (7-10) DAOH14 in the placebo group (p=0.90). The primary safety outcome, death from all causes on day 30, occurred for one patient in the intervention group versus two patients receiving placebo (p=0.52), and readmittance or death within 30 days occurred for nine patients in the intervention group versus six patients receiving placebo (p=0.57). CONCLUSIONS: The combination of azithromycin and hydroxychloroquine did not improve survival or length of hospitalisation in patients with COVID-19.

High World Heath Organization Performance Status Is Associated With Short- and Long-term Outcomes After Colorectal Cancer Surgery: A Nationwide Population-Based Study.

BACKGROUND: The value of performance status is widely used in medical oncology, but the association with surgical outcomes in colorectal cancer has not been described. OBJECTIVE: The aim of this study was to investigate the association between World Heath Organization performance status and 90-day mortality, 30-day mortality, complications, and overall survival after elective colorectal cancer surgery. DESIGN: The study was conducted as a nationwide population-based cohort study with prospectively collected data. SETTING: Data from 2014 through 2016 were provided by the Danish nationwide colorectal cancer database (Danish Colorectal Cancer Group). PATIENTS: All patients aged ≥18, who had elective surgery for colorectal cancer were included. MAIN OUTCOME MEASURES: Multiple logistic regressions were performed to investigate 90-day mortality, 30-day mortality, and complications. One-year mortality was determined by Cox regression, and overall survival was illustrated by Kaplan-Meier curves. RESULTS: A total of 10,279 patients had elective colorectal cancer surgery during the study period (6892 colonic and 3387 rectal). Thirty-four percent of the patients with colorectal cancer had a World Heath Organization performance status ≥1. The odds ratios of postoperative 90-day mortality in colon cancer for performance status 1, 2, and 3/4 compared with performance status 0 were 2.50 (95% CI, 1.67-3.73), 5.00 (95% CI, 3.19-7.86), and 17.34 (95% CI, 10.18-29.55). The odds ratios of postoperative 90-day mortality in rectal cancer for performance status 1, 2, and 3/4 were 3.90 (95% CI, 2.23-6.85), 9.25 (95% CI, 4.75-18.02), and 10.56 (95% CI, 4.07-27.41). Performance status was also associated with 30-day mortality, overall survival, and medical complications. LIMITATIONS: Only 1 year of follow-up was possible for all patients, and cancer-specific survival was not available. CONCLUSION: One of three patients has a performance status >0 and is associated with an increased risk of death, complications, and overall survival for both colonic and rectal cancers. See Video Abstract at http://links.lww.com/DCR/B540. EL ALTO NIVEL DE DESEMPEO DE LA ORGANIZACIN MUNDIAL DE LA SALUD SE ASOCIA CON RESULTADOS A CORTO Y LARGO PLAZO DESPUS DE LA CIRUGA DEL CNCER COLORRECTAL UN ESTUDIO POBLACIONAL A NIVEL NACIONAL: ANTECEDENTES:El valor del estado funcional se usa ampliamente en oncología médica, pero no se ha descrito la asociación con los resultados quirúrgicos en el cáncer colorrectal.OBJETIVO:El objetivo fue investigar la asociación entre el estado funcional de la Organización Mundial de la Salud y la mortalidad a 90 días, la mortalidad a 30 días, las complicaciones y la supervivencia general después de la cirugía electiva del cáncer colorrectal.DISEÑO:El estudio se realizó como un estudio de cohorte poblacional a nivel nacional con datos recolectados prospectivamente.ENTORNO CLINICO:Los datos fueron proporcionados por la base de datos de cáncer colorrectal a nivel nacional danés (DCCG.dk) en un período de estudio de 2014-2016.PACIENTES:Se incluyeron todos los pacientes de ≥18 años que se sometieron a cirugía electiva por cáncer colorrectal.PRINCIPALES MEDIDAS DE VALORACION:Para investigar la mortalidad a los 90 días, la mortalidad a los 30 días y las complicaciones se realizaron regresiones logísticas múltiples. La mortalidad a un año se determinó mediante regresión de Cox y la supervivencia general se ilustra mediante curvas de Kaplan-Meier.RESULTADOS:Un total de 10 279 pacientes se sometieron a cirugía electiva de cáncer colorrectal en el período de estudio (6892 colónico y 3387 rectal). Treinta y cuatro por ciento de los pacientes con cáncer colorrectal tenían un estado funcional de la Organización Mundial de la Salud ≥1. Los ratios de probabilidades (odds ratios) de mortalidad postoperatoria a los 90 días en cáncer de colon para el estado funcional 1, 2 y 3/4 en comparación con el estado funcional 0 fueron 2,50 (IC del 95%: 1,67-3,73), 5,00 (IC del 95%: 3,19-7,86) y 17,34 (IC del 95%: 10,18-29,55), respectivamente. Los ratios de probabilidades de mortalidad postoperatoria de 90 días en cáncer de recto para el estado funcional 1, 2 y 3/4 fueron 3,90 (IC del 95%: 2,23-6,85), 9,25 (IC del 95%: 4,75-18,02) y 10,56 (IC del 95%: 2,23-6,85) % CI: 4,07-27,41). El estado funcional también se asoció con la mortalidad a los 30 días, la supervivencia general y las complicaciones médicas.LIMITACIONES:Solo fue posible un año de seguimiento para todos los pacientes y la supervivencia específica del cáncer no estaba disponible.CONCLUSIÓN:Uno de cada tres pacientes tiene un estado funcional> 0 y se asocia con un mayor riesgo de muerte, complicaciones y supervivencia general para los cánceres de colon y recto. Consulte Video Resumen en http://links.lww.com/DCR/B540.

Hydroxychloroquine as a primary prophylactic agent against SARS-CoV-2 infection: A cohort study.

OBJECTIVE: Hydroxychloroquine has been proposed as a primary prophylactic agent against coronavirus disease 2019 (COVID-19). This study aimed to investigate if patients treated with hydroxychloroquine for a non-COVID-19 indication had a lower risk of verified infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) compared with matched controls. METHODS: A cohort comprising all persons in Denmark collecting hydroxychloroquine prescriptions in 2020 and 2019 (i.e., both during and before SARS-CoV-2 was confirmed in Denmark), matched by age and sex with controls, was studied. Data were collected using the Danish national registries, which contain complete information on patient health data, prescriptions and microbiological test results. The main outcome was microbiologically verified SARS-CoV-2 infection. RESULTS: In total, 5488 hydroxychloroquine users were matched with 54,486 non-users. At baseline, the groups differed in terms of diagnoses of pulmonary disease, cardiovascular disease, renal disease, gastrointestinal/metabolic disease and dementia, as well as treatment with antirheumatic drugs. The final model was adjusted for these potential confounders. Use of hydroxychloroquine for non-COVID-19 indications was not associated with any change in confirmed SARS-CoV-2 (hazard ratio 0.90, 95% confidence interval 0.76-1.07). This result was robust in the propensity-score-matched sensitivity analysis. CONCLUSION: This study, which is the largest to date to investigate the primary prophylactic effect of hydroxychloroquine against SARS-CoV-2, does not support any prophylactic benefit of hydroxychloroquine in the prevention of infection with SARS-CoV-2.

The dynamic effects of preoperative intravenous iron in anaemic patients undergoing surgery for colorectal cancer.

AIM: The aim of this study was to describe the dynamic changes in blood work following individual adjusted dosage of intravenously administered iron(III) isomaltoside in a 4-week period prior to surgery in patients with colorectal cancer. METHODS: This was a single-centre, observational cohort study with prospectively collected data, including patients with colorectal cancer receiving preoperative treatment with iron(III) isomaltoside. Blood samples were taken at baseline, 1 week, 2 weeks and 4 weeks after initial treatment. Sixty-two patients were included in the study. RESULTS: Sixty-two patients were included for final analysis. The mean increase in haemoglobin was 0.77 g/dl (95% CI 0.52-1.03 g/dl, P < 0.0001) at week 1, 1.5 g/dl (95% CI 1.21-1.80 g/dl, P < 0.0001) at week 2 and 2.13 g/dl (95% CI 1.71-2.55 g/dl, P < 0.0001) at week 4. Patients with severe anaemia (<9.02 g/dl) showed the largest increase in haemoglobin during the treatment course (2.92 g/dl, 95% CI 2.27-3.58 g/dl, P < 0.0001). Patients with mild anaemia (>10.31 g/dl) did not show a significant increase (0.66 g/dl, 95% CI -0.29-1.61 g/dl, P = 0.17). The mean of transferrin saturation after 4 weeks was 8% (95% CI 6%-10%, P < 0.0001). CONCLUSIONS: After intravenously administered iron, patients with severe anaemia had the most substantial increase in haemoglobin, and the increase was largest after 4 weeks. Patients with mild anaemia did not have an increase in haemoglobin during the treatment course. The vast majority of patients still had iron deficiency at surgery 4 weeks after the initial treatment.

Proactive Prophylaxis With Azithromycin and HydroxyChloroquine in Hospitalised Patients With COVID-19 (ProPAC-COVID): A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: The aim of this randomised GCP-controlled trial is to clarify whether combination therapy with the antibiotic azithromycin and hydroxychloroquine via anti-inflammation/immune modulation, antiviral efficacy and pre-emptive treatment of supra-infections can shorten hospitalisation duration for patients with COVID-19 (measured as "days alive and out of hospital" as the primary outcome), reduce the risk of non- invasive ventilation, treatment in the intensive care unit and death. TRIAL DESIGN: This is a multi-centre, randomised, Placebo-controlled, 2-arm ratio 1:1, parallel group double-blind study. PARTICIPANTS: 226 participants are recruited at the trial sites/hospitals, where the study will take place in Denmark: Aalborg, Bispebjerg, Gentofte, Herlev, Hillerød, Hvidovre, Odense and Slagelse hospitals. INCLUSION CRITERIA: • Patient admitted to Danish emergency departments, respiratory medicine departments or internal medicine departments • Age≥ 18 years • Hospitalized ≤48 hours • Positive COVID-19 test / diagnosis during the hospitalization (confirmed). • Men or non-fertile women. Fertile women* must not be pregnant, i.e. negative pregnancy test must be available at inclusion • Informed consent signed by the patient *Defined as after menarche and until postmenopausal (no menstruation for 12 months) Exclusion criteria: • At the time of recruitment, the patient uses >5 LO2/min (equivalent to 40% FiO2 if measured) • Known intolerance/allergy to azithromycin or hydroxychloroquine or hypersensitivity to quinine or 4-aminoquinoline derivatives • Neurogenic hearing loss • Psoriasis • Retinopathy • Maculopathy • Visual field changes • Breastfeeding • Severe liver diseases other than amoebiasis (INR> 1.5 spontaneously) • Severe gastrointestinal, neurological and hematological disorders (investigator-assessed) • eGFR <45 ml/min/1.73 m2 • Clinically significant cardiac conduction disorders/arrhythmias or prolonged QTc interval (QTc (f) of> 480/470 ms). • Myasthenia gravis • Treatment with digoxin* • Glucose-6-phosphate dehydrogenase deficiency • Porphyria • Hypoglycaemia (Blood glucose at any time since hospitalization of <3.0 mmol/L) • Severe mental illness which significantly impedes cooperation • Severe linguistic problems that significantly hinder cooperation • Treatment with ergot alkaloids *The patient must not be treated with digoxin for the duration of the intervention. For atrial fibrillation/flutter, select according to the Cardiovascular National Treatment Guide (NBV): Calcium antagonist, Beta blocker, direct current (DC) conversion or amiodarone. In case of urgent need for digoxin treatment (contraindication for the aforementioned equal alternatives), the test drug should be paused, and ECG should be taken daily. INTERVENTION AND COMPARATOR: Control group: The control group will receive the standard treatment + placebo for both types of intervention medication at all times. If part or all the intervention therapy being investigated becomes standard treatment during the study, this may also be offered to the control group. Intervention group: The patients in the intervention group will also receive standard care. Immediately after randomisation to the intervention group, the patient will begin treatment with: Azithromycin: Day 1-3: 500 mg x 1 Day 4-15: 250 mg x 1 If the patient is unable to take the medication orally by themselves, the medication will, if possible, be administered by either stomach-feeding tube, or alternatively, temporary be changed to clarithromycin 500 mg x 2 (this only in agreement with either study coordinator Pradeesh Sivapalan or principal investigator Jens-Ulrik Stæhr Jensen). This will also be done in the control group if necessary. The patient will switch back to azithromycin when possible. Hydroxychloroquine: Furthermore, the patient will be treated with hydroxychloroquine as follows: Day 1-15: 200 mg x 2 MAIN OUTCOMES: • Number of days alive and discharged from hospital within 14 days (summarises both whether the patient is alive and discharged from hospital) ("Days alive and out of hospital") RANDOMISATION: The sponsor (Chronic Obstructive Pulmonary Disease Trial Network, COP:TRIN) generates a randomisation sequence. Randomisation will be in blocks of unknown size and the final allocation will be via an encrypted website (REDCap). There will be stratification for age (>70 years vs. <=70 years), site of recruitment and whether the patient has any of the following chronic lung diseases: COPD, asthma, bronchiectasis, interstitial lung disease (Yes vs. No). BLINDING (MASKING): Participants and study personnel will both be blinded, i.e. neither will know which group the participant is allocated to. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): This study requires 226 patients randomised 1:1 with 113 in each group. TRIAL STATUS: Protocol version 1.8, from April 16, 2020. Recruitment is ongoing (first patient recruited April 6, 2020; final patient expected to be recruited October 31, 2020). TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04322396 (registered March 26, 2020) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Driver Gene Mutations and Epigenetics in Colorectal Cancer.

OBJECTIVE: The majority of patients with colorectal cancer are diagnosed with locally advanced and/or disseminated disease, and treatment options include surgery in combination with cytotoxic chemotherapy regimens, biologics, and/or radiotherapy. Thus, colorectal cancer remains a heavy burden on society and health care systems.Mounting evidence show that driver gene mutations play only part of the role in carcinogenesis. Epigenetics are strongly implicated in initiation and progression of colorectal cancer along with major players such as intestinal microbiotic dysbiosis and chronic mucosal inflammation.To assess phenotypic changes in proteins and gene expression, multigene expression signatures based on sequencing techniques have been developed to hopefully improve predictors of the tumor profile, immune response, and therapeutic outcomes. Our objective was to review current advances in the field and to update surgeons and academics on driver gene mutations and epigenetics in colorectal cancer. BACKGROUND AND METHODS: This is a narrative review studying relevant research published in the PUBMED database from 2012-2018. RESULTS AND CONCLUSION: Increased understanding of the molecular biology will improve options to characterize colorectal cancer with regard to mutations and molecular pathways, including microsatellite instability, epigenetics, microbiota, and microenvironment. Research will inevitably improve risk group stratification and targeted treatment approaches.Epigenetic profiling and epigenetic modulating drugs will increase risk stratification, increase accessibility for DNA targeting chemotherapeutics and reduce cytotoxic drug resistance.New generation antibiotics such as biofilm inhibitors and quorum sensing inhibitors are being developed to target the carcinogenetic impact of colonic dysbiosis and inflammation.

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.

Inflammatory Bowel Disease and Small Bowel Cancer Risk, Clinical Characteristics, and Histopathology: A Population-Based Study.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) may increase risk of small bowel cancer (SBC). However, little is known of the characteristics and features of IBD-SBC, due to a low number of cases worldwide. We performed a population-based study of IBD and SBC to calculate risk and increase our understanding of clinical characteristics and histopathological and molecular features. METHODS: The study population consisted of all individuals aged 16 years or older living in Denmark during 1978-2010. Through linkage between national registers and subsequent scrutiny of medical records and pathology descriptions, we identified 40 cases of IBD-SBC. Risk was calculated by standardized incidence ratio (SIR) (observed/expected); patient characteristics were derived from medical files, and surgery specimens were obtained from hospitals nationwide for histopathological and molecular analyses. RESULTS: During 241,620 person-years of follow-up, 23 patients with Crohn's disease developed small bowel adenocarcinoma (SIR, 14.38; 95% confidence interval, 8.78-22.20) and 9 developed neuroendocrine tumors (SIR, 6.83; 95% confidence interval, 3.13-12.97). No significantly increased risk of SBC was found among patients with ulcerative colitis. Most patients with SBC had moderate-to-severe Crohn's disease with small bowel and upper gastrointestinal involvement. Assessment of surgical specimens of small bowel adenocarcinomas revealed a clear transition from inflammation to dysplasia and cancer, whereas no tumors had evidence of microsatellite instability. CONCLUSIONS: In a population-based study of patients in Denmark with IBD and SBC, we found risk of adenocarcinomas and neuroendocrine tumors to be increased among persons with Crohn's disease. Most patients with IBD-SBC had extensive IBD of moderate-to-severe activity. Adenocarcinomas appeared to develop via an inflammation-dysplasia-carcinoma pathway, but differed from IBD-related colorectal adenocarcinomas in their molecular features.

Incidence of, phenotypes of and survival from small bowel cancer in Denmark, 1994-2010: a population-based study.

BACKGROUND: Small bowel cancer (SBC) is a rare and highly heterogeneous disease in respect to both anatomical distribution and histological morphology. We aimed to conduct a Danish nationwide population-based cohort study of the incidence of, phenotypes of, stage of, synchronous/metachronous cancer occurrence of and survival from SBC during 1994-2010. METHODS: The study population included all individuals aged 16 years or older living in Denmark during 1994-2010 (n = 7,070,142). Patients with SBC were identified through the Danish Cancer Registry. Incidence rates were calculated overall and according to the anatomical origin and morphological subtype. Patients were followed up from the date of cancer diagnosis to the date of emigration, death or the end of the study (31 December 2010). RESULTS: SBC was diagnosed in 1088 patients during 1994-2010. The total annual incidence of SBC was 1.10 per 100,000 [95 % confidence interval (CI) 1.04 to 1.17 per 100,000], with an annual percentage change of 1.9 % (95 % CI 0.6-3.1 %, p = 0.003) during the observation period. This increase was mainly explained by an increase in the occurrence of duodenal adenocarcinomas, with an annual percentage change of 7.5 % (95 % CI 4.9-10.2 %, p < 0.001). Further, 29 % of all SBC patients had metastatic cancer at the time of diagnosis and 32 % had one or more synchronous/metachronous cancers. All morphological subtypes were associated with poor 5-year prognoses, in particular duodenal adenocarcinomas, with a 5-year survival rate of only 16 % (95 % CI 12-22 %). CONCLUSIONS: The incidence of SBC has increased in recent decades, mainly because of a large increase in the incidence of duodenal adenocarcinomas, which are also associated with the poorest prognosis.