Preoperative risk assessment and prehabilitation strategies in patients undergoing an esophagectomy for cancer resections: a single center retrospective analysis and a review of the literature

Esophagectomy remains being a surgical procedure with a high morbidity and mortality rate. Therefore, prehabilitation, defined as the group of interventions performed on the patient in the preoperative period to improve their functional capacity and clinical condition, becomes highly important to ensure that the patient faces the stress that surgery entails under the best possible clinical situation. Hereby, we describe our prehabilitation protocol that has been implementedsince 2017 and we present the clinical results achieved so far. Preoperative risk assessment and various modalities of prehabilitation protocols are discussed to enhance the patient´s preoperative physiological condition and to reduce the impact of the neuroendocrine and inflammatory response induced by an esophagectomy. Finally, we describe the protocol we intend to implement to improve our clinical practice and reduce complications.

1 Introduction

Esophageal cancer ranks as the eighth most common neoplasm and the sixth leading cause of death due to cancer worldwide, with about 604,127 new cases per year and approximately 544,000 deaths (1). Due to its natural history, esophageal cancer is often diagnosed in advanced stages, leading to high mortality, with a 5-year overall survival (OS) rate of 20%. The estimated average survival after 5 years in localized tumors is 45%, 24% in tumors with lymph node involvement, and 5% in disseminated tumors (1). The two most common histological types worldwide are squamous cell carcinoma and adenocarcinoma. Despite being a disease with a poor prognosis, improvements have been made in the management of esophageal cancer in recent decades. The cornerstone of curative treatment is surgical resection with lymphadenectomy, sometimes combined with neoadjuvant treatment with chemotherapy (CT) or chemoradiotherapy (CRT) with the intention of improving oncological outcomes (2). The choice of the most appropriate surgical technique should be individualized and it is mainly determined by the location of the tumor (3–5). In recent years, the development of minimally invasive surgery has succeeded in reducing complications related to laparotomy and thoracotomy, hospital stay, and respiratory complications, while presenting comparable oncological outcomes and similar rates of anastomotic leak or number of resected lymph nodes (6–9).

The preoperative risk assessment becomes of great importance (modifiable and non-modifiable risks), evaluating comorbidities of the patient, as well as cardiopulmonary function, functional capacity, and nutritional status in order to optimize all possible aspects to ensure that the patient undergoes surgery in the best possible clinical condition, thereby improving outcomes (10, 11). Enhanced recovery after surgery protocols (ERAS programs) aim to improve postoperative outcomes by accelerating the patient's recovery and reducing hospital stay and the associated costs (12). While intra- and postoperative measures have been maximized in these protocols, the preoperative period has been the most neglected one.

Prehabilitation, defined as the combination of interventions performed on the patient in the preoperative period, aims to accompany and prepare patients to face surgery under the best possible clinical conditions (13, 14). Initially based on a three-pillar conception: improvement of the patient's physical condition, nutritional optimization and cognitive intervention to reduce stress and anxiety; it has evolved into a multimodal strategy including smoking cessation, correction of anemia and pharmacological adjustment (15–17). It is worth noting that we are increasingly operating on older patients with a higher rate of associated comorbidities, meeting “frailty” criteria, and with diminished physiological and functional capacity. In these patients, the implementation of different measures from the ERAS program brings benefits, but we need better preoperative optimization of their baseline state, by improving their functional status (physical, nutritional, and psychological capacity), as it is one of the modifiable factors related to poor postoperative outcomes (18). It can be stated that patients who most clearly benefit from these programs are those at high risk (ASA III and IV), as well as those with preoperative studies showing a deteriorated functional status (19).

Regarding prehabilitation, particularly in patients undergoing esophagogastric surgery, the evidence seems to confirm its beneficial effects despite the heterogeneous design of the studies (20).

The main objective of this article is to present our preoperative management protocol for patients undergoing these surgeries and the results obtained with it from January 2017 to November 2023, and, furthermore, to compare it with the results published in the literature.

We also aim to perform a review of the existing evidence regarding specific prehabilitation programs for esophagectomies (within the context of ERAS programs) and their relationship with improving the patients’ functional status and their postoperative outcomes. Additionally, it aims to describe and convey the most important components within these programs.

In addition, we want to present the new prehabilitation protocol of our center, incorporating new measures not previously implemented and aiming to compare, in the future, the results obtained in patients undergoing it with those who underwent surgery before implementing the new protocol, in order to determine if postoperative complications (especially respiratory ones) and mortality are reduced by implementing a more comprehensive (multimodal) prehabilitation approach.

2 Material and methods

A descriptive, retrospective and single-center study has been designed. This study has been reviewed and approved by the Ethics Committee for Scientific Research of the Donostia University Hospital. Our center is a third-level hospital, serving as the provincial reference center for esophageal surgery. Since January 2017 until November 2023, patients undergoing neoadjuvant CRT prior to an esophagectomy participate in the prehabilitation program designed for this purpose.

Variables such as demographic data, associated comorbidities, toxic habits, clinical data at the time of the diagnosis of the desease, analytical and endoscopic data, imaging tests, anatomopathological data, clinical staging, treatment received, treatment-associated complications, surgical aspects, post-intervention complications, definitive anatomopathological results, and survival data were collected.

To review the existing literature related to the topic, a research in Medline, PubMed, Embase, Cinahl, and Cochrane was carried out, including the references that we considered more relevant.

In Tables 1, 2 we show the most relevant publications.

Table 1

Table 1. Included studies.

Table 2

Table 2. Reviews and meta-analysis.

3 Statistical analysis

This is a descriptive analysis where quantitative variables are expressed as mean (minimum and maximum), and categorical variables are expressed as absolute frequencies and relative percentages.

4 Results

Below, we present the preoperative protocol that we applied to patients undergoing esophagectomies between January 2017 and November 2023:

After completing the preoperative study, patients were evaluated in the multidisciplinary tumor committee of the esophagogastric area, where the optimal therapeutic modality was decided based on tumor staging, location, and associated comorbidities. The therapeutic algorithm of our center is attached (21) (Figure 1).

Figure 1

Figure 1. Therapeutic management of patients with esophageal cancer at the Donostia University Hospital. Scheme based on the therapeutic management of esophageal cancer at the Donostia University Hospital.

Patients were considered operable or non-operable based on age and comorbidities. Tumors were considered unresectable if they were staged cT4b or located in the cervical or upper high thoracic region. In all patients eligible for a radical treatment, an initial assessment of nutritional and physical status was conducted. Nutritional status was analyzed using the MUST tool and if there was a risk of malnutrition, a Patient-Generated Subjective Global Assessment (PG-SGA) test was performed. Functional capacity was not assessed. Based on the result of this latter test, corresponding nutritional recommendations were provided as depicted in Figure 2. Following the completion of neoadjuvant CRT, patients eligible for surgery were referred to the Rehabilitation Service to improve their physical condition before the intervention. For this purpose, patients attended 1-h hospital supervised sessions three times per week until the day of the surgery (approximately for 6–8 weeks), during which the following exercises were performed:

• Aerobic exercise (cycling or treadmill, 20–30 min, Borg 11–13).

• Strength training (10–12 repetitions of quadriceps, biceps, latissimus dorsi, Borg 11–13).

• Inspiratory muscle training starting at 30% of MIP (maximum inspiratory pressure), 10–12 repetitions twice a day, progressing 10% every 2 weeks until reaching 50%–60% of MIP).

Figure 2

Figure 2. Assessment of nutritional Status in patients with esophageal cancer eligible for curative intent treatment at Donostia University Hospital.

After reviewing the patients during this period, these was the data obtained:

Since the implementation of this protocol in January 2017 until now, 46 patients have undergone neoadjuvant CRT and surgery. The mean age was of 63.7 years (ranging from 46 to 76 years), 37 (80.4%) of them being male patients and 9 (19.5%) female. According to the protocol, patients underwent surgery 6–8 weeks after completing the treatment, during which they were referred to the Rehabilitation Service. They were all patients that had completed the physical training program and had undergone nutritional assessment. Demographic data are collected in Table 3.

Table 3

Table 3. Demographic data.

13 patients (28.2%) did not experience any complications, 23 (50%) had complications classified as Clavien-Dindo I or II (minor), and 11 (23.9%) had Clavien-Dindo III or IV (major) complications. Postoperative mortality was 8.7% at 30 days. The postoperative results are collected in Table 4.

Table 4

Table 4. Postoperative results.

5 Prehabilitation measures

A review of the current evidence on prehabilitation in esophageal cancer has been conducted, aiming to identify measures of particular interest and have an impact on outcomes, thus enabling future protocols to be tailored and evidence to be published. These measures are described below:

5.1 Proper preoperative assessment and pharmacological adjustment

Carrying out a proper preoperative assessment is extremely important due to the high obesity rate, respiratory and cardiovascular pathologies, and the increasing age of the patients. Approximately 30% of surgery candidates are ASA III or IV. There is not a complete consensus on this matter yet, and predicting which patients will develop complications is not an easy task (22). However, risk factors that increase morbidity and mortality after an esophagectomy have been established: poor cardiopulmonary reserve, advanced age, tumor stage, diabetes mellitus, liver dysfunction and overall a poor clinical condition (11).

There is no consensus either regarding the mortality scale to be used in the assessment of these patients. Some of the scales described in the literature are the POSSUM and the P-POSSUM, which seem to be directly related to worse perioperative quality of life in patients with high scores (23). One of the most commonly used is the American Society of Anesthesiologists (ASA) scale, which relates the anesthesia risk to the patient's various comorbidities, not the anesthesia risk itself (24). This scale on its own does not predict perioperative risks. Associated with other factors, such as the type of surgery and frailty, it can be more accurate in determining perioperative risks. The Clinical Frailty Scale (CFS) has been shown to be reliable predicting complications in patients undergoing major abdominal surgery (25).

Several tools have been described for determining the patient's functional capacity, such as the Duke Activity Status Index (DASI), the Shuttle Walk Test (SWT), and the Cardiopulmonary Exercise Testing (CPET) (26, 27).

In a review of different tools to identify patients at risk of malnutrition, the Malnutrition Universal Screening Tool (MUST) was found to be the most sensitive, specific, and accurate identifying malnourished patients (28).

The adjustment of the patient's pharmacological treatment for surgery should be done since the pre-anesthesia consultation.

5.2 Preoperative anemia

Anemia in cancer patients is quite common. The causes are varied: losses caused by the tumor itself, anemia due to chronic illnesses, marrow suppression induced by chemotherapy and radiotherapy, deficiencies due to nutritional deficiencies, or acute losses during surgery, among others. Additionally, both anemia and transfusions have been established as independent risk factors for increased mortality in esophageal cancer patients. Therefore, diagnosing it becomes essential to establish a treatment targeted at the cause to correct it before surgery, thus minimizing the number of transfusions (29, 30). Patient Blood Management (PBM) programs are evidence-based guidelines, implemented in hospitals progressively, aiming to detect anemia in the preoperative period to treat it in time before surgery, thereby minimizing the use of blood products in the perioperative period (intravenous iron, erythropoietin). They also promote other measures with the same objective, such as reducing intraoperative bleeding with the use of antifibrinolytic drugs like tranexamic acid and employing more restrictive transfusion thresholds (Hb 7 g/dl) (30, 31).

5.3 Exercise training

Exercise has beneficial effects on individual health, including those patients with cancer. Physical activity improves patients’ functional capacity, reduces cancer-related fatigue, and enhances quality of life (32, 33). The postoperative period is associated with a decrease of 20%–40% in functional capacity. Traditionally, the postoperative period has been used for the recovery of this functional capacity (rehabilitation). However, it has been demonstrated that this is not the ideal time to do so, due to the clinical and personal situation experienced by the patient after surgery. The preoperative period is the optimal time to intervene and improve the patient's physical and functional capacity (prehabilitation) (19), as demonstrated by Gillis et al. in a clinical trial with patients undergoing colorectal surgery. They showed a significant increase in functional capacity measured with the 6MWT in patients undergoing a prehabilitation program between 3 and 4 weeks before surgery, within the context of an enhanced recovery program (34). Previously, a low preoperative 6MWT had been associated with an increased risk of respiratory complications in patients (35). Therefore, exercise is one of the pillars of prehabilitation programs.

Nevertheless, there is no agreement on which exercise regimen is best, resulting in a wide variety of interventions. These programs should include at least 4 weeks of a combination of aerobic training, resistance training, and inspiratory muscle training to ensure endurance. The frequency, intensity, and duration of each exercise should differ depending on each patient's initial fitness and their health status and should be managed by skilled individuals. Unsupervised or tele-exercise with remote supervision exercises may also be possible in selected patients. Exercise and physical activity programs should also include the promotion of daily physical activity, reducing sitting or sedentary time, and promoting long-term behavior changes to embrace a more active lifestyle.

5.4 Nutritional status

There is evidence that malnutrition is an independent predictor of poor postoperative outcomes (36). This is particularly important considering that the prevalence of malnutrition in patients with this type of cancer can reach up to 80% (37, 38).

Therefore, detecting patients at risk of malnutrition is a fundamental task during the preoperative period, establishing the specific situation of each patient to initiate an individualized nutritional treatment (15, 39, 40).

In those with a MUST ≥2, a nutritional treatment should be initiated to improve their state before surgery and maintain it throughout the perioperative period. Evidence supports starting treatments at least 2 weeks before surgery (41). Depending on the severity of the patients’ malnutrition, patients will receive counseling from a nutritionist, who will assess the appropriate treatment for the patient, instructing them on nutrition and healthy habits. Diet enrichment, either with natural ingredients or with hyperproteic and caloric supplements, is recommended. Micronutrient intake will be recommended in particular cases (42). According to the ESPEN guidelines, supplements should provide at least 400 Kcal with ≥30 g of protein per day (43). Enteral and parenteral nutrition will be considered in cases where oral intake is not possible (28).

Regarding new nutritional therapies, the evidence is limited at the moment. The benefits of probiotic and symbiotic interventions in patients with gastrointestinal cancer are controversial. There is a phase II study investigating the possible beneficial action of fecal microbiota transplantation from obese patients to cachectic patients with esophagogastric cancer (44).

5.5 Mental support

We must not forget the psychological effect that a cancer diagnosis has on patients. Although there is not much evidence, partly due to the limited availability of these resources in hospitals, it does seem that therapies aimed at reducing stress and anxiety in the preoperative period would have a beneficial effect on the patient (45, 46). Depression and anxiety generated by the process can influence a lower treatment compliance, thereby worsening the prognosis, and it also seems to favor a disease progression (47–49). There is not much evidence regarding the type of psychological treatment to employ (45).

5.6 Patient educational and hygienic interventions

5.6.1 Smoking cessation

Smoking has also been linked to a higher rate of postoperative complications and increased costs. It has been established that a reduction of respiratory complications is noticeable after 4 weeks. The responsible physician should advise the patient and provide all available therapeutic tools to facilitate smoking cessation before surgery (50).

5.6.2 Alcohol consumption

Harmful alcohol consumption is associated with increased postoperative complications, such as increased bleeding, infections, pulmonary complications, interference with anesthetic drugs, and delayed recovery, leading to increased admissions to critical care units and hospital stays.

In a review of RCTs evaluating the effects of preoperative alcohol cessation on postoperative complications, the primary objectives were postoperative complications and 30-day mortality. Secondary objectives included the length of the hospital stay and alcohol use in the postoperative period.

A significant reduction in the rate of postoperative complications was observed, but not in the 30-day mortality rate or the length of stay (51).

The ideal therapy to implement for alcohol abuse cessation (counselling sessions and/or pharmacologic therapies) and the optimal cessation period before surgery is yet to be determined. Cessation between 6 and 8 weeks before surgery is recommended, but it appears that cessation of 2–4 weeks could already be associated with a decrease in the risk of postoperative complications.

5.6.3 Other drugs

Patients with drug abuse disorders such as opioids, benzodiazepines, etc., are at higher risk of postoperative complications such as delirium, pneumonia, respiratory failure, mechanical ventilation, prolonged hospital stays, and difficult postoperative pain control.

Ideally, the patient should be provided with a personalized perioperative plan, if possible, combined with an addiction specialist and a pain management expert. It would be necessary to establish an evidence-based protocol to ensure adequate pain control while avoiding the development of withdrawal symptoms. More studies are required (52, 53).

5.6.4 Dental care

Improving the patients’ dental hygiene could reduce the cases of postoperative pneumonia that may arise from the aspiration of oropharyngeal secretions. Ishimaru et al. conducted a retrospective cohort study to evaluate the relationship between preoperative oral care and postoperative complications in patients undergoing major oncological surgery. Between May 2012 and December 2015, they studied patients undergoing head and neck, esophagogastric, colorectal, hepatic, and pulmonary surgery. The primary objectives were postoperative pneumonia and 30-day mortality. Of a total of 509 patients, 179, only 16%, received oral treatments from a dentist. They concluded that preoperative oral care by a dentist significantly reduced the incidence of pneumonia and 30-day mortality (54).

In any case, we must provide personalized attention and try to provide an individualized program for each of our patients (10).

6 Discussion

Firstly, we have compared our results with our current prehabilitation protocol to those published in the literature.

Regarding our series, the most common histological types include squamous cell carcinoma and adenocarcinoma. The mean age at diagnosis in our population has been 63.7 years, which is 5 years lower than the national average (55). The prevalence, as reflected in the literature, has been higher in males for both histological types (56). As recommended by the The National Comprehensive Cancer Network (NCCN) guidelines, optimal treatment should be based on accurate disease staging, tumor location and histology, and therapeutic approach should be discussed by a multidisciplinary team (57). In our center, the creation of the Multidisciplinary Committee for Gastroesophageal Tumors took place in 2005, it consisted of pathologists, medical oncologists, radiation oncologists, surgeons, radiologists, and nursing staff, discussing all the cases of esophageal cancer individually. Surgery-related complications, in addition to increasing the average length of hospital stay, costs, and resource utilization; have a negative impact on postoperative survival and quality of life (58). They act as independent prognostic factors after an esophageal resection, with 5-year survival rates and disease-specific survival rates lower than those of patients who do not present them (59). The most common complications after resective esophageal surgery are pneumonia, atrial fibrillation, and anastomotic leakage, occurring in 14.6%, 14.5%, and 11.4%, respectively, according to the Esophageal Complications Consensus Group (ECCG) benchmark (60). Respiratory complications are the most common major complications, resulting from the impact of surgery on the thoracic wall, diaphragm, and abdominal wall, and are responsible for 50%–65% of surgery-related mortality. In our series, the rate of postoperative pneumonia was 6.5% lower than the one reported by the ECCG, with rates of 14.6%. The rate of anastomotic leakage after a neoadjuvant therapy reached 10.8%, also lower than reported while the 30-day mortality rate was 8.7%, similar to the reported rates in the literature ranging from 6% to 8.9% at 30 days and 13.3–15.8% at 90 days (61, 62).

Therefore, although we have observed lower morbidity rates in our series when compared to the current literature, we believe that we could improve these results by implementing new measures in the prehabilitation protocol, making it more comprehensive.

As we have already mentioned throughout the article, prehabilitation has gained importance as a tool aimed at improving patient recovery and postoperative outcomes, encompassing a set of measures aimed at optimizing, among others, the physical, nutritional, and psychological status of the patient. While there is strong evidence supporting its utility in improving postoperative outcomes following abdominal surgery, in the context of the ERAS programs, specific evidence in esophagectomies remains limited. However, due to, on the one hand, the high rate of postoperative morbidity associated with this type of surgery, and, on the other hand, the impact on functional reserve caused by cachexia and neoadjuvant therapy, as well as the psychological impact of cancer diagnosis, it seems logical to think that these patients would greatly benefit their functional, physiological, and psychological capacity by undergoing these prehabilitation programs to face surgery and recover from it.

In that sense, Bausys et al. conducted a review of the existing evidence, concluding that there is still considerable variability among prehabilitation programs, as well as in the interventions performed and the outcomes collected (21). They also asserted that one of the main problems with these programs is the low adherence to them. However, their beneficial effect can be confirmed.

Minella et al. in 2018, published the results of a clinical trial in which they noted a significant improvement in the functional capacity of patients before and after surgery in those undergoing prehabilitation (18).

Furthermore, in 2023, An et al., in another systematic review and meta-analysis, with studies from 2000 to 2023 (1,803 patients from 584 clinical trials and 1,219 from observational studies), concluded that prehabilitation reduced respiratory complications and pneumonia in observational studies, but not in clinical trials. These results highlight the low quality of existing evidence in esophagectomies. Regarding the stay in the intensive care unit, operative mortality, and severe complications (Clavien-Dindo ≥3), there were no differences between groups (63).

Zhao et al. have recently published a meta-analysis with the purpose of evaluating the effect of uni- or multimodal prehabilitation in esophagogastric cancer. They included 6 clinical trials and another 6 cohort studies in their analysis, and concluded that multimodal prehabilitation was effective in reducing the risk of severe complications, unlike unimodal prehabilitation (64).

Therefore, in summary, the objective of prehabilitation is to prevent the functional consequences that oncological treatment has on patients, acting on modifiable factors such as exercise, nutrition, anemia, or smoking habits. It aims to improve the patient's overall situation (65).

6.1 Future protocol changes

Taking into account the evidence and being critical of our clinical practice, we believe that despite our results being in line with published series, there are still areas that need to be improved in the preoperative period.

Having reduced our prehabilitation protocol to a trimodal program (nutrition, anemia and exercise) so far, our goal is to expand it into a multimodal program with the inclusion of additional measures.

Firstly, we are beginning with the incorporation of anesthesiologists into the Tumor Committee, as their involvement will provide a valuable perspective in the initial decision-making process.

Furthermore, we will expand the screening of physical fitness to include not only patients eligible for preoperative chemotherapy or radiotherapy but also those selected for direct surgery. We will also assess functional capacity (Duke Activity Status Index, DASI). Thus, all patients with a DASI ≤34 or a CFS ≤4 will be referred to the rehabilitation clinic to determine the appropriate physiotherapy program.

Regarding nutritional status, patients with a MUST = 1 and/or albumin <3 g/dl or a MUST ≥2 will be referred to the nutritionist's clinic (a clinical figure we now have in our hospital) to initiate appropriate nutritional treatment.

Additionally, we have updated our PBM program in these patients and thus, all patients will undergo a blood test with an iron profile, so those with an Hb < 13 g/dl will be evaluated to initiate treatment with intravenous iron, erythropoietin, or both (consensus protocol with the Hematology Department) depending on the etiology of the anemia.

Furthermore, we will conduct an assessment of the patient's social and family situation. If any social alarm indicators are detected (living alone, lack of self-care capacity, homelessness), we will collaborate with the social worker to implement appropriate measures for home discharge after surgery.

Regarding the need for psychological support, while we currently lack a psychologist for this purpose in the hospital, we are actively working to include psychological well-being optimization as soon as possible. This will involve identifying patients who require psychological intervention (using SF-36, HADS) and providing anxiety-reducing techniques for all patients based on their preference. It is one of the areas we are actively working on as we consider it of vital importance. While we cannot guarantee it in all cases yet, we will strive to provide support to those patients we deem most in need with the current resources available in the hospital (psycho-oncology unit).

We will emphasize smoking cessation, providing patients with all necessary information and tools for quitting.

In addition to expanding our protocol to make it more comprehensive, we are developing a strategy to record patients included in the program and register the implemented measures in a dedicated database. Subsequently, we will conduct a review of patients to assess, on the one hand, the compliance of the measures included in the protocol and, on the other hand, to assess the effect of their implementation in terms of outcomes to determine if we, indeed, have improved these, reducing complications.

Conclusion

Enhanced Recovery After Surgery (ERAS) improves postoperative outcomes of esophageal surgery, although many ERAS society recommendations are based on low or moderate levels of evidence and require further evaluation and research. Considering that esophagectomies remain associated with major surgical trauma and significant morbidity, the preoperative risk assessment gains great importance, playing a crucial role in identifying potential risks and optimizing the patient outcomes. Taking advantage of the preoperative period is crucial to ensure that patients arrive in the best clinical and psychological condition, known as prehabilitation, which includes nutrition optimization, exercise (both physical and cognitive), anxiety/stress reduction, smoking and alcohol cessation, identification and treatment of anemia, and adjustment of medical treatments. We advocate for a multimodal prehabilitation program.

Data availability statement

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

Author contributions

SG: Data curation, Writing – original draft, Writing – review & editing, Formal Analysis, Investigation. LM: Writing – review & editing. NG: Writing – review & editing. MG: Data curation, Investigation, Writing – review & editing. NR: Data curation, Formal Analysis, Investigation, Writing – original draft, Writing – review & editing.

Funding

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

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