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Should the Use of Biologic Agents in Patients With Renal and Lung Cancer Affect Our Surgical Management of Femoral Metastases?

Gutowski, Christina J., MD, MPH; Zmistowski, Benjamin, MD; Fabbri, Nicola, MD; Boland, Patrick J., MD; Healey, John H., MD

Clinical Orthopaedics and Related Research®: April 2019 - Volume 477 - Issue 4 - p 707–714
doi: 10.1097/CORR.0000000000000434
2017 MUSCULOSKELETAL TUMOR SOCIETY PROCEEDINGS
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Background Biologic agents may prolong survival of patients with certain kidney and lung adenocarcinomas that have metastasized to bone, and patient response to these agents should be considered when choosing between an endoprosthesis and internal fixation for surgical treatment of femoral metastases.

Questions/purposes Among patients undergoing surgery for femoral metastases of lung or renal cell carcinoma, (1) Does survival differ between patients who receive only cytotoxic chemotherapy and those who either respond or do not respond to biologic therapy? (2) Does postsurgical incidence of local disease progression differ between groups stratified by systemic treatment and response? (3) Does implant survival differ among groups stratified by systemic treatment and response?

Methods From our institutional longitudinally maintained orthopaedic database, patients were identified by a query initially identifying all patients who carried a diagnosis of renal cell carcinoma or lung carcinoma. Patients who underwent internal fixation or prosthetic reconstruction between 2000 and 2016 for pathologic fracture of the femur and who survived ≥ 1 year after surgery were studied. Patients who received either traditional cytotoxic chemotherapy or a biologic agent were included. Patients were classified as responders or nonresponders to biologic agents based on whether they had clinical and imaging evidence of a response recorded on two consecutive office visits over ≥ 6 months. Endpoints were overall survival from the time of diagnosis, survival after the femoral operation, evidence of disease progression in the femoral operative site, and symptomatic local disease progression for which revision surgery was necessary. Our analysis included 148 patients with renal (n = 26) and lung (n = 122) adenocarcinoma. Fifty-one patients received traditional chemotherapy only. Of 97 patients who received a biologic agent, 41 achieved a response (stabilization/regression of visceral metastases), whereas 56 developed disease progression. We analyzed overall patient survival with the Kaplan-Meier method and used the log-rank test to identify significant differences (p < 0.05) between groups.

Results One-year survival after surgery among patients responsive to biologic therapy was 61% compared with 20% among patients nonresponsive to biologics (p < 0.001) and 10% among those who received chemotherapy only (p < 0.009). With the number of patients we had to study, we could not detect any difference in local progression of femoral disease associated with systemic treatment and response. Radiologic evidence of periimplant local disease progression developed in three (7%) of 41 patients who responded to biologic treatment, two (3%) of 56 patients nonresponsive to biologics, and one (2%) of 51 patients treated with traditional chemotherapy. With the numbers of patients we had, we could not detect a difference in patients who underwent revision. All three patients responsive to biologics who developed local recurrence underwent revision, whereas the two without a response to biologics did not.

Conclusions Biologic therapy improves the overall longevity of some patients with lung and renal metastases to the femur in whom a visceral disease response occurred. In our limited cohort, we could not demonstrate an implant survival difference between such patients and those with shorter survival who may have had more aggressive disease. However, an increased life expectancy beyond 1 year among patients responsive to biologics may increase risk of mechanical failure of fixation constructs.

Level of Evidence Level III, therapeutic study.

C. J. Gutowski, MD Anderson Cancer Center at Cooper, Department of Orthopaedic Surgery, Cooper University Hospital, Camden, NJ, USA

C. J. Gutowski, N. Fabbri, P. J. Boland, J. H. Healey, Orthopaedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA

B. Zmistowski, Department of Orthopaedic Surgery, Thomas Jefferson University Hospital, Philadelphia, PA, USA

N. Fabbri, P. J. Boland, J. H. Healey, Department of Surgery, Weill Cornell Medical College, New York, NY, USA

J. H. Healey, Orthopaedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA, email: healeyj@mskcc.org

All research at Memorial Sloan Kettering is supported in part by a grant from the National Institutes of Health/National Cancer Institute (#P30 CA008748) (CJG, NF, PJB, JHH). One of the authors (CJG) was supported by an unrestricted educational fellowship from the Major Family Fellowship Fund at Memorial Sloan Kettering Cancer Center. In addition, the MSK Musculoskeletal Oncology Fellowship program acknowledges the Omega Medical Grants Association and the support of Genentech for its generous 2016-2017 Orthopaedic Oncology Fellowship grant.

All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request.

Clinical Orthopaedics and Related Research® neither advocates nor endorses the use of any treatment, drug, or device. Readers are encouraged to always seek additional information, including FDA approval status, of any drug or device before clinical use.

Each author certifies that his or her institution approved the human protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research.

This work was performed at Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Received December 17, 2017

Accepted July 17, 2018

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Introduction

Approximately one-third of skeletal metastases arising from visceral cancer occur in the proximal femur, and metastatic femoral lesions are a leading cause of morbidity in these patients [4, 10]. Other than in occasional examples when survival can be improved with resection of a solitary bone metastasis, the primary goals of surgical management of metastatic lesions anywhere in the femur are to relieve pain, restore functional mobility, and improve the patient’s overall quality of life [6].

In addition to ensuring that the patient is healthy enough to undergo surgery, the surgeon must understand the overall prognosis when planning surgery for an impending or completed pathologic fracture of the femur [1]. Historically, it has been shown that 40% of patients with pathologic femoral fractures will survive at least 6 months after the injury, and only 30% will survive longer than 12 months [14]. In recent years, however, the prognoses for many forms of metastatic carcinoma have improved considerably [3, 21]. Recently there have been exciting advances in the area of biologic therapies for advanced cancer: enhanced durable response to targeted or immunotherapeutic options has been demonstrated in renal cell carcinoma, lung adenocarcinoma, and melanoma. Gettinger et al. [9] demonstrated a 56% 1-year survival rate in patients with advanced nonsmall cell lung cancer (NSCLC) who received the dosing regimen of nivolumab with an overall response rate of 24% for this 3-mg/kg dose. This is a much higher overall response rate than the 7% to 9% rate shown historically for second-line therapies in NSCLC. Of the responders to nivolumab, the authors found that median progression-free survival was 20.6 months, also a notable improvement compared with cytotoxic chemotherapy that has been used up to this point. In a phase II trial, Motzer et al. [19] demonstrated similar improvements associated with nivolumab administered to patients with renal cell carcinoma (RCC): median overall survival was shown to be 25.5 months and overall response rate was 22% among patients receiving the 2-mg/kg dosing regimen. In their favorable risk group of patients with metastatic RCC, Heng et al. [12] were able to show a median overall survival of 43.2 months in their development of a novel prognostic model for RCC that has resulted from development of these revolutionary biologic agents. These data serve as testimony of the efficacy of these biologic therapies and support the argument that now more than ever orthopaedic surgeons must recognize the potential for prolonged survival in some of the patients receiving these drugs.

Surgical treatment of femoral metastases generally involves either stabilizing the area of involved bone with plate or rod fixation or resecting the area and replacing it with a prosthesis. Failure of the internal fixation strategy is usually associated with local tumor progression and implant fatigue/mechanical failure [11]. The probability of plate or rod failure increases with longer patient survival and the presence of persistent nonunion [5], because these implants are designed to act as temporary load-sharing devices that transfer load back to the bone as the fracture heals [2]. When this paradigm of fracture management is applied to pathologic fracture in the presence of viable tumor, bone healing is unreliable and the implant is apt to eventually undergo a revision. Harvey et al. [11] and Jacofsky et al. [13] have found that most of these mechanical failures occur at approximately 12 months to 15 months, and Dijstra et al. [5] showed that the most important risk factor for treatment failure in a series of 228 pathologic long bone fractures was the length of survival after surgery. An analysis of 298 consecutive patients at Memorial Sloan Kettering demonstrated a difference in treatment failure rates among endoprosthetic replacement (3.1%), intramedullary nailing (6%), and plating (42.1%) in the setting of femoral metastases [23].

Because of the improved survival experienced by a subset of patients with lung or renal cell carcinoma treated with biologic therapies, we believe surgeons should think differently about their choice of reconstruction of metastatic femoral lesions. The survival impact of biologics has never been specifically investigated in patients undergoing surgical treatment for impending or established pathologic fractures, and it is unknown how this survival advantage impacts the longevity of their femoral construct. The premise of this report is that those patients whose visceral metastases respond well to systemic treatment will live longer than those who do not respond to biologic treatment and that these patients may carry a higher risk of local tumor progression and revision of the surgical construct.

When evaluating patients undergoing an operation for femoral metastases of lung or renal cell carcinoma, we therefore asked the following questions: (1) Does survival differ between patients who receive only cytotoxic chemotherapy and those who either respond or do not respond to biologic therapy? (2) Does postsurgical incidence of local disease progression differ between groups stratified by systemic treatment and response? (3) Does implant survival differ among the groups stratified by systemic treatment and response?

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Patients and Methods

After obtaining institutional review board approval for this retrospective study, we searched and reviewed patient records from the longitudinally maintained orthopaedic patient database of our institution, a tertiary care comprehensive cancer hospital. All operations were performed by fellowship-trained orthopaedic oncologists (NF, PJB, JHH).

Between November 2000 and January 2016, a total of 2383 patients were treated by the orthopaedic service for bone metastases. Of these, we identified those patients who had undergone an operation for impending or completed femoral pathologic fracture resulting from metastatic lung or kidney cancer; 160 patients were identified. Exclusion criteria were absence of femoral reconstruction (amputation, Girdlestone procedure), absence of systemic treatment, and followup < 1 year from surgery, except for patients who died within this timeframe. For the first two reasons, 12 were excluded. One hundred six patients died < 1 year from surgery. Other than those who died, there were no patients who were lost to followup within a year. Data were ultimately collected (CJG) from 148 patients on patient demographics, oncologic diagnosis, surgical details, systemic treatment history, and followup status of the femoral surgical construct as well as their overall disease course. Biologic agents of interest included tyrosine kinase inhibitors, monoclonal antibodies, mechanistic target of rapamycin inhibitors, and cytokine therapy (Table 1).

Table 1

Table 1

Stabilizations with plate/screws or intramedullary nails were considered internal fixation procedures, whereas tumor excision and hemiarthroplasty, THA, proximal femoral replacement, or distal femoral replacement were considered endoprosthetic reconstructive procedures. There were no TKAs performed using primary components.

Systemic treatment decisions were made by the patient and his or her medical oncologist. In general, all patients began their systemic treatment with a first-line chemotherapy regimen. Many of them between years 2000 and 2008 were only treated with chemotherapy. The first patient in our study who received a biologic agent received it in 2000, and the indications for receiving these agents were progressive metastatic disease and lack of response to several lines of chemotherapy in patients whose tumors carried a targetable mutation. The administration of biologic agents became more prevalent in years after 2009, when the FDA approval of the agents allowed nonprotocol use. If the patient received a biologic agent at any time during their treatment course, they were included in the biologic group (even if this was a second- or third-line regimen after receiving traditional chemotherapy). Within the biologic group, some patients had a response in visceral disease, whereas other patients did not as subsequently outlined.

Orthopaedic followup office notes and radiographs were studied for detection of symptomatic or radiographic disease recurrence as well as need for revision surgery. Medical oncology office notes and surveillance CT scans were also reviewed to determine each patient’s disease response status to systemic treatment, and medical oncologic surveillance and followup were performed according to National Comprehensive Cancer Network guidelines [8, 17] and specific research study protocols, where applicable. The patients receiving biologic therapy at any time were further stratified into two groups: those patients whose tumor exhibited a positive response to the agent(s) and those with tumor that had no response. Response was determined specifically by visceral response to the biologic regimen, where tumor response was considered positive if at least two sequential office notes documented either objective temporal stability or regression of visceral disease burden for a minimum of 6 months, confirmed on cross-sectional imaging. Survival was measured using two intervals: time from diagnosis to death and time from femoral surgery to death.

The overall cohort included 148 patients with metastatic lung carcinoma (n = 122) or RCC (n = 26), 51 of whom received only cytotoxic chemotherapy and 97 of whom attempted biologic therapy at some point in their treatment course. Approximately 42% of the patients who received biologic therapy exhibited a visceral response according to our definition of response (stabilization or regression of visceral lesions for at least 6 months, documented over at least two sequential CT scans and office visits). A higher proportion of patients in the traditional chemotherapy group had lung cancer, but the mean age in all three groups was between 60 and 65 years, and a majority had undergone endoprosthetic reconstruction (Table 2).

Table 2

Table 2

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Statistical Analysis

We performed statistical analysis to assess the outcomes of the two groups. If the data were normal, we used a Student’s t-test to compare the difference in mean duration among diagnosis, surgery, and death. If data were nonparametric, we used the Wilcoxon rank-sum test. Overall patient survival analysis was performed using the Kaplan-Meier method. For categorical data, comparisons were made with chi-square analysis. All statistical analyses were performed with RStudio, Version 1.0.036 (RStudio Inc, Boston, MA, USA).

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Results

Patients who received biologics and experienced a visceral response demonstrated improved overall survival compared with those who did not demonstrate a response to biologics (Fig. 1) and compared with those who received only chemotherapy (Fig. 2). Kaplan-Meier analysis of survival comparing all patients who received biologics with those who only received chemotherapy demonstrates prolonged survival in the former group; however, this difference is driven by those whose tumors respond to the biologic agent raising the mean for the biologics group. Those whose disease did not respond to biologics experienced the same survival as those who only received chemotherapy (p = 0.09) (Figs. 1-4). Of the 41 patients with tumors that responded to biologics, 25 of them (61% [confidence interval {CI}, 47.7%–77.9%]) were alive 1 year after surgery. Of the 56 patients who received biologics but whose tumors did not respond, only 11 were alive 1 year after surgery (19.6% [CI, 11.6%-33.4%]). Of the 51 patients who received chemotherapy only, five were alive 1 year from surgery (9.8% [CI, 4.3%-22.5%]; p < 0.001). Those who responded to biologics had longer survival than all others, namely those who received chemotherapy alone or those who failed to get a response to biologics (61% [CI, 47.4%–77.9%] versus 16.8% [CI, 11%-25.6%]; p = 0.001).

Fig. 1

Fig. 1

Fig. 2

Fig. 2

Fig. 3

Fig. 3

Fig. 4

Fig. 4

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Local Progression

With the available numbers, we could not demonstrate a difference in the proportion of patients who developed local disease progression after orthopaedic reconstruction or fixation of a femoral metastasis. Among the 41 patients with tumors responsive to biologics, three patients (7.3%) developed local disease progression, diagnosed either symptomatically or radiographically. This progression was noted at a mean of 424 days from the index surgery. Among the 52 patients with tumors that did not respond to biologic therapy, two patients (3.5%) demonstrated progression of disease at a mean of 476 days from surgery. In one of the 51 patients (1.6%) in the chemotherapy group, the disease progressed locally 106 days after femoral surgery.

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Implant Survival

With the available numbers and the low overall incidence of revision surgery, we could not demonstrate a difference in implant survival based on the type of systemic treatment used or whether a patient’s disease responded to biologic therapy. In total, there were four patients who underwent revision surgery as a result of local progression of disease; all had originally undergone internal fixation procedures. No revisions of endoprosthetic replacements were performed in the time period of this study. Three of these patients who underwent revision had received biologic treatment and their tumors responded, yet local tumor progression developed at the femoral site of metastasis causing pain, bone resorption around the hardware, and loosening. There were two patients in the group whose disease did not respond to chemotherapy or biologics and who developed local progression radiographically, but neither of them underwent revision surgery because they were too medically ill to sustain it.

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Discussion

Femoral metastases are a common cause of morbidity among patients with adenocarcinoma of the lung and kidney [4, 10]. Recent development of biologic treatments has prolonged survival considerably for certain patients with these diseases when compared with traditional chemotherapy options [9, 12, 15, 19]. This has not been shown specifically in patients undergoing internal fixation or endoprosthetic reconstruction for pathologic fracture, and it is unclear whether improved survival afforded by biologic agents impacts local tumor recurrence or need for revision. Our analysis demonstrates a measurable impact of biologic treatments on survival in some patients who undergo internal fixation or prosthetic replacement to manage femoral metastases. The improved survival is exhibited by patients who respond viscerally to the biologic agent. Those who do not have a visceral response exhibit the same survival as those treated only with traditional chemotherapy. With the numbers available, we could not demonstrate a difference in either the local tumor recurrence rate or implant survival as a result of systemic treatment.

There were several limitations to our study. First, because it was a retrospective and nonrandomized study, there exists potential for selection bias. In determining eligibility for biologic therapy, oncologists are more likely to select the strongest patients who meet strict physiological and functional criteria; those deemed too sick for biologic agents by the oncologist were not offered that treatment, but may have received chemotherapy. This difference in patient status could have biased our survival analysis. However, criteria for initiating biologic treatment also included progressive disease burden, partly mitigating this selection bias. Further bias was introduced by not utilizing an independent objective measure of visceral tumor response to systemic treatment such as RECIST [7], but we attempted to standardize the delineation of patients responding or not responding to biologic treatment by using documentation of stability or regression over a 6-month period. A more formal method of quantifying response using objective criteria would have been ideal but was not available.

An important source of bias was introduced by our decanting of patients who did not respond to biologic treatment from the overall biologics group during the analysis. We identified and designated the strongest patients who responded to the best systemic treatment and compared them with a combined group of patients who received only chemotherapy plus those who did not respond to biologics; this design inflated the apparent survival benefit of biologic agents. The rationale for this decision was our intent to investigate orthopaedic implant survival among the class of patients with the best overall prognosis among the metastatic lung/renal cell carcinoma population and compare this with a class of patients whose disease continues to progress despite the best available medical management. The authors recognize the significant bias that this methodology introduces into the survival analysis and for this reason, these results must be considered preliminary. Future randomized controlled trials with clear criteria and intent-to-treat analysis will further elucidate the true survival impact these drugs have on patients and their orthopaedic implants.

Our analysis was also hampered by the small sample size and low incidence of events, because mechanical failure or revision of any type of orthopaedic construct is a relatively rare occurrence. Because we divided the patients by both systemic treatment and response to treatment, the resultant groups were small and this made comparison of recurrence and revision rates between individual groups difficult. Therefore, our finding of no difference in risk of revision should be interpreted with caution, because a true difference may exist but has gone undetected here as a result of the insufficient sample size. Lastly, although postoperative radiation was performed in some patients, detailed data on radiation therapy were not available, and it is beyond the scope of this project to investigate the potential impact radiotherapy had on the local recurrence rate. The authors recognize that failure to include radiation status is a confounding factor when analyzing tumor recurrence rate, although we do not believe it introduces systematic bias into the survival analysis.

The first conclusion from our analysis is that patients who receive biologics and experience a visceral response can survive longer than those who do not exhibit a visceral response to them or who are treated only with chemotherapy. This survival benefit associated with biologic agents has been shown in large studies in the medical oncology literature [9, 12, 19, 22] but not specifically in patients with Stage IV disease undergoing fixation or endoprostheses for impending or pathologic fractures. Only a subset of those patients who receive a biologic agent will respond to it; Motzer et al. [18] demonstrated an objective response rate (partial plus complete response) of 44% with an additional 22% of their cohort experiencing stable disease for at least 3 months among their cohort of 105 patients who received sunitinib for second-line treatment of metastatic RCC. Our analysis demonstrates a similar response rate despite slightly different criteria used to define response; 41 of our 97 (42%) patients who received a biologic agent experienced stable or regressive visceral disease over at least 6 months. Those who fell into this category demonstrated prolonged overall survival. It is critical to note, however, that 58% of the patients who received a biologic agent did not respond to it, and these patients’ survival was not longer than the survival of those who only receive chemotherapy. It is critical to understand that the difference in survival observed between the 97 patients who received biologics and the 51 who received chemotherapy is driven by the minority who respond to the biologic agent, raising the overall mean for the biologics group.

With the available numbers, we could not demonstrate a difference in the proportion of patients who developed local disease progression after orthopaedic surgery for femoral metastasis. Seven percent of patients responding to biologics experienced local progression of tumor in their femur as compared with 3.5% of those in the nonresponders group and 2% in the chemotherapy group. Small sample size and low incidence of events could have contributed to a lack of statistical power to detect a difference, if one truly exists in this comparison. In terms of time to local recurrence, recurrence was noted at nearly the same time from index surgery among patients who both responded and did not respond to biologic treatment. These findings suggest that despite the positive impact that biologics can have on visceral disease, these agents may not postpone skeletal progression of disease, but because it is often more difficult to discern response in a bone compared with viscera, we cannot be sure. Further large studies investigating this relationship are needed, because the impact of biologic therapy on bony metastases is not well described in the literature to date.

With the available numbers and the low overall incidence of revision surgery, we could not demonstrate a difference in implant survival based on the type of systemic treatment used or whether a patient responded to biologic therapy. We did observe that all four revisions were performed in patients who had initially undergone internal fixation, which is consistent with multiple reports that demonstrate increased mechanical failure rates after internal fixation of femoral metastases compared with endoprosthetic replacement [11, 23]. Three of the four were among the group who responded to biologic treatment. Two patients in the nonresponder group developed local progression radiographically, but neither of them underwent revision surgery to address this because they were too medically ill to undergo surgery. Although the numbers are not large enough to explicitly identify a difference, these data may reflect orthopaedic decision-making regarding two classes of patients: a surgeon may be more aggressive in revising a painful nonunion or local recurrence in patients who are viscerally responding to systemic treatment and may be less apt to reoperate on patients who are in decline despite the best treatment available. The former group is physiologically more fit to undergo, and recover from, revision surgery; patients with extremely poor prognoses are often treated with palliative, nonoperative measures [20].

Improved survival among patients with RCC and lung cancer associated with biologic treatment has been well described [3, 9, 12, 19, 21], and our study has found that a subset of patients with lung or renal cancer undergoing femoral surgery who receive and respond to biologic treatment can experience prolonged survival. A much higher proportion of patients who responded to biologics were alive 1 year after surgery compared with those who did not receive, or did not respond to, biologics (61% versus 10% and 20%, respectively). There are no validated nomograms or biomarkers of response to help the surgeon determine how to treat an impending or established pathologic fracture [16].

This comparison may be particularly relevant when selecting an orthopaedic implant. Those patients who live longer because of their response to these agents and who undergo internal fixation might be at a higher risk of implant failure based on previous data published on the association between overall survival and revision rates [5]. Unfortunately, we cannot currently predict who will or will not respond to the biologics when planning the operation. To reduce the likelihood of revision surgery, it is critical that a patient’s first surgery be the most appropriate procedure for his or her clinical circumstances. The orthopaedic surgeon has always weighed the recovery time needed against the desire to provide a durable surgical treatment, and reconciliation of these potentially competing concepts hinges on a thorough and patient-specific understanding of the overall prognosis. We have shown that the use of biologic therapies prolongs the survival of some patients who receive them. This introduces another variable for the surgeon to consider when deciding how to treat a patient with a fracture or impending fracture of the femur. Should he or she internally fix the lesion or resect and reconstruct with an endoprosthesis? Currently, we cannot predict who will respond to biologics, but what we have shown is that some patients treated with biologics will respond, so this potential should be considered when making the decision. Larger, prospective studies will be needed to determine if the patients who respond are indeed at higher risk for implant failure related to their prolonged survival.

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Acknowledgments

We thank Drs Carol Morris, Daniel Prince, and Edward Athanasian for their contribution of patients to our longitudinally maintained institutional database.

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