M.R.V. is a 48-year-old Filipino female who presented with a five-month history of intermittent, profuse vaginal bleeding with no other symptoms. She was previously healthy with no known comorbidities. The patient is married, G2P2 (2002), with no other past or present sexual partners aside from her husband. She works as a marketing executive and is an occasional alcohol beverage drinker and a never-smoker. Her family history is unremarkable. She was and is still independent in all activities of daily living.
In early 2020, she sought consult with a gynecologic oncologist who, on internal-rectovaginal exam, noted an expanded, nodular cervix approximately 5 × 4 cm in dimensions. The parametria were noted to be nodular bilaterally, with extension to both pelvic sidewalls. A whole abdominal computed tomography (CT) scan with intravenous contrast was subsequently performed, revealing an enlarged uterus measuring about 13.6 × 10.2 × 10.2 cm with a heterogeneously enhancing parenchyma, widening of the cervical region, and fairly-defined heterogeneous mass within the left lateral myometrial region measuring approximately 4.0 × 3.8 × 3.0 cm. The enlarged uterus was noted to be compressing and displacing the urinary bladder inferiorly, the rectum posteroinferiorly, and the rest of the small and large bowels laterally. Endocervical curettage and endometrial and cervical punch biopsies were subsequently performed; the finding was invasive squamous cell carcinoma, large cell non-keratinizing, visualized in all the histopathologic specimens submitted.
Having subsequently been diagnosed with Cervical Squamous Cell Carcinoma, International Federation of Gynecology and Obstetrics (FIGO) Stage IIIB, the patient underwent concurrent chemoradiation (CCRT) at our institution. From February 17 to March 27, 2020, she received external beam radiation therapy (EBRT) via a computed tomography (CT)-based, three-dimensional conformal radiation therapy (3D-CRT) technique, with the following borders: superiorly, L4–L5 interspace to encompass the bifurcation of the abdominal aorta into the common iliac arteries; inferiorly; bottom of the obturator foramina; laterally, 1.5 cm into the pelvic brim; anteriorly; 1 cm in front of the pubic symphysis; and posteriorly, the whole sacrum. Anteroposterior (AP), posteroanterior (PA), left-lateral, and right-lateral fields were used. Multileaf collimators (MLC) were used to block off the spinal cord posteriorly, the iliac fossae superolaterally, and bowels superoanteriorly. A total of 5040 cGy in 28 fractions (180 cGy/fraction) was delivered to the pelvic isocenter via 6-megavoltage (MV) photons using a Varian ClinaciX linear accelerator. Planar kilovoltage (kV) imaging was performed once-weekly for treatment verification. A midline block (MLB) was delivered after 3960 cGy. Given the absence of any enlarged or suspicious lymph nodes on the patient’s diagnostic workups, there was no additional paraaortic field delivered. Concurrent weekly cisplatin 40 mg/m2 was given.
Towards the final week of EBRT, internal exam revealed the bilateral parametria to still be nodular, though much less so prior to initiation of therapy. As such, bilateral parametrial boost via 3D-CRT technique, of 1000 cGy in 5 fractions was delivered after the originally planned 28 fractions of EBRT.
Upon completion of the EBRT, the patient then underwent image-guided brachytherapy (IGBT). Four fractions of IGBT were delivered; for each fraction, 700 cGy was delivered to 90% of the high-risk clinical target volume (HR-CTV). Upon completion of all 4 fractions, the calculated total equivalent dose in 2-Gy fractions (EQD2) for both EBRT and IGBT received by the tumor target was 94.67 Gy, 72.09 Gy for the bladder D2cc, 45.16 Gy for the sigmoid D2cc, and 58.87 Gy for the rectum D2cc. All planning target goals were, as such, met. The patient tolerated the entire course of her therapy well with no treatment interruptions.
In the interim, the patient was asymptomatic, with full resolution of the previously bothersome vaginal bleeding. A year after treatment completion, a whole-body Fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scan was performed. No undue focal FDG uptake was noted in the uterus, cervix, and adnexae. However, a small- approximately 4.58 × 6.12 × 6.38 mm- FDG-avid (Standardized Uptake Value = 7.55) right common iliac node was visualized.
For confirmation, a sectional FDG PET/CT scan of the abdomen was performed a month after, with noted persistence of the previously visualized FDG-avid node in the right common iliac area with similar intensity (SUV 6.5, previously 7.6).
As such, in light of this imaging finding, the patient was deemed as having oligo-recurrent disease to an isolated pelvic lymph node. A multi-disciplinary approach comprised of the patient’s gynecologic oncologist, radiation oncologist, and a general surgeon was done to determine the best treatment approach for the patient. Surgery was considered to carry a high risk for peri-operative morbidity given the proximity of the isolated nodal recurrence to neurovascular structures and the inherent difficulty of identifying the actual metastatic node intra-operatively. Systemic treatment was deemed as carrying a greater risk for toxicity compared to the benefit it may bring for an otherwise localized recurrence. As such, radiation therapy that is ablative and extremely conformal- in the form of stereotactic body radiation therapy (SBRT)- was deemed as the most appropriate option.
Prior to simulation, the patient was put on bowel preparation of high-fiber diet a week prior and two tablets of calcium sennosides the night prior. The patient was asked to be on nil per os (NPO) six hours and on empty bladder prior to simulation.
Given the small size of the target which was previously identified only on PET/CT, the patient was simulated in the PET/CT department of our tertiary hospital rather than on the CT Simulation suite of the Radiation Oncology Department. Set-up and patient positioning tools- namely a firm and flat couch top, Civco Vac-LokTM cushion for immobilization, and laser beams for patient alignment- were present in the PET/CT suite during the simulation. The patient was subsequently scanned in a Siemens Biograph Vision 64-slice PET/CT scanner, with intravenous contrast, in the treatment position (i.e. supine, head-first, arms up), from the whole liver down to mid-thigh. Contouring was, as such, facilitated by direct registration of PET/CT images which were acquired simultaneously in the treatment position during the simulation.
By a careful study of the previous conventional radiation plan of the patient last 2020, it was determined that the present SBRT target falls within the prior radiation field. As such, the present SBRT would be classified as re-irradiation. Borrowing from a systematic review by Murray et al. (2017)  on SBRT as used for re-irradiation of malignant recurrences in the pelvis, a dose of 30 Gy in 5 fractions (EQD210Gy = 40 Gy; EQD23Gy = 54 Gy) was used. A 0 mm GTV-CTV margin, with a direct expansion from GTV to PTV of 0.5 cm, was utilized, as is also recommended by most studies. Dose was prescribed to the 88% peripheral isodose line to ensure rapid dose fall-off beyond and escalation within the target.
Determining organ-at-risk (OAR) constraints for SBRT re-irradiation, given the paucity of data and the wide variety of constraints- if at all reported- in the literature, is one of the most difficult aspects of the treatment. Given their proximity to the target, the following structures were deemed as appropriate OARs: the common iliac vessels, the right ureter, the bowels, and the thecal sac/cauda equina. As discussed in more detail later on, the most conservative approach to OAR constraints determination would be to use traditional first irradiation constraints and to subtract the original normal tissue dose from this. Subsequently, the remaining dose for the SBRT re-irradiation may be determined.
Based from the previous plan, for the common iliac vessels, it was determined that, likely, they received a previous Dmax of 53.16 Gy (d = 1.8 Gy/fx). This original dose was then converted to EQD2 and BED (α/β = 3 Gy, as recommended by Murray et al. (2017) ):
For the constraint, a maximum cumulative point dose of 120 Gy in 1.8 Gy/fx was utilized based on a retrospective analysis by Evans et al. (2013)  which found a 25% rate of grade 5 aortic- and, as a surrogate, arterial- toxicity for patients receiving cumulative doses > 120 Gy in 1.8 Gy/fx vs 0% for patients receiving less than this dose (p = 0.047). This dose was then converted to EQD2 and BED (α/β = 3 Gy, as recommended by Murray et al. (2017) ):
The original maximum point dose was then subtracted from the cumulative constraint to establish the remaining dose.
Remaining dose for the common iliac vessels as EQD2 = 115.2–51.03 = 64.17 Gy
Remaining dose for the common iliac vessels as BED = 192–85.06 = 106.94 Gy
Finally, this remaining dose is converted to the equivalent dose for 5-fraction SBRT:
Hence, the remaining dose constraint for 5-fraction SBRT for the common iliac vessels is 34.2 Gy. The actual Dmax to the common iliac vessels in the SBRT re-irradiation was 33.531 Gy. As such, the constraint to the common iliac vessels was met.
For the right ureter, it was determined from the previous plan that the Dmax in the first irradiation was 50.64 Gy (d = 1.8 Gy/fx). Converting again this original dose to EQD2 and BED (α/β = 3 Gy):
For the constraint, a maximum cumulative point dose of 75 Gy in 2 Gy/fx was adopted based on the constraints posited by Choi and Hsu (2018) . This was, as before, converted to EQD2 and BED (α/β = 3 Gy):
For the right ureter, the dose constraints would not be met if no recovery was assumed to have occurred, thus 50% recovery from prior radiation was assumed. As such, only half of the original maximum point dose was subtracted from the cumulative constraint to establish the remaining dose.
Remaining dose for the right ureter as
EQD2 = 75–24.305 = 50.695
Remaining dose for the right ureter as
BED = 125–40.51 = 84.49 Gy
Finally, this remaining dose is converted to the equivalent dose for 5-fraction SBRT:
|DMAX RECEIVED BY BOWELS AT FIRST IRRADIATION (GY)||NUMBER OF FRACTIONS||DOSE PER FRACTION (GY)||EQD2 (α/β = 3 GY)||REMAINING D10CC DOSE CONSTRAINT FOR 5-FX SBRT (GY)|
Hence, the remaining dose constraint for 5-fraction SBRT for the right ureter is 28.80 Gy. The actual Dmax to the right ureter in the SBRT re-irradiation was 28.407 Gy. As such, the constraint to the right ureter was met.
Due to the proximity of the target to the bowels, using the method of remaining dose constraints from the first radiation course or assuming 50% recovery for the bowels would have been impractical in this case. Instead of such manual calculations, where available, SBRT re-irradiation constraints for specific OARs may be utilized based on existing literature. This was the case for the bowels. The bowels were contoured as one bowel bag structure rather than as individual bowel loops due to the inherent mobility of the latter; this contouring technique is also espoused by Murray et al. (2017)  A dosimetric analysis by Abusaris et al. (2012)  proposed remaining normal tissue doses for SBRT small bowel re-irradiation based on a variety of initial radiation therapy normal tissue doses. Based from the previous plan, it was determined that the bowels likely received a Dmax of 54.07 Gy. Given such a previous dose to the bowels, for 5-fraction SBRT, Abusaris et al. (2012)  proposes a remaining SBRT dose constraint of D10cc ≤ 30.90 Gy (α/β = 3 Gy). The actual D10cc to the bowels in the SBRT re-irradiation was 7.326 Gy. As such, the constraint to the bowels was met.
Finally, for the thecal sac/cauda equina, the Memorial Sloan Kettering Cancer Center (MSKCC) adopts dose constraints for such in the setting of multi-fraction spine SBRT where previous radiation has already been delivered, pooled from their institutional data. Specifically, for a five-fraction re-irradiation SBRT regimen, Dmax = 20 Gy is the proposed constraint. The conditions for this constraint to be valid, however, are that the first irradiation was more than 3 months prior to the current re-irradiation and that the original irradiation had a dose regimen of 45–50.4 Gy in 1.8-2 Gy/fx, ≤ 30 Gy in 3 Gy/fx, or other similar conventional dose regimen given at ≤ 3 Gy/fx. Since these conditions have been met in this case, the aforementioned dose constraint was thus adopted. From the previous plan, the Dmax to the thecal sac/cauda equina in the first irradiation was likely 35.91 Gy. The actual Dmax to the thecal sac/cauda equina in the SBRT re-irradiation was reported to be 5.141 Gy. Hence, the constraint to this OAR has likewise been met.
Finally, with regards to the actual treatment delivery, the SBRT was delivered using 6-MV photons via dynamic conformal arc technique (DCAT) of a Varian TrueBeam linear accelerator. Treatment was delivered on a Monday-Wednesday-Friday schedule. For each session, the same bowel and bladder preparation during simulation was maintained. Cone beam CT (CBCT) image verification was performed in every treatment session. Treatment was well-tolerated and there were no interruptions. The patient did not report any subjective complaints during and even after the course of treatment.
A month after completion of SBRT, the patient was well and asymptomatic, with no recurrence of the previous vaginal bleeding. A whole-body PET/CT scan was performed; the previously identified FDG-avid right common iliac node was no longer seen.
Three months after the SBRT, the patient continues to be well and asymptomatic. A whole-body PET/CT was again done for monitoring, again no longer revealing any FDG-avid lymph node.
|Minimum dose to 95% of PTV (D95%)||D95% > 95% of prescribed dose||D95% = 3008.7 cGy (100%)|
|Volume receiving 100% of prescribed dose (V100%)||V100% > 95% of PTV||V100% = 95.8%|
|Conformity Index (CI)||CI < 2||CI = 1.137|
|OAR||REMAINING DOSE CONSTRAINT FOR 5-FRACTION SBRT||ACTUAL SBRT DOSES|
|Bowels||D10cc ≤ 30.90 Gy||D10cc = 7.326 Gy|
|Right ureter||Dmax = 28.80 Gy||Dmax = 28.407 Gy|
|Common iliac vessels||Dmax = 34.20 Gy||Dmax = 33.531 Gy|
|Thecal sac/cauda equina||Dmax = 20.00 Gy||Dmax = 5.141 Gy|
The concept of an intermediate state (i.e. <5 metastases) between organ-confined primary and polymetastatic cancers in which local therapy could achieve long-term survival or cure was first proposed more than 25 years ago by Hellman and Weichselbaum (1995) which they coined “oligometastatic disease” . As this definition did not qualify the state of the primary lesion, Niibe et al. (2010) expounded further on a situation of oligometastasis wherein the primary lesion was controlled. They subsequently coined this state “oligo-recurrence” . For this reason, as such, our patient was deemed as having an oligo-recurrent disease.
While polymetastatic disease is typically addressed with systemic therapy and palliative interventions, local ablative therapy for oligometastatic disease has been found to provide not only durable local control but a survival benefit as well [3, 4, 5]. Local control of oligometastatic disease, consequently, may improve systemic control and achieve potential cure as it is hypothesized that the malignancy in such a state has not yet acquired the requisite genetic variations for widespread dissemination [1, 2, 3].
For patients who are not good surgical candidates, who desire a less invasive approach, and/or whose oligometastatic site is difficult to surgically access, stereotactic body radiation therapy (SBRT) has emerged as another local treatment option [5, 6, 7, 8, 9]. The term “stereotactic” refers to “using a precise three-dimensional mapping technique to guide a procedure .” Though the terminology used in stereotactic radiation is highly variable and non-uniform, SBRT generally refers to “a type of radiotherapy [utilizing] specialized technology to more precisely and conformally target extracranial tumors with [ablative] doses of radiotherapy in a few fractions while limiting normal tissue dose compared to conventional radiotherapy .”
In the setting of oligometastatic disease, SBRT has been most commonly employed for the local treatment of liver and lung oligometastases, achieving local control rates of up to 90% at 2 years of follow-up [11, 12, 13]. The role of SBRT in the management of oligometastatic- and, specifically, as with the case of our patient, oligo-recurrent- lymph node disease is less well-defined. A systematic review of 38 case reports and series on SBRT utilized for oligo-recurrent lymph nodes was conducted by Jereczek-Fossa, Ronchi, and Orrechia (2014). Of the 290 patients (350 lymph nodes) included in the systematic review, majority (198 patients, 232 lymph nodes) were exclusively treated for abdominopelvic lymph nodes, similarly with our patient. The primary malignancy was quite heterogeneous, majority being gastrointestinal, gynecologic, and genitourinary primaries. Various techniques were used to deliver the SBRT, including CyberKnife, Tomotherapy, RapidArc, and other linear accelerators. A median of three fractions (1–6 fractions) was used, with a dose of 5–16 Gy per fraction. The overall response rate was excellent at up to 80%. The dominant pattern of failure was out-of-field in the form of distant metastasis/es or regional nodal metastasis/es. Regional nodal recurrence was observed in only about 10% of all patients and comprised around 50–80% of all events of progressive disease. Three-year progression-free survival exceeded 20%. Overall survival rates up to 93.3% at 2 years and 71.4% at 3 years were observed. Both acute and late toxicity were limited, with mostly mild (Grade 1 or 2) acute events having been observed; majority of the series reported no late toxicity/ies .
Aside from the direct effect of SBRT on the clonogenic cancer cells residing in the oligometastatic target/s, an abscopal effect (i.e. regression of non-irradiated lesions distant from the irradiated site/s) was also hypothesized. Though clinical data is still in its infancy, proposed mechanisms for such include post-radiation anti-tumor immune responses, inflammatory reaction, and reduction of cancer cell seeding [35, 36, 37]. Admittedly, what little data we have on the utility and outcomes of SBRT for oligometastatic lymph node disease is derived from small case reports and series. To cement its benefit on local control and survival, more comparative research is needed.
A further complicating factor- one present in the case of our patient- is when SBRT is used in the setting of re-irradiation, a factor not studied in the aforementioned systematic review by Jereczek-Fossa, Ronchi, and Orrechia (2014). A systematic review specifically in such a setting of SBRT as used for re-irradiation of recurrent malignant disease in the pelvis was conducted by Murray et al. (2017) . A total of 195 articles were identified after a thorough search; eventually 17 were deemed appropriate for inclusion. All studies were retrospective, from single institutions, and with low patient numbers (i.e. the largest study only included 31 patients ). There was considerable variability and inhomogeneity in the disease-specific, technical, and outcome-related factors surrounding pelvic SBRT re-irradiation. Majority of the patients had a prostate (n = 86 lesions, at least 82 patients), cervical or endometrial (n = 58 lesions, at least 50 patients), and rectal (n = 50 patients) cancer primaries. SBRT re-irradiation was most frequently performed for local and pelvic lymph node recurrence. Majority of the patients had only one lesion re-irradiated. The degree of overlap between the former and re-irradiation plans was not well-described. In almost all cases, the reported locations of re-irradiated lesions indicated that the re-irradiation volumes were likely to have been contained within at least the 50% isodose line of the former radiation therapy plan and, wholly or partially, within the high dose region, as was the case with our patient.
The time between the first and re-irradiation was likewise highly variable, ranging from 3 to 336 months, with a median of 22 months. Similarly with our patient, the previous conventionally fractionated radiation therapy dose was 45 to 50.4 Gy. The re-irradiated volumes were likewise highly variable, ranging from 7 cm3 to 1115 cm3, with a median of 154 cm3. In our patient, we recall that the PTV volume was 1.5 cm3. With regards to delivery technique, majority- 13 of the 17 studies- delivered SBRT using Cyberknife while 4 utilized linear accelerator technology [39, 40, 41, 42]. GTV-CTV margins of 0–3 mm and CTV-PTV margins of 3–10 mm were used. The prescription strategies were likewise different- some studies prescribed to peripheral isodose while others prescribed to the isocenter. Given that narrow treatment margins and high plan conformity are necessary to limit the potential toxicity to normal tissues, Murray et al. (2017) recommend a 0 mm GTV-CTV margin with a a direct expansion from GTV to PTV, as well as ensuring rapid dose fall-off beyond and escalation within the target achievable by prescribing to the peripheral isodose, as was used in our patient.
Re-irradiation SBRT prescription doses were highly variable, ranging from 15 Gy in 3 fractions to 60 Gy in 3 fractions (EQD2 to tumor with an α/β = 10 ranged from 18.8 to 150 Gy; EQD2 to late tissues with an α/β = 3 ranged from 24–276 Gy). The median physical dose was 30 Gy in a median of 4.5 fractions. Similarly, we recall that our patient was prescribed a dose of 30 Gy in 5 fractions (EQD210Gy = 40 Gy; EQD23Gy = 54 Gy).
In terms of outcome, local control at 1 year for re-irradiation patients ranged from 51.4% to as high as 100%. Overall survival at 1 year for mixed primaries ranged from 46% to 52% [43, 44]. For gynecologic primaries, specifically, it was reported at 60% . In terms of patterns of failure, more relapses following SBRT re-irradiation are in the form of distant metastatic rather than local disease [39, 42, 45, 46]. Finally, SBRT re-irradiation was reported to be well-tolerated, with 10 of the 17 studies reporting no high-grade toxicity. Six studies reported a total of 9 grade 3 events and 6 grade 4 events in 13 patients [40, 47, 48, 49], giving a crude high-grade toxicity rate of only 6.3%.
The optimal OAR constraints for SBRT re-irradiation are yet unknown and, hence, form one of the most challenging aspects of this modality. In the systematic review by Murray et al. (2017), majority- 10 out of the 17 included studies- actually did not report any OAR constraints. Six utilized maximum point doses though the bases for such were not well-defined. Only in one- a retrospective dosimetric analysis by Abusaris et al. (2012)  – were constraints clearly based on cumulative doses from the previous irradiation and the present re-irradiation. The original doses from the first irradiation were subtracted from cumulative constraints to determine the normal tissue doses remaining for SBRT re-irradiation. As Murray et al. (2017) asserts, however, what the cumulative constraints should be remains uncertain. The most conservative approach would be to use traditional first irradiation constraints and to subtract the original normal tissue dose from this and, thus, establish the remaining dose that may be delivered safely via SBRT re-irradiation, corrected for fractionation. This approach would hence accept the uncertainties of the linear-quadratic equation for changing fractionations at high doses per fraction [50, 51]. It was this approach which was used to calculate the constraints for the common iliac vessels. Depending on the interval to re-irradiation, a degree of repair may also be permitted, thus allowing a higher re-irradiation dose to be delivered. When used, the most commonly assumed degree of repair in general is 50% , as was used for the right ureter’s dose constraints for our patient. How much repair is appropriate and after what time period, however, remain uncertain . Finally, where available, SBRT re-irradiation constraints for specific OARs may be utilized based on existing literature. This was the case for the bowels’ constraints which made use of the constraints proposed by Abusaris et al. (2012) , and the thecal sac/cauda equina’s constraints which made use of the constraints by MSKCC for multi-fraction spine SBRT with previous radiation .
The precise target delineation incumbent upon SBRT, most especially for small but metabolically active targets as is the case with the oligo-recurrent lymph node of our patient, highlights the utility of PET/CT planning. To date, PET/CT provides “the most accurate available information on tumor extent and distribution of many common cancers, including lymphomas and epithelial malignancies of the lung, esophagus, cervix, and head and neck .” The functional information provided by PET/CT, when integrated with the structural-anatomic information provided by the traditional planning CT scan has been shown by clinicopathologic studies to improve delineation of tumor extent [14, 15, 16]. As emphasized by the International Atomic Energy Agency (IAEA), PET can reveal targets that are not well-visualized by CT/MRI structural imaging, such as an unsuspected lymph node, as with the case of our patient. Second, PET decreases the likelihood of delivering radiation to equivocal regions on CT/MRI which do not actually contain tumor, such as benign reactive lymphadenopathy . In the field of PET oncology, 18F-FDG is the most widely used radiopharmaceutical, being the best imaging agent available for most cancer types [17, 18].
In direct PET/CT planning, the PET suite effectively becomes part of the radiation therapy department and the chain of radiation therapy quality control extends to the acquisition of the PET images . As with our patient’s case, set-up and patient positioning tools- such as a firm and flat couch top, immobilization devices, and laser beams for patient alignment- must be present in the PET suite during the PET/CT planning . Needless to say, the patient is scanned in the treatment position with the applicable immobilization device/s. Software for imaging analysis, including PET volume contouring and image quantification, must be available and connected with the treatment planning system either directly or via remote transfer . The latter was the case with our patient, the PET/CT planning imaging being incorporated into the treatment planning system workstation, thereafter checked for correct normalization and quantification. The use of PET/CT planning has been most extensively reported in the setting of non-small cell lung cancer (NSCLC) [22, 23, 24, 25], improving accuracy in target volume delineation. Its use has likewise been reported for small cell lung cancer (SLCL) [26, 27, 28], lymphomas [29, 30, 31], and head and neck tumors [32, 33, 34].
SBRT is a promising option for nodal oligo-recurrence, especially in the setting of re-irradiation, where the delivery of highly conformal, ablative doses to the tumor target while respecting normal tissue limits are all the more crucial. The literature on this subject is promising, reporting excellent local control rates, survival outcomes, and acceptable toxicity. Admittedly, more studies- especially prospective ones- are necessary to further establish the role of this novel therapeutic modality.
This case report adheres to the SCARE 2020 guidelines .
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
The authors have no competing interests to declare.
Not commissioned, externally peer-reviewed.
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