Endoscopic endonasal pituitary sacrifice for select tumors with retrochiasmatic and/or retrosellar extension: surgical anatomy, operative technique, and case series.

OBJECTIVE: Tumors located in the retrochiasmatic region with extension to the third ventricle might be difficult to access when the pituitary-chiasmatic corridor is narrow. Similarly, tumor extension into the interpeduncular and retrosellar space poses a major surgical challenge. Pituitary transposition techniques have been developed to gain additional access. However, when preoperative pituitary function is already impaired or the risk of postoperative panhypopituitarism (PH) is considered to be particularly high, removal of the pituitary gland (PG) might be the preferred option to increase the working corridor. The aim of this study was to describe the relevant surgical anatomy, operative steps, and clinical experience with the endoscopic endonasal pituitary sacrifice (EEPS) and transsellar approach. METHODS: This study comprised anatomical dissections to highlight the relevant surgical steps and a retrospective case series reporting clinical characteristics, indications, and outcomes of patients who underwent EEPS. The surgical technique is as follows: both lateral opticocarotid recesses are exposed laterally, the limbus sphenoidale superiorly, and the sellar floor inferiorly. After opening the dura, the PG is detached circumferentially and mobilized off the medial walls of the cavernous sinuses. The descending branches of the superior hypophyseal artery are coagulated, and the stalk is transected. After removal of the PG, drilling of the dorsum sellae and bilateral posterior clinoidectomies are performed to gain access to the hypothalamic region, interpeduncular, and prepontine cisterns. RESULTS: From 2018 to 2023, 11 patients underwent EEPS. The cohort comprised mostly tuberoinfundibular craniopharyngiomas (n = 8, 73%). Seven (64%) patients had partial or complete anterior PG dysfunction preoperatively, while 4 (36%) had preoperative diabetes insipidus. Because of the specific tumor configuration, the chance of preserving endocrine function was estimated to be very low in patients with intact function. The main reasons for pituitary sacrifice were impaired visibility and surgical accessibility to the retrochiasmatic and retrosellar spaces. Gross-total tumor resection was achieved in 10 (91%) patients and near-total resection in 1 (9%) patient. Two (18%) patients experienced a postoperative CSF leak, requiring surgical revision. CONCLUSIONS: When preoperative pituitary function is already impaired or the risk for postoperative PH is considered particularly high, the EEPS and transsellar approach appears to be a feasible surgical option to improve visibility and accessibility to the retrochiasmatic hypothalamic and retrosellar spaces, thus increasing tumor resectability.

The Temporoparietal Fascia Flap Transposition Technique for Ventral Skull Base Reconstruction: Anatomic Analysis and Surgical Application.

BACKGROUND AND OBJECTIVES: The temporoparietal fascia (TPF) flap is an alternative for revision endoscopic skull base reconstruction in the absence of the nasoseptal flap, and we aimed to investigate the anatomy and surgical application of TPF flap transposition in endoscopic endonasal surgery. METHODS: Six lightly embalmed postmortem human heads and 30 computed tomography angiography imaging scans were used to analyze the anatomic features of the TPF flap transposition technique. Three cases selected from a 512 endoscopic endonasal cases database were presented for the clinical application of the TPF flap. RESULTS: The TPF flap, composed by the deepest 3 scalp layers (galea aponeurotica, loose areolar connective tissue, and pericranium), can be harvested and then transposed through the infratemporal-maxillary-pterygoid tunnel to the ventral skull base. The superficial temporal artery as its feeding artery, gives frontal and parietal branches with similar diameter (1.5 ± 0.3 mm) at its bifurcation. The typical bifurcation was present in 50 sides (83.3%), with single (frontal) branch in 5 sides (8.3%), single (parietal) branch in 2 sides (3.3%), and multiple branches (>2) in 3 sides (5%). The transposed TPF flap was divided into 3 parts according to its anatomic location: (1) infratemporal part with an area of 19.5 ± 2.5 cm2, (2) maxillary part with an area of 23.7 ± 2.8 cm2, and (3) skull base part with an area of 44.2 ± 4 cm2. Compared with the nasoseptal flap, nasal floor flap, inferior turbinate flap, and extended septal flap, the coverage area of the skull base part of the TPF flap was significantly larger than any of them (P < .0001). CONCLUSION: The TPF flap technique is an effective alternative for endoscopic endonasal skull base reconstruction. The TPF flap could successfully cover large skull base defects through the infratemporal-maxillary-pterygoid tunnel.

Detection of diagnostic and prognostic methylation-based signatures in liquid biopsy specimens from patients with meningiomas.

Recurrence of meningiomas is unpredictable by current invasive methods based on surgically removed specimens. Identification of patients likely to recur using noninvasive approaches could inform treatment strategy, whether intervention or monitoring. In this study, we analyze the DNA methylation levels in blood (serum and plasma) and tissue samples from 155 meningioma patients, compared to other central nervous system tumor and non-tumor entities. We discover DNA methylation markers unique to meningiomas and use artificial intelligence to create accurate and universal models for identifying and predicting meningioma recurrence, using either blood or tissue samples. Here we show that liquid biopsy is a potential noninvasive and reliable tool for diagnosing and predicting outcomes in meningioma patients. This approach can improve personalized management strategies for these patients.

The Pterygosphenoidal Triangle: Surgical Anatomy and Case Series in Endoscopic Endonasal Skull Base Surgery.

BACKGROUND: Safe exposure of the lacerum segment of the carotid artery remains a challenge in endoscopic endonasal surgery. OBJECTIVE: To introduce the pterygosphenoidal triangle as a novel and reliable landmark for facilitating access to the foramen lacerum. METHODS: Fifteen colored silicone-injected anatomic specimens were dissected using an endoscopic endonasal approach to the foramen lacerum region in a stepwise manner. Twelve dried skulls were studied and 30 high-resolution computed tomography scans were analyzed to measure the borders and angles of the pterygosphenoidal triangle. Surgical cases incorporating the foramen lacerum exposure between July 2018 and December 2021 were reviewed to provide surgical outcomes of the proposed surgical technique. RESULTS: The pterygosphenoidal triangle is delineated by the pterygosphenoidal fissure medially and the vidian nerve laterally. The palatovaginal artery is located at the base of the triangle anteriorly, while the apex is formed by the pterygoid tubercle posteriorly, which leads to the anterior wall of the foramen lacerum and lacerum internal carotid artery. In the reviewed surgical cases, 39 patients underwent 46 foramen lacerum approaches for resection of pituitary adenoma (12 patients), meningioma (6 patients), chondrosarcoma (5 patients), chordoma (5 patients), or other lesions (11 patients). There were no carotid injuries or ischemic events. Near-total resection was achieved in 33 (85%) of 39 patients (gross-total in 20 [51%]). CONCLUSION: This study details the pterygosphenoidal triangle as a novel and practical anatomic surgical landmark for safe and effective exposure of the foramen lacerum in endoscopic endonasal surgery.

Cytodifferentiation of pituitary tumors influences pathogenesis and cavernous sinus invasion.

OBJECTIVE: Pituitary tumors (PTs) continue to present unique challenges given their proximity to the cavernous sinus, whereby invasive behavior can limit the extent of resection and surgical outcome, especially in functional tumors. The aim of this study was to elucidate patterns of cavernoinvasive behavior by PT subtype. METHODS: A total of 169 consecutive first-time surgeries for PTs were analyzed; 45% of the tumors were functional. There were 64 pituitary transcription factor-1 (PIT-1)-expressing, 62 steroidogenic factor-1 (SF-1)-expressing, 38 T-box transcription factor (TPIT)-expressing, and 5 nonstaining PTs. The gold standard for cavernous sinus invasion (CSI) was based on histopathological examination of the cavernous sinus medial wall and intraoperative exploration. RESULTS: Cavernous sinus disease was present in 33% of patients. Of the Knosp grade 3 and 4 tumors, 12 (19%) expressed PIT-1, 7 (11%) expressed SF-1, 8 (21%) expressed TPIT, and 2 (40%), were nonstaining (p = 0.36). PIT-1 tumors had a significantly higher predilection for CSI: 53% versus 24% and 18% for TPIT and SF-1 tumors, respectively (OR 6.08, 95% CI 2.86-13.55; p < 0.001). Microscopic CSI-defined as Knosp grade 0-2 tumors with confirmed invasion-was present in 44% of PIT-1 tumors compared with 7% and 13% of TPIT and SF-1 tumors, respectively (OR 11.72, 95% CI 4.35-35.50; p < 0.001). Using the transcavernous approach to excise cavernous sinus disease, surgical biochemical remission rates for patients with acromegaly, prolactinoma, and Cushing disease were 88%, 87%, and 100%, respectively. The granule density of PIT-1 tumors and corticotroph functional status did not influence CSI. CONCLUSIONS: The likelihood of CSI differed by transcription factor expression; PIT-1-expressing tumors had a higher predilection for invading the cavernous sinus, particularly microscopically, compared with the other tumor subtypes. This elucidates a unique cavernoinvasive behavior absent in cells from other lineages. Innovative surgical techniques, however, can mitigate tumor behavior and achieve robust, reproducible biochemical remission and gross-total resection rates. These findings can have considerable implications on the surgical management and study of PT biology and behavior.

Reappraisal of the anatomy of the frontotemporal branches of the facial nerve.

OBJECTIVE: The anatomy of the temporal branches of the facial nerve (FN) has been widely described in the neurosurgical literature because of its relevance in anterolateral approaches to the skull base and implication in frontalis palsies from these approaches. In this study, the authors attempted to describe the anatomy of the temporal branches of the FN and identify whether there are any FN branches that cross the interfascial space of the superficial and deep leaflets of the temporalis fascia. METHODS: The surgical anatomy of the temporal branches of the FN was studied bilaterally in 5 embalmed heads (n = 10 extracranial FNs). Exquisite dissections were performed to preserve the relationships of the branches of the FN and their relationship to the surrounding fascia of the temporalis muscle, the interfascial fat pad, the surrounding nerve branches, and their final terminal endpoints near the frontalis and temporalis muscles. The authors correlated their findings intraoperatively with 6 consecutive patients with interfascial dissection in which neuromonitoring was performed to stimulate the FN and associated twigs that were observed to be interfascial in 2 of them. RESULTS: The temporal branches of the FN stay predominantly superficial to the superficial leaflet of the temporal fascia in the loose areolar tissue near the superficial fat pad. As they course over the frontotemporal region, they give off a twig that anastomoses with the zygomaticotemporal branch of the trigeminal nerve, which crosses the superficial layer of the temporalis muscle, spanning the interfascial fat pad, and then pierces the deep temporalis fascial layer. This anatomy was observed in 10 of the 10 FNs dissected. Intraoperatively, stimulation of this interfascial segment yielded no facial muscle response up to 1 mA in any of the patients. CONCLUSIONS: The temporal branch of the FN gives off a twig that anastomoses with the zygomaticotemporal nerve, which crosses the superficial and deep leaflets of the temporal fascia. Interfascial surgical techniques aimed at protecting the frontalis branch of the FN are safe in their efforts to protect against frontalis palsy with no clinical sequelae when executed properly.

Redox cycling of quinones reduced by ascorbic acid.

In aqueous solutions containing ascorbic acid and O2, many quinones undergo reduction to the semiquinone followed by reoxidation. This redox cycling mediates the oxidation of ascorbic acid and the reduction of O2 to superoxide and ultimately hydrogen peroxide. For that reason, redox cycling has attracted attention as a source of reactive oxygen species. This redox cycling is paradoxical, however, because the one-equivalent reduction potentials of the reactants are unfavorable, so the concentrations of the products, monodehydroascorbate and superoxide, must be kept extremely low. Disproportionation is not fast enough to eliminate these products. We have investigated the mechanism of ascorbate-driven redox cycling by monitoring the redox status of the quinone and the rate of redox cycling in parallel. Evidence is presented for a mechanism in which monodehydroascorbate is oxidized by the semiquinone. The result is that cycling of the semiquinone and hydroquinone mediates a rapid disproportionation of monodehydroascorbate. This mechanism accounts for the dependence of the redox cycling rate on quinone and ascorbate concentrations as well as on the reduction potential of the quinone. Therefore, it predicts how fast ascorbate-driven redox cycling will generate hydrogen peroxide under a variety of conditions and with different quinones.

Combined transpetrosal approach for giant petroclival meningioma: 2-dimensional operative video.

Petroclival meningiomas are extremally challenging lesions due to their deep location and close relation to critical neurovascular structures. Several approaches have been described to achieve gross-total resection with low morbidity and mortality. In this 2-dimensional operative video, the authors show a simultaneous combined transpetrosal approach. The patient is a 44-year-old woman with an 8-month history of gait imbalance with evidence of a giant petroclival meningioma on neuroimaging. She underwent a combined middle fossa approach with anterior petrosectomy and retrosigmoid/retrolabyrinthine approach to achieve gross-total tumor resection. The postoperative course was characterized by trigeminal neuralgia, and neuroimaging showed gross-total resection of the tumor. The video can be found here: https://stream.cadmore.media/r10.3171/2022.1.FOCVID21248.

Sinonasal Packing is Not a Requisite for Successful Cerebrospinal Fluid Leak Repair.

Background Numerous methods have been described to repair nasal cerebrospinal fluid (CSF) leaks. Most studies have focused on optimizing CSF leak repair success, leading to closure rates of 90 to 95%. Objective This study aimed to determine if excellent reconstruction rates could be achieved without using sinonasal packing. Methods A prospective case series of 73 consecutive patients with various CSF leak etiologies and skull base defects was conducted to evaluate reconstruction success without sinonasal packing. The primary outcome measure was postoperative CSF leak. Secondary outcome measures were postoperative epistaxis requiring intervention in operating room or emergency department, infectious sinusitis, and 22-item sinonasal outcome test (SNOT-22) changes. Results Mean age was 54.5 years and 64% were female. Multilayered reconstructions were performed in 55.3% of cases, with collagen or bone epidural inlay grafts, and nasal mucosal grafts or nasoseptal flaps for onlay layers. Onlay-only reconstructions with mucosal grafts or nasoseptal flaps were performed in 44.7% of cases. Tissue sealants were used in all cases, and lumbar drains were used in 40.8% of cases. There were two initial failures (97.4% initial success), but both resolved with lumbar drains alone (no revision surgeries). There were no instances of postoperative epistaxis requiring intervention in the operating room or emergency department. Infectious sinusitis occurred in 2.7% of patients in the first 3 months postoperatively. SNOT-22 did not change significantly from preoperatively to first postoperative visits, then improved over time. Conclusion Nasal CSF leaks from various etiologies and defect sites were successfully repaired without using sinonasal packing, and patients experienced minimal sinonasal morbidity.

Intracranial Breakthrough Through Cavernous Sinus Compartments: Anatomic Study and Implications for Pituitary Adenoma Surgery.

BACKGROUND: Pituitary adenomas (PAs) with cavernous sinus (CS) invasion can extend into the intradural space by breaking through the CS walls. OBJECTIVE: To elaborate on the potential breakthrough route through CS compartments for invasive PAs and describe relevant surgical anatomy and technical nuances, with an aim to improve resection rates. METHODS: Twelve colored silicon-injected human head specimens were used for endonasal and transcranial dissection of the CS walls; ligaments, dural folds, and cranial nerves on each compartment were inspected. Two illustrative cases of invasive PA are also presented. RESULTS: The potential breakthrough routes through the CS compartments had unique anatomic features. The superior compartment breakthrough was delimited by the anterior petroclinoidal ligament laterally, posterior petroclinoidal ligament posteriorly, and interclinoidal ligament medially; tumor extended into the parapeduncular space with an intimate spatial relationship with the oculomotor nerve and posterior communicating artery. The lateral compartment breakthrough was limited by the anterior petroclinoidal ligament superiorly and ophthalmic nerve inferiorly; tumor extended into the middle fossa, displacing the trochlear nerve and inferolateral trunk to reach the medial temporal lobe. The posterior compartment breakthrough delineated by the Gruber ligament, petrosal process of the sphenoid bone, and petrous apex inferiorly, posterior petroclinoidal ligament superiorly, and dorsum sellae medially; tumor displaced or encased the abducens nerve and inferior hypophyseal artery and compressed the cerebral peduncle. CONCLUSION: The superior lateral and posterior components of the CS are potential routes for invasion by PAs. Better identification of CS breakthrough patterns is crucial for achieving higher gross total resection and remission rates.

Prospective intraoperative and histologic evaluation of cavernous sinus medial wall invasion by pituitary adenomas and its implications for acromegaly remission outcomes.

Recurrence and biochemical remission rates vary widely among different histological subtypes of pituitary adenoma. In this prospective study, we evaluated 107 consecutive primary pituitary adenomas operated on by a single neurosurgeon including 28 corticotroph, 27 gonadotroph, 24 somatotroph, 17 lactotroph, 5 null-cell and 6 plurihormonal. In each case, we performed direct endoscopic intraoperative inspection of the medial wall of the cavernous sinus, which was surgically removed when invasion was visualized. This was performed irrespective of tumor functional status. Medial wall resection was performed in 47% of pituitary adenomas, and 39/50 walls confirmed pathologic evidence of invasion, rendering a positive predictive value of intraoperative evaluation of medial wall invasion of 78%. We show for the first-time dramatic disparities in the frequency of medial wall invasion among pathological subtypes. Somatotroph tumors invaded the medial wall much more often than other adenoma subtypes, 81% intraoperatively and 69% histologically, followed by plurihormonal tumors (40%) and gonadotroph cell tumors (33%), both with intraoperative positive predictive value of 100%. The least likely to invade were corticotroph adenomas, at a rate of 32% intraoperatively and 21% histologically, and null-cell adenomas at 0%. Removal of the cavernous sinus medial wall was not associated with permanent cranial nerve morbidity nor carotid artery injury, although 4 patients (all Knosp 3-4) experienced transient diplopia. Medial wall resection in acromegaly resulted in the highest potential for biochemical remission ever reported, with an average postoperative day 1 GH levels of 0.96 ug/L and surgical remission rates of 92% based on normalization of IGF-1 levels after surgery (mean = 15.56 months; range 3-30 months). Our findings suggest that tumor invasion of the medial wall of the cavernous sinus may explain the relatively low biochemical remission rates currently seen for acromegaly and illustrate the relevance of advanced intradural surgical approaches for successful and durable outcomes in endonasal pituitary surgery for functional adenomas.

Detection of tumor-specific DNA methylation markers in the blood of patients with pituitary neuroendocrine tumors.

BACKGROUND: DNA methylation abnormalities are pervasive in pituitary neuroendocrine tumors (PitNETs). The feasibility to detect methylome alterations in circulating cell-free DNA (cfDNA) has been reported for several central nervous system (CNS) tumors but not across PitNETs. The aim of the study was to use the liquid biopsy (LB) approach to detect PitNET-specific methylation signatures to differentiate these tumors from other sellar diseases. METHODS: We profiled the cfDNA methylome (EPIC array) of 59 serum and 41 plasma LB specimens from patients with PitNETs and other CNS diseases (sellar tumors and other pituitary non-neoplastic diseases, lower-grade gliomas, and skull-base meningiomas) or nontumor conditions, grouped as non-PitNET. RESULTS: Our results indicated that despite quantitative and qualitative differences between serum and plasma cfDNA composition, both sources of LB showed that patients with PitNETs presented a distinct methylome landscape compared to non-PitNETs. In addition, LB methylomes captured epigenetic features reported in PitNET tissue and provided information about cell-type composition. Using LB-derived PitNETs-specific signatures as input to develop machine-learning predictive models, we generated scores that distinguished PitNETs from non-PitNETs conditions, including sellar tumor and non-neoplastic pituitary diseases, with accuracies above ~93% in independent cohort sets. CONCLUSIONS: Our results underpin the potential application of methylation-based LB profiling as a noninvasive approach to identify clinically relevant epigenetic markers to diagnose and potentially impact the prognostication and management of patients with PitNETs.

Reducing Superfluous Opioid Prescribing Practices After Brain Surgery: It Is Time to Talk About Drugs.

BACKGROUND: Opioids are prescribed routinely after cranial surgery despite a paucity of evidence regarding the optimal quantity needed. Overprescribing may adversely contribute to opioid abuse, chronic use, and diversion. OBJECTIVE: To evaluate the effectiveness of a system-wide campaign to reduce opioid prescribing excess while maintaining adequate analgesia. METHODS: A retrospective cohort study of patients undergoing a craniotomy for tumor resection with home disposition before and after a 2-mo educational intervention was completed. The educational initiative was composed of directed didactic seminars targeting senior staff, residents, and advanced practice providers. Opioid prescribing patterns were then assessed for patients discharged before and after the intervention period. RESULTS: A total of 203 patients were discharged home following a craniotomy for tumor resection during the study period: 98 who underwent surgery prior to the educational interventions compared to 105 patients treated post-intervention. Following a 2-mo educational period, the quantity of opioids prescribed decreased by 52% (median morphine milligram equivalent per day [interquartile range], 32.1 [16.1, 64.3] vs 15.4 [0, 32.9], P < .001). Refill requests also decreased by 56% (17% vs 8%, P = .027) despite both groups having similar baseline characteristics. There was no increase in pain scores at outpatient follow-up (1.23 vs 0.85, P = .105). CONCLUSION: A dramatic reduction in opioids prescribed was achieved without affecting refill requests, patient satisfaction, or perceived analgesia. The use of targeted didactic education to safely improve opioid prescribing following intracranial surgery uniquely highlights the ability of simple, evidence-based interventions to impact clinical decision making, lessen potential patient harm, and address national public health concerns.

DNA methylation-based signatures classify sporadic pituitary tumors according to clinicopathological features.

BACKGROUND: Distinct genome-wide methylation patterns cluster pituitary neuroendocrine tumors (PitNETs) into molecular groups associated with specific clinicopathological features. Here we aim to identify, characterize, and validate methylation signatures that objectively classify PitNET into clinicopathological groups. METHODS: Combining in-house and publicly available data, we conducted an analysis of the methylome profile of a comprehensive cohort of 177 tumors (Panpit cohort) and 20 nontumor specimens from the pituitary gland. We also retrieved methylome data from an independent PitNET cohort (N = 86) to validate our findings. RESULTS: We identified three methylation clusters associated with adenohypophyseal cell lineages and functional status using an unsupervised approach. Differentially methylated probes (DMP) significantly distinguished the Panpit clusters and accurately assigned the samples of the validation cohort to their corresponding lineage and functional subtypes memberships. The DMPs were annotated in regulatory regions enriched with enhancer elements, associated with pathways and genes involved in pituitary cell identity, function, tumorigenesis, and invasiveness. Some DMPs correlated with genes with prognostic and therapeutic values in other intra- or extracranial tumors. CONCLUSIONS: We identified and validated methylation signatures, mainly annotated in enhancer regions that distinguished PitNETs by distinct adenohypophyseal cell lineages and functional status. These signatures provide the groundwork to develop an unbiased approach to classifying PitNETs according to the most recent classification recommended by the 2017 WHO and to explore their biological and clinical relevance in these tumors.

A serum-based DNA methylation assay provides accurate detection of glioma.

BACKGROUND: The detection of somatic mutations in cell-free DNA (cfDNA) from liquid biopsy has emerged as a noninvasive tool to monitor the follow-up of cancer patients. However, the significance of cfDNA clinical utility remains uncertain in patients with brain tumors, primarily because of the limited sensitivity cfDNA has to detect real tumor-specific somatic mutations. This unresolved challenge has prevented accurate follow-up of glioma patients with noninvasive approaches. METHODS: Genome-wide DNA methylation profiling of tumor tissue and serum cfDNA of glioma patients. RESULTS: Here, we developed a noninvasive approach to profile the DNA methylation status in the serum of patients with gliomas and identified a cfDNA-derived methylation signature that is associated with the presence of gliomas and related immune features. By testing the signature in an independent discovery and validation cohorts, we developed and verified a score metric (the "glioma-epigenetic liquid biopsy score" or GeLB) that optimally distinguished patients with or without glioma (sensitivity: 100%, specificity: 97.78%). Furthermore, we found that changes in GeLB score reflected clinicopathological changes during surveillance (eg, progression, pseudoprogression, and response to standard or experimental treatment). CONCLUSIONS: Our results suggest that the GeLB score can be used as a complementary approach to diagnose and follow up patients with glioma.

Contemporary Analysis of Minimal Clinically Important Difference in the Neurosurgical Literature.

BACKGROUND: Minimal clinically important difference (MCID) is determined when a patient or physician defines the minimal change that outweighs the costs and untoward effects of a treatment. These measurements are "anchored" to validated quality-of-life instruments or physician-rated, disease-activity indices. To capture the subjective clinical experience in a measurable way, there is an increasing use of MCID. OBJECTIVE: To review the overall concept, method of calculation, strengths, and weaknesses of MCID and its application in the neurosurgical literature. METHODS: Recent articles were reviewed based on PubMed query. To illustrate the strengths and limitations of MCID, studies regarding the measurement of pain are emphasized and their impact on subsequent publications queried. RESULTS: MCID varies by population baseline characteristics and calculation method. In the context of pain, MCID varied based on the quality of pain, chronicity, and treatment options. CONCLUSION: MCID evaluates outcomes relative to whether they provide a meaningful change to patients, incorporating the risks and benefits of a treatment. Using MCID in the process of evaluating outcomes helps to avoid the error of interpreting a small but statistically significant outcome difference as being clinically important.