Endoscopic endonasal surgery for prolactinomas: prognostic factors for disease control and management of persistent disease.

Only a limited number of studies have focused on the results of the Endoscopic Endonasal Approach (EEA) for treatment of prolactinomas. We sought to assess the effectiveness of EEA for prolactinoma surgery, identify factors for disease remission, and present our approach for the management of persistent disease. Forty-seven prolactinomas operated over 10 years, with a mean follow-up of 59.9 months, were included. The primary endpoints were early disease remission and remission at last follow-up. Resistance/intolerance to DA were surgical indications in 76.7%. Disease remission was achieved in 80% of microprolactinomas and 100% of microprolactinomas enclosed by the pituitary. Early disease remission was correlated with female gender (p=0.03), lower preoperative PRL levels (p=0.014), microadenoma (p=0.001), lack of radiological hemorrhage (p=0.001), absence of cavernous sinus (CS) invasion (p<0.001), and extent of resection (EOR) (p<0.001). Persistent disease was reported in 48.9% of patients, with 47% of them achieving remission at last follow-up with DA therapy alone. Repeat EEA and/or radiotherapy were utilized in 6 patients, with 66.7% achieving remission. Last follow-up remission was achieved in 76.6%, with symptomatic improvement in 95.8%. Factors predicting last follow-up remission were no previous operation (p=0.001), absence of CS invasion (p=0.01), and EOR (p<0.001). Surgery is effective for disease control in microprolactinomas. In giant and invasive tumors, it may significantly reduce the tumor volume. A multidisciplinary approach may lead to long-term disease control in three-quarters of patients, with symptomatic improvement in an even greater proportion.

Different Approaches in Skull Base Surgery Carry Risks for Different Types of Complications.

Complications are not uncommon in the complex field of skull base surgery. The intrinsic relationship of lesions in this region to important neurovascular structures, dura mater, and bone may lead to significant morbidity and mortality. The evolution of endoscopic endonasal surgery has had a significant impact on this field as a less invasive option for treatment of selected lesions, but major morbidity may still occur; moreover, endoscopic approaches have been associated with higher rates of some specific complications, such as cerebrospinal fluid leaks. Based on a presented case report, the authors discuss the management of various complications associated with different approaches for resection of skull base malignancies, including epidural and intradural pneumocephalus, subdural hematoma, and subdural empyema. Important lessons learned by the senior author throughout more than 30 years of his skull base surgery practice are highlighted. The inherent risk of complications in skull base surgery emphasizes the importance of their avoidance, prevention, and learning from one's unfavorable experience so as not to repeat them.

Endoscopic Treatment of Rathke's Cleft Cysts: The Case for Simple Fenestration.

BACKGROUND: Rathke's cleft cysts (RCC) arise from the pars intermedia because of incomplete regression of the embryologic Rathke pouch. A subset of RCC becomes symptomatic causing headaches, visual and endocrinological disturbances such that surgical intervention is indicated. Several points in surgical management remain controversial including operative strategy (simple fenestration (SF) vs complete cyst wall resection (CWR)) as well as reconstructive techniques. METHODS: A retrospective analysis was conducted of pathologically confirmed RCC operated on by endoscopic endonasal approach from 2006 to 2019. Pre-operative symptoms, imaging characteristics, operative strategy, symptom response, complications and recurrences were recorded. RESULTS: Thirty-nine patients were identified. Thirty-three underwent SF and six underwent CWR. Worsening pituitary function was significantly increased with CWR (50%) compared to SF (3%) (p = 0.008). All patients underwent "closed" reconstruction with a post-operative CSF leak rate of 5% (3% SF vs 16% CWR, p = 0.287). Six (15%) recurrences necessitating surgery were reported. Recurrence rates stratified by surgical technique (18% SF vs 0% CWR, p = 0.564) were not found to be significantly different. CONCLUSIONS: The current series illustrates variability in the surgical management of RCCs. SF with closed reconstruction is a reasonable operative strategy for most symptomatic RCCs cases while CWR can be reserved for selected cases.

Management of cavernous sinus meningiomas: Consensus statement on behalf of the EANS skull base section.

Introduction: The evolution of cavernous sinus meningiomas (CSMs) might be unpredictable and the efficacy of their treatments is challenging due to their indolent evolution, variations and fluctuations of symptoms, heterogeneity of classifications and lack of randomized controlled trials. Here, a dedicated task force provides a consensus statement on the overall management of CSMs. Research question: To determine the best overall management of CSMs, depending on their clinical presentation, size, and evolution as well as patient characteristics. Material and methods: Using the PRISMA 2020 guidelines, we included literature from January 2000 to December 2020. A total of 400 abstracts and 77 titles were kept for full-paper screening. Results: The task force formulated 8 recommendations (Level C evidence). CSMs should be managed by a highly specialized multidisciplinary team. The initial evaluation of patients includes clinical, ophthalmological, endocrinological and radiological assessment. Treatment of CSM should involve experienced skull-base neurosurgeons or neuro-radiosurgeons, radiation oncologists, radiologists, ophthalmologists, and endocrinologists. Discussion and conclusion: Radiosurgery is preferred as first-line treatment in small, enclosed, pauci-symptomatic lesions/in elderly patients, while large CSMs not amenable to resection or WHO grade II-III are candidates for radiotherapy. Microsurgery is an option in aggressive/rapidly progressing lesions in young patients presenting with oculomotor/visual/endocrinological impairment. Whenever surgery is offered, open cranial approaches are the current standard. There is limited experience reported about endoscopic endonasal approach for CSMs and the main indication is decompression of the cavernous sinus to improve symptoms. Whenever surgery is indicated, the current trend is to offer decompression followed by radiosurgery.

Ergonomics in Endoscopic Transsphenoidal Surgery: A Survey of the North American Skull Base Society.

Objective Different surgical set-ups for endoscopic transsphenoidal surgery (ETS) have been described, but studies on their ergonomics are limited. The aim of this article is to describe present trends in the ergonomics of ETS. Design and Participants A 33-question, web-based survey was sent to North American Skull Base Society members in 2018 and 116 responded to it (16% of all members). Most respondents were from North America (76%), in academic practice (87%), and neurosurgeons (65%); they had more than 5 years of experience in ETS (73%), had received specific training (66%), and performed at least 5 procedures/mo (55%). Results Mean reported time for standard and complex procedures were 3.7 and 6.3 hours, respectively. The patient's body is usually positioned in a straight, supine position (84%); the head is in a neutral position (46%) or rotated to the side (38%). Most surgeons perform a binostril technique, work with a partner (95%), and operate standing (94%), holding suction (89%) and dissector (83%); sometimes the endoscope is held by the primary surgeon (22-24%). The second surgeon usually holds the endoscope (72%) and irrigation (42%). During tumor removal most surgeons stand on the same side (65-66%). Many respondents report strain at the dorsolumbar (50%) or cervical (26%) level. Almost one-third of surgeons incorporate a pause during surgery to stretch, and approximately half exercise to be fit for surgery; 16% had sought medical attention for ergonomic-related symptoms. Conclusion Most respondents value ergonomics in ETS. The variability in surgical set-ups and the relatively high report of complaints underline the need for further studies to optimize ergonomics in ETS.

Endoscopic Treatment of Sellar Arachnoid Cysts via a Simple Cyst-Opening Technique: Long-Term Outcomes From a Single Center.

BACKGROUND: Sellar arachnoid cysts (SACs) are rare lesions that require treatment only if symptomatic. The endoscopic endonasal approach has been widely used. Despite their simple cystic appearance and the straight-forward surgical intervention, important associated risks exist, with cerebrospinal fluid (CSF) leak the prevalent risk. METHODS: A retrospective analysis of patients with pathologically confirmed SAC between January 2006 and December 2019 was conducted. A homogeneous simple cyst-opening technique and skull base reconstruction with nasoseptal flaps was used. RESULTS: A total of 10 patients were identified (7 women and 3 men; median age, 54.5 years; range, 20-77 years). Of the 10 patients, 8 had had newly diagnosed SACs and 2 patients had had recurrence from a previously microsurgically fenestrated SAC. Eight patients had presented with visual symptoms, one with visual symptoms and fatigue, and one with intractable headaches. Neuro-ophthalmological and endocrinological assessments had revealed visual field deficits in 6, visual acuity decline in 5, and hypopituitarism in 2 patients. The median calculated volume was 1.71 mL (range, 0.27-2.54 mL). Postoperatively, no CSF leak and no further surgical complications were noted. The visual field had improved in 4 of 6 patients and visual acuity had improved in 4 of 5 patients. Anterior pituitary function had improved in 1, worsened in 1, and remained stable in 8 patients. One patient had developed diabetes insipidus. One recurrence was recorded at 54 months postoperatively. CONCLUSIONS: The results from the present study have shown that SACs can be effectively treated using a simple cyst-opening technique. The routine use of nasoseptal flaps significantly reduced the risk of CSF leakage without compromising nasal quality of life in the long term or mandating additional incisions. Long-term follow-up is important to monitor for late recurrence.

Importance of Cobalt-60 Dose Rate and Biologically Effective Dose on Local Control for Intracranial Meningiomas Treated With Stereotactic Radiosurgery.

BACKGROUND: Radiosurgery dose rate and biologically effective dose (BED) are associated with outcomes after stereotactic radiosurgery (SRS) for functional neurosurgical conditions and some benign tumors. It is not known if these factors affect the efficacy of SRS for meningioma. OBJECTIVE: To determine the association between cobalt-60 dose rate and BED on outcomes in patients with meningioma treated with SRS. METHODS: A single-institution cohort of 336 patients treated between 2005 and 2018 with cobalt-based SRS for 414 separate meningioma lesions was assembled. BED was calculated using an SRS-specific monoexponential model accounting for treatment time per lesion, assuming α/ß = 2.47 Gy. Cumulative incidences of local failure (LF) were reported after considering the competing risk of death, on a per-lesion basis. Multivariable analysis of LF was performed using a proportional hazards model. RESULTS: The most common SRS dose was 12 Gy (n = 227); 140 lesions received 14 Gy. Five-year LF was 15.6% (95% confidence interval 10.4-21.9) and 4.3% (1.4-9.8) in patients who had a dose rate of <2.95 and ≥2.95 Gy/min, respectively (P = .0375). Among 354 grade I or unresected lesions treated with SRS, BED >50 Gy2.47 was associated with a lower incidence of LF (P = .0030). Each 1 Gy/min increase in dose rate was associated with an adjusted hazard ratio of 0.53 (95% confidence interval, 0.29-0.97, P = .041) for LF. Prescription dose >12 Gy was not associated with a lower incidence of LF. CONCLUSION: Patients with meningiomas treated with lower dose rates experienced a higher incidence of LF than those treated with higher dose rates.

Radiation Dose Rate, Biologically Effective Dose, and Tumor Characteristics on Local Control and Toxicity After Radiosurgery for Acoustic Neuromas.

OBJECTIVE: To evaluate the relationships between calibration dose rate, calculated biologically effective dose (BED), and clinical factors and tumor control after stereotactic radiosurgery (SRS) for acoustic neuroma. METHODS: We performed a retrospective study of all patients with acoustic neuromas treated with frame-based cobalt-60 SRS at a single institution between 2005 and 2019. The calibration dose rate and cobalt-60 half-life were used to calculate the nominal dose rate during treatment. An SRS-specific monoexponential model accounting for treatment time per lesion was used to estimate BED. RESULTS: The study included 607 patients with 612 acoustic neuromas. Median follow-up was 5.0 years. There was no association between dose rate or BED with local failure (LF), radiologic edema, or symptomatic edema. Cystic tumors (adjusted hazard ratio 0.26, P = 0.028) were associated with lower LF, while use of SRS as salvage treatment for growing tumors (adjusted hazard ratio 4.9, P < 0.0001) was associated with higher LF. LF occurred more frequently in larger-diameter tumors, while radiologic or symptomatic edema occurred more frequently in larger-volume tumors. CONCLUSIONS: Radiosurgery dose rate and BED were not associated with tumor control or radiologic or symptomatic edema. Salvage SRS and larger tumors were associated with a higher LF rate, while cystic tumors were associated with a lower LF rate. Patients with larger tumors should be counseled appropriately about potential side effects and when to seek follow-up care.

Endoscopic extra-capsular resection of a giant pituitary adenoma: how I do it.

BACKGROUND: Giant pituitary adenomas are characterized by their large size and potential to invade parasellar and suprasellar regions leading to visual decline and hypopituitarism. Thus, they remain a significant surgical challenge, and gross total removal is only achieved in the minority of cases. METHOD: We aim to describe the key surgical steps for endoscopic extra-capsular resection of a giant pituitary adenoma with the aim of achieving complete tumor resection with description of the relevant surgical anatomy, indications and limitations. CONCLUSION: Endoscopic extra-capsular resection of giant pituitary tumors when feasible allows for complete tumor resection, early identification of the gland and avoidance of manipulation of the optic apparatus.

Significance of Crooke's Hyaline Change in Nontumorous Corticotrophs of Patients With Cushing Disease.

Background: Glucocorticoid excess in Cushing disease (CD) leads to negative feedback suppression, resulting in Crooke's hyaline change (CC) of nontumorous pituitary corticotrophs. We aimed to determine the predictive value of CC of nontumorous corticotrophs in CD. Methods: The retrospective chart review study included patients with clinical, biochemical, radiologic and outcome data and evaluable histopathology specimens from pituitary surgery for CD. The main outcome was remission of CD, defined by clinical features, biochemical testing, and corticosteroid dependency. Results: Of 144 CD patients, 60 (50 women, mean age 43.6±14) had clinical follow-up, biochemical data and histopathology specimens that included evaluable nontumorous adenohypophysis. Specimens from 50 patients (83.3%) demonstrated CC in nontumorous corticotrophs, and 10 (16.7%) had no CC (including 3 with corticotroph hyperplasia). One patient with CC was lost to follow-up and one without CC had equivocal outcome results. During a mean (SD) follow-up period of 74.9 months (61.0), recurrent or persistent disease was documented in 18 patients (31.0%), while 40 (69.0%) were in remission. In patients with CC, the remission rate was 73.5% (95% CI, 59.7%-83.7%) (36/49), whereas it was 44.4% (95% CI, 18.9%-73.3%) (4/9) in patients with no CC. The combination of serum cortisol >138 nmol/L within a week of surgery coupled with absence of nontumorous CC greatly improved the prediction of recurrent or persistent disease. Conclusions: CC of nontumorous corticotrophs was observed in 83% of patients with CD, and most patients with CC experienced remission. Absence of CC in nontumorous corticotrophs may serve as a predictor of reduced remission in patients with CD.

Psychometric testing of the Skull Base Inventory health-related quality of life questionnaire in a multi-institutional study of patients undergoing open and endoscopic surgery.

PURPOSE: The skull base inventory (SBI) was developed to better assess health-related quality of life (HR-QOL) in patients with anterior and central skull base neoplasms treated by endoscopic and open approaches. The primary objective of this study was to prospectively assess the psychometric properties of the SBI. METHODS: This study is part of a multi-center study of patients undergoing endoscopic and open procedures completed between 2012 and 2018. Participants were eligible if they were over 18 years of age; had benign or malignant anterior, antero-lateral, or central skull base tumors; and required either an open or endoscopic skull base surgical approach. In order to assess the psychometric properties of the SBI, patients completed the instrument at six time points (preoperative, 2 weeks, 3 months, 6 months, 12 months postoperative). Patients also completed the Anterior Skull Base (ASB) questionnaire and the Sinonasal Outcome Test (SNOT-22) to allow comparison to the SBI. RESULTS: One hundred and eighty-seven patients were included across five centers, with 121 having an endoscopic procedure. Internal consistency (Cronbach's alpha = 0.95) and test-retest at 12 months and 12 months plus 2 weeks (intraclass correlation > 0.90) were excellent. Concurrent validity was demonstrated by very strong correlation between total SBI scores and ASB scores (r = 0.810 to 0.869, p < 0.001) and moderate correlation between nasal domain SBI scores and SNOT-22 scores (r = - 0.616 to - 0.738, p < 0.001). Convergent validity was demonstrated by moderate correlation between change in SBI scores and global QOL change (rs = 0.4942, p < 0.001). The minimally important clinical difference (global HR-QOL change of "a little better" or "a little worse") was 6.0. CONCLUSION: The SBI questionnaire is reliable and valid for patients treated by both endoscopic and open approaches and can be used for assessment of HR-QOL in these settings.

Cost-effectiveness of endoscopic endonasal vs transcranial approaches for olfactory groove meningioma.

BACKGROUND: Endoscopic endonasal approaches (EEAs) have been adopted as an alternative to standard transcranial approaches for olfactory groove meningiomas (OGMs). However, the relative cost-effectiveness remains controversial. METHODS: Cost-utility analysis from a societal perspective comparing EEA vs transcranial approaches for OGM was used in this study. Surgical treatment was modeled using decision analysis, and a Markov model was adopted over a 20-year horizon. Parameters were obtained from literature review. Costs were expressed in 2017 Canadian dollars. RESULTS: In the base case, EEA was cost-effective compared with transcranial surgery with an incremental cost-effectiveness ratio of $33 523 ($30 475 USD)/QALY. There was a 55% likelihood that EEA was cost-effective at a willingness-to-pay of $50 000/QALY. EEA remained cost-effective at a cerebrospinal fluid leak rate below 60%, gross total resection rate above 25%, and base cost less than $66 174 ($60 158 USD). CONCLUSION: EEA may be a cost-effective alternative to transcranial approaches for selected OGM.

Surgical anatomy and technical nuances of the endoscopic endonasal approach to the anterior cranial fossa.

Endoscopic endonasal approaches (EEA) to the skull base have significantly impacted the management of lesions located in the cranial base. Specifically, lesions arising from the anterior cranial fossa, such as pituitary macroadenomas, craniopharyngiomas meningiomas and craniofacial malignancies have benefited from the development of such approaches. Understanding of the anatomy of the anterior fossa is of utmost importance for the successful selection of the approach and application of surgical techniques in EEA. In the current manuscript, we review the most relevant points of surgical anatomy and nuances of the surgical technique of EEA to the anterior fossa. Anatomical landmarks for the transtuberculum transplanum and transcribriform approaches are discussed and a step-by-step description for those approaches is presented. We reinforce that safe and effective application of such techniques follow the same principles of other skull base surgery techniques: mastering of surgical anatomy, adequate case selection, correct instrumentation and surgical experience.

Endoscopic Endonasal Pituitary Surgery For Nonfunctioning Pituitary Adenomas: Long-Term Outcomes and Management of Recurrent Tumors.

INTRODUCTION: Endoscopic endonasal approaches (EEAs) provide improved access and operative visualization for resection of pituitary adenomas. Although the technique has gained wide acceptance, there is a paucity of data regarding late recurrence. OBJECTIVE: We aim to assess long-term outcomes of patients with nonfunctioning pituitary adenomas (NFPAs) who underwent EEA. METHODS: We reviewed 269 patients operated on for an NFPA between 2005 and 2015. Clinical and radiologic factors including those potentially related to higher chances of recurrence were analyzed. Progression-free survival was analyzed using the Kaplan-Meier method, and univariate and multivariate survival were analyzed using a Cox regression model. RESULTS: The study included 269 patients. The gross total resection rate was 46.0% (n = 124) but cavernous sinus involvement was present in almost half the patients (n = 115). The probability of recurrence at 5 years and 10 years was 22.0% and 47.2%, respectively. The median time to recurrence was 10 years for patients without cavernous sinus involvement and 6 years for those with cavernous sinus involvement. Univariate and multivariate analysis showed that tumor size, cavernous sinus invasion, anterior skull base extensions, and residual tumor were significantly associated with recurrence. CONCLUSIONS: Recurrence rate of NFPA remains high despite the better visualization offered by EEA, especially in those tumors involving the cavernous sinus and/or previously operated on. Repeat surgery is adequate for tumor debulking and decompression of the optic apparatus but is unlikely to achieve gross total resection if a successful previous EEA has been performed. Radiation therapy is an effective option for management of recurrent tumors.

Reirradiation for recurrent craniopharyngioma.

PURPOSE: Reirradiation is rarely administered to patients with recurrent craniopharyngioma owing to concerns regarding visual and endocrine side effects. The purpose of this case series was to evaluate our institutional experience of patients with craniopharyngioma treated with 2 courses of fractionated radiation therapy. METHODS AND MATERIALS: A retrospective study was performed of all patients with craniopharyngioma treated with 2 courses of fractionated radiation therapy at a single institution. Electronic medical records and radiation therapy records were reviewed. RESULTS: We identified 4 eligible patients with recurrent craniopharyngioma. With a median follow-up of 33 months after reirradiation, 3 patients attained disease control; 1 patient developed progressive disease, 27 months after reirradiation. In 3 evaluable patients, vision remained stable or improved after reirradiation; one patient had no light perception before reirradiation. None of the patients experienced additional endocrine toxicities after reirradiation, apart from one patient who had low serum thyroid stimulating hormone before reirradiation and later developed hypothyroidism after treatment. CONCLUSIONS: Reirradiation may represent a safe and effective therapeutic option for selected patients with recurrent, refractory craniopharyngioma and without other salvage treatment options. Larger studies with longer-term follow up are warranted to better understand outcomes in these patients.

Postural Changes and the Trans-Lamina Cribrosa Pressure Difference: A Pilot Study in Neurosurgical Patients without Glaucoma.

PURPOSE: To evaluate the effect of changes in position in the trans-lamina cribrosa pressure difference (TLCPD) by simultaneously measuring and comparing intracranial pressure (ICP) with intraocular pressure (IOP) in seated and supine positions. DESIGN: Prospective cohort study. PARTICIPANTS: Patients admitted to the neurosurgery unit at Toronto Western Hospital with an external ventricular drain placed for ICP monitoring. Exclusion criteria were any ophthalmic surgical procedures within the preceding 6 months, history of glaucoma, and corneal abnormalities affecting IOP measurement. METHODS: Intraocular pressure and ICP were recorded simultaneously in both the supine and seated positions with the order of positions randomized. Measurements were made 10 minutes after assuming each position. The TLCPD (IOP minus ICP) was calculated for the sitting and supine positions. The paired t test was used to assess significance of differences. MAIN OUTCOME MEASURE: The TLCPD. RESULTS: Twenty patients were included in the study. The average age was 54±17 years. Results were similar for left and right eyes. Data are shown for right eyes only. Mean sitting and supine IOPs were 15.3±3.5 mmHg and 15.9±3.7 mmHg, respectively (P = 0.32). Mean sitting and supine ICPs were 12.5±6.8 mmHg and 12.8±5.1 mmHg, respectively (P = 0.66). Mean TLCPD was 3.1±6.0 mmHg in the sitting position and 3.1±7.0 mmHg in the supine position (P = 1.00). Supine TLCPD increased in 10 patients (50%), decreased in 8 patients (40%), and was unchanged in 2 patients (10%). CONCLUSIONS: In this pilot study of 20 neurosurgical patients without glaucoma, posture-induced TLCPD changes were variable.

Craniopharyngiomas: Challenges and Controversies.

Despite its benign histopathology, the treatment of craniopharyngioma remains one of the most formidable challenges faced by skull base surgeons. The technical challenges of tackling these complex central skull base lesions are paralleled by clinical challenges related to their unique tumor biology and the often-complex decision making required. In this article, we critically appraise the most recent literature to explore the challenges and controversies surrounding the management of these lesions. The role of curative resections and the shift in the surgical paradigm toward the multidisciplinary goal-directed management approach are discussed.

Current Results of Surgical Treatment of Craniopharyngiomas: The Impact of Endoscopic Endonasal Approaches.

Surgery is the main treatment option for the management of craniopharyngiomas. Transcranial microsurgical approaches, such as pterional and subfrontal approaches, have constituted the classic operative strategy for resection of these tumors. However, the development of endoscopic endonasal approaches has revolutionized the treatment of craniopharyngiomas in the last 15 years, and endoscopic resection is favored for most craniopharyngiomas. In this article, we discuss our experience with the management of craniopharyngiomas and review the current results of the surgical treatment of those tumors, including discussion of goals of surgery, complications, recurrences, and the role of adjuvant treatment.

Creative and Innovative Methods and Techniques for the Challenges in the Management of Adult Craniopharyngioma.

Craniopharyngioma remains a major challenge in daily clinical practice. The pathobiology of the tumor is still elusive, and there are no consensus or treatment guidelines on the optimal management strategy for this relatively rare tumor. However, recent technical and scientific advances, including genomic and radiomic profiling, innovation in surgical approaches, more precise radiotherapy protocols, targeted therapy, and restoration of lost functions all have the potential to significantly improve the outcome of patients with craniopharyngioma in the near future. Although many of these innovative tools in the new armamentarium of the clinician are still in their infancy, they could reduce craniopharyngioma-related morbidity and mortality and improve the patients' quality of life. In this article, we discuss these creative and innovative approaches that may offer solutions to the obstacles faced in treating craniopharyngioma and future possibilities in improving the care of these patients.