[Intradural Mucocele Associated with a Frontoethmoidal Osteoma:A Case Report].

The formation of symptomatic intradural mucocele associated with a paranasal osteoma is rare, and no standard treatment has been established. Here, we present a case of intradural mucocele in a 27-year-old man complaining of headache and generalized convulsion. Cranial CT and brain MRI showed a left frontoethmoidal osteoma extending into the left anterior cranial fossa and orbit along with a mass in the left frontal lobe. He underwent resection of both intracranial osteomas and the mass through left frontal craniotomy. Histological findings were consistent with a mucocele, and the diagnosis of an intradural mucocele associated with a frontoethmoidal osteoma was confirmed. The postoperative course was uneventful. Although both osteoma and mucocele are benign, they may cause life-threatening symptoms by expanding intracranially. A tailored treatment considering the invasiveness and postoperative long-term follow-up of the patient is essential for this uncommon condition.

[Two Cases of Venous Malformation of the Orbit Treated by Endoscopic Endonasal Surgery].

Venous malformation of the orbit(VMO), previously called orbital cavernous hemangioma, has been classified as a vascular malformation according to the International Society for the Study of Vascular Anomalies. Among various surgical approaches for VMO, endoscopic endonasal surgery(EES)has recently been developed, especially for those in the inferomedial quadrant of the orbit. Two 67-year-old and 69-year-old women presented with decreased visual acuity and visual field deficit, respectively. Their CT and MRI scans revealed retrobulbar masses, suggestive of the inferomedial type of VMO. The first case was diagnosed as an intraconal VMO, and subtotal removal was achieved through binostril EES using a two-surgeon four-handed technique after palliative partial resection through a prior frontal craniotomy. In the second case, diagnosed as an extraconal VMO, total en bloc removal was achieved using the same surgical technique as above. In both cases, the visual functions improved after the procedures, with uneventful postoperative courses. Although the inferomedial VMO is an uncommon type, EES is well indicated for this condition. The international consensus of surgical techniques and staging from a surgical point of view should be established in the near future.

Comparative study of pulsed-continuous arterial spin labeling and dynamic susceptibility contrast imaging by histogram analysis in evaluation of glial tumors.

PURPOSE: Arterial spin labeling (ASL) is a non-invasive perfusion technique that may be an alternative to dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) for assessment of brain tumors. To our knowledge, there have been no reports on histogram analysis of ASL. The purpose of this study was to determine whether ASL is comparable with DSC-MRI in terms of differentiating high-grade and low-grade gliomas by evaluating the histogram analysis of cerebral blood flow (CBF) in the entire tumor. METHODS: Thirty-four patients with pathologically proven glioma underwent ASL and DSC-MRI. High-signal areas on contrast-enhanced T1-weighted images or high-intensity areas on fluid-attenuated inversion recovery images were designated as the volumes of interest (VOIs). ASL-CBF, DSC-CBF, and DSC-cerebral blood volume maps were constructed and co-registered to the VOI. Perfusion histogram analyses of the whole VOI and statistical analyses were performed to compare the ASL and DSC images. RESULTS: There was no significant difference in the mean values for any of the histogram metrics in both of the low-grade gliomas (n = 15) and the high-grade gliomas (n = 19). Strong correlations were seen in the 75th percentile, mean, median, and standard deviation values between the ASL and DSC images. The area under the curve values tended to be greater for the DSC images than for the ASL images. CONCLUSIONS: DSC-MRI is superior to ASL for distinguishing high-grade from low-grade glioma. ASL could be an alternative evaluation method when DSC-MRI cannot be used, e.g., in patients with renal failure, those in whom repeated examination is required, and in children.

Small Hyperintensities in the Area of the Perforating Arteries in Patients with Seizure.

BACKGROUND/AIM: We previously observed spotty hyperintense lesions in the region of the perforating arteries on peri-ictal diffusion-weighted imaging (DWI); however, no report has formally described these findings. The aim of this study was to investigate focal intensities on peri-ictal DWI, and to evaluate the clinical significance of these lesions. METHODS: We conducted a retrospective review of 677 consecutive patients with seizure who completed peri-ictal DWI within 24 h after seizure onset. Patients were grouped according to the presence or absence of diffusion hyperintense lesions (DHLs) in the region of the perforating arteries. We compared clinical and imaging characteristics between these 2 groups. RESULTS: Among 677 patients, 23 patients (3.4%) had DHLs. Analyses of apparent diffusion coefficient values and fluid attenuated inversion recovery images suggested that DHLs were acute or subacute ischemic lesions that had appeared prior to seizure onset. Patients with DHLs were more likely to be older in age, have atrial fibrillation, and coronary artery disease, and have more severe deep white matter hyperintensity or leukoaraiosis compared to patients without DHLs. CONCLUSION: DHLs detected on peri-ictal DWI may represent incidental acute cerebral microinfarcts in the aging brain, especially in patients with small vessel disease.

Vessel-Masked Perfusion Magnetic Resonance Imaging With Histogram Analysis Improves Diagnostic Accuracy for the Grading of Glioma.

OBJECTIVE: Dynamic susceptibility contrast magnetic resonance imaging is widely used to assess glioma grade; histogram analyses are used for precise tumor perfusion evaluations. We evaluated the effect of vessel contamination in normalized cerebral blood volume (nCBV) to differentiate high- and low-grade gliomas. METHODS: Thirty-four patients with gliomas underwent dynamic susceptibility contrast magnetic resonance imaging. Both traditional and vessel-masked nCBV maps were constructed. Histogram analyses of whole tumors and statistical comparisons were performed to compare traditional and vessel-masked images. RESULTS: Mean values of all the histogram metrics were lower in vessel-masked images than in traditional images. Receiver operating characteristic curve analyses for every histogram metric showed a higher area under the curve for vessel-masked images than for traditional images. The integrated discrimination improvement showed that the vessel-masked images were superior to the traditional images significantly for predicting the glioma grading. CONCLUSIONS: Vessel-masked nCBV maps can prevent overestimations of CBV measurements and can improve diagnostic accuracy for glioma grading.

Voxel-Based Lesion Mapping of Cryptogenic Stroke in Patients with Advanced Cancer: A Detailed Magnetic Resonance Imaging Analysis of Distribution Pattern.

BACKGROUND: Ischemic stroke is one form of cancer-associated thrombosis that can greatly worsen a patient's performance status. The present investigation aimed to elucidate the characteristic distribution pattern(s) of cryptogenic stroke lesions using a voxel-based lesion-mapping technique and examine the differences in clinical manifestations between cryptogenic and conventional strokes in patients with advanced cancer. METHODS: Data from 43 patients with advanced cancer who developed acute ischemic stroke were retrospectively collected. Stroke etiology was grouped into either cryptogenic or conventional stroke etiology according to the ASCO stroke score. Clinical data were reviewed, and voxel-based lesion mapping using diffusion-weighted imaging (DWI) was performed to visualize the cross-patient spatial distribution of the lesions. RESULTS: Of the 43 patients, 25 were classified as having cryptogenic stroke etiology and 18 were classified as having conventional stroke etiology. Median survival time of patients from stroke onset was 96 days for cryptogenic stroke etiology and 570 days for conventional stroke etiology (P = .01). D-dimer of patients was significantly higher in cryptogenic stoke etiology than in conventional stroke etiology (P = .006). Voxel-based lesion mapping showed that DWI hyperintense lesions accumulated at cortical and internal watershed areas of the cerebrum and at the vascular border zone of the superior cerebellar and posterior inferior cerebellar arteries at the cerebellum. CONCLUSIONS: Voxel-based lesion mapping for cryptogenic stroke in patients with advanced cancer showed that lesions accumulated at vascular border zones within the brain both at the cerebrum and at the cerebellum, but not at perforating arterial territories.

Clinical and radiological features of endodermal cyst in the oculomotor nerve: A case report.

We present a 9-year-old girl with an endodermal cyst of the oculomotor nerve in the left interpeduncular cistern, who had a history of left ptosis. We suggest that a cyst localized at the exit of the oculomotor nerve from the midbrain associated with oculomotor palsy may suggest this rare entity.

Regulatory effects of Spirulina complex polysaccharides on growth of murine RSV-M glioma cells through Toll-like receptor 4.

This study is the first to report that Spirulina complex polysaccharides (CPS) suppress glioma growth by down-regulating angiogenesis via a Toll-like receptor 4 signal. Murine RSV-M glioma cells were implanted s.c. into C3H/HeN mice and TLR4 mutant C3H/HeJ mice. Treatment with either Spirulina CPS or Escherichia coli (E. coli) lipopolysaccharides (LPS) strongly suppressed RSV-M glioma cell growth in C3H/HeN, but not C3H/HeJ, mice. Glioma cells stimulated production of interleukin (IL)-17 in both C3H/HeN and C3H/HeJ tumor-bearing mice. Treatment with E. coli LPS induced much greater IL-17 production in tumor-bearing C3H/HeN mice than in tumor-bearing C3H/HeJ mice. In C3H/HeN mice, treatment with Spirulina CPS suppressed growth of re-transplanted glioma; however, treatment with E. coli LPS did not, suggesting that Spirulina CPS enhance the immune response. Administration of anti-cluster of differentiation (CD)8, anti-CD4, anti-CD8 antibodies, and anti-asialo GM1 antibodies enhanced tumor growth, suggesting that T cells and natural killer cells or macrophages are involved in suppression of tumor growth by Spirulina CPS. Although anti-interferon-γ antibodies had no effect on glioma cell growth, anti-IL-17 antibodies administered four days after tumor transplantation suppressed growth similarly to treatment with Spirulina CPS. Less angiogenesis was observed in gliomas from Spirulina CPS-treated mice than in those from saline- or E. coli LPS-treated mice. These findings suggest that, in C3H/HeN mice, Spirulina CPS antagonize glioma cell growth by down-regulating angiogenesis, and that this down-regulation is mediated in part by regulating IL-17 production.

Decompressive craniectomy and head injury: brain morphometry, ICP, cerebral hemodynamics, cerebral microvascular reactivity, and neurochemistry.

There has been renewed interest in decompressive craniectomy as a surgical treatment for elevated intracranial pressure (ICP), although evidence-based clinical data are still lacking and some experimental results are conflicting. Ongoing clinical trials on the use of this operation after traumatic brain injury (TBI) may clarify the clinical application of this technique, however, some pathophysiological issues, such as the timing of this operation, its effect on brain edema formation, and its role for secondary brain damage, are still controversial. This review addresses recent clinical data on the influence of decompressive craniectomy on the brain pathophysiology in TBI. Decompressive craniectomy with dural augmentation enlarges intracranial space so that the swollen cerebral hemisphere could expand out of normal cranial limits, avoiding progression of brain herniation. The gain in intracranial volume results in both the improvement of cerebral compliance and a decrease in ICP; the latter favors a rise in both cerebral blood flow and cerebral microvascular perfusion, which can be accompanied by elevation in brain tissue oxygen tension (PbtO2) as well as the return of abnormal metabolic parameters to normal values in cases of cerebral ischemia. Enhancement of edema formation, impairment of cerebrovascular pressure reactivity, and non-restoration of brain aerobic metabolism due to metabolic crisis may occur after craniectomy and require further investigations. This review suggests that decompressive craniectomy as the sole treatment is likely to be insufficient; efforts must be made to maintain adequate brain hemodynamics, preferably coupled with brain metabolism, in addition to treating brain metabolic abnormalities, during postoperative stages.

Evaluation of two- and three-dimensional visualization for endoscopic endonasal surgery using a novel stereoendoscopic system in a novice: a comparison on a dry laboratory model.

BACKGROUND: Three-dimensional (3-D) stereoscopic vision is theoretically superior to two-dimensional (2-D) vision in endoscopic endonasal surgery. However, only few reports have quantitatively compared endoscopic performance under the two visual conditions. We introduced a newly designed stereoendoscopic system with a "dual-lens and single camera" for endoscopic endonasal surgery and objectively compared the performances under 3-D and high-definition 2-D visualizations on a dry laboratory model. METHODS: Thirty subjects without experience performing endoscopic surgery, computer-simulated training or any 3-D video system were recruited and divided into two groups (Group A and Group B) for performing two different tasks. The novel 4.7-mm-diameter stereoendoscope provided high-definition (HD) images. In Task 1, Group A started the task under the 3-D condition followed by the 2-D condition, and Group B vice versa. In Task 2, Group A started the task under the 2-D condition followed by the 3-D condition, and Group B vice versa. The performance accuracy and speed under the two visual conditions were analyzed. RESULTS: Significant improvement in performance accuracy and speed was seen under 3-D conditions in the both "3-D first" and "2-D first" subgroups during both tasks (P < .001). Regardless of order, the inaccuracy rate and performance time under 3-D conditions was significantly lower than that under 2-D conditions in each subject. CONCLUSIONS: We demonstrated the advantage of 3-D visualization over 2-D visualization for inexperienced subjects. Further quantitative clinical studies are required to confirm whether stereoendoscopy actually provides benefits in clinical settings.

Continuous Monitoring of Changes in Heart Rate during the Periprocedural Course of Carotid Artery Stenting Using a Wearable Device: A Prospective Observational Study.

This prospective observational study will evaluate the change in heart rate (HR) during the periprocedural course of carotid artery stenting (CAS) via continuous monitoring using a wearable device. The participants were recruited from our outpatient clinic between April 2020 and March 2023. They were instructed to continuously wear the device from the last outpatient visit before admission to the first outpatient visit after discharge. The changes in HR of interest throughout the periprocedural course of CAS were assessed. In addition, the Bland-Altman analysis was adopted to compare the HR measurement made by the wearable device during CAS with that made by the electrocardiogram (ECG). A total of 12 patients who underwent CAS were included in the final analysis. The time-series analysis revealed that a percentage change in HR decrease occurred on day 1 following CAS and that the most significant HR decrease rate was 12.1% on day 4 following CAS. In comparing the measurements made by the wearable device and ECG, the Bland-Altman analysis revealed the accuracy of the wearable device with a bias of -1.12 beats per minute (bpm) and a precision of 3.16 bpm. Continuous HR monitoring using the wearable device indicated that the decrease in HR following CAS could persist much longer than previously reported, providing us with unique insights into the physiology of carotid sinus baroreceptors.

¹¹C-methionine uptake and intraoperative 5-aminolevulinic acid-induced fluorescence as separate index markers of cell density in glioma: a stereotactic image-histological analysis.

BACKGROUND: The extent of tumor resection is acknowledged as 1 of the prognostic factors for glioma. 5-Aminolevulinic acid (5-ALA)-induced fluorescence guidance and neuronavigation integrated with (11) C-methionine positron emission tomography (PET) are widely utilized under the expectation of improving the extent of resection. These 2 novel approaches are beneficial for glioma resections, and the combination of these approaches appears rational. However, biological characteristics reflecting 5-ALA-induced fluorescence and (11) C-methionine uptake have not been clearly elucidated, and studies about the relationship between 5-ALA-induced fluorescence and (11) C-methionine uptake have been limited. The present study aimed to clarify this issue. METHODS: Data from 11 consecutive patients harboring astrocytic tumors were analyzed: 2 grade II and 2 grade III, and 7 grade IV tumors were included. Thirty samples from these patients were obtained from the relative periphery of each tumor. Relationships among histology, 5-ALA-induced fluorescence and (11) C-methionine uptake were analyzed by stereotactic sampling and image analysis. RESULTS: Uptake of (11) C-methionine correlated with cell density (R(2) = 0.322, P = .0059). Cell density was higher in fluorescence-positive areas than in negative areas (2760 ± 1080 vs 1450 ± 1380/mm(2) , P = .0132). Although both (11) C-methionine uptake and fluorescence seemed to correlate with cell density, no significant difference in (11) C-methionine uptake was seen between fluorescence-positive and -negative areas (P = .367). Multiple linear regression analysis revealed (11) C-methionine uptake and 5-ALA-induced fluorescence as independent indices for tumor cell density. CONCLUSIONS: These results indicate that 5-ALA fluorescence and (11) C-methionine PET image are separate index markers for cytoreduction surgery of gliomas.

Clinical characteristics of meningiomas assessed by ¹¹C-methionine and ¹8F-fluorodeoxyglucose positron-emission tomography.

The clinical course of meningioma varies from case to case, despite similar characteristics on magnetic resonance (MR) imaging. Functional imaging including (11)C-methionine and (18)F-fluorodeoxyglucose (FDG) positron-emission tomography (PET) has been widely studied for noninvasive preoperative evaluation of brain tumors. However, few reports have examined correlations between meningiomas and findings on (11)C-methionine and FDG PET. The objective of this study was to clarify the relationship between tumor characteristics and (11)C-methionine and FDG uptake in meningiomas. For 68 meningiomas in 51 cases, (11)C-methionine uptake was evaluated by measuring both mean and maximum tumor/normal (T/N) ratio for the whole area of the tumors. FDG uptake in 44 of those meningiomas was also analyzed. Tumor size was measured volumetrically, and tumor-doubling time was estimated. Histopathological evaluation was performed in 19 surgical cases. Mean and maximum T/N ratios of (11)C-methionine PET were significantly higher in skull-base lesions than in non-skull-base lesions. Correlations of mean and maximum T/N ratio of (11)C-methionine PET with tumor-doubling time, MIB-1 labeling index, microvessel density and World Health Organization grading were not significant. Mean T/N ratio of (11)C-methionine PET correlated significantly with tumor volume according to logarithm regression modeling (P < 0.0001, R = 0.544). However, mean and maximum T/N ratio of FDG-PET correlated with none of the tumor characteristics described above. These results suggest that (11)C-methionine uptake correlates with tumor volume, but not with tumor aggressiveness.

Imaging ¹8F-fluorodeoxy glucose/¹¹C-methionine uptake decoupling for identification of tumor cell infiltration in peritumoral brain edema.

Discriminating tumor infiltrative and vasogenic brain edema in malignant gliomas is important although challenging in clinical settings. This study challenged this issue by performing voxel-wise analysis of (18)F-fluorodeoxy glucose (FDG) and (11)C-methionine positron emission tomography (PET) in peritumoral brain edemas. The authors studied ten malignant glioma and nine meningioma patients with peritumoral brain edema. A voxel-wise analysis of FDG and (11)C-methionine PET was performed in order to quantify the correlation between uptake of these tracers in normal brain tissue and peritumoral brain edema. Decoupling score of the uptake of two tracers was calculated as the z-score from the estimated correlation between uptake of the two tracers in normal brain tissue. The decoupling score was also converted into images for visual inspection. Average decoupling score in the peritumoral brain edema was calculated and compared between those obtained from malignant gliomas and meningiomas. FDG and (11)C-methionine uptake showed a reproducible linear correlation in normal brain tissue. This correlation was preserved in peritumoral edema of meningioma, but not in that of malignant gliomas. In malignant gliomas, higher (11)C-methionine uptake compared to that estimated by the FDG uptake in normal brain tissue was observed, thus suggesting that decoupling was caused by tumor infiltration. Visual inspection of the decoupling score enabled discrimination of tumor infiltrative and vasogenic edema. The average decoupling scores of the peritumoral brain edema in malignant gliomas were significantly higher than those in meningiomas (2.9 vs. 0.7, P = 0.0003). As a conclusion, FDG/(11)C-methionine uptake decoupling score can be used for the discrimination of tumor infiltrative and vasogenic brain edema. The proposed method also suggests the possibility of accurately detecting tumor infiltration into brain tissues in gliomas, providing significant information for treatment planning and follow-up.

Hepatitis B virus reactivation associated with temozolomide for malignant glioma: a case report and recommendation for prophylaxis.

Hepatitis B virus (HBV) reactivation during anticancer chemotherapy or immunosuppressive therapy in chronic carriers can lead to fatal liver failure. We report a rare case of severe HBV reactivation during postoperative radiotherapy with concomitant and adjuvant temozolomide (TMZ) for malignant glioma. A 49-year-old Japanese woman with a history of HBV carrier status with positive results for hepatitis B surface antigen presented with persistent headache due to a tumor in the left frontal lobe. The tumor was partially resected and anaplastic astrocytoma was diagnosed. Postoperative liver function was normal and radiotherapy plus concomitant and adjuvant TMZ was started. Impaired liver function became apparent just before administration of adjuvant TMZ, and acute liver failure developed. Antiviral therapy including entecavir, a nucleoside analog, led to a successful outcome and the patient survived. This case underlines the possibility of HBV reactivation due to TMZ and suggests the utility of HBV screening and antiviral prophylaxis before administration of TMZ to patients with malignant glioma.

Transient total mesencephalic locked-in syndrome after bilateral ptosis due to basilar artery thrombosis.

Locked-in syndrome (LIS) usually occurs as a result of pontine lesions and has been classified into various categories on the basis of neurologic conditions, of which transient total mesencephalic LIS is extremely rare. A 53-year-old man presented with bilateral ptosis followed by a total locked-in state. In the clinical course, the patient successfully recovered with only left slight hemiparesis and skew deviation remaining. Magnetic resonance imaging revealed multiple ischemic lesions caused by thrombosis at the top of basilar artery, including the bilateral cerebral peduncles, tegmentum of the midbrain, and the right cerebellar hemisphere. Antecedent bilateral ptosis before the locked-in state may be related to ischemia in the central caudal nucleus of the oculomotor nuclei. We should pay attention to this easily missed condition during the treatment of ischemic stroke involving the basilar artery.

Revisiting the definition of glioma recurrence based on a phylogenetic investigation of primary and re-emerging tumor samples: a case report.

A recurrent tumor is defined as a re-emerging subclone originating from an ancestorial clone of the primary neoplasm. Hence, it should be distinguished from de novo tumor emerging from other clones. Herein, we describe an exceptional case in which the locally re-emerging glioma did not share genetic alterations of the primary tumor. While the initial tumor harbored mutations in IDH1 and TERT genes as well as 1p/19q codeletion, the re-emerging tumor did not present any of these genetic abnormalities. Variant calling for tumor samples using whole-genome sequencing revealed that 1696 mutations within the primary tumor faded in the re-emerging tumor, and that 4591 mutations were newly detected in the re-emerging tumor. These results suggested that the initial and re-emerging tumors did not share same clonal origins, although the second tumor appeared adjacent to the old surgical cavity 5 years after the initial surgery. We finally speculated that the re-emerging tumor could be a "de novo glioma" or "radiation-induced glioblastoma following treatment of a diffuse glioma." This case highlights the importance of molecular re-evaluation of clinically diagnosed "recurrent" glioma lesions.

Primary intracranial leiomyosarcoma in an immunocompetent patient: case report.

We report a case of intracranial leiomyosarcoma (LMS) arising after resection of neurofibroma at the cerebellopontine angle. A 45-year-old immunocompetent woman presented with recurrence of a tumor 9 years after resection performed in another hospital. Magnetic resonance imaging demonstrated a heterogeneously enhancing, dura-based mass at the left cerebellopontine angle. The tumor was subtotally removed via lateral suboccipital craniotomy. LMS was diagnosed based on histological and immunohistochemical findings. Postoperatively, although the patient was treated using local radiotherapy, she died due to rapid regrowth of the tumor. Reevaluation of the specimen obtained in the first operation led to a diagnosis of neurofibroma. Both LMS and neurofibroma rarely occur intracranially. LMS is generally thought to arise from smooth muscle cells of the blood vessels or pluripotent mesenchymal cells. In this case, LMS might also have originated from smooth muscle cells of the vessels in the neurofibroma, possibly associated with mechanical and/or heat stimulation during the previous surgery.

A survey of disclosure of diagnosis to patients with glioma in Japan.

BACKGROUND: There have been few studies investigating neuro-oncologists' attitudes toward the disclosure of the diagnosis. This study aimed to determine the current status of disclosure to glioma patients in Japan and to analyze the factors associated with disclosure. METHODS: A set of questionnaires about disclosure to patients with malignant glioma was distributed by e-mail to 191 physicians participating in the 27th Annual Meeting of the Japan Society for Neuro-Oncology. RESULTS: The response rate was 73.8% (141/191). Of these, 44.3% disclosed the correct diagnosis to glioblastoma patients aged < 60 years and 41.4% disclosed the correct diagnosis to those aged ≥ 70 years; for anaplastic astrocytoma patients, these proportions were 61.5 and 51.9%, respectively. Physicians working at facilities performing surgery on more than 50 cases of glioma per year, those in metropolitan areas, and those with other patient psychosocial support systems available disclosed the diagnosis and prognosis more frequently. The physicians' gender and postgraduate period of practice did not influence disclosure. When the family opposed disclosing the diagnosis to the patient, more than half of the physicians respected the family's wishes. CONCLUSIONS: This survey revealed that most of the physicians told at least the malignant nature of the disease to patients with malignant glioma, but they did not always tell the exact diagnosis. Physicians tended to modify their attitudes toward disclosing a diagnosis or prognosis of glioma depending on the histopathological grading, the hospital volume of cases, the location, the availability of patient psychological support systems, and the patient's family's wishes.