Faculty Bibliography

BACKGROUND:The frequency of residual angina and its impact on health status and death following anatomic complete revascularization in symptomatic patients with chronic coronary disease are unknown. METHODS:Data were analyzed from ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) trial participants randomized to invasive management with baseline angina (Seattle Angina Questionnaire Angina Frequency score <100), no prior coronary artery bypass graft surgery, and anatomic complete revascularization within 90 days of randomization. The primary outcome was frequency of residual angina after revascularization, defined as a Seattle Angina Questionnaire Angina Frequency score <100 within 6 months of randomization. Secondary outcomes included 6-month health status and medication use and 5-year all-cause and cardiovascular death. RESULTS:=0.006). Five-year all-cause and cardiovascular death did not differ significantly between groups. CONCLUSIONS:Residual angina is common (>40%) following anatomic complete revascularization for chronic coronary disease and is associated with reduced quality of life and greater antianginal medication use but no increase in death. REGISTRATION/BACKGROUND:Unique Identifier: NCT01471522.

Persons with disorders of consciousness (DoC) occupy an ethically charged space in modern medicine and biomedical research. Their decisional capacity is characteristically absent or limited or unpredictably fluctuates, requiring clinicians and investigators to rely on surrogates. Although there is general guidance for informed consent (IC) for research studies, there is no specific guidance for research involving persons with DoC. There are inconsistencies in IC forms for these studies related to explanation of a DoC, evaluation of capacity, description of risks/benefits, and sharing investigational results. This is problematic for persons with DoC, their surrogates, researchers, and institutional review boards (IRBs)/research ethics boards (REBs). To address these issues, the Curing Coma Campaign (CCC) Ethics Workgroup developed the Common Consent Elements for Research Involving Persons with Disorders of Consciousness (CCE-DoC). This practical framework aims to clarify and standardize consent processes in this complex and ethically sensitive research area. Through this structured, adaptable approach, CCE-DoC may have the potential to enhance participant protections, strengthen trust, help families and decision-makers understand studies, reduce duplicative efforts across research groups, and guide investigators and IRBs/REBs in navigating the complex ethical terrain of consent in DoC research. In so doing, CCE-DoC seeks to extend respect for autonomy and trust and promote responsible research urgently needed to advance paradigms of diagnosis, prognosis, and treatment for individuals with disorders of consciousness. The framework offers example language to encourage standardization, while allowing teams flexibility to customize to local needs.

CONTEXT/BACKGROUND:Temozolomide (TMZ) can be an effective medical treatment for aggressive pituitary tumors. In case of disease recurrence following TMZ treatment, however, treatment with the drug generally does not control tumor regrowth. OBJECTIVE:This work aimed to better understand the mechanisms of resistance of corticotroph tumors to TMZ in the context of heterogeneity of methylguanine-DNA methyltransferase (MGMT) expression. METHODS:We performed immunohistochemical analysis of the MGMT expression pattern in 25 corticotroph tumors to evaluate intratumoral heterogeneity. In addition, we created in vitro models of AtT20 corticotroph tumor cells with acquired TMZ-resistance after exposure to high- and low-dose TMZ, the latter representing a clinically achievable TMZ level. RESULTS:MGMT immunostaining in corticotroph tumors showed a considerable heterogeneous intertumoral and intratumoral distribution pattern in 80% of tumors. In the in vitro model, high- and low-dose TMZ challenges induced a 6.3- and 3.4-fold decreased sensitivity to the growth inhibitory effect of TMZ. TMZ-induced changes in cell cycle phases were lower in TMZ-resistant cells than in vehicle-challenged cells. TMZ-resistant cells had higher Mgmt messenger RNA and protein expression and 1.8-fold higher number of Mgmt-positive cells. No difference was observed in the level of Mgmt promoter methylation. CONCLUSION/CONCLUSIONS:Corticotroph pituitary tumors demonstrate a high intertumoral and intratumoral heterogeneity in MGMT expression. In an acquired TMZ-resistant corticotroph pituitary tumor cell model, TMZ resistance was associated with strong increase in MGMT expression and percentage of MGMT-positive cells. We hypothesize that clonal selection of high MGMT-expressing cells is involved in this acquired TMZ resistance.

OBJECTIVE:This study reports patient outcomes and predictors of outcomes after total contact casting (TCC) for diabetic stump ulceration in patients with partial-foot amputations. METHODS:Retrospective review of patients treated with TCC for diabetic stump ulcerations with ipsilateral partial-foot amputation at a tertiary center from 2015 to 2022 was performed. Patients lost to follow-up, those unable to tolerate TCC, and those with partial amputations of digits 2 to 5 were excluded. Patient demographics, outcomes, and complication rates of TCC were collected and compared. Multivariable linear regression was performed to identify demographic predictors of time to ulcer closure. RESULTS:Forty-three patients were included in this study, with a 93.5% rate of primary ulcer closure, 46.5% rate of re-ulceration, and 9.3% rate of re-amputation. Patients without re-ulceration were significantly more likely to be nonsmokers. Regression analysis also found that smoking history trended toward a longer delay to ulcer closure (P=.097). Age, body mass index, presence of contralateral amputation, and type of amputation did not affect patient outcomes or complication rates. CONCLUSIONS:TCC effectively promotes ulcer closure in diabetic patients with high comorbidity burden and partial-foot amputation, although smoking history increases re-ulceration rates.

PURPOSE OF THE REPORT/OBJECTIVE:To determine the prevalence, etiology, and clinical significance of incidental focal small bowel FDG uptake in patients undergoing PET/CT for staging of non-small bowel cancers. MATERIAL AND METHODS/METHODS:Retrospective review of consecutive FDG PET/CT examinations obtained for cancer staging with incidental focal small bowel radiotracer uptake was performed. Exclusion criteria included known small bowel pathology or insufficient reference standard. Imaging findings assessed included lesion location, number, CT correlate, SUVmax, and presence of metastases outside the bowel. Clinical data included age, sex, cancer clinical setting, origin, and stage. Focal small bowel FDG uptake etiology (benign vs. metastatic) was determined by composite reference standard (histopathology, clinical, and imaging follow-up). Statistical analyses included Wilcoxon rank-sum test, Pearson's χ2 test, Fisher exact test, and ROC curve analyses. RESULTS:In a review of 147,516 PET/CT examinations, incidental focal small bowel FDG uptake was rare, with a prevalence of 0.1% (88/147,516). Most cases were metastatic, 60.2% (53/88), most commonly spread from lymphoma [32.1% (17/53)] and melanoma [30.2% (16/53)]. Metastatic lesions were evenly distributed throughout the ileum [47.2% (25/53)] and jejunum [39.6% (21/53)]. Metastatic focal small bowel FDG uptake was associated with presence of other sites of distant metastases, higher SUVmax, and presence of a CT correlate (P <0.01). CONCLUSIONS:Incidental focal small bowel FDG uptake is rare. Most small bowel hypermetabolic foci are metastatic and are predominantly encountered with melanoma and lymphoma. Multiple imaging and clinical factors helped differentiate between benign and metastatic focal small bowel FDG uptake.

IMPORTANCE/UNASSIGNED:Bronchoscopic biopsy is conventionally performed with forceps, which can result in small specimen sizes and poor specimen quality due to crush artifact. Cryoprobe use localizes freezing at the probe tip, enabling retrieval of larger, more intact biopsy specimens. OBJECTIVE/UNASSIGNED:To evaluate the diagnostic yield of a 1.1-mm cryoprobe for transbronchial biopsy. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This open-label, outcome assessor-masked, multicenter randomized clinical trial included 500 patients aged 18 years or older scheduled to undergo transbronchial biopsy for lung nodules or masses, lung transplant, or diffuse parenchymal lung disease. The trial was conducted in 9 US medical centers and enrolled patients between February 27, 2023, and September 11, 2024. The date of last follow-up was October 12, 2024. INTERVENTION/UNASSIGNED:Patients were randomized 1:1 to transbronchial biopsy using a 1.1-mm cryoprobe (n = 250) or 2.0-mm forceps (n = 250). MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary outcome was diagnostic yield, defined as the percentage of patients for whom the transbronchial biopsy sample led to a specific diagnosis based on histologic examination. Of the 8 prespecified secondary analyses, key secondary analyses were the diagnostic yield for each of the 3 conditions (lung nodules or masses, lung transplant, and diffuse parenchymal lung disease) and complication rates. RESULTS/UNASSIGNED:Of 774 patients assessed for eligibility, 609 provided consent, 500 were randomized, and 490 were included in the primary analysis; the mean age was 62.6 years (SD, 12.7 years) and 252 of 500 (50.4%) were male. The primary outcome of diagnostic yield was significantly higher in patients randomized to transbronchial biopsy with cryoprobes vs forceps (217 of 245 [88.6%] vs 193 of 245 [78.8%]; absolute difference, 9.8%; 95% CI, 3.3%-16.3%; P = .003). For the key secondary analyses, compared with that of forceps, the diagnostic yield of cryoprobes was significantly higher among patients with pulmonary nodules or masses (79 of 95 [83.2%] vs 68 of 97 [70.1%]; absolute difference, 13.1%; 95% CI, 1.0%-24.6%; P = .04) and lung transplant (120 of 125 [96.0%] vs 110 of 124 [88.7%]; absolute difference, 7.3%; 95% CI, 0.6%-14.4%; P = .03) but did not differ significantly in diffuse parenchymal lung disease (18 of 25 [72.0%] vs 15 of 24 [62.5%]; absolute difference, 9.5%; 95% CI, -16.0% to 33.6%; P = .55). For the secondary safety analysis, there were 4 pneumothoraces requiring chest tube placement in the forceps group (1.6%) vs none in the cryoprobe group; no patients experienced significant bleeding or respiratory failure events. CONCLUSIONS AND RELEVANCE/UNASSIGNED:Transbronchial lung biopsy performed with a 1.1-mm cryoprobe had a significantly higher diagnostic yield compared with 2.0-mm forceps in a group of patients with lung nodules or masses, lung transplant, and diffuse parenchymal lung disease. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT05751278.

The guest editors introduce the Biomedical Optics Express feature issue "Optics and the Brain." This issue highlights a range of important neuroscientific questions and clinical needs, and illustrates novel optical methodologies being developed to address them by this research community.

Deep venous drainage (DVD) is considered a negative prognostic factor in AVM surgery, yet its effect on postoperative functional decline remains incompletely defined. This study evaluates whether DVD predicts worsened functional status after surgical resection of Spetzler-Martin Grade II-III AVMs. This retrospective multicenter study analyzed 129 patients with Spetzler-Martin Grade II-III AVMs across nine centers in North America and Europe who underwent primary surgical resection. We excluded cases with prior endovascular or stereotactic interventions. The primary outcome measured was poor functional status, defined as modified Rankin Scale (mRS) score 3-6 at last follow up. Among 129 patients with Spetzler-Martin Grade II-III AVMs, 38 (29.5%) exhibited deep venous drainage (DVD). Poor functional outcome (mRS ≥ 3) at last follow-up occurred in 14 patients (10.9%). This occurred in 6 of 38 patients with DVD (15.8%) compared with 8 of 91 without DVD (8.8%; Fisher's exact p = 0.244). On univariate Firth-penalized logistic regression, DVD was not significantly associated with poor outcome (OR 1.96, 95% CI 0.65-5.89; p = 0.228). In the primary reduced Firth model adjusting for age and pre-existing functional disability, DVD was independently associated with poor outcome (OR 6.87, 95% CI 1.07-44.20; p = 0.042). Increasing age (OR 1.08 per year, 95% CI 1.02-1.13; p = 0.004) and pre-existing functional disability (OR 6.53, 95% CI 1.63-26.22; p = 0.008) were also independently associated with poor outcome. DVD is associated with functional decline following surgical resection of Spetzler-Martin Grade II-III AVMs after adjustment for age and pre-existing functional disability.

Primary graft dysfunction (PGD) is a proinflammatory syndrome occurring within the first days following lung transplantation. It is initiated by ischemia-reperfusion injury and perpetuated by donor and recipient immunologic factors, resulting in alveolar damage and progressive hypoxemic respiratory failure.¹ PGD is a known risk factor for both early allograft failure and chronic lung allograft dysfunction (CLAD).² Incidence of severe PGD remains high at 10-25%, though is variable; risk factors for PGD include center experience, underlying recipient disease type, size matching, donor lung storage conditions, operative time, and post-operative management.² Strategies to prevent PGD or mitigate the long -term consequences after it develops, are sorely needed. However, lack of specificity of the current PGD definition may hamper further progress in the field, especially as it pertains to the development of robust and relevant clinical trials. We propose that future modifications of the PGD definition incorporate more objective surrogates of allograft injury and subsequent diffuse alveolar damage, which may improve our ability to accurately study disease pathogenesis and improve outcomes.

BACKGROUND:Hip resurfacing arthroplasty (HRA) is a femoral bone-preserving alternative to total hip arthroplasty (THA) for younger, active patients. However, complications such as fractures, loosening, and metal wear can require conversion to THA. In some cases, revision of both the acetabular and femoral components is required. METHODS:We conducted a retrospective review of 15 patients who underwent conversion of HRA to THA at a single, academic tertiary care centre between January 2011 and April 2024. Demographic data, surgical details, implant characteristics, and indications for conversion were collected. Postoperative outcomes including complications, reoperations, and revisions were investigated. Revision-free survival was estimated using Kaplan-Meier analysis. RESULTS: = 3). Dual-mobility (DM) constructs were used in 11 cases (73.3%). There were no dislocations. There was 1 90-day readmission due to persistent wound drainage which underwent debridement, antibiotics, and implant retention (DAIR) 14 days post-conversion. The average follow-up duration after the conversion procedure was 6.1 years. Kaplan-Meier analysis demonstrated 93% revision-free survival at one-year, which remained stable through 13 years. CONCLUSIONS:In this study of 15 both-component HRA conversions, we observed 93% revision-free survivorship at mid-term follow-up. While the small cohort size limits definitive conclusions, our findings suggest that revision of the acetabulum during conversion, particularly with dual-mobility constructs, may be an effective strategy to mitigate instability and manage metal-on-metal failure in appropriate patients. Further research with larger cohorts is warranted to confirm our findings.