Citations

Abstract Background Real-world first-line maintenance (1LM) treatment data are limited for advanced/metastatic non-small cell lung cancer (a/mNSCLC). Materials and Methods In this electronic health record-derived, deidentified database study, eligible patients (≥18 years; diagnosed with stage III/IV non-small cell lung cancer [June 1, 2017-September 30, 2021]) initiated pembrolizumab-based 1LM after 4-6 cycles of first-line (1L) platinum-based chemotherapy-pembrolizumab ± pemetrexed. Study outcomes were real-world time to next treatment or death (rwTTNTD), overall survival (rwOS), and predictors of outcomes. Results Of 1944 patients analyzed (median follow-up, 12.2 months), 51.9% received 1LM pembrolizumab-pemetrexed and 48.1% pembrolizumab monotherapy. Median rwTTNTD and rwOS were 9.2 (95% CI: 8.5-9.8) and 18.7 (95% CI: 17.7-20.3) months, respectively. In multivariable analyses, factors significantly associated with shorter rwTTNTD included 5%-<10% (hazard ratio [HR], 1.34; 95% CI: 1.17-1.54) or ≥10% (HR, 1.69; 95% CI: 1.42-2.01) weight loss during 1L versus 0% or <5% weight loss. Programmed death-ligand 1 (PD-L1) expression 1%–49% (HR, 0.81; 95% CI: 0.71-0.93) or ≥50% (HR, 0.55; 95% CI: 0.47-0.64) and female sex (HR, 0.85; 95% CI: 0.75-0.95) were significantly associated with longer rwTTNTD. These variables were also significantly associated with shorter (weight loss 5%-<10%: HR, 1.52; 95% CI: 1.30-1.77; ≥10% HR, 2.06; 95% CI: 1.71-2.48) and longer rwOS (PD-L1 expression: 1%-49% HR, 0.84; 95% CI: 0.72-0.98; ≥ 50% HR, 0.57; 95% CI: 0.48-0.68; female sex: HR, 0.81; 95% CI: 0.71-0.92). Conclusions Predictors of real-world clinical outcomes included 1L treatment, weight loss, PD-L1 status, and sex. Poor outcomes persisted despite immunotherapy-based 1LM availability, revealing an unmet need in this population.

AbstractBackgroundPrevious publications have described the presence and severity of insomnia amongst those with persistent post‐traumatic headache (PPTH), but there has been a paucity of studies investigating insomnia during the acute phase of post‐traumatic headache (APTH). The primary study objective was to investigate insomnia symptoms and their severity in individuals with APTH due to mild traumatic brain injury (mTBI), and the secondary objective was to assess how psychological factors, sensory hypersensitivities, headache burden, and cognitive performance might associate with insomnia.MethodsIn this clinic‐based, cross‐sectional study, 82 individuals with APTH due to mTBI and 82 healthy controls (HC) were included. Participants completed the Insomnia Severity Index (ISI), Trail Making Test (TMT A and B), 12‐item Allodynia Symptom Checklist (ASC‐12), State–Trait Anxiety Inventory, Photosensitivity Assessment Questionnaire (PAQ), Beck Depression Inventory (BDI), Hyperacusis Questionnaire (HQ), Rey Auditory Verbal Learning Test (RAVLT), and a detailed headache characteristics questionnaire within 59 days of their mTBI to assess insomnia severity, psychological features, sensory hypersensitivities, headache symptoms, and cognitive performance. The questionnaire and test results were compared between APTH and HC groups. Within the APTH group, ISI scores were correlated with the other assessments to determine underlying clinical relationships.ResultsParticipants with APTH, evaluated an average of 27.2 days after their mTBI, had significantly higher ISI scores (median [interquartile range, IQR] score 12 [6–17]) compared to HC (0 [1.3–6], p < 0.001). Twenty‐four (29%) individuals with APTH had ISI scores categorized as moderate clinical insomnia compared to two (2%) in the HC group. Additionally, seven (9%) in the APTH group and none of the HC had ISI scores indicative of severe clinical insomnia. Those with APTH significantly differed from the HC on the BDI (median [IQR] score APTH: 9 [5–16.8] vs. HC: 2 [0–4]; p < 0.001), state anxiety (median [IQR] score APTH: 36.5 [26–45] vs. HC: 23 [20–27.5]; p < 0.001), trait anxiety (median [IQR] score APTH: 38 [27.3–46.8] vs. HC: 26 [23–30]; p < 0.001), photosensitivity (median [IQR] PAQ score APTH: 2 [1–4] vs. HC: 0 [0–1]; p < 0.001), allodynia (median [IQR] ASC‐12 score APTH: 2 [0–5.8] vs. HC: 0 [0–0], p < 0.001), hyperacusis (median [IQR] HQ score APTH: 15.5 [7–23] vs. HC: 4 [2.3–7], p < 0.001), and RAVLT‐delayed recall (median [IQR] score APTH: −0.8 [−1.5 to 0] vs. HC: −0.1 [−0.9 to 0.7], p = 0.019). For participants with APTH, the ISI was most significantly associated with the BDI (standardized regression coefficient (RC) [95% confidence interval, CI] 0.68 [0.52–0.84], p < 0.001), followed by state anxiety (RC [95% CI] 0.60 [0.42–0.78], p < 0.001), trait anxiety (RC [95% CI] 0.56 [0.37–0.74], p < 0.001), headache severity (RC [95% CI] 0.40 [0.19–0.60], p < 0.001), HQ (RC [95% CI] 0.36 [0.16–0.57], p = 0.001), and PAQ (RC [95% CI] 0.35 [0.15–0.56], p = 0.001).ConclusionsIndividuals with APTH have more symptoms of insomnia compared to HC with 38% of individuals with APTH experiencing moderate or severe insomnia symptoms. Insomnia symptoms may be associated with more severe depression, anxiety, photophobia, hyperacusis, headache severity, and cognitive impairment. To address the overall well‐being of patients with APTH, clinicians should screen for and appropriately manage insomnia along with other symptoms following mTBI.

ABSTRACT Peritoneal fibrosis is one of the main causes of peritoneal dysfunction and withdrawal of patients from peritoneal dialysis (PD). Our previous study has shown that high‐glucose dialysis solution promotes glycolysis in peritoneal mesothelial cells, leading to mesothelial‐to‐mesenchymal transition (MMT) and peritoneal fibrosis. However, the molecular mechanisms remain unclear. Using single‐cell RNA sequencing (scRNA‐seq) analysis of cells from the effluent of patients undergoing PD from our previous study, we found that pyruvate kinase isozymes M2 (PKM2), a key rate‐limiting enzyme of glucose metabolism, was significantly upregulated in the mesothelial cells of patients with long‐term peritoneal dialysis (LPD). Using co‐immunoprecipitation, chromatin immunoprecipitation assay, and gene silencing techniques, we revealed that PKM2 promotes the expression of transcription factor SNAI2 by acetylating histone H3K9 (H3K9ac), thereby promoting the occurrence of MMT and hence peritoneal fibrosis. l ‐cysteine, a known PKM2 inhibitor, blocked these responses and prevented PD‐induced peritoneal fibrosis. These results could provide a novel therapeutic strategy for treating peritoneal fibrosis.

We report a case of a triazole and echinocandin-resistant C. glabrata right shoulder prosthetic joint infection in a 60-year-old woman. The patient underwent surgery and received the novel triterpenoid antifungal agent ibrexafungerp. She initially improved, but relapsed four months post-treatment. This case highlights the potential role of ibrexafungerp in multidrug-resistant Candida infections.

Objective: To evaluate the first 3 years of compliance with the American College of Surgeons Commission on Cancer (CoC) Operative Standards. Background: CoC implemented evidence-based standards to improve the quality of sentinel lymph node biopsy and axillary lymph node dissection for breast cancer (operative standards 5.3 and 5.4), wide local excision for melanoma (5.5), colectomy for colon cancer (5.6), proctectomy for rectal cancer (5.7), and pulmonary resection for lung cancer (5.8) at ∼1400 programs treating >74% of US cancer patients. Each operative standard defines a technical element of the operation and structured documentation. Methods: Compliance data are from site visits conducted between January 1, 2022, and December 31, 2024 (implementation/site visits began in 2021/2022 for 5.7 and 5.8 and 2023/2024 for 5.3–5.6). Compliance with each operative standard was determined by evaluation of 7 operative (5.3–5.6) or pathology (5.7, 5.8) reports. Deficiency in technical performance, documentation, or both was considered noncompliance. Results: Reviewers conducted 974 site visits of Comprehensive Community (44%), Community (23%), Academic Comprehensive (16%), network (12%), NCI-Designated Comprehensive (4%), and other (1%) cancer programs. Program compliance rates ranged from 53% to 88%. Documentation noncompliance was more common for standards 5.3 to 5.6 (based on operative reports), and technical noncompliance was more common for 5.7 and 5.8 (based on pathology reports). Compliance significantly (P=0.006) varied by program type for 5.8 (highest: 66% at NCI-designated Comprehensive programs; lowest: 37% at Community Cancer programs). Conclusions: Early compliance with CoC operative standards varied, indicating local and large-scale national quality improvement efforts are needed.

ABSTRACT Human alanine:glyoxylate aminotransferase (AGT) is a liver peroxisomal enzyme that metabolizes glyoxylate, the oxalate precursor, to glycine. AGT deficiency, due to recessive pathogenic changes in the AGXT gene, results in calcium oxalate accumulation and kidney stones, a condition known as primary hyperoxaluria type 1 (PH1). Most missense variants lead to PH1 by causing AGT misfolding, but their effects manifest differently based on the presence of two polymorphic variants, p.Pro11Leu (p.P11L) and p.Ile340Met (p.I340M), which are usually present in linkage disequilibrium and generate the minor haplotype. While the p.P11L substitution reduces AGT global stability and worsens the effects of pathogenic changes, the p.I340M exerts a stabilizing effect whose role on PH1 pathogenesis has never been elucidated. The p.Ile279Thr (p.I279T) variant is frequent in healthy populations (0.29%), mainly on the major allele, but we present data from six PH1 families (eight patients) suggesting p.I279T as a PH1 pathogenic allele. Interestingly, in these families, p.Thr279 is always associated with p.Leu11 and p.Ile340, thus with a split AGXT haplotype. Analysis of the effects of the p.I279T mutation by in silico predictions, biochemical analyses on purified proteins, and expression in two cellular models of disease ( AGXT1 ‐KO HepG2 and CHO cells) shows that it causes a folding defect that is exacerbated by p.P11L but mitigated by p.I340M, thus explaining why p.Thr279 is pathogenic just on the p.Leu11–p.Ile340 haplotype. These data indicate that genetic screenings for PH1 should document the AGXT haplotype, including its components, to obtain an accurate diagnosis and possible prognostic information.

Introduction. Increased steatosis on preimplant liver frozen section is associated with delayed graft function and primary nonfunction. Efforts to standardize histologic assessment have proven difficult. Frozen section artifact and lipopeliosis complicate the detection of steatosis. We aimed to develop and validate an AI model to recognize large droplet fat and fat induced artifact (FIA)/lipopeliosis on preimplantation frozen section and to correlate the AI results with post-transplant clinical parameters. Methods. The model was applied to 161 consecutive liver transplant specimens with preimplant slides. Results were correlated with traditional and Banff histologic assessment and clinical parameters. Results. By traditional assessment, steatosis ranged from 0%–40%. The AI model identified a range of 0 to 15.9% steatosis. There was no difference in patient survival by any measures of steatosis. AI steatosis correlated with increased risk of early allograft dysfunction (OR = 1.63, P < .001), respiratory failure (OR = 1.21, P = .003), and more advanced fibrosis (OR = 1.18, P = .030), but was not correlated with graft or patient survival. FIA/lipopeliosis were identified in a range of 0 to 6.42%. In univariate analysis the percentage of FIA/lipopeliosis correlated with both graft and patient survival ( P = .044 and P = .009, respectively), but was not associated with increased risk of early allograft dysfunction, respiratory failure, or advanced fibrosis. Conclusions. We developed an AI model that quantitates large droplet fat and FIA/lipopeliosis on frozen section slides and found a correlation with post-transplant outcomes. Further studies on larger, multi-institutional cohorts with higher fat containing donors are necessary to determine the role this model may have in organ acceptance decisions.

ABSTRACTObjectivesTo achieve consensus among expert laser surgeons on standards for the prevention and management of adverse events from fully ablative laser resurfacing of the face.Materials and MethodsDelphi study with two rounds of ratings and revisions until consensus was achieved. The draft set of statements was developed by a steering committee based on expert clinical experience. This was followed by two rounds of rating and revisions completed by an expert panel, then a virtual consensus meeting. In both rounds, respondents rated the draft statements on a 9‐point Likert scale (1 = strongly disagree; 9 = strongly agree) and optionally provided comments. The consensus meeting was supplemented by the results of a systematic review of the literature (from 2000 to 2023).ResultsTwo rounds of Delphi survey were completed by 34 participants across four countries. Represented specialties were dermatology, facial plastic surgery, plastic surgery, and oculoplastic surgery. The initial 105 statements from round 1 expanded to 112 in round 2, with 96 statements achieving consensus. These included possible adverse events (11 statements); absolute and relative contraindications to treatment (5 statements); preoperative care and antimicrobial prophylaxis precautions (16 statements); intraoperative precautions (17 statements); postoperative care (21 statements); monitoring for and management of infection (16 statements); management of pigmentation changes (6 statements); and management of scarring and incipient scarring (4 statements).ConclusionAn international consensus statement was developed for the prevention and management of complications associated with fully ablative laser resurfacing of the face. While expert practices vary, key factors for optimizing outcomes include careful patient selection, counseling, and meticulous pre‐ and postoperative care. Further research will improve our understanding of this treatment technique.