Citations

Background: The complex nature and heterogeneity involving pituitary surgery results have increased interest in machine learning (ML) applications for prediction of outcomes over the last decade. This study aims to systematically review the characteristics of ML models involving pituitary surgery outcome prediction and assess their reporting quality. Methods: We searched the PubMed, Scopus, and Web of Knowledge databases for publications on the use of ML to predict pituitary surgery outcomes. We used the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) to assess report quality. Our search strategy was based on the terms “artificial intelligence”, “machine learning”, and “pituitary”. Results: 20 studies were included in this review. The principal models reported in each article were post-surgical endocrine outcomes (n = 10), tumor management (n = 3), and intra- and postoperative complications (n = 7). Overall, the included studies adhered to a median of 65% (IQR = 60–72%) of TRIPOD criteria, ranging from 43% to 83%. The median reported AUC was 0.84 (IQR = 0.80–0.91). The most popular algorithms were support vector machine (n = 5) and random forest (n = 5). Only two studies reported external validation and adherence to any reporting guideline. Calibration methods were not reported in 15 studies. No model achieved the phase of actual clinical applicability. Conclusion: Applications of ML in the prediction of pituitary outcomes are still nascent, as evidenced by the lack of any model validated for clinical practice. Although studies have demonstrated promising results, greater transparency in model development and reporting is needed to enable their use in clinical practice. Further adherence to reporting guidelines can help increase AI’s real-world utility and improve clinical practice.

9 Background: The efficacy of neoadjuvant platinum-based chemotherapy (NAPC) in penile squamous cell carcinoma (PSCC) was provided by small clinical trials, leaving clinicians with scant evidence-based guidance. Thus, we aimed to analyze real-world outcomes of patients with PSCC who received NAPC prior to surgical resection. Methods: Patients from 9 tertiary care centers who had undergone NAPC prior surgical resection for PSCC were included with locally advanced (cTany, cN+), non-metastatic (M0) disease. The primary and secondary outcomes were overall survival (OS) and progression-free survival (PFS), Response was determined via best overall response measured with RECIST 1.1 criteria. Results: 167 patients were included, 137 (84%), of which received TIP prior to surgical resection. Ninety-two (55%) patients died during follow up, and the mean follow up for survivors was 57 months. The median OS was 42 months, while the median PFS was 17 months. The table details the response rates to NAPC, the associated survival, and Cox Proportional Hazards Modelling of OS and PFS. Predictors for OS and RFS included lymphovascular invasion, positive number of lymph nodes, extranodal extension, downstaging, best overall response, and ypN status. Figure 1 demonstrates OS outcomes by RECIST best response after chemotherapy, presence of downstaging after NAPC, ypN stage, and presence of extranodal extension. Conclusions: Upfront NAPC is effective in patients with lymph node metastases from penile carcinoma. Unsurprisingly, patients who demonstrated a robust response to therapy had improved survival outcomes compared to those who had not—as measured by RECIST criteria, tumor downstaging, pN staging, and presence of extranodal extension. This study represents the largest conglomeration of multi-institutional penile carcinoma patients treated with NAPC, and provides further supportive data for multimodal therapy for advanced penile cancer patients while prospective clinical trials complete accrual. [Table: see text]

Abstract MT-5111 is a 55kD engineered toxin body targeting HER2 in solid tumors that binds to an epitope distinct from trastuzumab and pertuzumab, offering potential combination strategies with other HER2-targeting agents. MT-5111 works by internalizing, self-routing through intracellular compartments to the cytosol, and inducing potent cell-kill via the enzymatic and permanent inactivation of ribosomes. This is a phase 1 study in adults with advanced HER2+ solid tumors. MT-5111 is dosed weekly IV over 30 min in every 21-day cycle until disease progression, unacceptable toxicity, death, or withdrawn consent. The study has dose escalation (Part A) cohorts enrolling patients (pts) with any HER2+ cancer (CA) and expansion (Part B) cohorts for HER2+ breast cancer (BC), Gastric or Gastroesophageal junction adenocarcinoma (GEA), or other HER2+ solid CA. As of 30 June 2022, 42 total pts had enrolled (36 in Part A on 0.5-23 µg/kg/dose, 6 pts with BC in Part B1 on 10 µg/kg/dose). Median age 65 years, 28 (66.78%) pts were female, median of 4 prior systemic and 2 prior HER2-targeting treatment (tx). 17 pts with BC, 6 with biliary CA, 9 with GEA, and 10 with other solid CA have enrolled. Of the 17 BC pts, 15 received ≥ 10 µg/kg/dose. Tx emergent adverse events (TEAEs) have been reported in 40 (95%) pts, and tx-related AEs (TRAE) occurred in 23 (55%) pts. No pt experienced G4-G5 TRAE. G1 troponin elevations were noted in 5 pts without clinical signs of cardiotoxicity (1 pt 6.75 µg/kg, 2 pts 10 µg/kg, 1 pt 17 µg/kg, 1 pt 23 µg/kg). Reversible G1/G2 infusion-related reactions were reported in 2 pts. Tx-related G1-G3 rash was observed in 5 pts (4 pts ≥ 10 µg/kg/dose); maculopapular in 2 pts, acneiform in 1 pt and associated with pruritus in 3 pts. The G3 rash developed one wk after first dose of 23 µg/kg, was declared a DLT, improved with systemic steroid therapy and the pt continued tx at the same dose without recurrence. Best overall response per RECIST thus far is stable disease (SD) in 17 pts, non-CR/non-PD in 1 pt, and progressive disease (PD) in 14 pts. 1 pt had non-CR/non-PD for 30 wks (1 μg/kg, BC); 1 pt had SD for 24wks (10 μg/kg, pancreatic); 1 pt is on tx with SD through 8 cycles (10 μg/kg, BC). Of the 10 BC pts who received ≥ 10 μg/kg/dose, the best response was 5 SD. The mean serum concentration of MT-5111 has increased in a dose-proportional manner starting at 6.75µg/kg/dose (Table 1). The soluble HER2 (sHER2) levels at end of tx were higher compared to baseline in cohorts that received ≤ 4.5µg/kg/dose, but similar or lower in cohorts that received ≥ 6.75µg/kg/dose. Higher MT-5111 doses have been well tolerated and may saturate circulating sHER2, leading to more predictable serum concentrations and tumor penetration. The Cmax in humans at doses ≥6.75 µg/kg/dose is above the in vitro IC50 for high HER2+ cell lines (0.029nM) and at 17 µg/kg/dose, above the IC50 for moderate HER2+ cells (1.6nM). In conclusion, the dose proportionate increase in serum concentration with levels above the in vitro IC50 and the leveling off/reduction of sHER2 indicate exposure to MT-5111 is at clinically therapeutic levels. Skin toxicity at higher doses may indicate on-target effect as observed in other EGFR-targeted therapies where it is associated with clinical response and a better prognosis. sHER2 biomarker data is expected for all cohorts with PK correlation and 23µg/kg safety and efficacy data. PK profile of MT-5111, C1D1 values Citation Format: Meena Okera, Brian A. Van Tine, Joleen M. Hubbard, Minal Barve, Erika Hamilton, Monica M. Mita, Frances Valdes-Albini, Daniel Ahn, Admasu Mamuye, Joshua Pelham, Amy Yuet, Diana Yurewicz, Yanning Liu, Andres Machado Sandri, William J. Edenfield, Aki Morikawa, William Gradishar, Rajiv Kumar, Zev A. Wainberg. A phase 1 study of the novel immunotoxin MT-5111 in patients with HER2+ tumors: interim results [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-11-01.

Abstract There are few causes of treatable neurodevelopmental diseases described to date. Branched-chain ketoacid dehydrogenase kinase (BCKDK) deficiency causes branched-chain amino acid (BCAA) depletion and is linked to a neurodevelopmental disorder characterized by autism, intellectual disability and microcephaly. We report the largest cohort of patients studied, broadening the phenotypic and genotypic spectrum. Moreover, this is the first study to present newborn screening findings and mid-term clinical outcome. In this cross-sectional study, patients with a diagnosis of BCKDK deficiency were recruited via investigators’ practices through a MetabERN initiative. Clinical, biochemical and genetic data were collected. Dried blood spot (DBS) newborn screening (NBS) amino acid profiles were retrieved from collaborating centres and compared to a healthy newborn reference population. Twenty-one patients with BCKDK mutations were included from 13 families. Patients were diagnosed between 8 months and 16 years (mean: 5.8 years, 43% female). At diagnosis, BCAA levels (leucine, valine and isoleucine) were below reference values in plasma and in CSF. All patients had global neurodevelopmental delay; 18/21 had gross motor function (GMF) impairment with GMF III or worse in 5/18, 16/16 intellectual disability, 17/17 language impairment, 12/17 autism spectrum disorder, 9/21 epilepsy, 12/15 clumsiness, 3/21 had sensorineural hearing loss and 4/20 feeding difficulties. No microcephaly was observed at birth, but 17/20 developed microcephaly during follow-up. Regression was reported in six patients. Movement disorder was observed in 3/21 patients: hyperkinetic movements (1), truncal ataxia (1) and dystonia (2). After treatment with a high-protein diet (≥ 2 g/kg/day) and BCAA supplementation (100–250 mg/kg/day), plasma BCAA increased significantly (P < 0.001), motor functions and head circumference stabilized/improved in 13/13 and in 11/15 patients, respectively. Among cases with follow-up data, none of the three patients starting treatment before 2 years of age developed autism at follow-up. The patient with the earliest age of treatment initiation (8 months) showed normal development at 3 years of age. NBS in DBS identified BCAA levels significantly lower than those of the normal population. This work highlights the potential benefits of dietetic treatment, in particular early introduction of BCAA. Therefore, it is of utmost importance to increase awareness about this treatable disease and consider it as a candidate for early detection by NBS programmes.

Abstract Repeated stress produces hyperalgesic priming in preclinical models, but underlying mechanisms remain uncertain. As stress engages kappa opioid receptors (KORs), we hypothesized that repeated administration of KOR agonists might mimic, in part, stress-induced hyperalgesic priming. The potential contribution of circulating prolactin (PRL) and dysregulation of the expression of PRL receptor (PRLR) isoforms in sensory neurons after KOR agonist administration was also investigated. Mice received 3 daily doses of U-69593 or nalfurafine as a “first-hit” stimulus followed by assessment of periorbital tactile allodynia. Sixteen days after the first KOR agonist administration, animals received a subthreshold dose of inhalational umbellulone, a TRPA1 agonist, as the second-hit stimulus and periorbital allodynia was assessed. Cabergoline, a dopamine D2 receptor agonist, was used to inhibit circulating PRL in additional cohorts. Prolactin receptor isoforms were quantified in the V1 region of the trigeminal ganglion after repeated doses of U-69593. In both sexes, KOR agonists increased circulating PRL and produced allodynia that resolved within 14 days. Hyperalgesic priming, revealed by umbellulone-induced allodynia in animals previously treated with the KOR agonists, also occurred in both sexes. However, repeated U-69593 downregulated the PRLR long isoform in trigeminal neurons only in female mice. Umbellulone-induced allodynia was prevented by cabergoline co-treatment during priming with KOR agonists in female, but not male, mice. Hyperalgesic priming therefore occurs in both sexes after either biased or nonbiased KOR agonists. However, a PRL/PRLR-dependence is observed only in female nociceptors possibly contributing to pain in stress-related pain disorders in females.

Abstract Decreased α-Klotho, a geroprotective factor, and increased senescent cell burden are both associated with early onset of physical disability, cognitive impairment, and premature all-cause mortality. It has been demonstrated that eliminating senescent cells can enhance physical function, cognition, and survival in mice, as does overexpressing α-Klotho. Mice with low α-Klotho exhibit accelerated senescent cell accumulation, recombinant α-Klotho decreases senescent cell burden and restores lifespan in these mice, and senescent epidermal cells are reduced in mice overexpressing α-Klotho. Here, we tested the hypothesis that senescent cells cause decreased α-Klotho and hence that reducing senescent cells can increase α-Klotho. Senescent cell conditioned medium (CM) reduced α-Klotho in cultured non-senescent human umbilical vein endothelial cells (HUVECs), renal tubular endothelial cells, and astrocytes. These effects of senescent CM were partially attenuated by neutralizing antibodies against the senescence-associated secretory phenotype (SASP) factors, activin A and IL-1α. Transplanting senescent cells into younger mice caused decreased urine and brain α-Klotho. Genetically reducing highly p16Ink4a-expressing cells in old INK-ATTAC mice or administering the senolytics, Dasatinib plus Quercetin (D+Q) or Fisetin (F), to young mice transplanted with senescent cells, young diet-induced obese (DIO) mice, or naturally-aged mice increased urine, kidney, and/or brain α-Klotho. Treating patients with idiopathic pulmonary fibrosis (IPF), a cellular senescence-related disease, with D+Q led to increased urinary α-Klotho. Thus, targeting senescent cells causes increases in the geroprotective factor α-Klotho, potentially amplifying the beneficial effects of senolytic drugs.

AbstractBackgroundMore than 300 variants in the presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) genes have been reported to cause Dominantly Inherited Alzheimer Disease (DIAD). However, most of these reports come from non‐Hispanic whites and the full extent of DIAD remains understudied in Latin American (LatAm) countries. Here we describe five AD affected families from LatAm carrying novel DIAD variants.MethodsFive novel variants in the presenilin1 (PSEN1) gene were identified in Brazilian (p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se and p.Ala275Thr) and Mexican families (p.Ile414Thr). To assign the likelihood of pathogenicity among these variants of unknown significance, we report pedigree information, frequency in control populations, in silico predictions, and cell‐based models.ResultThe mean age at onset in newly identified families was 43.5 years (range 36‐54). The novel variants were absent from gnomAD genome and exome databases. Two PSEN1 variants (p.Val103_Ser104delinsGly and p.Lys395Ile) showed segregation with the disease status; segregation studies were not possible in the other three families. Additionally, PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, p.Ala275Thr produced Aβ profiles consistent with known AD pathogenic mutations (i.e. increased extracellular Aβ42/40); thus, we consider them as likely pathogenic. PSEN1 p.Ile414Thr did not alter Aβ in a manner consistent with a known pathogenic mutation; therefore, PSEN1 p.Ile414Thr likely represents an AD risk factor or benign polymorphism.ConclusionOur study provides further insights into the genetics of AD in LatAm by identifying novel DIAD pathogenic variants in Brazil and Mexico, two countries with distinct genetic admixtures. Expanding the families eligible to participate in observational and clinical trials of DIAD enhances the generalizability of diagnosis and treatment approaches.

Background: Underrepresented persons are often not included in biomedical research. It is unknown if the general Asian American population is being represented in All of Us . The purpose of this study was to compare the Asian demographic data in the All of Us cohort with the Asian nationally representative data from the American Community Survey. Method: Demographic characteristics and health literacy of Asians in All of Us were examined. Findings were qualitatively compared with the Asian data in the 2019 American Community Survey 1-year estimate. Results: Compared with the national composition of Asians, less All of Us participants were born outside the United States (64% vs 79%), were younger, and had higher levels of education (76% vs 52%). Over 60% of All of Us participants reported high levels of health literacy. Conclusion: This study had implications for the development of strategies that ensure diverse populations are represented in biomedical research.

ObjectiveTo determine the association between race/ethnicity and COVID‐19 outcomes in individuals with systemic lupus erythematosus (SLE).MethodsIndividuals with SLE from the US with data entered into the COVID‐19 Global Rheumatology Alliance registry between March 24, 2020 and August 27, 2021 were included. Variables included age, sex, race, and ethnicity (White, Black, Hispanic, other), comorbidities, disease activity, pandemic time period, glucocorticoid dose, antimalarials, and immunosuppressive drug use. The ordinal outcome categories were: not hospitalized, hospitalized with no oxygenation, hospitalized with any ventilation or oxygenation, and death. We constructed ordinal logistic regression models evaluating the relationship between race/ethnicity and COVID‐19 severity, adjusting for possible confounders.ResultsWe included 523 patients; 473 (90.4%) were female and the mean ± SD age was 46.6 ± 14.0 years. A total of 358 patients (74.6%) were not hospitalized; 40 patients (8.3%) were hospitalized without oxygen, 64 patients (13.3%) were hospitalized with any oxygenation, and 18 (3.8%) died. In a multivariable model, Black (odds ratio [OR] 2.73 [95% confidence interval (95% CI) 1.36–5.53]) and Hispanic (OR 2.76 [95% CI 1.34–5.69]) individuals had higher odds of more severe outcomes than White individuals.ConclusionBlack and Hispanic individuals with SLE experienced more severe COVID‐19 outcomes, which is consistent with findings in the US general population. These results likely reflect socioeconomic and health disparities and suggest that more aggressive efforts are needed to prevent and treat infection in this population.