Citations

AbstractDespite advances in acute myeloid leukemia (AML) treatment, significant unmet medical needs remain. Surrogate end points for overall survival can accelerate the approval of novel therapies. Measurable residual disease (MRD) is a promising surrogate end point candidate, providing a sensitive and quantitative assessment of disease burden. Numerous studies have demonstrated that negative MRD status—across diverse methodologies, assessment timepoints and thresholds, patient subgroups, and clinical settings—independently predicts improved survival. Although MRD can inform therapeutic decisions at the patient level, its formal integration as a primary surrogate end point in regulatory frameworks for clinical trials requires rigorous validation. MRD Partnership and Alliance in AML Clinical Treatment (MPAACT) is a research consortium among industry and academic leaders. MPAACT actively engages with regulatory agencies, health technology assessment bodies, technology vendors, and patient groups to establish a pathway for validating MRD as a surrogate end point in AML clinical trials. For the current article, the authors reviewed the status of MRD assessment, its use in recent clinical trials, current MRD assessment methodologies, standardization, regulatory guidance, statistical approaches, and patient access considerations necessary for MRD to become a surrogate clinical trial end point. The extensive collaboration between MPAACT, global industry, and academic partners—including data sharing and resource integration—underscores the collective commitment to advancing AML therapies. Establishing MRD as a surrogate end point could accelerate the development and approval of innovative treatments, ultimately improving patient outcomes.

AbstractWe investigated how obesity impacts the response of circulating insulin‐like growth factor‐1 (IGF‐1) to a single bout of endurance exercise in humans with and without obesity. Blood samples were collected before exercise, at 15 and 40 min during a 45‐min cycling session at 65% of heart rate reserve, and 15 min post‐exercise. Serum levels of total IGF‐1, free IGF‐1, IGF binding proteins 1 (IGFBP‐1) and 3 (IGFBP‐3), growth hormone, and insulin were measured. Both total IGF‐1 and IGFBP‐3 serum concentrations increased significantly (p < 0.05) during exercise in the study participants without obesity but not in those with obesity, returning to basal levels immediately after exercise. There was a statistically significant main effect on the growth hormone response, with circulating levels being higher in participants without obesity (p < 0.05). No significant effects were observed for either free IGF‐1 or IGFBP‐1 serum concentrations in response to exercise in either group (p > 0.05). We conclude that humans with obesity have blunted serum total IGF‐1 response during exercise. However, a concurrent attenuation in serum IGFBP‐3 response, which regulates free (i.e., biologically active) IGF‐1 in circulation, results in no change in circulating free IGF‐1 levels during endurance exercise in individuals with obesity.

Background Prompt diagnosis of acute central retinal artery occlusion (CRAO) is crucial for therapeutic management and stroke prevention. However, most stroke centers lack onsite ophthalmic expertise before considering fibrinolytic treatment. This study aimed to develop, train, and test a deep learning system to detect hyperacute CRAO on retinal fundus photographs within the critical 4.5‐hour treatment window and up to 24 hours after visual loss to aid in secondary stroke prevention. Methods Our retrospective, cross‐sectional study included 1322 color fundus photographs from 771 patients with acute visual loss due to CRAO, central retinal vein occlusion, nonarteritic anterior ischemic optic neuropathy, and healthy controls. Photographs were collected from 9 expert neuro‐ophthalmology centers in 6 countries, including 3 randomized clinical trials. Training included 1039 photographs (517 patients), followed by testing on 2 data sets: (1) hyperacute CRAO (54 photographs, 54 patients) and (2) CRAO within 24 hours after visual loss (110 photographs, 109 patients). Results The deep learning system achieved an area under the receiver operating characteristic curve of 0.96 (95% confidence interval (CI), 0.95–0.98), a sensitivity of 92.6% (95% CI, 87.0–98.0), and a specificity of 85.0% (95% CI, 81.8–92.8) for detecting CRAO at hyperacute stage, with similar results within 24 hours. The deep learning system outperformed stroke neurologists on a subset of hyperacute testing data set (120 photographs, 120 patients). Conclusions A deep learning system can accurately detect hyperacute CRAO on retinal photographs within a time window compatible with urgent fibrinolysis. If further validated, such systems could improve patient selection for fibrinolytic trials and optimize secondary stroke prevention. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06390579.

Abstract Aim Major abdominal surgery (MAS) can have a diverse impact on patient’s life, including physical, emotional and socio-economic effects. At present, there is no patient reported outcome (PRO) instrument that was specifically developed for MAS population. The aim of this study was to develop a hypothesised conceptual framework of the key domains that underpin the process of recovery following major abdominal surgery in the adult population. This framework will serve as a foundation for developing a valid PRO instrument for the target population of interest. Method The development of the hypothesised conceptual framework included the following stages: 1) defining major abdominal surgery and verification of its discriminative properties, 2) systematic review of currently available PRO instruments, 3) mapping of the domains within identified PRO instruments to WHO International Classification of Functioning, Disability and Health (ICF) conceptual framework, 4) derivation of the hypothesised conceptual framework by linking of the ICF domains and the health-related quality of life theoretical framework. Results Fourteen PRO instruments were identified by the systematic review. The individual PRO items within each instrument collectively covered 25 ICF domains and 53 sub-domains. A hypothesised conceptual framework was derived based on the “conceptual model of health-related quality of life” and the ICF framework, applied within three principles of exposure, moderating factors and outcomes. Conclusions This study proposed a hypothesised conceptual framework for the development of PRO instruments to evaluate recovery following major abdominal surgery. However, its relevance, content validity and comprehensiveness remain to be examined in future studies.

BACKGROUND: The impact of covert cerebrovascular disease on falls in the general population is not well-known. Here, we determine the time to a first fall following incidentally detected covert cerebrovascular disease during a clinical neuroimaging episode. METHODS: This longitudinal cohort study assessed computed tomography (CT) and magnetic resonance imaging from 2009 to 2019 of patients aged >50 years registered with Kaiser Permanente Southern California which is a healthcare organization combining health plan coverage with coordinated medical services, excluding those with before stroke/dementia. We extracted evidence of incidental covert brain infarcts (CBI) and white matter hyperintensities/hypoattenuation (WMH) from imaging reports using natural language processing. We examined associations of CBI and WMH with falls requiring medical attention, using Cox proportional hazards regression models with adjustment for 12 variables including age, sex, ethnicity multimorbidity, polypharmacy, and incontinence. RESULTS: We assessed 241 050 patients, mean age 64.9 (SD, 10.42) years, 61.3% female, detecting covert cerebrovascular disease in 31.1% over a mean follow-up duration of 3.04 years. A recorded fall occurred in 21.2% (51 239/241 050) during follow-up. On CT, single fall incidence rate/1000 person-years (p-y) was highest in individuals with both CBI and WMH on CT (129.3 falls/1000 p-y [95% CI, 123.4–135.5]), followed by WMH (109.9 falls/1000 p-y [108.0–111.9]). On magnetic resonance imaging, the incidence rate was the highest with both CBI and WMH (76.3 falls/1000 p-y [95% CI, 69.7–83.2]), followed by CBI (71.4 falls/1000 p-y [95% CI, 65.9–77.2]). The adjusted hazard ratio for single index fall in individuals with CBI on CT was 1.13 (95% CI, 1.09–1.17); versus magnetic resonance imaging 1.17 (95% CI, 1.08–1.27). On CT, the risk for single index fall incrementally increased for mild (1.37 [95% CI, 1.32–1.43]), moderate (1.57 [95% CI, 1.48–1.67]), or severe WMH (1.57 [95% CI, 1.45–1.70]). On magnetic resonance imaging, index fall risk similarly increased with increasing WMH severity: mild (1.11 [95% CI, 1.07–1.17]), moderate (1.21 [95% CI, 1.13–1.28]), and severe WMH (1.34 [95% CI, 1.22–1.46]). CONCLUSIONS: In a large population with neuroimaging, CBI and WMH are independently associated with greater risks of an index fall. Increasing severities of WMH are associated incrementally with fall risk across imaging modalities.

Abstract Introduction Multiple Primary Malignancies (MPMs) are characterized by the presence of at least two distinct primary malignancies in a patient. The occurrence rate of MPMs is between 1.63% and 10.9% across articles. To our knowledge, this combination of tumours has not been documented in the existing literature. Case: A 44-year-old male, presented with complaints of abdominal pain, chronic constipation, and multiple episodes of bleeding per rectum for one month. Colonoscopy showed proliferative irregular growth at junction of recto-sigmoid colon; Biopsy showed well-differentiated adenocarcinoma. CT scan abdomen and MRI pelvis showed focal eccentric thickening at the rectosigmoid region and enhancing, partly exophytic left renal mass 3.6 x 2.2 x 2.0 cm from the lower pole, another exophytic soft tissue nodule 2.2 x 1.6 x 1.9 cm on inferior surface of body of pancreas. The biopsy of pancreatic mass was neuroendocrine tumour WHO grade 1. KRAS, BRAF, and MSI were negative. A multidisciplinary team discussion was done, and patient underwent laparoscopic-assisted low anterior resection, open left partial nephrectomy, and enucleation of the pancreatic mass in a single setting. The postoperative course remained uneventful. Histopathology showed rectosigmoid tumour: moderately differentiated mucinous adenocarcinoma, 3/19 lymph nodes positive for metastatic carcinoma. Renal tumour Histopathology: 28mm clear cell renal carcinoma. Pancreatic tumour histopathology: solid pseudopapillary neoplasm. All resection margins free of tumour. He received 4 cycles of adjuvant chemotherapy and now he is on surveillance. Conclusions The occurrence of synchronous triple primary malignancies presents a complex clinical challenge and requires meticulous diagnostic evaluation, multidisciplinary collaboration, and personalized treatment strategies.

Abstract Introduction Synchronous carcinomas are second neoplasms that occur within 6 months of the primary lesion. After this period, they are considered metachronous neoplasms. Literature reported the incidence of synchronous and metachronous carcinoma in the oral cavity from 8% to 21% which is a poor prognostic factor with a subsequently poor overall survival rate. Case Report A 57-year-old male presented with ulcerative lesions in the oral cavity for the last 2 years. He had 25-year history of betel nut chewing. On examination, two ulcerative lesions noted in the oral cavity: on the right upper gingival area measuring approximately 1 x 1 cm with the exposed underlying bone, and another on the left lower gingival area measuring 2 x 2 cm from canine to premolar, subsequently confirmed with MRI. Biopsy confirmed squamous cell carcinoma (SCC). After discussion in the multidisciplinary meeting, he underwent right partial maxillectomy, left marginal mandibulectomy, bilateral neck dissection, and dental extractions, with uneventful post-operative recovery. Histopathology of right partial maxillectomy was moderately differentiated SCC (pT4a), Left marginal mandibulectomy; well-differentiated SCC in the canine area, as well as molar teeth area, and no involved lymph nodes (0/88). All resection margins were free of tumour. Radiotherapy was given to the right maxilla postoperatively. Conclusions To our knowledge, this is the first reported case of triple synchronous SCC oral cavity in our country. Detection of three Synchronous SCCs in the oral cavity follows the concept of field cancerization. A multidisciplinary treatment strategy in a high-volume cancer-dedicated centre is required to aggressively treat such tumours.

Abstract Aim To measure the textbook outcomes of pancreaticoduodenectomy for pancreatic adenocarcinoma. Textbook outcomes include negative surgical margin, &gt;12 Lymph nodes examined, no prolonged hospitalization &gt;14 days, no ≥ 3 days ICU treatment, no 30-day readmission or mortality, and no Clavien-Dindo complication grade≥ 3 or above. It is all or none response, if all of these parameters are met in a single patient, then the textbook outcome is met for that individual patient. Method All patients from 1st January 2014 to 31st December 2023 who were &gt;18 years old. Patients who underwent emergency surgery, those with histopathologies other than adenocarcinomas, who had pancreaticoduodenectomies for duodenal cancers were also excluded. Results Total number of patients were 269, of which 68% were male and 32% female. Mean age was 53 years, mean BMI 23.3 kg/m2. Classical Whipple’s procedure performed in 224 patients, 36 underwent Pylorus preserving pancreaticoduodenectomy and 7 patients had Laparoscopic assisted Whipple’s resection. In Textbook surgical outcomes, Negative margin achieved in 251 patients, and more than 12 lymph nodes were retrieved in 249 patients. Prolonged ICU stay more than 3 days was in 11 patients. 39 patients had &gt; 14 days of hospital stay. Readmission was observed in 34 patients. 114 patients had complications out of which Clavien Dindo grade ≥3 was in 28 patients. Pancreatic fistula in 81 patients and of these, 51 patients had Grade A fistula. Complete Textbook Outcomes (TO) were achieved in 57% (153) patients. Conclusions Our center achieved high Textbook outcomes compared to international standards and depicts patient-centered care of our institution.