Molecular Characterization and Prognostication of Large Cell Neuroendocrine Carcinoma and Large Cell Carcinoma

PurposeLarge cell neuroendocrine carcinoma (LCNEC) and classic large cell carcinoma (LCC) are two distinct entities with different histological and biological characteristics. However, the mutational profiles and the clinical behavior of the two subtypes of lung cancer remain to be explored.Patients and MethodsPathological diagnoses of all screened patients were finally confirmed by three or four experienced pathologists. Patients with uncertain pathological diagnoses were excluded. Finally, we genetically profiled ten patients with LCNEC and seven with LCC. ALL patients were subjected to next-generation sequencing (NGS) test, which included nine patients sequenced with a 139-gene panel and eight patients with a 425-gene panel. Including only intersected mutations from these two panels, survival analysis was further conducted.ResultsBoth LCNEC and LCC showed high prevalence in male patients, with no clear association with smoking history. Potential targetable mutations in KRAS and RET were detected in the study cohort. However, LCNEC and LCC showed distinct mutational profiles with an enrichment of RB1/TP53 co-mutations in a subset of LCNEC patients. SMARCA4 and KEAP1 mutations were exclusively found in LCC patients, and RICTOR, BRAF, ROS1 and TET2 mutations were only detected in LCNEC. LCC patients in the cohort had shorter survival compared to LCNEC patients (p=0.006). Survival analysis revealed an association between SMARCA4 mutations and poor outcome in the study cohort and in the LCC subset. Mutations in BRAF were associated with a trend of increased survival in the study cohort, as well as in the LCNEC subset. Finally, TET2 mutations were associated with poor outcome in the LCNEC cohort.ConclusionLCC and LCNEC were both heterogeneous diseases with limited treatment options. Our study identified potential targetable mutations and prognostic biomarkers that might provide more therapeutic options and improve individualized patient care.

Polygenic Ara-C Response Score Identifies Pediatric Patients With Acute Myeloid Leukemia in Need of Chemotherapy Augmentation

PURPOSE To establish a patient-specific polygenic score derived from cytarabine (ara-C) pathway pharmacogenomic evaluation to personalize acute myeloid leukemia (AML) treatment. MATERIALS AND METHODS Single nucleotide polymorphisms (SNPs) in the ara-C-pathway genes were analyzed with outcome in patients from the multicenter-AML02 trial (N = 166). Multi-SNP predictor modeling was used to develop 10-SNP Ara-C_SNP score (ACS10) using top SNPs predictive of minimal residual disease and event-free survival (EFS) from the AML02-cohort and four SNPs previously associated with ara-C triphosphate levels in the AML97 trial. ACS10 was evaluated for association with outcomes in each clinical trial arms: the standard low-dose ara-C (LDAC, n = 91) and augmented high-dose ara-C (HDAC, n = 75) arms of AML02 and the standard Ara-C, daunorubicin and etoposide (ADE) (n = 465) and the augmented ADE + gemtuzumab ozogamicin (GO; n = 466) arms of AAML0531 trial. RESULTS In the standard LDAC-arm of AML02 cohort, the low-ACS10 score group (≤ 0) had significantly worse EFS (ACS10 low v high hazard ratio [HR] = 2.81; 95% CI, 1.45 to 5.43; P = .002) and overall survival (OS; HR = 2.98; 95% CI, 1.32 to 6.75; P = .009) compared with the high-ACS10 group (score > 0). These results were validated in the standard-ADE arm of AAML0531, with poor outcome in the low-ASC10 group compared with the high-ACS10 group (EFS: HR = 1.35, 95% CI, 1.04 to 1.75, P = .026; OS: HR = 1.64, 95% CI, 1.2 to 2.22, P = .002). Within the augmented arms (AML02-HDAC and AAML0531-ADE + GO), EFS and OS did not differ between low- and high-ACS10 score groups. In both cohorts, patients with low-ACS10 consistently showed a 10-percentage point improvement in 5-year EFS with augmented therapy (AML02-HDAC or AAML0531-ADE + GO arms) than with standard therapy (AML02-LDAC or AAML0531-ADE arms). CONCLUSION Patients with low-ACS10 score experienced significantly poor outcome when treated on standard regimen. Augmentation with either high-dose ara-C or GO addition improved outcome in low-ACS10 group. A polygenic ACS10 score can identify patients with unfavorable pharmacogenetic characteristics and offers a potential for an elective augmented therapy option.

The Relationship Between the Fibrinogen to Albumin Ratio and Early Outcomes in Patients with Acute Pontine Infarction

Background and purpose Previous studies have indicated that fibrinogen and low serum albumin levels are associated with poor outcomes of acute ischemic stroke. The role of the fibrinogen-to-albumin ratio (FAR) as a novel inflammatory and thrombotic biomarker in acute ischemic stroke is unclear. This study aims to investigate the relationship between the FAR and 3-month outcomes of acute pontine infarction. Methods: Patients with acute pontine infarction were consecutively included. All patients were followed up at 3 months after onset, and the 3-month outcome was evaluated using modified Rankin Scale (mRS) scores. A score of 0 to 2 was defined as a good outcome, and a score ≥ 3 was defined as a poor outcome. Receiver operating curve (ROC) analysis was used to calculate the optimal cutoff values for patients with acute pontine infarction. Then, a binary logistic regression model was used to evaluate the risk factors for a poor outcome after acute pontine infarction. Results: A total of 264 patients with acute pontine infarction were included. Eighty (30.3%) patients were included in the poor outcome group. The optimal cutoff value of the FAR for predicting the 3-month outcome of acute pontine infarction was 8.199. The FAR was independently associated with a poor outcome at 3 months in patients with acute pontine infarction (odds ratio [OR] = 1.293, 95% confidence interval [CI]: 1.150-1.453). Conclusions: We found that a high FAR predicted poor 3-month outcomes in patients with acute pontine infarction.

Lower GCS is Related to Poor Outcome among Acute Stroke Patients with COVID-19 in A Tertiary Referral Hospital in Indonesia

BACKGROUND: The Coronavirus disease 2019 (COVID-19) pandemic has forced the health workforce to take mitigative measures such as physical distancing, screening, personal protective equipment donning, and confinement on patient care. We aimed to study the outcome of acute stroke patients with suspected, probable, or confirmed COVID-19 in a tertiary referral hospital in Indonesia during the first year of COVID-19 pandemic.METHODS: This was a retrospective study examining all medical records of adult patients suffering from acute stroke with suspected or confirmed COVID-19 who were admitted to R.D. Kandou Hospital, Manado, Indonesia, between March 2020 to March 2021. Clinical and laboratory parameters were compared between subjects with poor and good outcomes based on Glasgow Outcome Scale (GOS), divided into poor outcome (GOS 1-3) and good outcome (GOS 4-5).RESULTS: Fourty-six eligible subjects were enrolled in the study. Based on the GOS, 36 subjects (78.3%) were admitted to the hospital with poor prognosis. On admission, the median Glasgow Coma Scale (GCS) was 11, breathlessness was found in 54.3% of subjects, fever was found in only 15 subjects (32.6%), and the lowest oxygen saturation on admission 95%. We found that GCS significantly related to outcome after controlled for other factors using the logistic regression method (p=0.03; 95% CI=1.08-4.78).CONCLUSION: Lower GCS can be used to predict poor outcome in acute stroke patients with COVID-19.KEYWORDS: COVID-19, acute stroke, Glasgow Coma Scale, outcome, Indonesia