Correction to: Palbociclib use with grade 3 neutropenia in hormone receptor-positive metastatic breast cancer.

In the original publication of the article, under the Results section, subheading "Patient survival", the second sentence that reads as "The 6-month PFS was 92.4%, 81.8%, and 93.3% and the one-year PFS was 72.0%, 88.9%, and 78.9% in Groups 1-3, respectively." should read as "The 6-month PFS was 82.8%, 75.0%, and 68.0% and the one-year PFS was 77.0%, 62.0%, and 63.8% in Groups 1-3, respectively.".

Palbociclib use with grade 3 neutropenia in hormone receptor-positive metastatic breast cancer.

PURPOSE: Neutropenia is the most common toxicity of CDK4/6 inhibitors, causing frequent dose interruptions. However, CDK4/6 inhibitor-induced neutropenia shows a benign clinical course in contrast to that caused by chemotherapy. Here, we investigated the safety of a new dose scheme for palbociclib, which avoids dose delays or reductions due to afebrile grade 3 neutropenia. METHODS: A consecutive cohort of ER( +)/HER2( -) advanced breast cancer patients who received palbociclib between 2017 and 2018 was analyzed. The patients were classified into Group 1 (patients who maintained palbociclib dose with afebrile grade 3 neutropenia), Group 2 (patients who experienced any dose modification with afebrile grade 3 neutropenia), and Group 3 (patients without afebrile grade 3 neutropenia). The primary endpoint was febrile neutropenia incidence; other toxicities were compared with those of the PALOMA-2 trial. RESULTS: Among the 107 patients, 54.2%, 22.4%, and 23.4% were classified into Groups 1, 2, and 3, respectively. There was no febrile neutropenia in Groups 1 and 2 during palbociclib treatment. Group 1 showed higher incidence of thrombocytopenia (all-grade, 32.8%; grade 3-4, 8.6%) than Group 2 and the PALOMA-2 data, but there was no bleeding related to thrombocytopenia. Group 1 showed higher incidence of all-grade non-hematologic adverse events than Group 2; only one grade 3 non-hematologic toxicity was observed in Group 1. There were no treatment-related hospitalizations or deaths in Group 1. CONCLUSIONS: Thus, omitting palbociclib dose modification with afebrile grade 3 neutropenia is safe and tolerable without febrile neutropenia events. This scheme could be useful to avoid unnecessary reductions in palbociclib doses in future practice.

Functional characterization of genetic variations in the MDR3 promoter.

Multidrug resistance 3 (MDR3) is present on the canalicular membrane of the hepatocyte and plays an important role in protecting the liver from bile acids. In this study, we characterized the transcriptional effects of four common haplotypes and four polymorphic variants in the promoter region of MDR3 that were identified in 126 DNA samples from Koreans. We measured the luciferase activities of the four MDR3 promoter haplotypes using in vitro reporter assays. Among them, two haplotypes showed a significant decrease in reporter activity compared to the reference. One of the mechanisms by which these haplotypes might decrease MDR3 transcriptional activity was determined: one of the polymorphisms that are present in haplotype 3, was associated with a significant reduction in the promoter activity of MDR3, and the transcription factor NF-Y was predicted to bind to the promoter in the region of g.-1584C>T. Electrophoretic mobility shift assays showed that the g.-1584C allele exhibited greater binding to NF-Y than did the g.-1584T allele. Through the measurement of promoter activity after the overexpression of NF-Y, we found that NF-Y can act as a transcriptional activator of MDR3. These data suggest that the reduced transcriptional activity of g.-1584C>T results from a reduction in the binding affinity of the activator NF-Y to the MDR3 promoter region. Our study suggests that two common haplotypes of MDR3 can regulate the transcriptional rate of MDR3 and that NF-Y may be one of the transcriptional factors involved in this regulation.

Real-World Outcomes of Nivolumab, Pembrolizumab, and Atezolizumab Treatment Efficacy in Korean Veterans with Stage IV Non-Small-Cell Lung Cancer.

PURPOSE: To provide a comprehensive analysis of ICI usage and treatment outcomes in elderly Korean veterans with stage IV NSCLC. METHODS: Patients diagnosed with stage IV NSCLC between 2016 and 2021 were included, and three cohorts were derived according to the type of ICI received. Thereafter, the clinical characteristics and survival outcomes were compared. RESULTS: Of the 180 patients with NSCLC (median age, 76 years) included in this study, 49 (27.7%), 61 (33.9%), and 70 (38.9%) received pembrolizumab, nivolumab, and atezolizumab, respectively, and 19.4%, 36.1%, and 34.4% had PD-L1 expressions < 1%, 1-49%, and ≥50%, respectively. The pembrolizumab, nivolumab, and atezolizumab groups, the objective response rates (ORR), and the disease control rates (DCR) were 22.4%, 8.2%, and 4.3% (p = 0.004), and 59.2, 55.7%, and 30.0% (p = 0.001), respectively. However, no difference in the overall survival (OS) rate was noted among the groups (12.6 months vs. 8.4 months vs. 7.7 months, p = 0.334). Similarly, there was no treatment specific OS benefit with respect to the tumor PD-L1 expression status. Interestingly, multivariate analysis identified bone metastasis as a significant poor prognostic factor for OS (HR = 2.75 [95% CI, 1.31-5.76], p = 0.007). CONCLUSION: Pembrolizumab and nivolumab showed stronger associations with increases in ORR and DCR than atezolizumab, but no statistically significant differences were observed with respect to OS.

ß­catenin blockers enhance the effect of CDK4/6 inhibitors on stemness and proliferation suppression in endocrine­resistant breast cancer cells.

Wnt/ß­catenin signaling is involved in endocrine resistance and stem cell­like properties of hormone receptor­positive breast cancer cells. Palbociclib is a well­known inhibitor of cyclin­dependent kinase 4 and 6 (CDK4/6 inhibitor) that downregulates the activation of retinoblastoma protein, thereby inhibiting the cell cycle in breast cancer cells. The inhibitory effects of a combination of palbociclib and ICG­001, a ß­catenin small­molecule inhibitor, were investigated in tamoxifen­resistant breast cancer cell lines. Tamoxifen­resistant MCF­7 (TamR) cells were established by continuously exposing MCF­7 cells to tamoxifen. The characteristics associated with the stem cell­like property of cancer were assessed using western blotting, cell cycle analysis, and the mammosphere assay. The effects of the combination of palbociclib and ICG­001 were evaluated in control MCF­7 and TamR cell lines. Compared with control cells, TamR cells exhibited elevated levels of Nanog, Sox2, ALDH1, and p­STAT3, indicating stem cell­like characteristics, and elevated ß­catenin activity. TamR cells also showed significantly higher mammosphere­forming efficiency. Several markers of stem cell­like nature of TamR cells showed reduced levels upon treatment of cells with the drug combination; there was a greater reduction in the levels of these markers when the cells were treated with the combination than in the case where cells were treated with one of the drugs individually (combination index value for 25 µM palbociclib and 50 µM ICG­001 was 1.1±0.02). TamR cells treated with the palbociclib and ICG­001 combination demonstrated significantly reduced cell proliferation and mammosphere­forming efficiency compared with the cells treated with one of these drugs. The combination of the drugs could additively inhibit proliferation and suppress stem cell­like characteristics. These results suggest that ß­catenin plays a role in endocrine­resistant breast cancer; the inhibition of ß­catenin and CDK4/6 together can overcome endocrine resistance in breast cancer cells.

New-onset type 1 diabetes mellitus as a delayed immune-related event after discontinuation of nivolumab: A case report.

RATIONALE: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. However, they may cause immune-related adverse events. Although there have been a few reports of new-onset type 1 diabetes mellitus (T1DM) during ICI treatment, T1DM as a delayed immune-related event after discontinuing immunotherapy is extremely rare. Herein, we report the case of an elderly veteran who presented with diabetic ketoacidosis 4 months after the discontinuation of treatment with nivolumab. PATIENT CONCERNS: A 74-year-old veteran was treated with second-line nivolumab for advanced non-small cell lung cancer. After 9 treatment cycles, the administration was discontinued due to fatigue. Four months later, he was admitted to the emergency department in a stuporous mental state and hyperglycemia, with high glycosylated hemoglobin levels (10.6%). C-peptide levels were significantly decreased, with negative islet autoantibodies. DIAGNOSES: We diagnosed nivolumab-induced T1DM. There were no laboratory results indicating a new thyroid dysfunction or adrenal insufficiency, which are typical endocrine adverse reactions. INTERVENTIONS: Since the hypothalamic and pituitary functions were preserved and only the pancreatic endocrine capacity was impaired, we administered continuous intravenous insulin injections, with fluid and electrolyte replacement. OUTCOMES: His serum glucose levels decreased, and symptoms improved; hence, on the 8 day of hospitalization, we switched to multiple daily insulin injections. LESSONS: The present case indicates that regular glucose monitoring and patient education are needed for diabetic ketoacidosis after the discontinuation of ICI therapy.

Recurrent meningococcal meningitis with complement 6 (C6) deficiency: A case report.

RATIONALE: Late complement deficiency increases susceptibility to meningococcal disease and recurrent infections. In Korea, 5 case reports have described meningococcal disease with complement deficiency. However, C6 deficiency has not been described previously. PATIENT CONCERNS: A 21-year-old police trainee presented with recurrent meningococcal meningitis. He was housed in communal living quarters until 20 days before the initial symptom onset. DIAGNOSIS: He was diagnosed with meningococcal meningitis with C6 deficiency. INTERVENTIONS: He was treated with intravenous ceftriaxone. An additional dose of quadrivalent meningococcal conjugate vaccine was administered after discharge. OUTCOMES: He was discharged without complications. LESSONS: Screening for complement deficiency is necessary in patients with a history of recurrent meningococcal infections to provide appropriate care and prevent recurrent infections.

Role of Preoperative Chemoradiotherapy in Clinical Stage II/III Rectal Cancer Patients Undergoing Total Mesorectal Excision: A Retrospective Propensity Score Analysis.

BACKGROUND: Although the current standard preoperative chemoradiotherapy (PCRT) for stage II/III rectal cancer decreases the risk of local recurrence, it does not improve survival and increases the likelihood of preoperative overtreatment, especially in patients without circumferential resection margin (CRM) involvement. METHODS: Stage II/III rectal cancer without CRM involvement and lateral lymph node metastasis was radiologically defined by preoperative magnetic resonance imaging (MRI). Patients who received PCRT followed by total mesorectal excision (TME) (PCRT group) and upfront surgery (US) with TME (US group) between 2010 and 2016 were analyzed. We derived cohorts of PCRT group versus US group using propensity-score matching for stage, age, and distance from the anal verge. Three-year relapse-free survival rate, disease-free survival (DFS), and overall survival (OS) were compared between the two groups. RESULTS: A total of 202 patients were analyzed after propensity score matching. There were no differences in baseline characteristics. The median follow-up duration was 62 months (interquartile range, 46-87). There was no difference in the 3-year disease-free survival rate between the PCRT and US groups (83 vs. 88%, respectively; p=0.326). Likewise, there was no significant difference in the 3-year OS (89 vs. 91%, respectively; p=0.466). The 3-year locoregional recurrence rates (3 vs. 2% with US, p=0.667) and distant metastasis rates (16 vs. 11%, p=0.428) were not significantly different between the two groups. Time to completion of curative treatment was significantly shorter in the US group (132 days) than in the PCRT group (225 days) (p<0.001). CONCLUSION: Using MRI-guided selection for better risk stratification, US without neoadjuvant therapy can be considered in early stage patients with good prognosis. PCRT may not be required for all stage II/III rectal cancer patients, especially for the MRI-proven intermediate-risk group (cT1-2/N1, cT3N0) without CRM involvement and lateral lymph node metastasis. Further prospective studies are warranted.