Background Postoperative regional nodal irradiation (RNI) is a standard treatment for breast cancer at high risk of regional recurrence; however, the necessity of including the internal mammary node (IMN) region in the radiation field remains unclear. This study aimed to evaluate treatment outcomes in a large cohort of patients who received postoperative radiotherapy with RNI excluding the IMN region. Methods This study included patients with breast cancer who underwent surgery followed by RNI without IMN irradiation between 2007 and 2018. The primary endpoint was disease-free survival (DFS), and the secondary endpoints were overall survival (OS), breast cancer-specific mortality (BCM), distant metastasis-free survival (DMFS), recurrence patterns, and treatment-related adverse events. Results In total, 799 patients were included. The 5-year DFS, OS, BCM, and DMFS rates were 75.9, 88.3, 9.7, and 77.1%, respectively. Worse outcomes were associated with a higher number of positive lymph nodes and estrogen receptor (ER)-negative disease. Medial/central tumor location and younger age were each significantly associated with poorer outcomes, being associated with worse DFS and DMFS. Bone was the most common recurrence site. ER-negative disease, a higher number of positive lymph nodes, medial/central location, and younger age were significant risk factors for recurrence, particularly distant metastasis. IMN recurrence was rare. Conclusions In this cohort, medial/central tumor location, ER-negative disease, and extensive nodal involvement were associated with poorer outcomes, suggesting that these factors may identify patients who can benefit from IMN irradiation. These findings may serve as important reference data when determining the indication for IMN irradiation on an individual patient basis.
KRASG12C inhibitors, such as sotorasib, show clinical efficacy for non-small cell lung cancer (NSCLC) positive for the G12C mutations of KRAS, but primary and acquired resistance to these drugs remains a clinical problem. In this study, we show that the development of resistance to sotorasib in KRASG12C-positive NSCLC cells was mediated by constitutive activation of EGFR resulting from downregulation of the protein tyrosine phosphatase receptor type R (PTPRR). PTPRR has been identified as a physiologic regulator of ERK signaling in several cancer types. In our study, PTPRR was demonstrated to bind directly to EGFR, facilitating its dephosphorylation on tyrosine residues. Resumption of PTPRR expression in the resistant cells attenuated EGFR phosphorylation and restored sotorasib sensitivity. PTPRR downregulation was associated with gene promoter hypermethylation in the sotorasib-resistant cells and NSCLC tissue samples. Furthermore, low PTPRR expression in tumor specimens was associated with shorter progression-free and overall survival for patients with NSCLC treated with sotorasib. In contrast to sotorasib, high PTPRR expression was associated with a poor response to EGFR tyrosine kinase inhibitors in EGFR-mutated NSCLC, suggesting that PTPRR may broadly regulate EGFR dependence in NSCLC. Finally, dual blockade of KRASG12C and EGFR showed a substantial antitumor effect in a xenograft model of sotorasib-resistant NSCLC. This approach is therefore a rational therapeutic strategy for KRASG12C-positive NSCLC, especially for tumors showing PTPRR downregulation. SIGNIFICANCE:The current study shows that downregulation of PTPRR induces EGFR activation and resistance to KRASG12C inhibitors in NSCLC, suggesting dual KRAS-EGFR blockade as a rational therapy. PTPRR may help identify patient subgroups that would benefit from the addition of EGFR inhibitors to KRASG12C-targeted therapies.
AIMS:The relief of the symptoms is one of the major purposes in the treatment for acute decompensated heart failure. The aim of this study is to investigate the relationship between patient-reported perception of symptom change of heart failure during hospitalization and subsequent prognosis in patients with acute decompensated heart failure (ADHF). METHODS AND RESULTS:Among 4056 consecutive patients hospitalized due to ADHF from a multicentre cohort study in Japan (Kyoto Congestive Heart Failure study), the study population consisted of 3567 patients who assessed their perception of symptom change during index hospitalization by themselves on 7-point Likert scale. We classified them the study patients into 4 groups: marked improvement group (N = 1602; 44.9%), moderate improvement group (N = 1659; 46.5%), minimal improvement group (N = 240; 6.7%), and no improvement group (N = 66; 1.9%). Primary outcome measures were a composite of all-cause death or HF hospitalization. The cumulative 1-year incidence of the primary outcome was higher in the no, minimal, and moderate improvement groups than in the marked improvement group (56%, 45%, 36%, vs. 29%, log-rank P < 0.001). After adjustment, the hazard ratios of the no, minimal, and moderate improvement groups relative to the marked improvement group were 1.66, 95% confidence interval [CI]: 1.14-2.42; 1.26, 95% CI: 1.01-1.57; 1.08, 95% CI: 0.95-1.21, respectively, for the primary outcome. CONCLUSION:The patient-reported perception of symptom change at discharge was correlated with a composite of all-cause death or HF hospitalization at 1 year after discharge in patients admitted to the hospital for ADHF.
BACKGROUND:Maintaining activities of daily living is of great importance for patients who have cancer, and dependency is associated with psychological distress. However, evidence for rehabilitation remains scarce in this setting. The objective of this study was to evaluate the efficacy of a structured rehabilitation program for maintaining activities of daily living among patients with terminal cancer. METHODS:This multicenter randomized controlled trial across 19 Japanese inpatient hospices/palliative care units enrolled patients who had terminal cancer with an Eastern Cooperative Oncology Group performance status of 2-3, a life expectancy ≥3 weeks, and no severe symptoms. Participants were randomly assigned (1:1, stratified by performance status and site) to either a 3-week structured rehabilitation program that incorporated key elements of rehabilitation for patients with terminal cancer or usual unstructured rehabilitation. The primary outcome was a change in the total modified Barthel Index from baseline to day 22. Secondary outcomes included the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 15-Palliative Care score and safety. RESULTS:Between July 8, 2019, and February 20, 2024, 130 patients were randomized (59 to the intervention group, 71 to the control group; 56 patients [43.0%] were women). The primary analysis included 77 participants who had complete data available. The mean change in total modified Barthel Index was -1.31 (95% confidence interval [CI], -10.89, 8.08) in the intervention group and -15.51 (95% CI, -24.02, -7.01) in the control group. The between-group difference was 14.21 (95% CI, 1.77, 26.64; p = .026), exceeding the minimally clinically important difference (9.25). Patient-reported physical functioning on the European for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 15-Palliative Care instrument was also significantly higher in the intervention group than in the control group. No serious harms occurred. CONCLUSIONS:Structured rehabilitation maintained activities of daily living better than unstructured rehabilitation in patients with terminal cancer, supporting its integration into routine care even in the last stage of cancer.
Background Regression in cognitive, behavioral, or psychiatric functioning is the cardinal symptom of developmental and/or epileptic encephalopathy with spike and wave activation in sleep (D/EE-SWAS). Motor regression has also been reported but is very rare. We describe the case of a girl with EE-SWAS who developed fine motor dysfunction localized in the right hand. Case presentation A 4-year-old girl presented with focal seizure of the right upper extremity. Interictal EEG showed localized epileptic discharges predominantly in the left central area, and she was initially diagnosed with focal epilepsy. The seizures ceased completely after administration of levetiracetam and carbamazepine. However, she gradually developed clumsiness of the right hand. Long-term video EEG monitoring revealed electrical status epilepticus in sleep (ESES), predominantly in the left central area, and single photon emission computed tomography (SPECT) showed increased perfusion in the left central area. Subsequently a diagnosis of EE-SWAS was made. Adjustment of the anti-seizure medication led to disappearance of the ESES pattern on her sleep EEG, and the fine motor dysfunction in the right hand resolved completely. Conclusion Previous studies have suggested that specific neuropsychiatric regressions may depend on the cortical area involved by the epileptic activity of each ESES in patient with D/EE-SWAS. The present case clearly highlights the link between epileptiform activity and focal motor dysfunction in D/EE-SWAS.
