Ramucirumab has shown efficacy in combination with paclitaxel in the second-line treatment of advanced gastric cancer (AGC). The efficacy and safety regarding the combination therapy of ramucirumab and docetaxel have not been reported. This treatment could reduce the incidence of neuropathy and patients’ hospital visits. This was a multicenter, single-arm phase II trial. Patients with AGC who were refractory or intolerant to primary treatment were eligible. Patients received ramucirumab at a dose of 8 mg/kg on day1 and 15, and docetaxel at a dose of 60 mg/m2 on day1 of a 28-day cycle. The primary endpoint was overall response rate (ORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), relative dose intensity, and safety. A final analysis of efficacy and safety was performed in 35 patients. ORR was 25.7
418 Background: Based on the JCOG1109 trial, neoadjuvant docetaxel, cisplatin, and fluorouracil (DCF) followed by surgery has become the standard of care for resectable locally advanced esophageal squamous cell carcinoma (ESCC). Although the combination of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) demonstrated benefits for esophageal adenocarcinoma as a perioperative therapy, its safety and efficacy for locally advanced ESCC have not been evaluated. Methods: We conducted a multicenter phase II study of neoadjuvant FLOT therapy for ESCC. Patients with cT1N1-3M0-1 or cT2-3N0-3M0-1 (only supraclavicular lymph node (SCLN) metastasis is included as M1) based on the 8th edition of the UICC TNM staging system were eligible. Neoadjuvant chemotherapy consisted of oxaliplatin (85 mg/m 2 ), docetaxel (50 mg/m 2 ), and l-leucovorin (200 mg/m 2 ) on day 1, and continuous infusion of fluorouracil (2600 mg/m 2 /day) for 24 hours. This regimen was repeated every 2 weeks with a maximum of four cycles. The prophylactic antibody and G-SCF were not used mandatory. After completion of neoadjuvant chemotherapy, esophagectomy with extended lymphadenectomy was performed. Adjuvant treatment was prohibited for all patients. The primary endpoint was the pathological response rate (pRR), defined as the Grade 2 (more than two-thirds of the tumor is necrotic or fibrotic) or 3 (no viable tumor cells), based on the Japanese Classification of Esophageal Cancer. The sample size was determined based on an expected pRR of 38%, aiming for the lower bound of the 95% confidence interval to exceed the predetermined threshold of 20%. The expected number of patients to be enrolled was 60, with enrollment to be stopped when 45 patients with negative SCLN were enrolled. Results: Fifty-four patients were enrolled between September 2020 and January 2024. Patients with cStage I/II/III/IVB were 3/16/27/8. Of 54 patients, 45 patients were M0 without SCLN metastasis. Excluding 1 patient who did not receive any treatment after enrollment, 53 patients were included in the full analysis set. During chemotherapy, the most common grade 3 or 4 toxicities were neutropenia (73.6%), and leukopenia (22.6%). Febrile neutropenia was observed in 1 patient (1.9%). Finally, 46 patients underwent surgery. No treatment-related deaths were observed and the incidence of operative morbidity was tolerable. The pRR was 43.4% (23/53) (95% CI 29.8-57.7, p=00002). This study met the primary endpoint. The radical resection rate was 83.0% (44/53). The pathological complete response rate was 13.2% (7/53). Conclusions: Neoadjuvant FLOT therapy showed a promising pathological response with acceptable toxicities. It was noteworthy that the incidence of febrile neutropenia was relatively lower with compared to neoadjuvant DCF therapy. This regimen might be a treatment option for locally advanced ESCC. Clinical trial information: jRCTs031200094.
Anamorelin hydrochloride (ANAM), used to treat cancer cachexia, is often discontinued early in clinical practice. Herein, we explored the clinical factors associated with the early discontinuation (Ed) of ANAM and examined its effect on treatment outcomes. Clinical data of patients with gastrointestinal cancers who were administered ANAM between April and November 2021 from 16 institutions were retrospectively collected. Ed was defined as ANAM discontinuation within 4 weeks of initiation. ANAM efficacy was compared between the continuation (Co) and Ed groups. Of the 123 patients, 50 had an Ed of ANAM. The most common reasons were cancer progression (36
BACKGROUND/AIM:Pancreatic cancer (PC) has a poor prognosis and limited treatment options. The development of resistance to anticancer agents poses a significant challenge in the treatment of PC. Our previous study indicated that basic helix-loop-helix family member e41 (BHLHE41) is associated with the prognosis of lung cancer. Additionally, BHLHE41 affects the prognosis and response to anticancer drugs in several cancers. However, the functional role of BHLHE41 in cancer remains unclear. In PC, its expression has been reported to influence tumor malignancy; however, its impact on chemosensitivity has not yet been elucidated. Therefore, this study aimed to investigate the effects of BHLHE41 on PC chemosensitivity. MATERIALS AND METHODS:Genetic modification and MTT assays were performed to evaluate the effect of BHLHE41 on anticancer agents. RNA sequencing (RNA-seq) was conducted to analyze the downstream pathways of BHLHE41. Furthermore, anticancer agent sensitivity tests were performed for the candidate genes identified through RNA-seq. RESULTS:BHLHE41 enhanced the sensitivity of PC cells to gemcitabine (GEM) while suppressing the expression of insulin-like growth factor binding protein 4 (IGFBP4). Additionally, IGFBP4 affected sensitivity to GEM independently of BHLHE41, suggesting that IGFBP4 contributes to resistance to this agent in PC cells. CONCLUSION:These findings provide novel insights that may help identify potential targets for patients with PC undergoing chemotherapy and open new avenues for research and therapeutic strategies.
Background Sensorineural hearing loss is increasingly recognized in Niemann–Pick disease type C (NPC), but the underlying cochlear lesion remains undefined. While prior work emphasized hair-cell (HC) involvement, whether auditory dysfunction instead arises from lateral-wall failure and endocochlear potential (EP) decline is unknown. Methods Npc1−/− mice and littermate controls underwent auditory function test and electrophysiological recordings at postnatal day (P) 35 and P63. Cochlear cytoarchitecture was evaluated using immunohistochemistry and transmission electron microscopy (TEM). To probe cell-type susceptibility, NPC1 was inhibited in Spiral ligament (SLi)-like fibrocytes, HC-like HEI-OC1 cells in vitro. Results Npc1−/− mice showed elevated low-frequency auditory brainstem response (ABR) thresholds at P35, progressing to pan-frequency impairment and prolonged ABR wave IV–V latencies by P63. HCs, stereocilia bundles, and spiral ganglion cells were preserved. In contrast, EP was markedly reduced. Na⁺/K⁺-ATPase α1 and connexin-26 immunolabeling in the SLi decreased significantly without strial thinning, indicating impaired ion recycling and gap-junction coupling. Filipin staining and TEM revealed progressive free-cholesterol accumulation and vacuolar inclusions in SLi fibrocytes and supporting cells, with secondary involvement of HC regions. In vitro, NPC1 inhibition increased cholesterol in SLi-like fibrocytes but not in HEI-OC1 cells. Conclusions NPC-related hearing loss arises primarily from SLi dysfunction and EP failure, with secondary HC compromise, rather than degeneration. These findings reposition NPC hearing loss as a disorder of cochlear homeostasis and identify EP preservation and correction of cholesterol trafficking as rational therapeutic targets. Early auditory monitoring may improve clinical outcomes.
