Phase II Study of the Liposomal Formulation of Eribulin (E7389-LF) in Combination with Nivolumab: Results from the Gastric Cancer Cohort.

PURPOSE: E7389-LF is a liposomal formulation of the microtubule dynamics inhibitor eribulin and has shown preliminary efficacy in the treatment of gastric cancer. Study 120, a phase Ib/II open-label study, assessed efficacy and safety of E7389-LF in combination with nivolumab, a programmed cell death (PD)-1 inhibitor. This report focuses on the gastric cancer cohort within the expansion phase. PATIENTS AND METHODS: Eligible patients had unresectable, measurable gastric cancer, progression following a platinum drug plus fluoropyrimidine (1L), and a taxane-containing regimen (2L). The primary objective of the expansion phase was objective response rate, secondary objectives included safety and PFS, and exploratory objectives included overall survival and biomarker evaluation. Patients received E7389-LF 2.1 mg/m2 in combination with nivolumab 360 mg every 3 weeks, both as intravenous infusions. Tumor responses were assessed every 6 weeks by the investigators per RECIST v1.1. Plasma and tumor biomarkers were assessed. RESULTS: In the 31 patients who received E7389-LF in combination with nivolumab, the objective response rate was 25.8% [confidence interval (CI), 11.9-44.6]. The median progression-free survival was 2.69 months (95% CI, 1.91-2.99) and median overall survival was 7.85 months (95% CI, 4.47-not estimable). The most common treatment-related TEAE of any grade were neutropenia (77.4%), leukopenia (74.2%), and decreased appetite (51.6%). E7389-LF in combination with nivolumab significantly increased CD8-positive cells at C2D1 (P = 0.039), and six of seven vascular markers and four IFNγ-related markers showed increases from C1D1. CONCLUSIONS: Promising antitumor activity was observed with E7389-LF in combination with nivolumab in patients with gastric cancer, and no new safety signals were observed, compared with either monotherapy.

Real-World Treatment Sequencing in Vulnerable Patients with Metastatic Colorectal Cancer: A Multicenter Retrospective Study.

BACKGROUND: Data regarding treatment sequence for vulnerable patients with metastatic colorectal cancer (mCRC) in a real-world setting are lacking. OBJECTIVE: We aimed to assess treatment outcomes in second-line or later chemotherapy for vulnerable patients with mCRC in a real-world setting. PATIENTS AND METHODS: Vulnerable patients with mCRC who received less intensive treatment ('vulnerable') regimens, i.e. fluoropyrimidines with or without biologics (FP), reduced-dose doublet regimens with or without biologics (Doublet), and anti-epidermal growth factor receptor monotherapy (Anti-EGFR), as first-line therapy between June 2015 and December 2018 were retrospectively reviewed. RESULTS: A total of 210 patients from 15 hospitals were analyzed. The median age was 78 years (range 28-90), and 44 patients (21%) had an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 2. In the entire population, the median time to treatment failure (TTF) and overall survival (OS) were 7.6 and 21.4 months, respectively. Following the failure of first-line therapy in 195 patients, 74 (38%), 24 (12%), and 13 (7%) patients received vulnerable regimens, full-dose doublet regimens with or without biologics, and other regimens, respectively, whereas 84 (43%) received best supportive care (BSC). In patients receiving vulnerable regimens as second-line therapy, the median TTF and OS were 4.4 and 13.7 months, respectively, while response rate and disease control rate were 18% and 62%, respectively. In 84 patients who received BSC, the median OS was 3.5 months. CONCLUSIONS: Second-line chemotherapy for vulnerable patients with mCRC showed clinically meaningful outcomes; however, few patients received second-line therapy, and survival among patients who received BSC was dismal.

Prospective observational study of zinc deficiency symptoms during first-line chemotherapy for gastric and colorectal cancer.

Background: Zinc deficiency during long-term chemotherapy and its related symptoms, including skin rash, taste disorders, and oral mucositis, have not been sufficiently investigated. Methods: This prospective observational study enrolled patients with gastric and colorectal cancer who underwent standard first-line chemotherapy. According to the Practice Guidelines for Zinc Deficiency, zinc deficiency is defined as a serum level of <60 µg/dL. Serum zinc levels were measured before and after (1, 3, and 6 months) chemotherapy, and symptoms were assessed using the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events version 1.0. Repeated measures were analyzed using a generalized linear mixed model. Results: Of the 61 enrolled patients, 48 who underwent standard first-line chemotherapy with fluoropyrimidine plus oxaliplatin were analyzed. Zinc deficiency was observed in 18 patients (38%) before chemotherapy. The least-squares means of serum zinc levels significantly decreased at 3 and 6 months of chemotherapy in 30 patients without zinc deficiency at the start of chemotherapy (both P<0.01) but not in 18 with zinc deficiency at the beginning. Changes in serum zinc levels during chemotherapy negatively correlated with changes in taste, rash, and itching (all P<0.04) in patients without zinc deficiency before treatment initiation. Conclusions: Serum zinc levels decreased during chemotherapy in zinc-non-deficient patients at the beginning of chemotherapy and correlated with taste changes, skin rash, and itching. Therefore, investigating whether zinc supplementation ameliorates these symptoms is necessary.

WJOG13219G: The Efficacy and Safety of FOLFOXIRI or Doublet plus Anti-VEGF Therapy in Previously Untreated BRAFV600E Mutant Metastatic Colorectal Cancer: A Multi-Institutional Registry-Based Study (BRACELET Study).

BACKGROUND: The real-world survival benefit of FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus anti-VEGF therapy (Triplet) over doublet chemotherapy (Doublet) remains controversial in patients with BRAFV600E mutant metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: WJOG13219G was a multicenter, retrospective, registry-based study of patients with BRAFV600E mutant mCRC who received first-line triplet or doublet chemotherapy from January 2014 to December 2019 in Japan. Inverse probability of treatment weighting (IPTW) was used to adjust for patient background. RESULTS: The analysis included 79 and 91 patients in the Triplet and Doublet groups, respectively. The Triplet group was significantly younger and had better performance status. No statistical difference was noted in progression-free survival (PFS; HR, 0.82; 95% CI, 0.60-1.13; P = .22) and overall survival (OS; HR, 0.88; 95% CI, 0.62-1.25; P = .48) between both groups. IPTW analysis also showed no difference between the 2 groups in PFS (HR, 0.86; 95% CI, 0.69-1.08; P = .20) and OS (HR, 0.93; 95% CI, 0.73-1.20; P = .59). The Triplet and Doublet groups had an objective response rate of 53% and 41%, respectively (P = .10). At least one grade 3 or 4 adverse event was seen in 51 (65%) and 43 (47%) patients in the Triplet and Doublet groups, respectively, with the incidence of neutropenia being significantly higher in the former. CONCLUSION: Triplet therapy had no survival benefit versus doublet therapy in the overall and IPTW cohorts or specific subgroups for real-world patients with BRAFV600E mutant mCRC.

Association of ERBB2 Copy Number and Gene Coalterations With Trastuzumab Efficacy and Resistance in Human Epidermal Growth Factor Receptor 2-Positive Esophagogastric and Gastric Cancer.

PURPOSE: ERBB2 copy number (CN), measured using next-generation sequencing, is a predictive biomarker for trastuzumab efficacy in human epidermal growth factor receptor 2 (HER2)-positive advanced esophagogastric and gastric cancer (AGC). We aimed to investigate the association of ERBB2 amplification and gene coalterations with response and resistance to trastuzumab-combined chemotherapy. METHODS: The SCRUM-Japan GI-SCREEN was a comprehensive genomic profiling project of GI cancer tissues using Oncomine Cancer Research Panel and Oncomine Comprehensive Assay. From 885 patients with AGC who successfully underwent gene profiling, 74 with ERBB2 amplification (CN ≥ 4.0) and who received first-line trastuzumab-combined chemotherapy were selected, and ERBB2 CN and gene coalterations were assessed. RESULTS: ERBB2 CN did not differ in tumor response to trastuzumab-combined chemotherapy (one-way analysis of variance test, P = .37). Multivariate analysis using the Cox proportional hazard model revealed that ERBB2 CN (continuous log2-converted CN, hazard ratio, 0.76; 95% CI, 0.62 to 0.93; P < .01) and receptor/oncogene amplifications in the HER2 signaling pathway (hazard ratio, 2.5; 95% CI, 1.2 to 5.3; P = .01) were significant predictors for progression-free survival (PFS). ERBB2 variants coexisted in five patients (7%) and were missense mutations. Two patients with low variant allele frequencies (VAFs; 8%, 12%) showed high ERBB2 CN (55, 80) and durable response (≥ 20 months), whereas three patients with high VAFs (66%-90%) showed low ERBB2 CN (8-11) and no response with short PFS (1-10 months). CONCLUSION: ERBB2 CN and gene coamplification in the HER2 signaling pathway were positive and negative predictors of PFS in trastuzumab-treated HER2-positive AGC patients, respectively. HER2-positive AGC patients with a high VAF of ERBB2 showed poor outcomes and may need HER2 tyrosine kinase inhibitors and trastuzumab deruxtecan.

Clinical Outcomes of S-1 Monotherapy and Modified FOLFIRINOX Therapy after Gemcitabine plus Nab-paclitaxel Therapy in Unresectable Pancreatic Cancer.

Objective S-1 and modified FOLFIRINOX (mFFX) were often used as the second-line chemotherapies after failure of gemcitabine plus nab-paclitaxel (GnP) in unresectable pancreatic cancer (UPC) until nanoliposomal irinotecan plus 5-fluorouracil/leucovorin therapy was approved as an alternative in Japan in 2020. However, the clinical outcomes of S-1 and mFFX after GnP have scarcely been reported. Therefore, we retrospectively studied them. Methods We extracted the clinical data of 86 patients with UPC who received second-line chemotherapy after GnP between 2015 and 2020. Among the patients who had a good organ functions and no massive ascites, 41 patients treated with S-1 and 21 treated with mFFX were enrolled. Results Compared to S-1, mFFX tended to be used for younger patients with a good general condition (median age, 63 vs. 71 years, p<0.01; and performance status 0, 67% vs. 37%, p<0.05). The median progression-free and overall survival were similar between the S-1 (3.7 and 7.2 months, respectively) and mFFX (3.3 and 7.4 months, respectively) groups. The response rate in patients with measurable lesions was 4% (n=1/23) in the S-1 group and 17% (n=2/12) in the mFFX group. The incidence of grade 3 or 4 adverse events was 20% in the S-1 group and 57% (neutrophil count decreased in 43%) in the mFFX group (p<0.01). Conclusion S-1 and mFFX were both acceptable second-line chemotherapies after GnP therapy for UPC, although attention should be paid to myelosuppression during mFFX treatment. Further studies involving nanoliposomal irinotecan plus 5-fluorouracil/leucovorin therapy are necessary to facilitate the selection of the optimal regimen for each patient.

[Tolerability of Definitive Chemoradiotherapy in Elderly Patients with Esophageal Cancer].

Definitive chemoradiotherapy(CRT)for esophageal cancer is the standard treatment and alternative to surgery. However, the tolerability of CRT in elderly patients is not well known. In this study, we retrospectively analyzed 60 patients with esophageal cancer who were treated with CRT(5-FU 700 mg/m2, cisplatin 70 mg/m2, radiation 60 Gy)at our hospital between January 2015 and September 2017. The patients were divided into 2 groups: an elderly group comprising 16 patients aged >75 years and a non-elderly group comprising 44 patients aged <74 years. The relative dose intensity of cisplatin in the elderly group was significantly lower than that in the non-elderly group. Radiotherapy was successfully executed in both groups. More patients in the elderly(25%)than the non-elderly group(7%)developed pneumonitis, and all patients who developed severe pneumonitis in the elderly group died. Application of definitive CRT and irradiation methods in elderly patients with a subpleural reticular shadow should be carefully considered before initiating therapy.

Classification of atrophic mucosal patterns on Blue LASER Imaging for endoscopic diagnosis of Helicobacter pylori-related gastritis: A retrospective, observational study.

BACKGROUND: Atrophic gastritis can be classified according to characteristic mucosal patterns observed by Blue LASER Imaging (BLI) in a medium-range to distant view. AIMS: To facilitate the endoscopic diagnosis of Helicobacter pylori (HP)-related gastritis, we investigated whether atrophic mucosal patterns correlated with HP infection based on the image interpretations of three endoscopists blinded to clinical features. METHODS: This study included 441 patients diagnosed as having atrophic gastritis by upper gastrointestinal endoscopy at Nishikawa Gastrointestinal Clinic between April 1, 2015 and March 31, 2016. The presence/absence of HP infection was not taken into consideration. Endoscopy was performed using a Fujifilm EG-L580NW scope. Atrophic mucosal patterns observed by BLI were classified into Spotty, Cracked and Mottled. Image interpretation results were that 89, 122 and 228 patients had the Spotty, Cracked and Mottled patterns, respectively, and 2 patients an undetermined pattern. Further analyses were performed on 439 patients, excluding the 2 with undetermined patterns. RESULTS: The numbers of patients testing negative/positive for HP infection in the Spotty, Cracked and Mottled pattern groups were 12/77, 105/17, and 138/90, respectively. The specificity, positive predictive value and positive likelihood ratio for endoscopic diagnosis with positive HP infection based on the Spotty pattern were 95.3%, 86.5% and 8.9, respectively. In all patients with the Spotty pattern before HP eradication, the Cracked pattern was observed on subsequent post-eradication endoscopy. CONCLUSIONS: The Spotty pattern may represent the presence of HP infection, the Cracked pattern, a post-inflammatory change as seen after HP eradication, and the Mottled pattern, intestinal metaplasia.

Spinal fusion in a patient with Fukuyama congenital muscular dystrophy.

Many studies have evaluated surgical treatments for spinal deformities in patients with neuromuscular disease. However, few reports have described patients with Fukuyama congenital muscular dystrophy (FCMD). A 13-year-old boy with FCMD was unable to sit for long periods or sleep in the supine position because of progressive scoliosis. His Cobb angle worsened from 27° to 41° in 5months. He underwent standard posterior spinal fusion and pedicle-screw-alone fixation from T5 to S1. Postoperatively, his Cobb angle improved from 41° to 25° without exacerbation for 2years. After the surgery, he was able to sit for longer periods without pain, and he and his family were satisfied with the efficacy of the spinal fusion. Some patients with mild FCMD can sit at the age of puberty, but progression to scoliosis is possible. Therefore, spinal fusion for progressive scoliosis in patients with FCMD should be considered.