Dose-escalation study for the targeting of CD44v+ cancer stem cells by sulfasalazine in patients with advanced gastric cancer (EPOC1205).

BACKGROUND: Cancer stem cells (CSCs) have enhanced mechanisms of protection from oxidative stress. A variant form of CD44 (CD44v), a major CSC marker, was shown to interact with xCT, a subunit of cystine-glutamate transporter, which maintains high levels of intracellular reduced glutathione (GSH) which defend the cell against oxidative stress. Sulfasalazine (SSZ) is an inhibitor of xCT and was shown to suppress the survival of CD44v-positive stem-like cancer cells both in vitro and in vivo. To find the dose of SSZ which can safely reduce the population of CD44v-positive cells in tumors, a dose-escalation study in patients with advanced gastric cancer was conducted. METHODS: SSZ was given four times daily by oral administration with 2 weeks as one cycle. Tumor biopsies were obtained before and after 14 days of administration of SSZ to evaluate expression of CD44v and the intratumoral level of GSH. RESULTS: Eleven patients were enrolled and received a dosage from 8 to 12 g/day. Safety was confirmed up to a dosage of 12 g/day, which was considered the maximum tolerated dose. Among the eight patients with CD44v-positive cells in their pretreatment biopsy samples, the CD44v-positive cancer cell population appeared to be reduced in the posttreatment biopsy tissues of four patients. Intratumoral GSH levels were also decreased in two patients, suggesting biological effectiveness of SSZ at 8 g/day or greater. CONCLUSIONS: This is the first study of SSZ as an xCT inhibitor for targeting CSCs. Reduction of the levels of CD44v-positive cells and GSH was observed in some patients, consistent with the mode of action of SSZ in CSCs.

A feasibility study of outpatient chemotherapy with S-1 + cisplatin in patients with advanced gastric cancer.

BACKGROUND: Regimens of standard-dose cisplatin have usually been administered as inpatient chemotherapy in Japan. This prospective study evaluated the feasibility of outpatient chemotherapy with standard-dose cisplatin in Japanese patients with advanced gastric cancer. METHODS: Advanced gastric cancer patients received an S-1 + cisplatin regimen (S-1: 80-120 mg days 1-21; cisplatin: 60 mg/m(2) day 8, every 4-5 weeks), either as outpatient chemotherapy with oral hydration on days 9-10, or as inpatient chemotherapy with intravenous hydration on days 9-10, based on the results of an oral hydration test during days 1-7 of the first cycle. The primary endpoint was the completion rate of two cycles in the outpatient group. RESULTS: A total of 36 patients were enrolled: 32 were allocated to the outpatient group and 4 to the inpatient group. The completion rate of two cycles in the outpatient group was 78% [90% confidence interval (CI): 63-89]. The median of the total number of treatment cycles of S-1 + cisplatin and the median progression-free survival in the outpatient group were 5 (range 1-11) and 10.6 months (95% CI 4.2-16.9), respectively. Although seven patients in the outpatient group discontinued treatment, mainly owing to gastrointestinal toxicity, most of them could continue S-1 + cisplatin by switching to inpatient chemotherapy from the next cycle. CONCLUSION: Outpatient chemotherapy with S-1 + cisplatin in advanced gastric cancer patients can be safely and effectively administered in Japan with appropriate patient selection and supportive treatment.

Impaired CD4+ T cell response in older adults is associated with reduced immunogenicity and reactogenicity of mRNA COVID-19 vaccination.

Whether age-associated defects in T cells impact the immunogenicity and reactogenicity of mRNA vaccines remains unclear. Using a vaccinated cohort (n = 216), we demonstrated that older adults (aged ≥65 years) had fewer vaccine-induced spike-specific CD4+ T cells including CXCR3+ circulating follicular helper T cells and the TH1 subset of helper T cells after the first dose, which correlated with their lower peak IgG levels and fewer systemic adverse effects after the second dose, compared with younger adults. Moreover, spike-specific TH1 cells in older adults expressed higher levels of programmed cell death protein 1, a negative regulator of T cell activation, which was associated with low spike-specific CD8+ T cell responses. Thus, an inefficient CD4+ T cell response after the first dose may reduce the production of helper T cytokines, even after the second dose, thereby lowering humoral and cellular immunity and reducing systemic reactogenicity. Therefore, enhancing CD4+ T cell response following the first dose is key to improving vaccine efficacy in older adults.

Nucleostemin and TWIST as predictive markers for recurrence after neoadjuvant chemotherapy for esophageal carcinoma.

We recently demonstrated that overexpression of the nucleolar GTP-binding protein nucleostemin drives the fraction of genetically-defined tumor cells that exhibit markers and tumorigenic properties of tumor initiating cells. More specifically, cells that constitutively express elevated levels of nucleostemin exhibit increased TWIST expression; expression of genes that induced pluripotent stem cells; enhanced radioresistance; tumor formation, even when small numbers of cells are implanted; and an increased propensity to metastasize. An immunohistochemical analysis of cancer stem cell markers, such as nucleostemin and TWIST has not been conducted in surgically-resected esophageal squamous cell carcinomas after neoadjuvant chemotherapy. In the present study, we examined the expression of CD133, CD44, nucleostemin, guanine nucleotide-binding protein-like 3-like, and TWIST by immunohistochemistry in a series of 54 surgically-resected specimens of esophageal squamous cell carcinomas after neoadjuvant chemotherapy. We identified that high nucleostemin proportion, TWIST intensity, and advanced pathological N stage were significantly correlated with poor relapse-free survival. Together, these observations imply nucleostemin and TWIST as the predictive markers for postoperative recurrence.

Phase II study of bolus 5-fluorouracil and leucovorin combined with weekly paclitaxel as first-line therapy for advanced gastric cancer.

OBJECTIVE: We evaluated the efficacy and safety of bolus 5-fluorouracil (5-FU) and leucovorin combined with weekly paclitaxel (FLTAX) in advanced gastric cancer (GC) patients. METHODS: Patients with untreated stage IV GC received paclitaxel 80 mg/m(2) as a 1-hour infusion, followed by 5-FU 600 mg/m(2) as a bolus infusion and L-leucovorin 250 mg/m(2) as a 2-hour infusion on days 1, 8 and 15. Treatment cycles were repeated every 28 days. The primary endpoint was response rate. RESULTS: Thirty-five patients were enrolled. The median age was 62 years (range 34-75). Twenty-one patients (60%) had diffuse-type cancer and 11 had peritoneal metastasis. The confirmed response rate was 43% (95% CI 26-61) with 15 partial responses. Stable disease was observed in 16 (46%) patients. Median progression-free survival and overall survival were 6.8 months (95% CI 5.8-7.4) and 16.2 months (95% CI 10.0-22.8), respectively. Grade 3-4 adverse events were: neutropenia (54%), febrile neutropenia (3%), diarrhea (6%) and sensory neuropathy (11%). CONCLUSION: FLTAX showed a desirable safety profile, and the efficacy against advanced GC was encouraging. FLTAX may be a good option for GC patients with deteriorated general condition, and a randomized clinical trial in such patients is currently underway.

Neuroendocrine tumors of the stomach: chemotherapy with cisplatin plus irinotecan is effective for gastric poorly-differentiated neuroendocrine carcinoma.

BACKGROUND: Neuroendocrine tumors (NETs) occur in various primary sites, but rarely in the stomach. NETs are classified into three types, carcinoids, malignant carcinoids and poorly differentiated neuroendocrine carcinomas (PNECs), whose clinical behavior is different. Currently, clinical outcomes and standard chemotherapy for NETs of the stomach remain unclear. METHODS: We conducted a retrospective review of histopathologically confirmed NETs of the stomach at our hospital between January 2000 and August 2006. RESULTS: Thirty-seven NETs were identified. Fifteen patients had carcinoids while 22 had PNECs. Among the carcinoid patients, 7 underwent endoscopic mucosal resection and 5 had gastrectomy as first-line treatment. Three patients were observed without intervention. All patients were alive after an average follow-up period of 27 months. Among the 22 PNEC patients, 3 had no metastasis, 11 had regional lymph node metastasis, and 8 had distant metastasis. Eight of 14 patients relapsed at a median of 177 days (range 120-1459 days) after curative surgery. Twelve patients with metastatic or recurrent disease received palliative cisplatin plus irinotecan chemotherapy. The response rate was 75%, the median progression-free survival time was 212 days, and median survival time was 679 days. CONCLUSION: Gastric PNEC patients with distant metastasis had poor outcomes. Regimens containing cisplatin plus irinotecan produced a good response in gastric PNEC.

Clinical implications of using both fluoropyrimidine and paclitaxel in patients with severe peritoneal metastasis of gastric cancer: A post hoc study of JCOG1108/WJOG7312G.

BACKGROUND: In the JCOG1108/WJOG7312G trial, a combination (FLTAX) of 5-fluorouracil (FU) /leucovorin (FL) and paclitaxel (PTX) did not show superiority in overall survival (OS) to FL in untreated patients with severe peritoneal metastasis of gastric cancer (GC-SPM), some of whom received second-line chemotherapy with PTX after FL. This post hoc study aimed to investigate the clinical implications of using both FU and PTX either sequentially or in combination for patients with GC-SPM. METHODS: A total of 94 patients were enrolled and categorized into the following three subgroups: patients treated with (1) FL followed by PTX (FL/PTX, N = 25), (2) FL followed by best supportive care (BSC) (FL/BSC, N = 21), and (3) FLTAX (N = 48). OS was compared between the subgroups. By comparing baseline factors between the FL/PTX and FL/BSC subgroups, factors preventing the sequential use of PTX (SUP) were explored using logistic regression model. The efficacy of FL and FLTAX was compared according to the presence of risk factors preventing SUP. RESULTS: The FL/PTX subgroup showed better and equivalent OS compared to the FL/BSC (median 7.8 vs. 2.0 months, p < 0.01) and FLTAX (median 7.8 vs. 8.0, p = 0.49) subgroups, respectively. Glasgow Prognostic Score 2 and initially unresectable disease were identified as risk factors preventing SUP. Absence of both risks predicted SUP with a sensitivity of 13% and a specificity of 100%, whereas absence of any risks predicted SUP with a sensitivity of 67% and a specificity of 62%. FLTAX showed better OS than FL in patients with one or two of these risks but worse OS in those with none. CONCLUSIONS: Although sequential use of FU and PTX showed equivalent survival to FLTAX in patients with GC-SPM, FLTAX might be preferable given the difficulty in selecting patients likely to receive sequential use at the initiation of first-line chemotherapy.

Plasma concentrations of VCAM-1 and PAI-1: a predictive biomarker for post-operative recurrence in colorectal cancer.

This prospective study used antibody suspension bead arrays to identify biomarkers capable of predicting post-operative recurrence with distal metastasis in patients with colorectal cancer. One hundred colorectal cancer patients who underwent surgery were enrolled in this study. The median follow-up period was 3.9 years. The pre-operative plasma concentrations of 24 angiogenesis-related molecules were analyzed with regard to the TNM stage and the development of post-operative recurrence. The concentrations of half of the examined molecules (13/24) increased significantly according to the TNM stage (P < 0.05). Meanwhile, a multivariate logistic regression analysis revealed that the concentrations of vascular cell adhesion molecule 1 (VCAM-1) and plasminogen activator inhibitor-1 (PAI-1) were significantly higher in the post-operative recurrence group. The VCAM-1 and PAI-1 model discriminated post-operative recurrence with an area under the curve of 0.82, a sensitivity of 0.75, and a specificity of 0.73. A leave-one-out cross-validation was applied to the model to assess the prediction performance, and the result indicated that the cross-validated error rate was 12.5% (12/96). In conclusion, our results demonstrate that antibody suspension bead arrays are a powerful tool to screen biomarkers in the clinical setting, and the plasma levels of VCAM-1 and PAI-1 together may be a promising biomarker for predicting post-operative recurrence in patients with colorectal cancer.

Clinical significance of insulin-like growth factor type 1 receptor and epidermal growth factor receptor in patients with advanced gastric cancer.

OBJECTIVE: To better understand the clinical implications of insulin-like growth factor type 1 receptor (IGF-1R), epidermal growth factor receptor (EGFR) and HER2 expressions in gastric cancer (GC). METHODS: The study group comprised 86 patients who received first-line chemotherapy for advanced GC at the National Cancer Center Hospital. Using laser-captured microdissection and a real-time RT-PCR assay, we quantitatively evaluated mRNA levels of IGF-1R, EGFR and HER2 in paraffin-embedded cancer specimens of surgically removed primary tumors. RESULTS: In univariate analysis of the study group as a whole, patients with low expression of both IGF-1R and EGFR (n = 13) had a significantly longer overall survival than the other patients (n = 51; median, 24.6 vs. 12.8 months; log-rank p = 0.013). Multivariate survival analysis demonstrated that high EGFR expression [hazard ratio, HR: 2.94 (95% confidence interval, CI: 1.40-6.17), p = 0.004] and poor performance status [HR: 1.96 (95% CI: 1.12-3.42), p = 0.018] were significant predictors of poor survival. In patients given first-line S-1 monotherapy (n = 29), low IGF-1R (p = 0.002) and low EGFR (p = 0.035) gene expression correlated with a better response, without a significant prolongation of survival. CONCLUSION: Our data warrant further investigations on the strategy of co-targeting IGF-1R and EGFR in GC.

A phase i study of bolus 5-fluorouracil and leucovorin combined with weekly paclitaxel (FLTAX) as first-line therapy for advanced gastric cancer.

OBJECTIVE: To determine the dose-limiting toxicity (DLT) and the maximum-tolerated dose (MTD) of combination chemotherapy with leucovorin-modulated weekly bolus 5-fluorouracil (5-FU) and weekly paclitaxel in patients with advanced gastric cancer (GC). METHODS: Chemotherapy-naive patients with histologically proven metastatic or recurrent GC were enrolled. Paclitaxel was administered as a 1-h intravenous (i.v.) infusion followed by 5-FU as a bolus i.v. infusion on Days 1, 8 and 15. A 2-h i.v. infusion of l-leucovorin was started at the same time as the paclitaxel infusion on Days 1, 8 and 15. Treatment cycles were repeated every 28 days until disease progression or unacceptable toxicity occurred. Patients were scheduled to receive 5-FU, l-leucovorin and paclitaxel at four dose levels (mg/m(2)/week): 500/250/60 (level 1), 500/250/80 (level 2), 600/250/80 (level 3) and 600/250/100 (level 4), respectively. RESULTS: Eighteen patients were enrolled. During the first cycle of the highest dose level (level 4), two of the six patients had DLT involving Grade 3 diarrhea and Grade 3 skin rash. Furthermore, three of the four patients who received the second consecutive cycle of treatment at dose level 4 had Grade 4 neutropenia. Dose level 3 was thus determined to be the MTD. Eleven (61%) of the 18 patients had partial responses, and the median progression-free survival time was 6.8 months. CONCLUSIONS: The MTD and the recommended dose for phase II studies of this regimen were determined to be 5-FU 600 mg/m(2)/week, l-leucovorin 250 mg/m(2)/week and paclitaxel 80 mg/m(2)/week.

Sequential chemotherapy with methotrexate and 5-fluorouracil for chemotherapy-naive advanced gastric cancer with disseminated intravascular coagulation at initial diagnosis.

PURPOSE: Advanced gastric cancer (AGC) rarely presents with disseminated intravascular coagulation (DIC) at the time of diagnosis before treatment with no current standard chemotherapy (CTx) regimen. However the prognosis is extremely poor without CTx. We investigated the effectiveness of sequential CTx with methotrexate and 5-fluorouracil (MF) in chemotherapy-naive AGC patients with DIC. METHODS: We retrospectively examined AGC patients who received first-line CTx and selected those who were diagnosed with DIC before starting CTx to investigate clinical characteristics and responses. RESULTS: From July 1999 to January 2007, 1,365 patients with unresectable or recurrent AGC received first-line CTx at the National Cancer Center Hospital in Tokyo, Japan. DIC was diagnosed in 22 (1.6%) patients (16 men and 6 women; median age, 56 years) and the performance status of all the patients was 1/2/3 = 9/10/3. Nineteen patients (86%) had histologically diffuse-type adenocarcinoma and 18 (82%) had bone metastasis. Patients received sequential MF every week until progressive disease was confirmed, with DIC improving in 17 (77%) patients. The median time-to-treatment failure for AGC and overall survival were 98 days [95% confidence interval (CI), range 50-146 days] and 154 days (95% CI, range 126-180 days), respectively. Grade 3 or greater toxicities consisted of neutropenia (4 patients, 18%), anemia (9 patients, 40%), thrombocytopenia (4 patients, 18%), and bilirubinemia (1 patient, 5%). CONCLUSIONS: MF was an effective and well-tolerated regimen for improving DIC in chemotherapy-naive AGC patients with DIC; however, the prognosis of the patients remained poor even with improved DIC parameters.

Standard First-Line Chemotherapy for Metastatic Gastric Cancer in Japan Has Met the Global Standard: Evidence From Recent Phase III Trials.

In Japan, standard first-line chemotherapy for metastatic gastric cancer was initially 5-fluorouracil (5-FU) monotherapy. This is based on the Japan Clinical Oncology Group (JCOG) 9205 phase III trial. Based on recent Japanese phase III trials, S1 plus cisplatin combination chemotherapy was established as the standard first-line chemotherapy, and this combination has met the global standard regimen of 5-FU (capecitabine) plus a platinum analog (cisplatin or oxaliplatin). Since the same standard regimen has been established outside Japan, many global trials are currently ongoing in other countries aside from Japan. With the recent development of many molecular targeted agents, global collaboration in clinical trials is necessary for their immediate evaluation. We review the results of recent phase III trials of first-line chemotherapy for metastatic gastric cancer in Japan and other countries.