Hyun-Jeong Shim

Prognostic significance of a systemic inflammatory response in patients receiving first-line palliative chemotherapy for recurred or metastatic gastric cancer.

BackgroundThere is increasing evidence that the presence of an ongoing systemic inflammatory response is associated with poor prognosis in patients with advanced cancers. We evaluated the relationships between clinical status, laboratory factors and progression free survival (PFS), and overall survival (OS) in patients with recurrent or metastatic gastric cancer receiving first-line palliative chemotherapy.MethodsWe reviewed 402 patients with advanced gastric adenocarcinoma who received first-line palliative chemotherapy from June 2004 and December 2009. Various chemotherapy regimens were used. Eastern Cooperative Oncology Group performance status (ECOG PS), C-reactive protein (CRP), albumin, Glasgow prognostic score (GPS), and clinical factors were recorded immediately prior to first-line chemotherapy. Patients with both an elevated CRP (>1.0 mg/dL) and hypoalbuminemia (<3.5 mg/dL) were assigned a GPS of 2. Patients in whom only one of these biochemical abnormalities was present were assigned a GPS of 1, and patients with a normal CRP and albumin were assigned a score of 0. To evaluate the factors that affected PFS and OS, univariate and multivariate analyses were performed.ResultsAccording to multivariate analysis, the factors independently associated with PFS were ECOG PS (HR 1.37, 95% CI 1.02-1.84, P = 0.035), bone metastasis (HR 1.74, 95% CI 1.14-2.65, P = 0.009), and CRP elevation (HR 1.64, 95% CI 1.28-2.09, P = 0.001). The factors independently associated with OS were ECOG PS (HR 1.33, 95% CI 1.01-1.76, P = 0.037), bone metastasis (HR 1.61, 95% CI 1.08-2.39, P = 0.017), and GPS ≥ 1 (HR 1.76, 95% CI 1.41-2.19, P = 0.001).ConclusionsThe results of this study showed that the presence of a systemic inflammatory response as evidenced by the CRP, GPS was significantly associated with shorter PFS and OS in patients with recurrent or metastatic gastric cancer receiving first-line palliative chemotherapy. Bone metastasis and GPS were very useful indicator for survival in patients with recurrent or metastatic gastric cancer receiving palliative chemotherapy.

The prognostic significance of tumor human papillomavirus status for patients with anal squamous cell carcinoma treated with combined chemoradiotherapy.

The prognostic relevance of tumor human papillomavirus (HPV) status in anal squamous cell carcinoma (SCC) had not been previously investigated, although its relevance to cervical, head and neck SCC is known. We retrospectively evaluated outcomes in 47 patients with anal SCC treated with combined chemoradiotherapy (CCRT) and determined tumor HPV status by HPV DNA chip method and p16 expression by immunohistochemistry (IHC) from paraffin‐embedded tumor tissues. The median age was 65 years (range, 44–90 years). Sixteen (34%) patients were diagnosed with T stage 3 to 4, and 18 (38%) patients had regional nodal disease (N‐positive). Thirty‐five (75%) patients were HPV positive, and 31 (66%) patients were genotype 16 (HPV16‐positive). Thirty‐nine (83.0%) patients were positive for p16. After median follow‐up of 51.7 months (range, 5.1–136.0 months), HPV16‐positive group had significantly better 4‐year progression‐free survival (PFS, 63.1% vs. 15.6%, p < 0.001) and overall survival (84.6% vs. 39.8%, p = 0.008) than HPV genotype 16 negative (HPV16‐negative) group. Patients with p16‐positive tumor also had a better 4‐year PFS (52.5% vs. 25.0%, p = 0.014) than those with p16‐negative tumor. In multivariate analysis for PFS, N‐positive and HPV16‐negative were independent prognostic factors for shorter PFS. Comparing patterns of failure, time to loco‐regional failure was statistically superior in HPV16‐positive over HPV16‐negative groups (p = 0.006), but time to systemic failure was not different (p = 0.098). Tumor HPV genotype 16 status is a prognostic and predictive factor in anal SCC treated with CCRT, and p16 expression determined by IHC might be advocated as a surrogate biomarker of HPV integration in anal SCC. Further studies are warranted.

Concurrent chemoradiotherapy with S-1 and cisplatin in advanced esophageal cancer

How best to manage advanced esophageal cancer remains unresolved, especially in palliative care. Here, in a pilot study, we evaluated the efficacy and safety of concurrent chemoradiotherapy with S-1 and cisplatin in advanced esophageal cancer. Patients with locally advanced or metastatic squamous cell carcinoma of the esophagus received S-1 and cisplatin at doses of 70 mg/m(2)/day for 14 days and 70 mg/m(2) on day 1, respectively, every 3 weeks. Concurrently, radiotherapy was started at a dose of 200 cGy/day, up to a total of 5400 cGy. After concurrent chemoradiotherapy, additive chemotherapy was repeated up to six cycles. Thirty patients were enrolled in this study; of the 27 in whom efficacy could be evaluated, an objective response rate was seen in 20 (74.1%), including five (18.5%) complete pathologic responses in primary lesions. Improvement of dysphagia was seen in 21 (76%) patients. In patients with stage II or III esophageal cancer, the median progression-free survival and overall survival were 10.6 +/- 0.6 months (95% CI: 9.4-11.8) and 23.0 +/- 5.1 months (95% CI: 13.0-32.9), respectively. In patients with stage IV esophageal cancer, the median progression-free survival and overall survival were 5.4 +/- 1.6 months (95% CI: 2.2-8.6) and 11.6 +/- 1.6 months (95% CI: 8.4-14.8), respectively. The main hematological toxicity was neutropenia, but no neutropenic fever was observed. The major non-hematological toxicities were asthenia and vomiting, mostly of grades 1 and 2. Thus, concurrent chemoradiotherapy with S-1 and cisplatin may be a promising nonsurgical treatment in advanced esophageal cancer.

Phase II study of docetaxel and cisplatin chemotherapy in 5-fluorouracil/cisplatin pretreated esophageal cancer.

Background:This study was performed to determine the feasibility and safety of salvage chemotherapy, using docetaxel and cisplatin in 5-fluorouracil (5-FU) and cisplatin-pretreated esophageal cancer. Methods:Patients with metastatic or recurrent esophageal squamous cell carcinoma that had previously been treated with 5-FU and cisplatin chemotherapy or chemoradiotherapy were eligible for this study. Docetaxel (70 mg/m2) and cisplatin (75 mg/m2) were given as a 1-hour intravenous infusion on day 1, and the treatment was repeated every 3 weeks. Results:Thirty-eight male patients were enrolled, and 35 patients were available for evaluation. The median age was 64.5 years; Eastern Cooperative Oncology Group performance status was 0/1/2 = 2/18/18. The median and total numbers of cycles delivered were 3.5 (range, 1–9 cycles) and 162, respectively. One patient (2.6%) achieved complete response, 12 (31.6%) achieved partial response, 12 (31.6%) had stable disease, and 10 (26.3%) had progressive disease. The overall response rate was 34.2% (95% confidence interval, 19.6–51.3). The median progression-free survival and overall survival times were 4.5 ± 1.3 months (95% CI, 4.1–4.9) and 7.4 ± 0.4 months (95% CI, 7.3–7.5), respectively. The main hematological toxicities greater than grade 3 were neutropenia and leucopenia in 20 (52.6%) and 18 patients (47.3%), respectively. Nonhematological toxicities greater than grade 3 included asthenia in 12 patients (31.6%), nausea in 7 patients (18.4%), and peripheral neuropathy in 6 patients (15.8%). Conclusions:Chemotherapy with docetaxel and cisplatin was an effective and feasible treatment following treatment with 5-FU and cisplatin, and would be considered as a salvage option for patients with refractory esophageal cancer.

Does awareness of terminal status influence survival and quality of life in terminally ill cancer patients

Clinical studies, with a proper scientific design, on the impact of disclosing a prognosis on a patients psychological or physical conditions are rare. We investigated the effect of patient awareness of terminal status on survival and quality of life (QoL) in a palliative care setting.

Differential Associations Between Delirium and Mortality According to Delirium Subtype and Age: A Prospective Cohort Study.

Objective This study investigated the differential associations between delirium and mortality in terminally ill patients according to delirium subtype and age. Methods This was a prospective cohort study of terminally ill patients. Delirium was diagnosed using the confusion assessment method. Delirium subtypes were defined based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria and the Delirium Rating Scale-98-R. A multivariate Cox proportional hazards regression analysis was used to examine predictors of mortality. Results Of the 322 cases, 98 patients (30.4%) were diagnosed as having delirium. The median (interquartile range) number of survival days after admission was 17.0 (10.0–36.0) days for patients with delirium and 28.0 (16.0–57.0) days for patients without delirium (p = .002). A multivariate analysis revealed that patients with hypoactive and mixed subtypes of delirium survived for shorter periods compared with patients without delirium (hazard ratio [HR] = 1.65 [95% confidence interval {CI} = 1.05–2.59, p = .029] and HR = 2.30 [95% CI = 1.44–3.69, p = .001], respectively). The hypoactive and mixed delirium subtypes exhibited significant interactions with age: younger age was associated with shorter periods of survival in patients with hypoactive and mixed subtype delirium (HR = 0.95 [95% CI = 0.93–0.98, p < .001] and HR = 0.97 [95% CI = 0.93–1.00, p = .038], respectively). Conclusions The hypoactive and mixed subtypes of delirium were associated with shorter survival periods in terminally ill patients, and these associations interacted significantly with age. These findings support the clinical and academic value of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition specifiers that differentiate the diagnoses of delirium subtypes.

The Prognostic Significance of FGFR4 Gly388 Polymorphism in Esophageal Squamous Cell Carcinoma after Concurrent Chemoradiotherapy

Purpose The purpose of this study is to investigate the role of fibroblast growth factor receptor 4 (FGFR4) polymorphism in esophageal cancer after chemoradiotherapy (CRT). Materials and Methods Peripheral blood samples from 244 patients treated with CRT for esophageal squamous cell carcinoma were assessed for the role of FGFR4 genotype on treatment response and survival. Results A total of 94 patients were homozygous for the Gly388 allele, and 110 were heterozygous and 40 homozygous for the Arg388 allele. No significant association was found between the FGFR4 genotype and clinicopathological parameters. However, patients carrying the Gly388 allele showed a better overall response rate than Arg388 carriers (p=0.038). In addition, Gly388 allele patients at an earlier stage showed better overall survival (OS) and progression-free survival than Arg388 carriers. Among these, the Gly388 allele showed significantly improved OS compared to Arg388 carriers in the lymph node (LN) metastasis group (p=0.042) compared to the no LN metastasis group (p=0.125). However, similar survival outcomes were observed for advanced-stage disease regardless of genotype. Conclusion This result suggests that the role of FGFR4 Gly388 in treatment outcomes differs according to esophageal cancer stage. It showed a predictive role in the response of esophageal cancer patients to CRT with a better trend for OS in Gly388 than Arg388 carriers in the early stages. In particular, LN-positive early-stage patients carrying the Gly388 allele showed improved OS compared to those carrying Arg388.

Replication of results of genome‐wide association studies on esophageal squamous cell carcinoma susceptibility loci in a Korean population

Two recent genome-wide association studies have identified that the rs2274223 single-nucleotide polymorphism inphospholipase C epsilon 1 and the single-nucleotide polymorphism rs13042395 in C20orf54 are involved in esophageal squamous cell carcinoma (ESCC) in Chinese populations. We hypothesized that genetic polymorphisms of phospholipase C epsilon 1 and C20orf54 are also associated with ESCC in a Korean population. The rs2274223 and rs13042395 genotyping was performed using high-resolution melting analysis. The rs2274223 GG genotype was significantly associated with an increased risk of ESCC (odds ratio [OR]=1.86, 95% confidence interval [CI]=1.08-3.25) compared with the rs2274223 AA genotype. The rs13042395 G allele showed a significantly decreased risk of ESCC in the younger age group (OR=0.71, 95% CI=0.52-0.97) and no significant association in the older group (OR=1.19, 95% CI=0.87-1.62). We observed that the rs2274223 polymorphism was associated with an increased risk of ESCC in this Korean case-control study and that age may modify the association between the rs13042395 polymorphism and the risk of ESCC.

Dendritic cell-based immunotherapy for colon cancer using an HLA-A*0201-restricted cytotoxic T-lymphocyte epitope from tumor-associated antigen 90K

Tumor-associated antigen 90K is implicated in cell–cell and cell-extracellular matrix adhesion through its interaction with galectin-3 and integrin-β1 and is highly expressed in malignant tissues, making it a novel target for the development of new immunotherapies. We investigated a potential immunotherapy treatment for colon cancer using 90K-specific cytotoxic T lymphocytes induced by autologous dendritic cells and pulsed with 90K peptides. We selected three peptides (90K351, 90K5 and 90K523) that bind to HLA-A*0201 molecules on the basis of their binding affinity, as determined by a peptide-T2 binding assay. Dendritic cells pulsed with 90K peptides resulted in the efficient generation of mature dendritic cells and exhibited enhanced T-cell stimulation and polarization of naive T cells toward Th1. Dendritic cells pulsed with 90K peptides generated potent cytotoxic T-lymphocytes that lysed T2 cells loaded with each 90K peptide, and 90K+/HLA-A2+ colon cancer cell lines, including HCT116 and SW480, in a dose-dependent and HLA-A*0201-restricted manner. No killing was observed in 90K+/HLA-A2− DLD1 or 90K−/HLA-A2− K562 cells. Therefore, we believe that cytotoxic T-lymphocytes stimulated by 90K peptide-pulsed dendritic cells naturally recognize the 90K peptide presented by colon cancer cells in the context of HLA-A2, and kill 90K-positive tumor cells. Dendritic cells pulsed with 90K peptides led to the induction of granzyme B and perforin positive CD8+ T cells against HCT116 and SW480 cells, but not DLD1 cells. In conclusion, 90K-specific cytotoxic T lymphocytes, generated by stimulating T cells with 90K peptide-pulsed dendritic cells, could be useful effector cells for the immunotherapy treatment of colon cancer.

A Prospective Multicenter Study Evaluating Secondary Adrenal Suppression After Antiemetic Dexamethasone Therapy in Cancer Patients Receiving Chemotherapy: A Korean South West Oncology Group Study

BACKGROUND In a previous pilot study, adrenal suppression was found to be common after antiemetic dexamethasone therapy in cancer patients. The objective of this large prospective multicenter study was to confirm the incidence and factors associated with secondary adrenal suppression related to antiemetic dexamethasone therapy in cancer patients receiving chemotherapy. METHODS Chemotherapy-naïve patients who were scheduled to receive at least three cycles of highly or moderately emetogenic chemotherapy with dexamethasone as an antiemetic were enrolled. Patients with a suppressed adrenal response before chemotherapy or those administered corticosteroids within 6 months of enrollment in the study were excluded. RESULTS Between October 2010 and August 2014, 481 patients receiving chemotherapy underwent the rapid adrenocorticotropic hormone (ACTH) stimulation test to assess eligibility; 350 of these patients were included in the final analysis. Fifty-six patients (16.0%) showed a suppressed adrenal response in the rapid ACTH stimulation test at 3 or 6 months after the start of the first chemotherapy. The incidence of adrenal suppression was affected by age, performance status, stage, and use of megestrol acetate in univariate analysis. Multivariate analysis revealed that secondary adrenal suppression associated with antiemetic dexamethasone therapy was significantly associated with megestrol acetate treatment (odds ratio: 3.06; 95% confidence interval: 1.60 to 5.86; p < .001). CONCLUSION This large prospective study indicates that approximately 15% of cancer patients receiving chemotherapy with a normal adrenal response show suppressed adrenal responses after antiemetic dexamethasone therapy. This result was particularly significant for patients cotreated with megestrol acetate.