Correction to: The impact of caregiver's role preference on decisional conflicts and psychiatric distresses in decision making to help caregiver's disclosure of terminal disease status.

In the original publication of the article, the incorrect grant number HC13C1391 was published in the acknowledgement section. The correct grant number is HC15C1391.

Efficacy and tolerability of ramucirumab monotherapy or in combination with paclitaxel in gastric cancer patients from the Expanded Access Program Cohort by the Korean Cancer Study Group (KCSG).

BACKGROUND: Ramucirumab improves survival in gastric cancer patients. The efficacy and safety of ramucirumab outside of a clinical trial were evaluated using an expanded access program (EAP). METHODS: Advanced gastric cancer patients treated with ramucirumab in combination with paclitaxel or with ramucirumab monotherapy in a Korean EAP were evaluated. Baseline characteristics were assessed for progression-free survival (PFS) and overall survival (OS), and adverse events were evaluated according to the treatment regimen. RESULTS: Of 265 patients, 228 received ramucirumab plus paclitaxel, and 37 received ramucirumab monotherapy. Grade 3 or 4 neutropenia was more common with ramucirumab plus paclitaxel than with ramucirumab monotherapy (46.7 vs. 8.1%). Gastrointestinal (GI) perforation developed in seven patients (3.1%) in the ramucirumab plus paclitaxel group. The overall response and disease control rates were 16.6 and 66.3% in the ramucirumab plus paclitaxel group, and 5.4 and 37.8% in the ramucirumab monotherapy group, respectively. PFS and OS were 3.8 and 8.6 months in the ramucirumab plus paclitaxel group, and 1.8 and 6.4 months in the ramucirumab monotherapy group, respectively. In multivariate analysis, alkaline phosphatase, albumin, and neutrophil-to-lymphocyte ratio (NLR) were the independent prognostic factors for PFS, while albumin, NLR, number of metastatic sites, and large amount of ascites were independent prognostic factors for OS. CONCLUSION: In the Korean EAP cohort, ramucirumab showed similar efficacy to the results of the previous trials for gastric cancer. However, the level of GI perforation was slightly increased in the ramucirumab plus paclitaxel group.

The impact of caregiver's role preference on decisional conflicts and psychiatric distresses in decision making to help caregiver's disclosure of terminal disease status.

PURPOSE: The objective of this study was to investigate the impact of caregivers' role preference in decision making on conflicts and psychiatric distresses. METHODS: The responses of 406 caregivers of terminal cancer patients enrolled in a trial determining the efficacy of a decision aid focused on the disclosure of terminal disease status were included in this secondary analysis. The outcomes include the change scores of the Decision Conflict Scale (DCS) and depression and anxiety subscales of the Hospital Anxiety and Depression Scale (HADS) at the 1 and 3 months from baseline. The linear mixed model was employed to discover the impact of caregivers' decisional role preference on the outcomes. FINDINGS: Of the 406, 137 (33.7%) showed an active role preference and 269 (66.3%) showed a passive role preference. In the post hoc analysis of the adjusted differences of change scores between passive caregivers who received decision aid (passive-decision aid) and active caregivers with decision aid (active-decision aid), non-significant differences were observed in the DCS. However, at the 3-month, the change scores of the HADS depression subscale increased by 4.43 (effect size, 0.71) and those of the HADS anxiety subscale increased by 4.14 (effect size, 0.61) in the passive-decision aid group than in active-decision aid group, showing moderate to large difference. CONCLUSIONS: These findings suggest that information might be ethically recommended in a format that is interactive and tailored to how much an individual wishes to be involved in the decision-making process.

Modifiable factors associated with caregiver burden among family caregivers of terminally ill Korean cancer patients.

PURPOSE: Higher caregiver burden is associated with poor quality of life among family caregivers. However, in Korea, very few studies have examined factors associated with caregiver burden. The present study investigated factors associated with caregiver burden among family caregivers of terminally ill Korean cancer patients, particularly modifiable factors as a potential target of intervention strategies. METHODS: A cross-sectional study using self-administered questionnaires was performed. Sixty-four family caregivers of terminally ill cancer patients who were admitted to the hospice-palliative care unit of a university hospital in South Korea were included. To identify caregiver burden, the Caregiver Reaction Assessment scale (CRA) was used in this study. Time spent in providing care per day, number of visits per week from other family members, family functioning, and a positive subscale, self-esteem, of the CRA were deemed as modifiable factors. Other sociodemographic, caregiving characteristics of the subjects were non-modifiable factors. RESULTS: Longer time spent providing care per day, fewer weekly visits from other family members, poor family functioning, and low self-esteem were considered as modifiable factors associated with caregiver burden. Low monthly income and the spouse being the family caregiver were non-modifiable factors. CONCLUSIONS: Our study has practical significance in that it identifies modifiable factors that can be used to devise intervention strategies. Developing and applying such intervention strategies for alleviating the factors associated with high caregiver burden could be important for improving the quality of life of both patients and their families.

The life-sustaining treatments among cancer patients at end of life and the caregiver's experience and perspectives.

GOALS OF WORK: The goal of this study was to investigate the utilization of and attitudes toward life-sustaining treatments (LSTs) at the end of life. MATERIALS AND METHODS: We identified 4,042 families of cancer patients who had died at any of 17 hospitals in Korea during 2004. Among those, we analyzed the interviews provided by 1,592 (39.4%) primary caregivers. Only women who provided information in baseline and follow-up point could be included for internal comparison. MAIN RESULTS: Most caregivers did not discuss with their patient the option of utilizing the intensive care unit (ICU; 92.7%) or cardiopulmonary resuscitation (CPR; 93.7%) to prolong an ending life. Logistic regressions indicated that the ICU was more likely to be utilized when patients experienced an unexpected medical problem before dying, discussed the ICU with the family caregiver, or were low-educated. CPR was more likely to be used if the patient died within 6 months of diagnosis or the family caregiver was <65 years old. Family caregivers more likely to use the ICU if placed in the same situation again were those whose patients had a higher monthly income or died within 6 months of diagnosis, low-educated, or had utilized the ICU. CONCLUSIONS: Our findings underscore the importance of discussing LST with terminally ill patients based on adequate information.

Impact of caregivers' unmet needs for supportive care on quality of terminal cancer care delivered and caregiver's workforce performance.

GOALS OF WORK: Family caregivers play an important role in caring for cancer patients, but the impact of caregivers' unmet needs on the quality of end-of-life (EOL) care they deliver and on their workplace performance are less understood. PATIENTS AND METHODS: We identified 1,662 family caregivers of cancer patients who had died at any of 17 hospitals in Korea during 2004. The caregivers answered a telephone questionnaire about needs that were not met when they delivered terminal cancer care and how those unmet their needs affected their workplace performance; they also answered the Quality Care Questionnaire-End of Life (QCQ-EOL). RESULTS: Compared with caregivers who did not have unmet needs, caregivers who had unmet needs for symptom management, financial support, or community support showed poorer QCQ-EOL scores (P < 0.01). Caregivers who had unmet needs for financial support (adjusted odds ratio (aOR) = 7.55; 95% confidential interval (CI) 3.80-15.00), psychosocial support (aOR = 6.24; 95% CI 2.95-13.05), symptom management (aOR = 3.21; 95% CI 2.26-4.54), community support (aOR = 3.82; 95% CI 2.38-6.11), or religious support (aOR = 4.55; 95% CI 1.84-11.26) were more likely to experience work limitations. Caregivers of patients receiving conventional hospital care were more likely to have unmet needs for symptom management (aOR = 1.21; 95% CI 1.00-1.47), psychosocial support (aOR = 1.99; 95% CI 1.37-2.88), and religious support (aOR = 1.73; 95% CI 1.08-2.78) than those of patients receiving palliative hospice care. CONCLUSIONS: Caregivers' unmet needs negatively affected both the quality of EOL care they delivered and their workplace performance. More investment in caregiver support and public policies that meet caregiver needs are needed, and hospice use should be encouraged.

Chemokine receptor CXCR4 expression, function, and clinical implications in gastric cancer.

The chemokine receptor CXCR4 is associated with the biological behavior of cancer, but few studies have addressed the expression and function of CXCR4 in human gastric cancer and its impact on disease prognosis. We studied the expression of CXCR4 using RT-PCR, Western blotting, flow cytometry, and confocal microscopy in five gastric cancer cell lines. We also examined cell proliferation, migration, and anti-apoptotic activity in response to stromal cell-derived factor (SDF)-1alpha and evaluated SDF-1alpha/CXCR4 signaling pathways. Furthermore, we investigated the correlation between CXCR4 expression and the clinical features of 221 gastric cancer tissue samples. CXCR4 transcripts and proteins were detectable in all five gastric cancer cell lines. However, MKN-28, MKN-45, MKN-74, and SNU16 cells did not express membrane CXCR4. In contrast, KATO III cells expressed membrane CXCR4. In these cells, SDF-1alpha-induced migration was observed and was blocked by AMD3100, a specific inhibitor of CXCR4. SDF-1alpha induced rapid phosphorylation of Erk1/2 MAPK but did not promote phosphorylation of Stat3 or Akt. Gastric cancer tissue samples expressed CXCR4 with variable intensities. Strong CXCR4 expression was significantly associated with lymph node metastases (P=0.028) and higher stages III/IV (P=0.047), and further tended to be correlated with a reduced 5-year survival rate (42.6% vs. 53.9%; P=0.1). In conclusion, CXCR4 expression is associated with gastric cancer cell migration in vitro, and strong expression of CXCR4 by gastric cancer cells is significantly associated with lymphatic metastasis in patients with gastric cancer, suggesting that CXCR4 plays an important role during gastric cancer progression.

Biochemical and pathological response of prostate cancer in a patient with metastatic renal cell carcinoma on sunitinib treatment.

Sunitinib is a small molecular inhibitor of tyrosine kinases and is used to treat advanced renal cell carcinoma and gastrointestinal stromal tumour after disease progression or intolerance to imatinib therapy. Here, we describe biochemical and pathological response of prostate cancer in a patient with metastatic renal cell carcinoma during sunitinib treatment. A 62-year-old man was referred to our hospital because of a mass in the scalp. He was diagnosed with left renal cell carcinoma with right renal and scalp metastases. In addition, synchronous prostate cancer involving less than one-half of the right lobe was found with a prostate-specific antigen (PSA) value of 23.4 ng/ml. Treatment was begun with sunitinib (50 mg daily, 4 weeks on and 2 weeks off). Regarding the prostate cancer, active monitoring was planned considering the far advanced renal cell carcinoma. Surprisingly, the PSA level was 3.4 ng/ml at week 6 and 0.2 ng/ml at week 12, and it subsequently remained normal. At the time of writing (cycle 6 of sunitinib therapy), the prostate nodule significantly decreased in size. Furthermore, a 12-core re-biopsy revealed pathological evidence of regression with sunitinib treatment, with control of his renal cell carcinoma.

Methylprednisolone versus intravenous immune globulin as an initial therapy in adult primary immune thrombocytopenia.

BACKGROUND/AIMS: Few studies have addressed whether there are differences in clinical efficacy between intravenous methylprednisolone (methyl-Pd) and intravenous immunoglobulin (IVIg) use. METHODS: We retrospectively compared platelet responses and toxicities associated with these two treatments in adult patients with immune thrombocytopenia. Patients received intravenous methyl-Pd therapy followed by oral prednisolone (Pd) from 1993 to 2002 and IVIg together with oral Pd from 2003 to 2008. RESULTS: Early response and maintenance of the response were assessed at 7 days and 6 months after treatment, respectively. Of the 87 patients enrolled, 77 (88.5%) were eligible for analysis. Early responses occurred in 30 of 39 patients (76.9%) receiving methyl-Pd versus 33 of 38 patients (86.6%) receiving IVIg (p = 0.187). The response was maintained in 28 patients (71.8%) in the methyl-Pd arm and in 23 patients (60.5%) in the IVIg arm (p = 0.187). The time to a complete response in the IVIg arm (6 days; range, 1 to 35) was shorter than that in the methyl-Pd arm (13.5 days; range, 2 to 29) (p = 0.002). Side effects were mild and tolerable in both arms. Five years after initiating treatment, 7 of 18 patients (38.9%) and five of 14 patients (35.7%) were still maintaining a response in the methyl-Pd and IVIg arms, respectively. CONCLUSION: These results indicate that neither the early response rate nor the long-term outcome differed between the methyl-Pd and IVIg treatments. However, IVIg induced a complete response more rapidly than did methyl-Pd.

The impact of primary tumor location in patients with metastatic colorectal cancer: a Korean Cancer Study Group CO12-04 study.

BACKGROUND/AIMS: Colorectal cancer is associated with different anatomical, biological, and clinical characteristics. We determined the impact of the primary tumor location in patients with metastatic colorectal cancer (mCRC). METHODS: Demographic data and clinical information were collected from 1,115 patients from the Republic of Korea, who presented with mCRC between January 2009 and December 2011, using web-based electronic case report forms. Associations between the primary tumor location and the patient's clinical characteristics were assessed, and factors inf luencing overall survival were analyzed using Cox proportional hazards regression models. RESULTS: Of the 1,115 patients recruited to the study, 244 (21.9%) had right colon cancer, 483 (43.3%) had left colon cancer, and 388 (34.8%) had rectal cancer. Liver and lung metastases occurred more frequently in patients with left colon and rectal cancer (p = 0.005 and p = 0.006, respectively), while peritoneal and ovarian metastases occurred more frequently in patients with right and left colon cancer (p < 0.001 and p = 0.031, respectively). The median overall survival of patients with tumors originating in the right colon was significantly shorter than that of patients whose tumors had originated in the left colon or rectum (13.7 months [95% confidence interval (CI), 12.0 to 15.5] vs. 18.0 months [95% CI, 16.3 to 19.7] or 19.9 months [95% CI, 18.5 to 21.3], respectively; p = 0.003). Tumor resection, the number of metastatic sites, and primary tumor location correlated with overall survival in the univariate and multivariate analyses. CONCLUSION: Primary tumor location influences the metastatic sites and prognosis of patients with mCRC.

Chemotherapy use and associated factors among cancer patients near the end of life.

OBJECTIVES: We investigated the frequency of chemotherapy use and its associated factors in patients in all age groups in the last year of life. METHODS: We identified cancer patients who died in 2004 in any of 17 hospitals. We used demographic and treatment characteristics by computerized hospital information systems and by linking the identification numbers to the 2004 death registry. RESULTS: 48.7% of patients in the last 6 months of life, 43.9% in the last 3 months, and 30.9% in the last month of life received chemotherapy. The frequency of chemotherapy use was lower for older patients. In those > or =65 years old, there was no difference between women and men in the proportion that received chemotherapy. For patients <65 years of age, a larger proportion of women than men received chemotherapy, and chemotherapy use was significantly less frequent for patients with refractory disease than for those with responsive disease. Patients dying at a relatively small hospital without a hospice inpatient unit were significantly more likely to receive chemotherapy. CONCLUSIONS: Despite the fact that most cancer patients are resistant to chemotherapy at the end of life, it was administered often to all age groups.

VIP (etoposide, ifosfamide, and cisplatin) in patients with previously treated soft tissue sarcoma.

We retrospectively reviewed outcomes of treatment with VIP (combination of etoposide, ifosfamide, and cisplatin) in patients with previously treated soft tissue sarcoma (STS).We analyzed the medical records of patients with advanced or relapsed STS who had undergone VIP treatment as second-line or more chemotherapy between January 2000 and December 2015. The patients were treated with a combination of etoposide (100 mg/m for 5 days), ifosfamide (2000 mg/m for 2 days), and cisplatin (20 mg/m for 5 days) once every 4 weeks. Treatment response, progression-free survival (PFS), and overall survival (OS) were analyzed in all patients and between responder and nonresponder groups (responders showed a tumor response to any prior systemic chemotherapy before VIP).Twenty-four patients with a median age of 50 years (range: 20-68 years) were treated with VIP. Eleven (45.8%) patients were male and 7 (29.2%) received 2 or more chemotherapy regimens before VIP. Median PFS was 3.7 months (95% confidence interval [CI], 1.3-6.1 months) and median OS was 10.0 months (95% CI, 6.6-13.5). The overall response rate was 37.5%, and the disease control rate was 50%. The responder group showed better PFS (7.7 months vs 3.0 months; P = 0.101) and significantly improved OS (11.0 months vs 8.8 months; P = 0.039) compared to those of nonresponders. All patients reported some grade of hematological toxicity. The most frequently encountered hematological toxicity was neutropenia (any grade, 77.7%; grade 3 or 4, 74.0%).VIP might be effective in patients with previously treated STS.

Overexpression of stromal cell-derived factor-1 enhances endothelium-supported transmigration, maintenance, and proliferation of hematopoietic progenitor cells.

To clarify the direct effects of aberrant overexpression of stromal cell-derived factor-1 (SDF-1) by the human endothelium on circulating progenitor cells, we overexpressed the SDF-1 gene in human umbilical vein endothelial cells using an adenoviral vector (HUVEC/AdeSDF-1) and examined the endothelium-supported trafficking and growth of hematopoietic progenitor cells (HPCs) in mobilized peripheral blood (mPB). In culture, the HUVEC/AdeSDF-1 monolayers induced the migration of mPB CD34(+) cells underneath the endothelium within a few hours, whereas HUVEC monolayers that expressed the LacZ gene (HUVEC/AdeLacZ) did not have this effect. In the Transwell system, the HUVEC/AdeSDF-1 cells supported a higher level of spontaneous transmigration of mPB CD34(+) cells than did the HUVEC/AdeLacZ cells. The co-culturing of mPB CD34(+) cells with HUVEC/ AdeSDF-1 cells led to a greater expansion of CD45(+) cells and colony-forming cells and reduced cellular apoptosis. Furthermore, the co-culturing of mPB CD34(+) cells with HUVEC/AdeSDF-1 cells led to the formation of numerous cobblestone-like areas, whereas co-cultures of mPB CD34(+) cells and HUVEC/AdeLacZ supported only a few cobblestone-like areas. These results indicate that SDF- 1 produced by endothelial cells plays an important role not only in the transmigration but also in the growth of HPCs that are in contact with endothelial cells. Our findings suggest that the enhanced expression and production of SDF-1 in the endothelium are essential steps for stem cell or progenitor cell recruitment to specific tissues and for the maintenance of these cells in situ.

Interferon gamma has dual potential in inhibiting or promoting survival and growth of hematopoietic progenitors: interactions with stromal cell-derived factor 1.

We explored the possibility that interferon gamma (IFN-gamma) has bidirectional functions in the survival and growth of hematopoietic progenitors, especially with regard to interactions with stromal cell-derived factor 1 (SDF-1). IFN-gamma partially rescued normal bone marrow CD34+ cells and colony-forming cells from apoptosis induced by serum and hematopoietic growth factor (HGF) deprivation, and SDF-1 further enhanced cell survival. Short-term IFN-gamma treatment of CD34+ cells in the absence of serum and HGFs enhanced the clonal growth of the cells in synergy with SDF-1. In contrast, IFN-gamma inhibited the clonal growth of hematopoietic progenitor cells in a standard methylcellulose clonogenic assay and inhibited the HGF-mediated survival of normal CD34+ cells. The addition of SDF-1 did not alter these outcomes. IFN-gamma did not enhance SDF-1-induced activation of PI3K/Akt or up-regulate the expression of CXCR4 or its function in bone marrow CD34+ cells. IFN-gamma up-regulated Socs1 messenger RNA expression in normal CD34+ cells, which was further enhanced with the addition of HGFs. These results indicate that IFN-gamma, partly in concert with SDF-1, exerts dual effects on the survival and growth of hematopoietic progenitor cells; the effects of IFN-gamma on hematopoietic progenitor cells can differ, depending on the particular in vitro experimental conditions, especially the presence of HGFs.

Comparison of the therapeutic effects of total laryngectomy and a larynx-preservation approach in patients with T4a laryngeal cancer and thyroid cartilage invasion: A multicenter retrospective review.

BACKGROUND: In T4a laryngeal cancer with thyroid cartilage invasion, no optimal frontline treatment has yet been defined in controlled trials. METHODS: We reviewed data from 89 patients with T4a laryngeal cancer featuring thyroid cartilage invasion who were treated initially with either total laryngectomy (n = 53) or a larynx-preservation strategy (n = 36). RESULTS: The median progression-free survival (PFS) of the total laryngectomy group had not been attained at the time of analysis and was thus significantly longer than that of the larynx-preservation group (8.7 months). The median overall survival (OS) of patients who underwent total laryngectomy was 87.2 months, significantly longer than that of the larynx-preservation group (31.3 months). The survival benefit of primary surgery compared to a larynx-preservation strategy was more striking in patients of lower N classifications. CONCLUSION: Total laryngectomy may be a better therapeutic option to treat T4a laryngeal cancer featuring thyroid cartilage invasion, especially in patients exhibiting limited nodal involvement (N0/N1). © 2016 Wiley Periodicals, Inc. Head Neck, 2016 © 2016 Wiley Periodicals, Inc. Head Neck 38:1271-1277, 2016.

Adenovirus-mediated interleukin-12 gene transfer combined with cytosine deaminase followed by 5-fluorocytosine treatment exerts potent antitumor activity in Renca tumor-bearing mice.

BACKGROUND: Therapeutic gene transfer affords a clinically feasible and safe approach to cancer treatment but a more effective modality is needed to improve clinical outcomes. Combined transfer of therapeutic genes with different modes of actions may be a means to this end. Interleukin-12 (IL-12), a heterodimeric immunoregulatory cytokine composed of covalently linked p35 and p40 subunits, has antitumor activity in animal models. The enzyme/prodrug strategy using cytosine deaminase (CD) and 5-fluorocytosine (5-FC) has been used for cancer gene therapy. We have evaluated the antitumor effect of combining IL-12 with CD gene transfer in mice bearing renal cell carcinoma (Renca) tumors. METHODS: Adenoviral vectors were constructed encoding one or both subunits of murine IL-12 (Ad.p35, Ad.p40 and Ad.IL-12) or cytosine deaminase (Ad.CD). The functionality of the IL-12 or CD gene products expressed from these vectors was validated by splenic interferon (IFN)-gamma production or viability assays in cultured cells. Ad.p35 plus Ad.p40, or Ad.IL-12, with or without Ad.CD, were administered (single-dose) intratumorally to Renca tumor-bearing mice. The animals injected with Ad.CD also received 5-FC intraperitoneally. The antitumor effects were then evaluated by measuring tumor regression, mean animal survival time, splenic natural killer (NK) cell activity and IFN-gamma production. RESULTS: The inhibition of tumor growth in mice treated with Ad.p35 plus Ad.p40 and Ad.CD, followed by injection of 5-FC, was significantly greater than that in mice treated with Ad.CD/5-FC, a mixture of Ad.p35 plus Ad.p40, or Ad.GFP (control). The combined gene transfer increased splenic NK cell activity and IFN-gamma production by splenocytes. Ad.CD/5-FC treatment significantly increased the antitumor effect of Ad.IL-12 in terms of tumor growth inhibition and mean animal survival time. CONCLUSION: The results suggest that adenovirus-mediated IL-12 gene transfer combined with Ad.CD followed by 5-FC treatment may be useful for treating cancers.

Long-term treatment of residual or recurrent low-grade endometrial stromal sarcoma with aromatase inhibitors: A report of two cases and a review of the literature.

Endometrial stromal sarcoma (ESS) occurs rarely and accounts for only 0.2% of all uterine malignancies. ESS usually expresses estrogen and progesterone receptors, and is regarded as hormone-sensitive. Due to the rarity of these tumors, there are only few case series on the use of aromatase inhibitors in the treatment of low-grade ESS. The present study reports the cases of two patients with residual or recurrent low-grade ESS who experienced long-term disease-free survival following treatment with letrozole. The study also reviews the literature with regard to the data on aromatase inhibitors used in patients with low-grade ESS. In total, 30 patients with recurrent or residual low-grade ESS who were treated with aromatase inhibitors were identified, including the present cases. Among the 30 patients, the overall response rate of advanced low-grade ESS to aromatase inhibitors was 77.4% (complete response, 25.8%; partial response, 51.6%) and the disease control rate was 90.3%. The response rate of first-line treatment was similar to that of second-line therapy or higher (84.6 vs. 72.2%; P=0.453). Duration of aromatase inhibitor treatment ranged from 1.5 to 168 months (median, 26.5 months). The aromatase inhibitors showed minimal adverse effects. In conclusion, aromatase inhibitors, particularly third-generation drugs, are a well-tolerated class of medications that are effective in the treatment of advanced low-grade ESS, with a favorable toxicity profile.