Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours.

BACKGROUND: In this first-in-human, Phase 1 study of a microRNA-based cancer therapy, the recommended Phase 2 dose (RP2D) of MRX34, a liposomal mimic of microRNA-34a (miR-34a), was determined and evaluated in patients with advanced solid tumours. METHODS: Adults with various solid tumours refractory to standard treatments were enrolled in 3 + 3 dose-escalation cohorts and, following RP2D determination, expansion cohorts. MRX34, with oral dexamethasone premedication, was given intravenously daily for 5 days in 3-week cycles. RESULTS: Common all-cause adverse events observed in 85 patients enrolled included fever (% all grade/G3: 72/4), chills (53/14), fatigue (51/9), back/neck pain (36/5), nausea (36/1) and dyspnoea (25/4). The RP2D was 70 mg/m2 for hepatocellular carcinoma (HCC) and 93 mg/m2 for non-HCC cancers. Pharmacodynamic results showed delivery of miR-34a to tumours, and dose-dependent modulation of target gene expression in white blood cells. Three patients had PRs and 16 had SD lasting ≥4 cycles (median, 19 weeks, range, 11-55). CONCLUSION: MRX34 treatment with dexamethasone premedication demonstrated a manageable toxicity profile in most patients and some clinical activity. Although the trial was closed early due to serious immune-mediated AEs that resulted in four patient deaths, dose-dependent modulation of relevant target genes provides proof-of-concept for miRNA-based cancer therapy. CLINICAL TRIAL REGISTRATION: NCT01829971.

Detection of liver metastases using gadoxetic-enhanced dynamic and 10- and 20-minute delayed phase MR imaging.

PURPOSE: To assess the incremental value of hepatobiliary phase images in gadoxetate disodium-enhanced magnetic resonance imaging (MRI), and to compare diagnostic accuracy and lesion conspicuity on 10- and 20-minute delayed images for preoperative detection of hepatic metastases with subgroup analysis according to size and history of chemotherapy. MATERIALS AND METHODS: Forty-six patients with 107 metastases who underwent surgery after gadoxetate disodium-enhanced MRI were evaluated. Four observers independently interpreted three sets: dynamic set comprising precontrast T1-, T2-weighted, and dynamic images; 10-minute set comprising dynamic set and 10-minute delayed; 20-minute set comprising 10-minute set and 20-minute delayed. Diagnostic accuracy was compared with subgroup analysis. Liver-to-lesion signal ratio (SR) was calculated using the region of interest method and compared. RESULTS: Mean A(z) and sensitivities were significantly higher for 10- (A(z) = 0.894, sensitivity = 95.6%) and 20-minute (0.910, 97.2%) than dynamic set (0.813, 79.9%) (P < 0.001), with no significant difference between 10- and 20-minute sets (P = 0.140). In patients with small (≤1 cm) metastases and a history of chemotherapy, sensitivities were significantly higher with 10- (88.2%) and 20-minute (91.6%) sets than dynamic set (48.6%) (P < 0.001). SR was significantly higher for 10- and 20-minute delayed than precontrast and dynamic, with significantly higher SR on 20- than 10-minute delayed. CONCLUSION: Regardless of size or prior chemotherapy, detection of hepatic metastases was significantly improved by adding hepatobiliary phase images without significant differences between 10- and 20-minute delayed.

Sunitinib for Asian patients with advanced renal cell carcinoma: a comparable efficacy with different toxicity profiles.

OBJECTIVE: We aimed to describe the efficacy and safety of sunitinib in unselected Korean advanced renal cell carcinoma (RCC) patients. PATIENTS AND METHODS: From November 2005 to August 2008, 132 histologically confirmed advanced RCC patients (100 in the global expanded access program) were enrolled. Response and toxicity were assessed regularly according to the protocol. RESULTS: Within this population, 82.6% had clear cell RCC, and 28.8% were treatment naïve. Patients received a median of 5 cycles of sunitinib (range 1-30), and the mean relative dose intensity was 82.0 ± 14.20 (SD). The progression-free survival (PFS) and overall survival rates were 8.2 and 23.1 months, respectively. For the 130 evaluable patients, the objective response rate was 34.1% (n = 45); 44.7% (n = 59) exhibited stable disease. Reasons for discontinuation were disease progression (75.0%) and toxicity (7.6%). The most frequent adverse events were thrombocytopenia (75.0%), neutropenia (70.5%), and anemia (69.7%). Low body surface area (OR = 4.2, 95% CI 1.2-13.8, p = 0.02) and previously treated status (OR = 3.1, 95% CI 1.3-7.4, p = 0.01) were highly predictive of grade 3-4 toxicities. Based on these findings, a nomogram predicting the probability of 12-month PFS was constructed, giving a concordance index of 0.675. CONCLUSIONS: Despite the different toxicity profiles, maintaining adequate dose modifications and a careful follow-up enables comparable treatment outcomes for unselected Korean advanced RCC patients.

Response to COVID-19 in social welfare facilities and the psychological state of social workers in South Korea: The mediating role of satisfaction with government.

This paper investigated associations between COVID-19 responses in social welfare facilities and the psychological state of social workers together with the potential mediating role of satisfaction with the government. During the COVID-19 pandemic, following government guidelines, social workers have continued to provide social services to the vulnerable groups. However, no research has been conducted focusing on their psychological state. A cross-sectional survey was carried out in Incheon Metropolitan City, South Korea. Data from 332 participants were analyzed using structural equation modeling. Supplementary in-depth interviews were conducted with social workers. Analysis results show that higher levels of preventive measures against COVID-19 directly worsen levels of well-being, but this negative effect is offset by the satisfaction with the government (ß = .383, p < .001). In social workers, satisfaction with the government fully mediates the influence of preventive measures toward reduced negative emotionality (ß = -.288, p < .001). The implications of this study suggest that the government's active response to the social welfare sector is important to alleviate the negative psychological consequences of social workers.

The number of residual metastatic lymph nodes following neoadjuvant chemotherapy predicts survival in patients with stage III NSCLC.

The prognosis of patients with stage III non-small-cell lung cancer (NSCLC) who achieve a pathological complete response or downstaging following neoadjuvant therapies are better than the prognosis of patients with residual metastatic lymph nodes (LN). However, the prognostic significance of the number of residual metastatic LNs remains unclear. From January 2001 to January 2006, 42 consecutive patients with stage IIIAN2 (22 patients) and IIIB without pleural effusion (20 patients) were treated with neoadjuvant chemotherapy. Thirty-four (81.0%) of the 42 patients were pathologically staged by mediastinoscopy. Neoadjuvant chemotherapy consisted of 3 cycles of platinum-based doublet (21 patients with gemcitabine, 15 with paclitaxel, and 6 with docetaxel). After neoadjuvant chemotherapy, a pathological complete response was achieved in one patient and downstaging was achieved in 24 patients. Pathological LN metastasis was absent in 9 patients (21.4%) and present in 33 patients (78.6%). With a median follow-up of 23 months, the 2-year disease-free survival (DFS) rate of patients without residual LN metastasis was statistically better than that of patients with residual LN metastasis (46% vs. 18% respectively, P=0.03). Among 33 patients with residual LN metastasis, age (P=0.01), pathological downstaging (P=0.098) and the number of residual metastatic LNs (median 14 months in 1-4 LN vs. median 5 months in LN > or =5; P=0.011) were significant predictors of DFS in univariate analysis. In multivariate analysis, the number of residual metastatic LNs was an independent predictor of DFS among patients with residual LN metastasis, irrespective of pathological downstaging. The number of residual metastatic lymph nodes following neoadjuvant chemotherapy is an independent predictor of DFS in patients with stage III NSCLC.

Treatment outcome of patients with anaplastic thyroid cancer: a single center experience.

PURPOSE: Anaplastic thyroid cancer is known to have a poor prognosis due to its aggressive and rapid metastasis with median survival of less than 6 months. Multimodal treatment involving surgery and chemoradiotherapy has been used to improve the survival of patients. Here, we retrospectively review of treatment outcome of 13 consecutive patients who were treated at a single center. MATERIALS AND METHODS: We retrospectively reviewed medical records of 13 anaplastic thyroid cancer patients who received multidisciplinary treatment between 2006 and 2010. Kaplan-Meier survival curve was used to analyze progression-free survival and overall survival of patients. RESULTS: The median patient age at diagnosis was 69 years, and six patients had stage IVc diseases. Eight patients received primary surgery followed by radiotherapy or concurrent chemoradiotherapy (CCRT). Five patients received weekly doxorubicin-based definitive CCRT, but only one patient's condition remained stable, while the rest experienced rapid disease progression. The median progression-free survival was 2.8 months (95% CI, 1.2-4.4 months), and the median overall survival was 3.8 months (95% CI, 3.0-4.6 months). CONCLUSION: Patients with anaplastic thyroid cancer showed poor prognosis despite multimodality treatment. Therefore, identification of novel therapeutic targets is warranted to take an effective mode of treatment.

Clinical and cost effectiveness of bevacizumab + FOLFIRI combination versus FOLFIRI alone as first-line treatment of metastatic colorectal cancer in South Korea.

BACKGROUND: Bevacizumab has been extensively investigated in combination with various standard chemotherapies in the treatment of metastatic colorectal cancer (mCRC). However, a comparison to irinotecan + infusional 5-fluorouracil/leucovorin (FOLFIRI) is lacking. OBJECTIVE: To explore clinical effectiveness and cost-effectiveness of adding bevacizumab to a regimen of FOLFIRI for the first-line treatment of mCRC in the Republic of Korea by conducting an indirect treatment comparison. METHODS: A health-economic model was developed to investigate the possible health outcomes (life-years gained [LYG]), direct costs, and incremental cost-effectiveness ratio (ICER) of adding bevacizumab to a FOLFIRI regimen. Data on progression-free and overall survival were derived from randomized clinical trials and were used in the indirect treatment comparison. The annual discount rate for costs and outcomes was 5%. A lifetime horizon of 8 years was used. Sensitivity analyses were carried out on all pivotal model assumptions. RESULTS: Incremental mean overall survival among patients treated with bevacizumab + FOLFIRI varied between 8.6 and 15.7 months compared with patients treated with FOLFIRI alone. The deterministic base-case result was 1.177 LYG. The discounted ICERs ranged from µ31.8 to µ39.5 million/LYG, with the base-case result being µ34.5 million/LYG. Treatment effect had the most impact on the outcomes in this model. CONCLUSIONS: Although there is no formal threshold for ICER per LYG in Korea, funding may be considered for bevacizumab + FOLFIRI, particularly if the severity and end-of-life nature of mCRC is taken into account.

Treatment outcomes of sunitinib treatment in advanced renal cell carcinoma patients: a single cancer center experience in Korea.

PURPOSE: The retrospective study was performed to assess the efficacy and toxicity profiles of sunitinib in Korean patients with metastatic renal cell carcinoma (RCC). MATERIALS AND METHODS: Between January 2005 and December 2008, 76 Korean patients with recurrent/metastatic RCC who received sunitinib were retrospectively reviewed. The primary end point was progression-free survival and the secondary end points were overall survival and response rate. We also assessed the toxicities associated with sunitinib treatment. RESULTS: Of the 76 patients, 69 (90.1%) were diagnosed with clear cell RCC. The median progression-free survival and overall survival were 7.2 and 22.8 months, respectively in overall patients. Sixty-two patients (81.6%) received 50 mg 4 week and 2 week off schedule, and 14 patients (18.4%) received 37.5 mg daily on a daily continuous schedule. The objective response rate and disease control rate were 27.6% and 84.2%, respectively. A dose reduction or reduction in dose due to adverse events occurred in 76% of the patients, whereas 11% of the patients had discontinued treatment. Other common laboratory abnormalities were increased serum creatinine (75.6%), elevated alanine aminotransferase (71.0%), neutropenia (61.8%), anemia (69.7%), and increased aspartate aminotrasferase (53.3%). Grade 3/4 toxicities occurred as follows: thrombocytopenia (38.2%), fatigue (10.5%), stomatitis (10.5%), and hand-foot syndrome (9.2%). CONCLUSION: Our results indicate that sunitinib treatment is effective and tolerable for ecurrent/metastatic RCC patients in Korea. Further studies with prognostic or biochemical factors are needed to clarify the different toxicity profiles of this study.

Phase II study of erlotinib in advanced non-small-cell lung cancer after failure of gefitinib.

PURPOSE: This study was designed to evaluate the efficacy and toxicity of erlotinib in patients with advanced non-small-cell lung cancer (NSCLC) who experienced disease progression after treatment with gefitinib. PATIENTS AND METHODS: The study included stage IIIB/IV recurrent or metastatic NSCLC patients who received two or three prior chemotherapy regimens and showed progressive disease within 4 months of gefitinib therapy discontinuation. Patients received erlotinib 150 mg/d until disease progression or unacceptable toxicity. Epidermal growth factor receptor (EGFR) mutations and other genetic abnormalities were analyzed from available tumor samples. RESULTS: Patient and disease characteristics (N = 21) included median age 56 years; number of prior chemotherapy regimens (three; n = 11); female sex (n = 11); adenocarcinoma (n = 15); and never-smoker status (n = 11). Among the 17 patients with tumor samples available, EGFR mutations were detected in five. The disease control rate (DCR) and response rate (RR) for all patients were 28.6% and 9.5%, respectively. The median duration of disease control was 125 days. The median time to progression and overall survival were 60 days and 158 days, respectively. Patients who had stable disease (SD) while receiving gefitinib showed significantly higher DCR (75% v 17.6% in non-SD patients; P = .050) and RR (50.0% v 0% in non-SD patients; P = .029). Among 17 patients with biomarker results available, those lacking EGFR mutations who had SD while receiving gefitinib showed significantly higher DCR and RR. CONCLUSION: Erlotinib seems to be a potential therapeutic option for the treatment of advanced NSCLC patients with wild-type EGFR who had SD while receiving gefitinib.

Clinical overview of extrapulmonary small cell carcinoma.

The objective of this study was to review the natural history of extrapulmonary small cell carcinoma (EPSCC) with specific emphasis on clinical features, response to treatment and survival. The records of all patients (n=34) with EPSCC treated at Yeungnam University Medical Center and Catholic University of Daegu Medical Center between 1998 and 2005 were retrieved and reviewed. The primary sites of tumor were the esophagus and thymus in 6 patients (17.6%) each, pancreas and stomach in 5 patients each (14.7%); other sites included were the cervix, abdominal lymph nodes, abdominal wall, bladder, colon, maxillary sinus, nasal cavity, ovary, parotid gland and liver. Twenty three patients out of 34 had limited disease. The median survival of all patients was 14 months. Independent prognostic factors included stage and primary tumor location. The prognosis for the patients with extensive disease and in the gastrointestinal group was unfavorable. EPSCC is a non homogeneous disease entity. As a result of its frequent recurrence, multimodal therapy has a better outcome even in cases of limited disease. Combination chemotherapy plays a central role for treatment of extensive disease in EPSCC. Further multicenter studies are now needed to determine more details regarding disease sub-class and optimal treatment modality.

The efficacy of docetaxel and cisplatin combination chemotherapy for the treatment of advanced gastric cancer after failing to 5-fluorouracil based chemotherapy.

PURPOSE: This study was conducted to confirm the efficacy and toxicity of docetaxel and cisplatin combination chemotherapy (DP) in patients with advanced gastric cancer. MATERIALS AND METHODS: Patients with measurable gastric adenocarcinoma received intravenous docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) with premedication on day 1, which was repeated every 3 weeks. All patients received DP as a second-line treatment after failing to 5-FU based chemotherapy. RESULTS: 34 patients were enrolled in this study between January 1998 and August 2003. A total of 112 cycles (median 3 cycles) were administered. Responses were evaluable in 30 patients. The objective response rate was 16.7% (95% CI: 3.5 approximately 30.3), with a stable disease in 56.7% (95% CI: 40.0 approximately 74.4) and a progressive disease in 26.7% (95% CI: 10.9 approximately 42.5) of patients, with a median follow up duration of 20 months for all the patients, The median duration of response, time to progression and overall survival were 2.1 months (95% CI: 0.4 approximately 3.9), 4.2 months (95% CI: 2.3 approximately 6.1) and 6.8 months (95% CI: 1.3 approximately 12.3), respectively, with a 1-year survival rate of 32%. The toxicity was evaluated in 30 patients, with neutropenia being most common. Renal impairment was seen in two patients with grade 3 creatinine elevation and liver enzyme elevation in four with grades 3 and 4. CONCLUSION: Although DP was an active combination regimen, with a tumor control rate of about 73% and with moderate tolerance, adjustment of the administration schedule, with further evaluation of other combination chemotherapies of docetaxel with new agents, other than cisplatin, seem warranted.