Clinical practice consensus for the diagnosis and management of melanoma in Taiwan.

Melanoma is rare in Taiwan. Asian melanoma is distinct from Western melanoma because acral and mucosal melanoma accounts for the majority of melanoma cases, leading to distinct tumor behaviors and genetic profiling. With consideration of the clinical guidelines in Western countries, Taiwanese experts developed a local clinical practice consensus guideline. This consensus includes diagnosis, staging, and surgical and systemic treatment, based only on clinical evidence, local epidemiology, and available resources evaluated by experts in Taiwan. This consensus emphasizes the importance of surgical management, particularly for sentinel lymph node biopsies. In addition, molecular testing for BRAF is mandatory for patients before systemic treatment. Furthermore, immunotherapy and targeted therapy are prioritized for systemic treatment. This consensus aimed to assist clinicians in Taiwan in diagnosing and treating patients according to available evidence.

Prognostic predictors of adrenocortical carcinoma: A single-center thirty-year experience.

Background: The prognosis of adrenocortical carcinoma (ACC) is poor but highly variable. The present study aimed to characterize patients with ACC at a single center in Taiwan and to determine the prognostic predictors of overall and progression-free survival. Methods: Medical records of patients, who were diagnosed with ACC at Taipei Veterans General Hospital between January 1992 and June 2021, were reviewed. Patient demographics, tumor characteristics, and subsequent treatment were analyzed with regard to overall survival and progression-free survival using Kaplan-Meier methods and a Cox regression model. Results: Sixty-seven patients were included. Females (65.7%) were more susceptible to ACC, with a younger onset and active hormonal secretion. One-half of the patients exhibited distant metastases at the time of diagnosis. The European Network for the Study of Adrenal Tumours (ENSAT) stage (hazard ratio [HR] 3.60 [95% confidence interval (CI) 1.25-10.38]; p=0.018), large vessel invasion (HR 5.19 [95% CI 1.75-15.37]; p=0.003), and mitotane use (HR 0.27 [95% CI 0.11-0.70]; p=0.007) were significantly associated with overall survival (OS). There was no single factor independently associated with progression-free survival. Conclusion: ENSAT stage had a substantial impact on overall survival though there was no difference in OS between patients with stage II and stage III ACC. Large vessel invasion portended poor prognosis and influenced OS significantly. Moreover, mitotane only improved clinical outcomes of patients with stage IV disease.

Corrigendum: Compassionate use of ripretinib for patients with metastatic gastrointestinal stromal tumors: Taiwan and Hong Kong experience.

[This corrects the article DOI: 10.3389/fonc.2022.883399.].

A Single-Arm Phase Ib/II Study of Lenvatinib plus Eribulin in Advanced Liposarcoma and Leiomyosarcoma.

PURPOSE: Satisfactory treatment options for advanced leiomyosarcoma and liposarcoma are limited. The LEADER study (NCT03526679) investigated the safety and efficacy of lenvatinib plus eribulin. METHODS: LEADER is a multicenter phase Ib/II study for advanced leiomyosarcoma or liposarcoma. The phase Ib part enrolled 6 patients to determine the dose-limiting toxicity (DLT) and recommended phase II dose (RP2D) with the starting dose of lenvatinib 18 mg/day and eribulin 1.1 mg/m2 D1, D8 every 21 days. The primary endpoint of the phase II part was objective response rate (ORR) based on Response Evaluation Criteria in Solid Tumors 1.1, with phase Ib patients preplanned to be included in the efficacy analysis. Translational analyses were based on the transcriptomic data obtained from the NanoString nCounter platform. RESULTS: Thirty patients were enrolled (leiomyosarcoma 21, liposarcoma 9); the median age was 59. One patient had to temporarily stop lenvatinib due to grade 2 arthritis in the first cycle, meeting DLT criteria. Four of 6 patients had to decrease the dose of lenvatinib to 14 mg between cycles two and three. RP2D was determined at lenvatinib 14 mg/day and eribulin 1.1 mg/m2. The confirmed ORR was 20%, and the ORR was not significantly different between phase Ib/II cohorts (P = 0.23). The median progression-free survival was 8.56 months (95% confidence interval, 4.40-not reached). Translational studies suggested increased dendritic cells in the tumor microenvironment (TME) after treatment. CONCLUSIONS: Lenvatinib plus eribulin has a manageable safety profile and exhibits promising efficacy for treating advanced leiomyosarcoma and liposarcoma.

Compassionate Use of Ripretinib for Patients With Metastatic Gastrointestinal Stromal Tumors: Taiwan and Hong Kong Experience.

Background: Ripretinib was recently approved for the fourth-line targeted therapy for advanced gastrointestinal stromal tumor (GIST) refractory to imatinib, sunitinib, and regorafenib based on the pivotal INVICTUS phase III study. The INVICTUS study demonstrated significantly improved median progression-free survival (PFS) of 6.3 months and an overall survival (OS) insignificant benefit of ripretinib of 15.1 months as compared with placebo in 85 patients with advanced metastatic GIST. However, treatment outcome for the Chinese population, including in Taiwan and Hong Kong, was lacking. Material and Method: A compassionate study regarding ripretinib use for patients with advanced/metastatic GIST was conducted from March 2020 to March 2021 to assess the treatment efficacy and safety in Taiwan and Hong Kong patients. Result: Twenty evaluable patients (16 men and 4 women) with heavily pretreated metastatic GIST receiving ripretinib from March 2020 to March 2021 were enrolled to evaluate the treatment outcome. The response and clinical benefit rates to ripretinib were 25% (5/20) and 60% (12/20), respectively. The median PFS and OS in this compassionate cohort receiving ripretinib were 6.1 months and not reachable, respectively. Albumin less than 3.5 and disease progression after ripretinib use were the two independent unfavorable factors for PFS. There were 14 out of 20 (70%) experiencing any grade adverse event (AE). Loss of hair is the most common grade I to II AE with an incidence of 55%. Grade III AEs included diarrhea, skin rash, and anemia with one patient (5%) for each AE. Conclusions: Late-line ripretinib use in pretreated Taiwan and Hong Kong patients with advanced GIST showed efficacy consistent with the INVICTUS study. Albumin less than 3.5 and disease progression after ripretinib use were the two independent unfavorable factors for PFS. Ripretinib is generally tolerable, with loss of hair being the most common AE.

Three-Year Follow-Up and Response-Survival Relationship of Nivolumab in Previously Treated Patients with Advanced Esophageal Squamous Cell Carcinoma (ATTRACTION-3).

PURPOSE: Limited long-term data are available on immune checkpoint inhibitor use in patients with advanced esophageal squamous cell carcinoma (ESCC). We report 3-year follow-up data from our study of nivolumab versus chemotherapy (paclitaxel or docetaxel) in patients with previously treated ESCC. PATIENTS AND METHODS: ATTRACTION-3 was a randomized, multicenter, open-label, phase III trial. Overall survival (OS), time from randomization to death from any cause, was the primary endpoint. An exploratory subanalysis assessed OS according to the best overall response (BOR) with and without landmark at 4 months. RESULTS: Of the enrolled patients, 210 received nivolumab and 209 received chemotherapy. With a minimum follow-up of 36.0 months, OS was longer in the nivolumab versus the chemotherapy group (median, 10.9 vs. 8.5 months; HR, 0.79; P = 0.0264), with 3-year OS rates of 15.3% and 8.7%, respectively. The median OS was longer with nivolumab versus chemotherapy irrespective of the BOR (complete response/partial response: 19.9 vs. 15.4 months; stable disease: 17.4 vs. 8.8 months; and progressive disease: 7.6 vs. 4.2 months). Grade 3 or higher treatment-related adverse events were reported in 40 patients (19.1%) in the nivolumab group and 133 patients (63.9%) in the chemotherapy group. CONCLUSIONS: Nivolumab as second-line therapy demonstrated clinically meaningful long-term improvement in OS compared with chemotherapy in previously treated patients with advanced ESCC. The OS was consistently improved in the nivolumab group compared with the chemotherapy group regardless of BOR. Nivolumab was well tolerated over the 3-year follow-up. See related commentary by Yoon et al., p. 3173.

Treatment Patterns and Outcomes in Patients with Esophageal Cancer: An Analysis of a Multidisciplinary Tumor Board Database.

BACKGROUND: Multidisciplinary management strategies are standard in esophageal cancer. Based on a multidisciplinary tumor board (MTB) database in a high-volume center, we aimed to evaluate real-world treatment patterns and patient outcomes in patients with esophageal cancer. In addition, we determined the impact of MTB discussions on patient prognosis. METHODS: Patients diagnosed with esophageal cancer between 2010 and 2019 were retrospectively reviewed. The pattern of treatment modalities and overall survival (OS) of patients with limited, locally advanced, and advanced/metastatic disease were reported. RESULTS: Data from 1132 patients, including 247 patients with limited esophageal cancer, 606 patients with locally advanced esophageal cancer, and 279 patients with advanced/metastatic esophageal cancer were included. Upfront surgery was the most common (56.3%) treatment modality for patients with limited esophageal cancer, while treatment for locally advanced esophageal cancer included upfront surgery (19.1%), neoadjuvant chemoradiotherapy (44.9%), and definitive chemoradiotherapy (36.0%); however, 27.9% of patients undergoing neoadjuvant chemoradiotherapy did not receive planned esophagectomy. Definitive chemoradiotherapy was mainly used for patients with locally advanced and advanced/metastatic disease, but had an incompletion rate of 22.0% and 33.7%, respectively. Regarding survival, the 5-year OS rates were 56.4%, 26.3%, and 5.1% in patients with limited, locally advanced, and advanced/metastatic disease, respectively. Additionally, patients whose clinical management was discussed in the MTB had a significantly better 5-year OS rate than the other patients (27.3% vs. 20.5%, p < 0.001). CONCLUSIONS: We report the real-world data of treatment patterns and patient outcomes in patients with esophageal cancer with respect to multidisciplinary management, and demonstrate the positive impact of MTB discussions on patient prognosis.

Effect of Doxorubicin Plus Olaratumab vs Doxorubicin Plus Placebo on Survival in Patients With Advanced Soft Tissue Sarcomas: The ANNOUNCE Randomized Clinical Trial.

Importance: Patients with advanced soft tissue sarcoma (STS) have a median overall survival of less than 2 years. In a phase 2 study, an overall survival benefit in this population was observed with the addition of olaratumab to doxorubicin over doxorubicin alone. Objective: To determine the efficacy of doxorubicin plus olaratumab in patients with advanced/metastatic STS. Design, Setting, and Participants: ANNOUNCE was a confirmatory, phase 3, double-blind, randomized trial conducted at 110 sites in 25 countries from September 2015 to December 2018; the final date of follow-up was December 5, 2018. Eligible patients were anthracycline-naive adults with unresectable locally advanced or metastatic STS, an Eastern Cooperative Oncology Group performance status of 0 to 1, and cardiac ejection fraction of 50% or greater. Interventions: Patients were randomized 1:1 to receive doxorubicin, 75 mg/m2 (day 1), combined with olaratumab (n = 258), 20 mg/kg in cycle 1 and 15 mg/kg in subsequent cycles, or placebo (n = 251) on days 1 and 8 for up to 8 21-day cycles, followed by olaratumab/placebo monotherapy. Main Outcomes and Measures: Dual primary end points were overall survival with doxorubicin plus olaratumab vs doxorubicin plus placebo in total STS and leiomyosarcoma (LMS) populations. Results: Among the 509 patients randomized (mean age, 56.9 years; 58.2% women; 46.0% with LMS), all were included in the primary analysis and had a median length of follow-up of 31 months. No statistically significant difference in overall survival was observed between the doxorubicin plus olaratumab group vs the doxorubicin plus placebo group in either population (total STS: hazard ratio, 1.05 [95% CI, 0.84-1.30], P = .69, median overall survival, 20.4 months vs 19.7 months; LMS: hazard ratio, 0.95 [95% CI, 0.69-1.31], P = .76, median overall survival, 21.6 months vs 21.9 months). Adverse events of grade 3 or greater reported in 15% or more of total patients with STS were neutropenia (46.3% vs 49.0%), leukopenia (23.3% vs 23.7%), and febrile neutropenia (17.5% vs 16.5%). Conclusions and Relevance: In this phase 3 clinical trial of patients with advanced STS, treatment with doxorubicin plus olaratumab vs doxorubicin plus placebo resulted in no significant difference in overall survival. The findings did not confirm the overall survival benefit observed in the phase 2 trial. Trial Registration: ClinicalTrials.gov Identifier: NCT02451943.

Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Chemotherapy for patients with advanced oesophageal squamous cell carcinoma offers poor long-term survival prospects. We report the final analysis from our study of the immune checkpoint PD-1 inhibitor nivolumab versus chemotherapy in patients with previously treated advanced oesophageal squamous cell carcinoma. METHODS: We did a multicentre, randomised, open-label, phase 3 trial (ATTRACTION-3) at 90 hospitals and cancer centres in Denmark, Germany, Italy, Japan, South Korea, Taiwan, the UK, and the USA. We enrolled patients aged 20 years and older with unresectable advanced or recurrent oesophageal squamous cell carcinoma (regardless of PD-L1 expression), at least one measurable or non-measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, a baseline Eastern Cooperative Oncology Group performance status of 0-1, and who were refractory or intolerant to one previous fluoropyrimidine-based and platinum-based chemotherapy and had a life expectancy of at least 3 months. Patients were randomly assigned (1:1) to either nivolumab (240 mg for 30 min every 2 weeks) or investigator's choice of chemotherapy (paclitaxel 100 mg/m2 for at least 60 min once per week for 6 weeks then 1 week off; or docetaxel 75 mg/m2 for at least 60 min every 3 weeks), all given intravenously. Treatment continued until disease progression assessed by the investigator per RECIST version 1.1 or unacceptable toxicity. Randomisation was done using an interactive web response system with a block size of four and stratified according to geographical region (Japan vs rest of the world), number of organs with metastases, and PD-L1 expression. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival, defined as the time from randomisation until death from any cause, in the intention-to-treat population that included all randomly assigned patients. Safety was assessed in all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT02569242, and follow-up for long-term outcomes is ongoing. FINDINGS: Between Jan 7, 2016, and May 25, 2017, we assigned 419 patients to treatment: 210 to nivolumab and 209 to chemotherapy. At the time of data cutoff on Nov 12, 2018, median follow-up for overall survival was 10·5 months (IQR 4·5-19·0) in the nivolumab group and 8·0 months (4·6-15·2) in the chemotherapy group. At a minimum follow-up time (ie, time from random assignment of the last patient to data cutoff) of 17·6 months, overall survival was significantly improved in the nivolumab group compared with the chemotherapy group (median 10·9 months, 95% CI 9·2-13·3 vs 8·4 months, 7·2-9·9; hazard ratio for death 0·77, 95% CI 0·62-0·96; p=0·019). 38 (18%) of 209 patients in the nivolumab group had grade 3 or 4 treatment-related adverse events compared with 131 (63%) of 208 patients in the chemotherapy group. The most frequent grade 3 or 4 treatment-related adverse events were anaemia (four [2%]) in the nivolumab group and decreased neutrophil count (59 [28%]) in the chemotherapy group. Five deaths were deemed treatment-related: two in the nivolumab group (one each of interstitial lung disease and pneumonitis) and three in the chemotherapy group (one each of pneumonia, spinal cord abscess, and interstitial lung disease). INTERPRETATION: Nivolumab was associated with a significant improvement in overall survivaland a favourable safety profile compared with chemotherapy in previously treated patients with advanced oesophageal squamous cell carcinoma, and might represent a new standard second-line treatment option for these patients. FUNDING: ONO Pharmaceutical Company and Bristol-Myers Squibb.

Gene amplification and tumor grading in parosteal osteosarcoma.

BACKGROUND: Parosteal osteosarcoma (POS) is a unique low grade osteosarcoma. Two separate oncogenes, MDM2 and CDK4, are specifically amplified in POS. Its clinical behavior is usually indolent. In some occasions, it may progress to high grade and become fatal. Malignant transformation with high grade differentiation is the most reliable indicator to predict its aggressiveness and metastatic potential. This study is to discover the relationship between gene amplification and grading. METHODS: Retrospective analysis of MDM2/CDK4 expression/amplification using immunostaining, multiplex quantitative polymerase chain reaction (MQPCR) and fluorescence in situ hybridization (FISH) were studied on 14 patients with recurrent POS. RESULTS: Forty tumor specimens in formalin-fixed paraffin-embedded blocks from 14 patients of POS were included in this study. Twenty-seven tumors are low-grade, 13 are high-grade. All POS showed increased expression of both MDM2 and CDK4 proteins, but not those from conventional osteosarcoma. Except some tumors were non-informative (poor DNA quality), the rest of POS had a marked increase of MDM2 and CDK4 genes copies by MQPCR, and confirmed by MDM2 FISH. Moreover, the folds of amplification increase as tumors progress. And, the amplification folds in high-grade POS are consistently higher than those of conventional ones. CONCLUSION: FISH and MQPCR are both useful assays for estimating oncogene amplification status in bone tumors. Amplification levels of MDM2 and CDK4 are related to tumor grading and progression. Molecular determination of gene amplification status can be a reliable alternative for predicting clinical behavior of POS at small biopsies.

Expression profile­driven discovery of AURKA as a treatment target for liposarcoma.

Liposarcoma (LPS) is one of the most frequently reported type of soft­tissue sarcoma (STS). Well­differentiated (WD) LPS and dedifferentiated (DD) LPS are the two most common subtypes. Chemotherapy has been considered to be ineffective in LPS, and novel treatment agents are thus necessary. In this study, we reanalyzed two published microarray data sets of LPS. By comparing the top 50 upregulated genes in DD LPS in both sets of data, we identified 12 overlapping genes. Of note, the top five gene sets enriched in DD LPS in both sets of data were involved in cell cycle regulation. Among the 12 overlapping genes, aurora kinase A (AURKA) is a well­known gene involved in cell cycle regulation; we thus further investigated this gene. AURKA was significantly upregulated in DD LPS, compared with WD LPS. Among 40 cases of DD LPS in GSE30929, patients with high AURKA expression in tumors had significantly worse distant recurrence­free survival than those with low expression. In an in vitro model, MLN8237, an AURKA inhibitor, could inhibit AURKA in LPS cell lines with a resultant G2/M arrest. MLN8237 was also reported to exert a cytotoxic effect by inducing apoptosis in LPS cell lines. Furthermore, except for cisplatin, MLN8237 had a significantly synergistic effect with chemotherapy agents against LPS. MLN8237 induced cellular senescence in LPS cell lines with increased expression of DcR2, a senescence biomarker, and upregulated expression of cytokines associated with the senescence­associated secretory phenotype, including interleukin (IL)­1α, IL­6 and IL­8. Our study identified AURKA as a potential biomarker for predicting poor prognosis in LPS. The findings of the present study suggested the potential of AURKA as a therapeutic target in LPS cell line models, while the novel combination of AURKA inhibitors and chemotherapy requires further investigation.

Identification of phenothiazine as an ETV1­targeting agent in gastrointestinal stromal tumors using the Connectivity Map.

Gastrointestinal stromal tumors (GISTs) are gastrointestinal tract sarcomas that commonly contain a mutation in the tyrosine kinases, KIT and platelet­derived growth factor receptor A (PDGFRA). Imatinib, sunitinib and regorafenib are all effective tyrosine kinase inhibitors; however, acquired resistance is inevitable. The E26 variant 1 (ETV1) pathway has been found to be a key downstream effector of KIT and is therefore a reasonable therapeutic target for this disease. In this study, we explored the potential agents targeting ETV1 in GISTs by uploading an ETV1 knockout gene signature of GIST cell lines to the pattern­matching software 'Connectivity Map'. The activity and mechanisms of identified agents were examined using an in vitro model. Four drugs were identified: Suberanilohydroxamic acid and trichostatin [two histone deacetylase inhibitors (HDACIs)] and trifluoperazine and thioridazine (two phenothiazine­class drugs). Western blot analysis demonstrated that all four drugs had ETV1­downregulating effects. As HDACIs have been previously studied in GISTs, we focused on phenothiazine. Phenothiazine was found to exert cytotoxicity and to induce apoptosis and autophagy in GISTs. Treatment with phenothiazine had little effect on the KIT/AKT/mammalian target of rapamycin (mTOR) pathway, but instead upregulated extracellular­signal­regulated kinase (ERK) activity. A combination of phenothiazine and a MEK inhibitor had a synergistic cytotoxic effect on GISTs. Western blot analysis indicated that ELK1 and early growth response 1 (EGR1) were activated/upregulated following phenothiazine treatment, and the MEK inhibitor/phenothiazine combination downregulated the ERK/ELK1/EGR1 pathway, resulting in diminished autophagy, as well as enhanced apoptosis. On the whole, the findings of this study established phenothiazine as a novel class of therapeutic agents in GIST treatment and demonstrate that a combination of phenothiazine and MEK inhibitor has great potential for use in the treatment of GISTs.

Incidence of soft tissue sarcoma in Taiwan: A nationwide population-based study (2007-2013).

BACKGROUND: Asian studies on soft tissue sarcoma (STS) incidence, irrespective of the primary site, are scant. METHODS: STS data were acquired from the population-based 2007-2013 Taiwan Cancer Registry of the Health and Welfare Data Science Center, Taiwan. Histological subtype-, site-, sex-, and age-specific STS incidence rates were analyzed according to the 2013 classification of the World Health Organization. RESULTS: In total, 11,393 patients with an age-standardized incidence rate (ASIR) of 5.62 (95% confidence interval, 5.51-5.73) per 100,000 person-years were identified. Overall, a male predominance (sex-standardized incidence rate ratio, 1.2) was noted, and the rate increased with age, peaking at >75 years. Approximately 30% of STSs occurred in connective, subcutaneous, and other soft tissues and 70% in other sites. In addition to connective, subcutaneous, and other soft tissues, the three most common primary sites were the stomach (15.9%), skin (14.3%), and small intestines (10.5%). Gastrointestinal stromal tumor was the most common subtype (29.2%; ASIR, 1.55/100,000 person-years), followed by liposarcoma (11.5%; ASIR, 0.63/100,000 person-years) and leiomyosarcoma (9.7%; ASIR, 0.53/100,000 person-years). Compared with relevant data from Western countries, the incidence rate of angiosarcomas was higher than that in other regions, whereas the incidence rates of leiomyosarcoma and Kaposi sarcoma were lower than those in other regions. CONCLUSION: STS incidence varied by histological subtype, sex, age, and primary site in an Asian population. Our results suggested regional and racial discrepancies in the incidence rates of certain STS subtypes.

Role of PLK1 signaling pathway genes in gastrointestinal stromal tumors.

In previous studies by the authors, aurora kinase A (AURKA) was demonstrated as an independent poor prognostic marker for the recurrence of localized gastrointestinal stromal tumors (GISTs) and for the progression of advanced GISTs. In the present study, the prognostic effect of genes involved in cell cycle regulation in GISTs was further examined. Leading edge analysis in gene set enrichment analysis was used to identify the most common genes in the top 10 enriched gene sets of high-risk patients with GISTs in a Japanese study. The obtained gene list was uploaded to the Pathway Interaction Database to search for critical pathways. Selected genes within the pathway were subsequently verified through immunohistochemistry (IHC) in another cohort of patients. A total of 5 genes in 'PLK1 signaling events,' namely AURKA, polo-like kinase 1 (PLK1), cell division cycle 25C (CDC25C), budding uninhibited by benzimidazoles (BUB1), and targeting protein for Xklp2 (TPX2), were identified for subsequent study. Among the Japanese cohort, all 5 genes, except BUB1, were significant prognostic factors for poor recurrence-free survival (RFS). Among 141 patients enrolled for the IHC study, all 5 genes exhibited variable expression patterns. In the association study, only AURKA exhibited significant overexpression in non-gastric tumors. Although all 5 genes were considered as risk factors for poor RFS based on a univariate analysis, only the mitotic count and expression levels of CDC25C, BUB1, and TPX2 retained prognostic effects in the multivariate analysis. The PLK1 signaling pathway is crucial in the disease progression of GISTs. Genes within this pathway may serve as predictive markers for adjuvant therapy.

A phase II trial of regorafenib in patients with metastatic and/or a unresectable gastrointestinal stromal tumor harboring secondary mutations of exon 17.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are caused by the constitutive activation of KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutations. Imatinib selectively inhibits KIT and PDGFR, leading to disease control for 80%-90% of patients with metastatic GIST. Imatinib resistance can occur within a median of 2-3 years due to secondary mutations in KIT. According to preclinical studies, both imatinib and sunitinib are ineffective against exon 17 mutations. However, the treatment efficacy of regorafenib for patients with GIST with exon 17 mutations is still unknown. PATIENTS AND METHODS: Documented patients with GIST with exon 17 mutations were enrolled in this study. Patients received 160 mg of oral regorafenib daily on days 1-21 of a 28-day cycle. The primary end point of this trial was the clinical benefit rate (CBR; i.e., complete or partial response [PR], as well as stable disease [SD]) at 16 weeks. The secondary end points of this study included progression free survival (PFS), overall survival, and safety. RESULTS: Between June 2014 to May 2016, 18 patients were enrolled (15 of which were eligible for response evaluation). The CBR at 16 weeks was 93.3% (14 of 15; 6 PR and 8 SD). The median PFS was 22.1 months. The most common grade 3 toxicities were hand-and-foot skin reactions (10 of 18; 55.6%), followed by hypertension (5 of 18; 27.8%). CONCLUSION: Regorafenib significantly prolonged PFS in patients with advanced GIST harboring secondary mutations of exon 17. A phase III trial of regorafenib versus placebo is warranted. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov in November 2015, number NCT02606097.Key message: This phase II trial was conducted to assess the efficacy and safety of regorafenib in patients with GIST with exon 17 mutations. The results provide strong evidence that regorafenib significantly prolonged PFS in patients with advanced GIST harboring secondary mutations of exon 17.

Adjuvant FOLFOX treatment for stage III colon cancer: how many cycles are enough?

PURPOSE: Adjuvant FOLFOX (5-fluorouracil and oxaliplatin) chemotherapy benefits stage III colon cancer patients. However, it still results in side effects and increased cost. Reducing cycles had been thought to decrease these problems. This retrospective study aimed to find the appropriate number of treatment cycles that are sufficient for treating these patients. PATIENTS AND METHODS: A total of 213 stage III colon cancer patients receiving adjuvant FOLFOX therapy were retrospectively recruited. Demographic data were collected for analysis. Survival analyses were performed between all cases of patients receiving above and below a certain cycle number. If a significant difference was reached at that cycle number, multivariate Cox Regression was performed with those factors resulting in p < 0.2 to assess the independent prognostic factors. RESULTS: The 5-year overall survival rate of patients was 77.9 %, and the 3-year disease-free survival was 76.7 %. For overall survival, a significant benefit was noted for treatment of at least 8 cycles, for disease-free survival, significant differences were apparent from patient data of those who underwent from 7 to 12 treatment cycles. Multivariate survival analysis of that patient data at cycle 8 for overall survival and cycle 7 for disease free survival revealed cycle number as the only independent prognostic factor (p = 0.04, 0.048). CONCLUSION: Cycle number of adjuvant FOLFOX is a significant prognostic factor for stage III colon cancer patients. At least 8 cycles are needed to have an overall survival benefit, and 7 to disease-free survival.

Outcomes of 50 Patients With Ewing Sarcoma Family of Tumors Treated at a Single Institution in Taiwan.

To identify the prognostic factors and long-term outcome of the Ewing sarcoma family of tumors (ESFT), data on 50 patients with ESFT treated at Taipei Veterans General Hospital between February 1991 and March 2014 were retrospectively considered. The influence of patient demographics, tumor features, and clinical and therapeutic parameters on overall survival (OS) and progression-free survival (PFS) rates were assessed. The results revealed that 21 of the 50 patients (42%) were metastatic at diagnosis. The median follow-up time was 1.8 years. The 5-year OS and PFS for patients who were nonmetastatic were 61.6% and 55.5%, respectively, and 18.8% and 15.4% for patients who were metastatic, respectively. The key adverse prognostic factor was metastasis at diagnosis. Radiotherapy for local control was associated with improved PFS. The high rate of primary metastasis and poorer outcomes of nonmetastatic ESFT compared with results from Western studies, along with previously reported low rates of ESFT in Taiwanese people, suggest that genetic factors play a role in the pathogenesis of ESFT and chemotherapy pharmacokinetics and pharmacodynamics. Radiotherapy in local treatment should be considered more aggressively in Taiwanese patients with ESFT.

Decision-tree algorithm for optimized hematopoietic progenitor cell-based predictions in peripheral blood stem cell mobilization.

BACKGROUND: Enumerating hematopoietic progenitor cells (HPCs) by using an automated hematology analyzer is a rapid, inexpensive, and simple method for predicting a successful harvest compared with enumerating circulating CD34+ cells. However, the optimal HPC cutoff count and the indicating factors to be considered for improved predicting have not yet been determined. STUDY DESIGN AND METHODS: Between 2007 and 2012, a total of 189 consecutive patients who proceeded to peripheral blood stem cell (PBSC) harvesting were retrospectively recruited. Baseline characteristics were analyzed to identify the risk factors for a failed harvest, which were defined as less than 2 × 10(6) CD34+ cells/kg. Variables identified by multivariate logistic regression and correlation analysis for predicting a successful harvest were subjected to classification and regression tree (CART) analysis. RESULTS: PBSCs were successfully harvested in 154 (81.5%) patients. An age of at least 60 years, a diagnosis of a solid tumor, at least five prior chemotherapy cycles, prior radiotherapy, and mobilization with granulocyte-colony-stimulating factor alone or high-dose cyclophosphamide were independent baseline predictors of poor mobilization. In CART analysis, patients with zero to two host risk factors and either higher HPC (≥28 × 10(6) /L) or mononuclear cell (MNC; ≥3.5 × 10(9) /L) counts were categorized as good mobilizers and their harvest success rate was 92.3%. By contrast, 30.3% of harvests were adequate in the patients with three to five host risk factors and lower HPC and MNC counts. CONCLUSION: A CART algorithm incorporating host predictors and HPC and MNC counts improves predictions in a successful harvest and might reduce the necessity of monitoring peripheral CD34+ cells.

Improvement in High-Grade Osteosarcoma Survival: Results from 202 Patients Treated at a Single Institution in Taiwan.

The aim of this study was to compare survival before and after 2004 and define the prognostic factors for high-grade osteosarcomas beyond those of typical young patients with localized extremity disease. Few studies have reported the long-term treatment outcomes of high-grade osteosarcoma in Taiwan. A total of 202 patients with primary high-grade osteosarcoma who received primary chemotherapy at Taipei Veterans General Hospital between January 1995 and December 2011 were retrospectively evaluated and compared by period (1995-2003 vs 2004-2011). Patients of all ages and tumor sites and those following or not following controlled protocols were included in analysis of demographic, tumor-related, and treatment-related variables and survival. Overall survival and progression-free survival at 5 years were, respectively, 67.7% and 48% for all patients (n = 202), 77.3% and 57.1% for patients without metastasis (n = 157), and 33.9% and 14.8% for patients with metastasis (n = 45). The survival rates of patients treated after 2004 were significantly higher (by 13%-16%) compared with those of patients treated before 2004, with an accompanying 30% increase in histological good response rate (P = .002). Factors significantly contributing to inferior survival in univariate and multivariate analyses were diagnosis before 2004, metastasis at diagnosis, and being a noncandidate for a controlled treatment protocol. By comparison with the regimens used at our institution before 2004, the current results support the effectiveness of the post-2004 regimens, which consisted of substantially reduced cycles of high-dose methotrexate and a higher dosage of ifosfamide per cycle, cisplatin, and doxorubicin, for treating high-grade osteosarcoma in Asian patients.

Cytotoxic mechanism of PLK1 inhibitor GSK461364 against osteosarcoma: Mitotic arrest, apoptosis, cellular senescence, and synergistic effect with paclitaxel.

Polo-like kinase 1 (PLK1), a serine/threonine kinase and an oncogene, is crucial in regulating cell cycle progression. PLK1 also has been demonstrated as a potential target of osteosarcoma (OS) by using short hairpin RNA libraries in lentiviral vectors for screening of protein kinase. In preclinical studies, GSK461364, a potent and selective ATP-competitive PLK1 inhibitor, showed antiproliferative activity against multiple tumor cell lines. In the present study, we evaluated the expression level of PLK1 in OS and explored the cytotoxic mechanism of GSK461364 against OS. PLK1 was significantly overexpressed in OS compared with normal osteoblasts and other types of sarcoma. GSK461364 inhibited PLK1 and caused mitotic arrest by inducing G2/M arrest in OS cells. Moreover, GSK461364 exerted a cytotoxic effect by inducing apoptosis in OS, and induced cellular senescence in OS cell lines, as indicated by an increased senescence-associated ß-galactosidase activity and enhanced DcR2 and interleukin-1α expression. In addition, we demonstrated a synergistic cytotoxic effect of GSK461364 and paclitaxel, possibly resulting from combined mitotic arrest. In conclusion, the present study revealed that PLK1 was overexpressed in OS and that GSK461364 exerted its cytotoxic effect on OS by inducing mitotic arrest and subsequent apoptosis and induced cellular senescence; therefore, senescence-associated markers can be used as treatment biomarkers, and a combination of GSK461364 and paclitaxel can potentially treat OS.