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IMPORTANCEPatients 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/m 2 (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 RELEVANCEIn 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.

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Using in silico drug screening by Connectivity Map followed by empirical validations, we repurposed an existing phenothiazine-like antipsychotic drug, trifluoperazine, as a potential anti-CSC agent that could overcome epidermal growth factor receptor-tyrosine kinase inhibitor and chemotherapy resistance.

LEARNING OBJECTIVESAfter completing this course, the reader will be able to:1. Identify the clinical features of oxaliplatin-induced neuropathy.2. Discuss the current approaches for managing chemotherapy-induced neuropathy.3. Explain the rationale for using glutamine in preventing oxaliplatin-induced neuropathy.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME ABSTRACTOxaliplatin is effective in the treatment of metastatic colorectal cancer (MCRC) patients; however, severe neurotoxicity develops frequently. To assess the efficacy of oral glutamine for preventing neuropathy induced by oxaliplatin, a pilot study was performed. A total of 86 patients with MCRC treated at Taipei Veterans General Hospital were enrolled. Oxaliplatin (85 mg/m 2 , days 1 and 15) plus weekly bolus 5-fluorouracil (5-FU; 500 mg/m 2 ) and folinic acid (FA; 20 mg/m 2 ) on days 1, 8, and 15 were given every 28 days as firstline treatment. Patients were randomized to receive (glutamine group; n ‫؍‬ 42) or not receive (control group; n ‫؍‬ 44) glutamine (15 g twice a day for seven consecutive days every 2 weeks starting on the day of oxaliplatin infusion). Efficacy of chemotherapy, neurological toxicity, and electrophysiological alterations were assessed. A lower percentage of grade 1-2 peripheral neuropathy was observed in the glutamine group (16.7% versus 38.6%) after two cycles of treatment, and a significantly lower incidence of grade 3-4 neuropathy was noted in the glutamine group after four cycles (4.8% versus 18.2%) and six cycles (11.9% versus 31.8%). By adding glutamine, interference with activities of daily living was lower (16.7% versus 40.9%), and need for oxaliplatin dose reduction was lower (7.1% versus 27.3%). There were no significant between-group differences in response to chemotherapy (52.4% versus 47.8%), electrophysiological abnormalities, grade 3-4 non-neurological toxicities (26.2% versus 22.8%), or survival. These data indi- Disclosure of potential conflicts of interest is found at the end of this article.

Several reports recently found that patients with B cell non-Hodgkin's lymphoma (NHL) had a higher carrier rate of hepatitis B surface antigen (HBsAg). The current study aimed to examine the hepatitis B virus (HBV) infection status of NHL patients in Taiwan, an HBV-endemic area. Serum HBV and serum hepatitis C virus were measured in 471 NHL patients and 1,013 non-lymphoma cancer patients enrolled between February 2000 and March 2007. Furthermore, nested polymerase chain reaction of HBV-DNA was used to examine the sera from selected patients in these two populations and healthy volunteers for the presence of occult HBV infection. The infection rates (as indicated by the rates of HBsAg and occult HBV) were compared between different groups. There was a higher incidence of HBV infection in B cell NHL patients (23.5%), especially patients with diffuse large B lymphoma, than solid tumor patients (15.6%, P = 0.001). Among HbsAg-negative patients, those with B cell NHL had a higher prevalence of occult HBV infection (6%) than those with non-lymphoma solid tumors and healthy volunteers, 0% and 0.9%, respectively (P = 0.005). B cell NHL patients, even HBsAg-negative B cell NHL patients, but not T cell NHL patients, have a higher incidence of HBV infection than patients with solid tumors. Our findings support the etiologic role of HBV infection in B cell NHL.

Although adding oxaliplatin to fluorouracil and leucovorin in adjuvant chemotherapy for colon cancer may improve disease-free survival, grade 3-4 sensory neuropathy also increases. To determine whether oral N-acetylcysteine is neuroprotective against oxaliplatin-induced neuropathy, we did a pilot study. Fourteen stage III colon cancer patients with 4 or more regional lymph nodes metastasis (N2 disease) receiving adjuvant biweekly oxaliplatin (85 mg/m(2)) plus weekly fluorouracil boluses and low-dose leucovorin were randomized to oral N-acetylcysteine (1,200 mg) (arm A) or placebo (arm B). Clinical neurological and electrophysiological evaluations were performed at baseline and after 4, 8, and 12 treatment cycles. Treatment-related toxicity was evaluated based on National Cancer Institute (NCI) Criteria. After four cycles of chemotherapy, seven of nine patients in arm B and two of five in arm A experienced grade 1 sensory neuropathy. After eight cycles, five experienced sensory neuropathy (grade 2-4 toxicity) in arm B; none in arm A (p<0.05). After 12 cycles, grade 2-4 sensory neuropathy was observed in eight patients in arm B, one in arm A (p<0.05). There were no significant electrophysiological changes in arm A after 4, 8, or 12 cycles of chemotherapy. We concluded that oral N-acetylcysteine reduces the incidence of oxaliplatin-induced neuropathy in colon cancer patients receiving oxaliplatin-based adjuvant chemotherapy.

BRAF mutation is an independent prognostic biomarker for colorectal liver metastasectomy.