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Although testicular germ cell tumors are generally quite responsive to treatment with cisplatin, a small fraction of them acquire resistance during therapy. Even when cisplatin treatment is successful the patient is often left with a residual teratoma at the site of the primary tumor suggesting that cisplatin may trigger differentiation in some tumors. Using the human embryonal carcinoma cell line NTera2/D1, we confirmed that exposure to the differentiating agent retinoic acid produced a reduction in pluripotency markers NANOG and POU5F1 (Oct3/4) and an acute concentration-dependent increase in resistance to both cisplatin and paclitaxel that reached as high as 18-fold for cisplatin and 61-fold for paclitaxel within four days. A two day exposure to cisplatin also produced a concentration-dependent decrease in the expression of the NANOG and POU5F1 and increased expression of three markers whose levels increase with differentiation including Nestin, SCG10 and Fibronectin. In parallel, exposure to cisplatin induced up to 6.2-fold resistance to itself and 104-fold resistance to paclitaxel. Paclitaxel did not induce differentiation or resistance to either itself or cisplatin. Neither retinoic acid nor cisplatin induced resistance in cervical or prostate cancer cell lines or other germ cell tumor lines in which they failed to alter the expression of NANOG and POU5F1. Forced expression of NANOG prevented the induction of resistance to cisplatin by retinoic acid. We conclude that cisplatin can acutely induce resistance to itself and paclitaxel by triggering a differentiation response in pluripotent germ cell tumor cells.

Purpose REACH investigated second-line ramucirumab therapy for advanced hepatocellular carcinoma. Results: Median overall survival was 8.2 months for ramucirumab and 6.9 months for placebo (HR, 0.835; 95% CI, 0.634–1.100; p = 0.2046) for East Asians, and 10.1 months for ramucirumab and 8.0 months for placebo (HR, 0.895; 95% CI, 0.690–1.161; p = 0.4023) for non-East Asians. Median overall survival in patients with baseline alpha-fetoprotein ≥ 400 ng/mL was 7.8 months for ramucirumab and 4.2 months for placebo (HR, 0.749; 95% CI, 0.519–1.082; p = 0.1213) for East Asians (n = 139), and 8.2 months for ramucirumab and 4.5 months for placebo (HR, 0.579; 95% CI, 0.371–0.904; p = 0.0149) for non-East Asians (n = 111). The most common grade ≥ 3 treatment-emergent adverse events in East Asians and non-East Asians included hypertension and malignant neoplasm progression. Materials and methods A post-hoc analysis of East Asians (N = 252) and non-East Asians (N = 313) in the intent-to-treat population was performed. Conclusions: In East Asians and non-East Asians, ramucirumab did not significantly prolong overall survival. In patients with baseline alpha-fetoprotein ≥ 400 ng/mL, a potentially larger survival benefit was observed in both subgroups. Safety for East Asians was similar to non-East Asians.

Background & Aims: The albumin-bilirubin (ALBI) grade/score is derived from a validated nomogram to objectively assess prognosis and liver function in patients with hepatocellular carcinoma (HCC). In this post hoc analysis, we assessed prognosis in terms of survival by baseline ALBI grade and monitored liver function during treatment with ramucirumab or placebo using the ALBI score in patients with advanced HCC., Methods: Patients with advanced HCC, Child-Pugh class A with prior sorafenib treatment were randomised in REACH trials to receive ramucirumab 8 mg/kg or placebo every 2 weeks. Data were analysed by trial and as a meta-analysis of individual patient-level data (pooled population) from REACH (alpha-fetoprotein ≥400 ng/ml) and REACH-2. Patients from REACH with Child-Pugh class B were analysed as a separate cohort. The ALBI grades and scores were calculated at baseline and before each treatment cycle., Results: Baseline characteristics by ALBI grade were balanced between treatment arms among patients in the pooled population (ALBI-1, n = 231; ALBI-2, n = 296; ALBI-3, n = 7). Baseline ALBI grade was prognostic for overall survival (OS; ALBI grade 2 vs. 1; hazard ratio [HR]: 1.38 [1.13-1.69]), after adjusting for other significant prognostic factors. Mean ALBI scores remained stable in both treatment arms compared with baseline and were unaffected by baseline ALBI grade, macrovascular invasion, tumour response, geographical region, or prior locoregional therapy. Baseline ALBI grades 2 and 3 were associated with increased incidence of liver-specific adverse events and discontinuation rates in both treatments. Ramucirumab improved OS in patients with baseline ALBI grade 1 (HR 0.605 [0.445-0.824]) and ALBI grade 2 (HR 0.814 [0.630-1.051])., Conclusions: Compared with placebo, ramucirumab did not negatively impact liver function and improved survival irrespective of baseline ALBI grade., Lay Summary: Hepatocellular carcinoma is the third leading cause of cancer-related death worldwide. Prognosis is affected by many clinical factors including liver function both before and during anticancer treatment. Here we have used a validated approach to assess liver function using 2 laboratory parameters, serum albumin and bilirubin (ALBI), both before and during treatment with ramucirumab in 2 phase III placebo-controlled studies. We confirm the practicality of using this more simplistic approach in assessing liver function prior to and during anticancer therapy, and demonstrate ramucirumab did not impair liver function when compared with placebo., Competing Interests: M.K.: conflict with Daiichi Sankyo, Otsuka, Taiho, Astellas Pharma, Chugai, AbbVie, BMS, EA Pharma, Takeda, Gilead, Eisai, Ono, Bayer, MSD, BMS, and Eli Lilly and Company. P.G.: conflict with Bayer, BMS, MSD, Merck, SIRTEX, AstraZeneca, Sillajen, Eli Lilly and Company, Ipsen, Roche, and Eisai. G.B.: declares no conflicts of interest that pertain to this work. Y-K.K.: conflict with ONO, BMS, Eli Lilly and Company, Roche, Daehwa, and Taiho. C-J. Yen: declares no conflicts of interest that pertain to this work. R.S.F.: conflict with Astra Zeneca, Bayer, BMS, Eli Lilly and Company, Pfizer, Merck, Novartis, Roche/Genentech, and Eisai. J.M.L.: conflict with Bayer, Eisai Inc, BMS, IPSEN, Eli Lilly and Company, Celsion Corp, Elelixis, Merck, Glycotest, Can-Fite, Blueprint, Incyte, Navigant, Leerink Swann LLC, Midatech Ltd, Fortress Biotech Inc, and Spring Bank Pharmaceuticals. E.A.: received honoraria from IPSEN, Bayer, Terasphere, Sirtex, Sanofi, Novartis, and Servier; served as an advisor and consultant for IPSEN, Bayer, Terasphere, Sirtex, Sanofi, Novartis, and Servier; and reports receipt of research grant and funding from Eli Lilly and Company. P.M.: conflict with Bayer, Ipsen/Exelixis, BMS, Onxeo, MSD, AstraZeneca, Eisai, and Roche. S.L.C.: conflict with Eisai, Merck, and AstraZeneca. D.H.P.: conflict with Bayer, Eisai, BMS, and Sirtex. M.I.: conflict with Bayer, Bristol-Myers Squibb, Eisai, Sumitomo Dainippon, EA Pharma, Takeda Pharmaceutical, AstraZeneca, Chugai, Merck Serono, Gilead, ASLAN, Daiichi Sankyo, Novartis, Teijin Pharma, Kyowa Hakko Kirin, NanoCarrier, Shire, Yakult, Taiho, Baxalta, Nobelpharma, Otsuka, Ono, MSD, J-Pharma, Mylan, NIHON SERVIER, and Eli Lilly and Company. T.Y.: received personal fees from Eli Lilly and Eisai. A.V.: conflict with Eli Lilly and Company, EISAI, Roche, BMS, MSD, Bayer, BTG, AstraZeneca, Ipsen, Novartis; Y-H. Huang: Eisai, BMS, Merck, AstraZeneca, Bayer, Gilead, Abbvie, Roche, Eli Lilly, and IPSEN. P.B.A.: employed by Eli Lilly and Company, stocks held in Eli Lilly and Company. R.Y.: Eli Lilly Japan KK, stocks held in Eli Lilly and Company. K.S.: Eli Lilly Japan KK. C.W.: employed by Eli Lilly and Company, stocks held in Eli Lilly and Company. R.C.W.: employed by Eli Lilly and Company, stocks held in Eli Lilly and Company. A.X.Z.: conflict with Eisai, BMS, Merck, Novartis, Sanofi, AstraZeneca, Bayer, Roche, Eli Lilly and Company, and Exelixis. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2020 The Authors.)