Circulating Oncometabolite 2-hydroxyglutarate as a Potential Biomarker for Isocitrate Dehydrogenase (IDH1/2) Mutant Cholangiocarcinoma.

Isocitrate dehydrogenase (IDH) enzymes catalyze the decarboxylation of isocitrate to alpha-ketoglutarate (αKG). IDH1/2 mutations preferentially convert αKG to R-2-hydroxyglutarate (R2HG), resulting in R2HG accumulation in tumor tissues. We investigated circulating 2-hydroxyglutate (2HG) as potential biomarkers for patients with IDH-mutant (IDHmt) cholangiocarcinoma (CCA). R2HG and S-2-hydroxyglutarate (S2HG) levels in blood and tumor tissues were analyzed in a discovery cohort of patients with IDHmt glioma and CCA. Results were validated in cohorts of patients with CCA and clear-cell renal cell carcinoma. The R2HG/S2HG ratio (rRS) was significantly elevated in tumor tissues, but not in blood for patients with IDHmt glioma, while circulating rRS was elevated in patients with IDHmt CCA. There were overlap distributions of circulating R2HG and total 2HG in patients with both IDHmt and wild-type (IDHwt) CCA, while there was minimal overlap in rRS values between patients with IDHmt and IDHwt CCA. Using the rRS cut-off value of 1.5, the sensitivity of rRS was 90% and specificity was 96.8%. Circulating rRS is significantly increased in patients with IDHmt CCA compare with patients with IDHwt CCA. Circulating rRS is a sensitive and specific surrogate biomarker for IDH1/2 mutations in CCA. It can potentially be used as a tool for monitoring IDH-targeted therapy.

Increase in serum choline levels predicts for improved progression-free survival (PFS) in patients with advanced cancers receiving pembrolizumab.

BACKGROUND: Recent studies have demonstrated that T cells can induce vasodilation in a choline-acetyltransferase dependent manner, leading to an increase in T cell migration to infected tissues in response to viral infection, but its role in cancer is unclear. Choline acetyltransferase catalyzes the production of acetylcholine from choline and acetyl-CoA, however, acetylcholine is challenging to quantify due to its extremely short half-life while choline is stable. This study aims to correlate serum choline levels in patients with advanced solid tumors receiving pembrolizumab with treatment outcomes. METHODS: Blood samples were collected at baseline and at week 7 (pre-cycle 3) in patients treated with pembrolizumab in the INvestigator-initiated Phase 2 Study of Pembrolizumab Immunological Response Evaluation phase II trial (NCT02644369). Samples were analyzed for choline and circulating tumor DNA (ctDNA). Multivariable Cox models were used to assess the association between choline and overall survival (OS) and progression-free survival (PFS) when including ΔctDNAC3 (the change in ctDNA from baseline to cycle 3), cohort, PD-L1 expression and tumor mutation burden (TMB). An independent validation cohort from the LIBERATE study (NCT03702309) included patients on early phase trials treated with a PD-1 inhibitor. RESULTS: A total of 106 pts were included in the analysis. With a median follow-up of 12.6 months, median PFS and OS were 1.9 and 13.7 months, respectively. An increase in serum choline level at week 7 compared with baseline (ΔcholineC3) in 81 pts was significantly associated with a better PFS (aHR 0.48, 95% CI 0.28 to 0.83, p=0.009), and a trend toward a better OS (aHR 0.64, 95% CI 0.37 to 1.12, p=0.119). A combination of ΔctDNAC3 and ΔcholineC3 was prognostic for both OS and PFS. Multivariable analyses show ΔcholineC3 was a prognostic factor for PFS independent of ΔctDNAC3, cohort, PD-L1 and TMB. In the independent validation cohort (n=51), an increase in serum choline at cycle 2 was associated with a trend to improved PFS. CONCLUSIONS: This is the first exploratory report of serum choline levels in pan-cancer patients receiving pembrolizumab. The association between improved PFS and ΔcholineC3 suggests a possible role for the cholinergic system in the regulation of antitumor immunity. Further pre-clinical and clinical studies are required to validate this finding. TRIAL REGISTRATION NUMBER: NCT03702309.

Semen and serum platinum levels in cisplatin-treated survivors of germ cell cancer.

BACKGROUND: Testicular cancer survivors often have impaired gonadal function possibly related to chemotherapy. Platinum is a heavy metal that can be detected at low levels in serum many years after treatment, it is not known whether platinum also persists in semen and if platinum persistence in semen is associated with impaired fertility. METHODS: Adult cisplatin-treated testicular cancer survivors were enrolled. High-Performance Liquid Chromatography-tandem mass spectrometry was used to measure semen and serum platinum levels. Semen quality and DNA Fragmentation Index (DFI) were assessed. RESULTS: From 11/2017 to 12/2019, 38 patients (median age 32 years; range: 19-52) were enrolled. Median cumulative cisplatin dose was 301 mg/m2 (range: 274-404). Platinum levels were higher in semen than in blood (p = 0.03). Semen platinum levels were not significantly associated with time from last cisplatin dosing (r = -0.34; p = 0.09) nor cumulative dose (r = -0.10, p = 0.63). Sperm concentration was correlated with time from last cisplatin dosing (r = 0.58, p < 0.001) but not with semen platinum level (r = -0.15, p = 0.46). DFI was not significantly associated with time from last cisplatin dosing (r = 0.55, p = 0.08) or semen platinum level (r = -0.32, p = 0.33). In four patients with serial semen samples, platinum level decreased and sperm concentration and motility increased over time. CONCLUSIONS: Platinum is detected in semen of testicular cancer survivors at higher levels than matched blood samples. These preliminary findings may have important implications for the reproductive health of survivors of advanced testicular cancer, further study is needed to assess the relationship between platinum persistence in semen and recovery of fertility postchemotherapy.

A phase I study of the oral gamma secretase inhibitor R04929097 in combination with gemcitabine in patients with advanced solid tumors (PHL-078/CTEP 8575).

PURPOSE: To establish the recommended phase II dose of the oral γ-secretase inhibitor RO4929097 (RO) in combination with gemcitabine; secondary objectives include the evaluation of safety, tolerability, pharmacokinetics, biomarkers of Notch signaling and preliminary anti-tumor activity. METHODS: Patients with advanced solid tumors were enrolled in cohorts of escalating RO dose levels (DLs). Tested RO DLs were 20 mg, 30 mg, 45 mg and 90 mg. RO was administered orally, once daily on days 1-3, 8-10, 15-17, 22-24. Gemcitabine was administered at 1,000 mg/m(2) on d1, 8, and 15 in 28 d cycles. Dose limiting toxicities (DLTs) were assessed by CTCAE v4. Serial plasma was collected for RO (total and unbound) and gemcitabine pharmacokinetic analysis. Biomarkers of Notch signaling were assessed by immunohistochemistry in archival tissue. Antitumor activity was evaluated (RECIST 1.1). RESULTS: A total of 18 patients were enrolled to establish the recommended phase II dose. Of these, 3 patients received 20 mg RO, 7 patients received 30 mg RO, 6 patients received 45 mg RO and 2 patients received 90 mg RO. DLTs were grade 3 transaminitis (30 mg RO), grade 3 transaminitis and maculopapular rash (45 mg RO), and grade 3 transaminitis and failure to receive 75 % of planned RO doses secondary to prolonged neutropenia (90 mg); all were reversible. The maximum tolerated dose was exceeded at 90 mg RO. Pharmacokinetic analysis of both total and free RO confirmed the presence of autoinduction at 45 and 90 mg. Median levels of Notch3 staining were higher in individuals who received fewer than 4 cycles (p = 0.029). Circulating angiogenic factor levels did not correlate with time to progression or ≥ grade 3 adverse events. Best response (RECIST 1.1) was partial response (nasopharyngeal cancer) and stable disease > 4 months was observed in 3 patients (pancreas, tracheal, and breast primary cancers). CONCLUSIONS: RO and gemcitabine can be safely combined. The recommended phase II dose of RO was 30 mg in combination with gemcitabine 1,000 mg/m(2). Although RO exposure was limited by the presence of autoinduction, RO levels achieved exceeded the area under the concentration-time curve for 0-24 h (AUC(0-24)) predicted for efficacy in preclinical models using daily dosing. Evidence of clinical antitumor activity and prolonged stable disease were identified.

Phase I study of decitabine in combination with vorinostat in patients with advanced solid tumors and non-Hodgkin's lymphomas.

PURPOSE: This phase I study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the combination of decitabine with vorinostat. PATIENTS AND METHODS: Patients with advanced solid tumors or non-Hodgkin's lymphomas were eligible. Sequential and concurrent schedules were studied. RESULTS: Forty-three patients were studied in 9 different dose levels (6 sequential and 3 concurrent). The maximum tolerated dose (MTD) on the sequential schedule was decitabine 10 mg/m(2)/day on days 1 to 5 and vorinostat 200 mg three times a day on days 6 to 12. The MTD on the concurrent schedule was decitabine 10 mg/m(2)/day on days 1 to 5 with vorinostat 200 mg twice a day on days 3 to 9. However, the sequential schedule of decitabine 10 mg/m(2)/day on days 1 to 5 and vorinostat 200 mg twice a day on days 6 to 12 was more deliverable than both MTDs with fewer delays on repeated dosing and it represents the recommended phase II (RP2D) dose of this combination. Dose-limiting toxicities during the first cycle consisted of myelosuppression, constitutional and gastrointestinal symptoms and occurred in 12 of 42 (29%) patients evaluable for toxicity. The most common grade 3 or higher adverse events were neutropenia (49% of patients), thrombocytopenia (16%), fatigue (16%), lymphopenia (14%), and febrile neutropenia (7%). Disease stabilization for 4 cycles or more was observed in 11 of 38 (29%) evaluable patients. CONCLUSION: The combination of decitabine with vorinostat is tolerable on both concurrent and sequential schedules in previously treated patients with advanced solid tumors or non-Hodgkin's lymphomas. The sequential schedule was easier to deliver. The combination showed activity with prolonged disease stabilization in different tumor types.

Phase I study of decitabine in combination with vorinostat in patients with advanced solid tumors and non-Hodgkin's lymphomas.

PURPOSE: This phase I study evaluated the safety, tolerability, pharmacokinetics and preliminary efficacy of the combination of decitabine with vorinostat. PATIENTS AND METHODS: Patients with advanced solid tumors or non-Hodgkin's lymphomas were eligible. Sequential and concurrent schedules were studied. RESULTS: Forty-three patients were studied in 9 different dose levels (6 sequential and 3 concurrent). The maximum tolerated dose (MTD) on the sequential schedule was decitabine 10 mg/m(2)/day on days 1-5 and vorinostat 200 mg three times a day on days 6-12. The MTD on the concurrent schedule was decitabine 10 mg/m(2)/day on days 1-5 with vorinostat 200 mg twice a day on days 3-9. However, the sequential schedule of decitabine 10 mg/m(2)/day on days 1-5 and vorinostat 200 mg twice a day on days 6-12 was more deliverable than both MTDs with fewer delays on repeated dosing and it represents the recommended phase II (RP2D) dose of this combination. Dose-limiting toxicities during the first cycle consisted of myelosuppression, constitutional and gastrointestinal symptoms and occurred in 12/42 (29%) patients evaluable for toxicity. The most common ≥ grade 3 adverse events were neutropenia (49% of patients), thrombocytopenia (16%), fatigue (16%), lymphopenia (14%), and febrile neutropenia (7%). Disease stabilization for ≥ 4 cycles was observed in 11/38 (29%) evaluable patients. CONCLUSION: The combination of decitabine with vorinostat is tolerable on both concurrent schedules in previously treated patients with advanced solid tumors or non-Hodgkin's lymphomas. The sequential schedule was easier to deliver. The combination showed activity with prolonged disease stabilization in different tumor types.

[Effects of feixianping on serum interleukin-6 and oxygen partial pressure in pulmonary fibrosis rats].

OBJECTIVE: To study the effects of feixianping (FXP) in improving hypoxemia and on serum interleukin-6 (IL-6) in experimental rats with pulmonary fibrosis (PF). METHODS: Two hundred and forty healthy male SD rats were randomly divided into 5 groups, 48 in each group, i.e. the normal control group (A), the model group (B), the prednisone group (C) and the two FXP groups of high (21.6 mg x kg(-1)) and low (10.8 mg x kg(-1)) dosage (D and E). PF model rats were established by intratracheal instillation of bleomycin, excepting those in Group A, to which normal saline was administered. The corresponding treatment to various groups started from the 1st day after modeling. Rats were sacrificed in batch at 4 time points, i.e., the 7th, 14th, 21st and 28th day, their arterial blood was collected for determination of blood partial pressure of oxygen (PaO2) and serum IL-6 content. RESULTS: Serum IL-6 content in Group B at all the time points was higher than that in other groups at the same time points (P<0.01). In the FXP treated groups (D and E), levels of IL-6 at the 7th, 14th and 28th day showed no significant difference from those in Group A and C. Since the 14th day, FXP showed its effect in improving hypoxemia in experimental rats which could basically keep in accordance with the effect of prednisone. CONCLUSION: FXP can ameliorate hypoxemia and reduce the level of serum IL-6 in experimental PF rats.