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Supplementary Figure S3. Maximum change from baseline in the sum of target lesions and treatment duration ("other tumor types", intrahepatic cholangiocarcinoma, glioblastoma).

Supplemental Table S2 from Activity of PXD101, a histone deacetylase inhibitor, in preclinical ovarian cancer studies

Purpose: To evaluate the safety, pharmacokinetics, and pharmacodynamics of BAY 86-9766, a selective, potent, orally available, small-molecule allosteric inhibitor of mitogen-activated protein kinase 1/2 in patients with advanced solid tumors.Experimental Design: BAY 86-9766 was administered orally daily in 28-day courses, with doses escalated to establish the maximum-tolerated dose (MTD). An expanded cohort was evaluated at the MTD. Pharmacokinetic and pharmacodynamic parameters were assessed, with extracellular signal–regulated kinase (ERK) phosphorylation evaluated in paired biopsies from a subset of the expanded MTD cohort. Tumor specimens were evaluated for mutations in select genes.Results: Sixty-nine patients were enrolled, including 20 patients at the MTD. The MTD was 100 mg given once-daily or in two divided doses. BAY 86-9766 was well-tolerated. The most common treatment-related toxicities were acneiform rash and gastrointestinal toxicity. BAY 86-9766 was well-absorbed after oral administration (plasma half-life ∼12 hours), and displayed dose proportional pharmacokinetics throughout the tested dose range. Continuous daily dosing resulted in moderate accumulation at most dose levels. BAY 86-9766 suppressed ERK phosphorylation in biopsied tissue and tetradecanoylphorbol acetate–stimulated peripheral blood leukocytes. Of 53 evaluable patients, one patient with colorectal cancer achieved a partial response and 11 patients had stable disease for 4 or more courses. An ocular melanoma specimen harbored a GNAQ-activating mutation and exhibited reduced ERK phosphorylation in response to therapy.Conclusion: This phase I study showed that BAY 86-9766 was well-tolerated, with good oral absorption, dose proportional pharmacokinetics, target inhibition at the MTD, and some evidence of clinical benefit across a range of tumor types. Clin Cancer Res; 19(5); 1232–43. ©2012 AACR.

Purpose:BAY1436032, an inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), was active against multiple IDH1-R132X solid tumors in preclinical models. This first-in-human study was designed to determine the safety and pharmacokinetics of BAY1436032, and to evaluate its potential pharmacodynamics and antitumor effects.Patients and Methods:The study comprised of dose escalation and dose expansion cohorts. BAY1436032 tablets were orally administered twice daily on a continuous basis in subjects with mIDH1 solid tumors.Results:In dose escalation, 29 subjects with various tumor types were administered BAY1436032 across five doses (150–1,500 mg twice daily). BAY1432032 exhibited a relatively short half-life. Most evaluable subjects experienced target inhibition as indicated by a median maximal reduction of plasma R-2-hydroxyglutarate levels of 76%. BAY1436032 was well tolerated and an MTD was not identified. A dose of 1,500 mg twice daily was selected for dose expansion, where 52 subjects were treated in cohorts representing four different tumor types [lower grade glioma (LGG), glioblastoma, intrahepatic cholangiocarcinoma, and a basket cohort of other tumor types]. The best clinical outcomes were in subjects with LGG (n = 35), with an objective response rate of 11% (one complete response and three partial responses) and stable disease in 43%. As of August 2020, four of these subjects were in treatment for >2 years and still ongoing. Objective responses were observed only in LGG.Conclusions:BAY1436032 was well tolerated and showed evidence of target inhibition and durable objective responses in a small subset of subjects with LGG.

Histone deacetylase inhibitors represent a promising new class of anticancer agents. In the current investigation, we examined the activity of PXD101, a potent histone deacetylase inhibitor, used alone or in combination with clinically relevant chemotherapeutics (docetaxel, paclitaxel, and carboplatin), in preclinical in vitro and in vivo models of ovarian cancer. In vitro activity was examined in ovarian cancer and multidrug-resistant cell lines grown in monolayer culture, and in primary clinical ovarian cancer specimens grown in three-dimensional organoid culture. PXD101 was found to inhibit in vitro cancer cell growth at sub- to low micromolar IC50 potency, exhibited synergistic activity when used in combination with relevant chemotherapeutics, and effectively inhibited the growth of multidrug-resistant cells. In vivo, PXD101 displayed single-agent antitumor activity on human A2780 ovarian cancer s.c. xenografts which was enhanced via combination therapy with carboplatin. In support of these findings, PXD101 was shown to increase the acetylation of α-tubulin induced by docetaxel and the phosphorylation of H2AX induced by carboplatin. Taken together, these results support the clinical evaluation of PXD101 used alone or in combination therapy for the treatment of ovarian cancer. [Mol Cancer Ther 2006;5(8):2086–95]

Supplementary appendix: Includes 2 tables: (1) summary of analysis results for plasma biomarkers as predictive factors for treatment effect on overall survival; and (2) summary of analysis results for plasma biomarkers as predictive factors for time to progression. A figure legend for the supplemental figures is also included.

Supplementary Table S12. NGS analysis of select tumor-associated genes in archival tumor tissue obtained from a subset of subjects.

Supplementary Figure 2. Tumor mutations assayed by the Sequenom OncoCarta Panel 1.0.

Table S1: Dose-limiting toxicities; Table S2:Multiple-dose pharmacokinetic parameters (geometric mean (%CV) of BAY 86-9766 and metabolite M17 on Course 1, Day 22 (representing exposure after 15 days of continuous dosing) for once-daily dosing cohorts; Table S3: Multiple-dose pharmacokinetic parameters of BAY 86-9766 and metabolite M17 on Course 1, Day 22 (representing exposure after 15 days of continuous dosing) for twice-daily dosing cohorts

Revised Supplemental materials

Supplementary Figure 1. CONSORT diagram

Supplementary Figure 1. Kaplan-Meier survival curves of treatment effect on TTP in patients with low (left panel) and high (right panel) baseline levels of (A) epiregulin (max chi interaction P value = 0.193), (B) VEGF-A (max chi interaction P value = 0.153), (C) HGF (max chi interaction P value = 0.157), and (D) PDGF (max chi interaction P value = 0.167). All biomarkers were dichotomized using the max chi optimized cutoff. BL=baseline; Erlot=erlotinib; HGF=hepatocyte growth factor; PDGF=platelet-derived growth factor; Pla=placebo; Sor=sorafenib; TTP=time to progression; VEGF=vascular endothelial growth factor.

Purpose: Sorafenib is the current standard therapy for advanced hepatocellular carcinoma, but validated biomarkers predicting clinical outcomes are lacking. This study aimed to identify biomarkers predicting prognosis and/or response to sorafenib, with or without erlotinib, in hepatocellular carcinoma patients from the phase III SEARCH trial.Experimental Design: A total of 720 patients were randomized to receive oral sorafenib 400 mg twice daily plus erlotinib 150 mg once daily or placebo. Fifteen growth factors relevant to the treatment regimen and/or to hepatocellular carcinoma were measured in baseline plasma samples.Results: Baseline plasma biomarkers were measured in 494 (69%) patients (sorafenib plus erlotinib, n = 243; sorafenib plus placebo, n = 251). Treatment arm–independent analyses showed that elevated hepatocyte growth factor [HGF; HR, 1.687 (high vs. low expression); endpoint multiplicity adjusted (e-adj) P = 0.0001] and elevated plasma VEGFA (HR, 1.386; e-adj P = 0.0377) were significantly associated with poor overall survival (OS) in multivariate analyses, and low plasma KIT [HR, 0.75 (high vs. low); P = 0.0233; e-adj P = 0.2793] tended to correlate with poorer OS. High plasma VEGFC independently correlated with longer TTP (HR, 0.633; e-adj P = 0.0010) and trended toward associating with improved disease control rate (univariate: OR, 2.047; P = 0.030; e-adj P = 0.420). In 67% of evaluable patients (339/494), a multimarker signature of HGF, VEGFA, KIT, EPGN, and VEGFC correlated with improved median OS in multivariate analysis (HR, 0.150; P < 0.00001). No biomarker predicted efficacy from erlotinib.Conclusions: Baseline plasma HGF, VEGFA, KIT, and VEGFC correlated with clinical outcomes in hepatocellular carcinoma patients treated with sorafenib with or without erlotinib. These biomarkers plus EPGN constituted a multimarker signature for improved OS. Clin Cancer Res; 22(19); 4870–9. ©2016 AACR.

Supplementary Methods, Supplementary Results, Supplementary Tables S1-S11

Legend for supplementary figure

Supplementary Tables. Supplementary Table 1. Pre-defined dose modification levels for sorafenib and refametinib Supplementary Table 2. Single-dose refametinib and its metabolite M17 geometric mean (% coefficient of variation) pharmacokinetic parameters on cycle 1 day −3 Supplementary Table 3. Multiple-dose refametinib and its metabolite M17, and sorafenib and its metabolite M2, geometric mean (% coefficient of variation) pharmacokinetic parameters on cycle 2 day 1 Supplementary Table 4. Incidence of treatment-emergent adverse events (occurring in {greater than or equal to}25% of patients), by CTCAE grade Supplementary Table 5. Incidence of adverse events related to refametinib and sorafenib (occurring in {greater than or equal to}15% of patients), by CTCAE grade Supplementary Table 6. Incidence of treatment-emergent serious adverse events (occurring in {greater than or equal to}2 patients), by CTCAE grades 2-5 Supplementary Table 7. Incidence of treatment-emergent serious adverse events (occurring in {greater than or equal to}2 patients) of CTCAE grades 3-5, related to both study drugs

Treatment schema

Purpose: There is an unmet need for treatment options in hepatocellular carcinoma (HCC). Sorafenib is currently the only approved systemic treatment for HCC. Refametinib, an oral, allosteric MEK inhibitor, has demonstrated antitumor activity in combination with sorafenib in vitro and in vivo. A phase II study evaluated efficacy and safety of refametinib plus sorafenib in Asian patients with HCC (NCT01204177).Experimental Design: Eligible patients received twice-daily refametinib 50 mg plus twice-daily sorafenib 200 mg (morning)/400 mg (evening), with dose escalation to sorafenib 400 mg twice daily from cycle 2 if no grade ≥2 hand-foot skin reaction, fatigue, or gastrointestinal toxicity occurred. Primary efficacy endpoint: disease control rate. Secondary endpoints: time to progression, overall survival, pharmacokinetic assessment, biomarker analysis, safety, and tolerability.Results: Of 95 enrolled patients, 70 received study treatment. Most patients had liver cirrhosis (82.9%) and hepatitis B viral infection (75.7%). Disease control rate was 44.8% (primary efficacy analysis; n = 58). Median time to progression was 122 days, median overall survival was 290 days (n = 70). Best clinical responders had RAS mutations; majority of poor responders had wild-type RAS. Most frequent drug-related adverse events were diarrhea, rash, aspartate aminotransferase elevation, vomiting, and nausea. Dose modifications due to adverse events were necessary in almost all patients.Conclusions: Refametinib plus sorafenib showed antitumor activity in patients with HCC and was tolerated at reduced doses by most patients. Frequent dose modifications due to grade 3 adverse events may have contributed to limited treatment effect. Patients with RAS mutations appear to benefit from refametinib/sorafenib combination. Clin Cancer Res; 20(23); 5976–85. ©2014 AACR.

Purpose:The phase III DECISION trial (NCT00984282; EudraCT:2009-012007-25) established sorafenib efficacy in locally recurrent or metastatic, progressive, differentiated thyroid cancer (DTC) refractory to radioactive iodine. We conducted a retrospective, exploratory biomarker analysis of patients from DECISION.Experimental Design:Candidate biomarkers [15 baseline plasma proteins, baseline and during-treatment serum thyroglobulin, and relevant tumor mutations (BRAF, NRAS, HRAS, and KRAS)] were analyzed for correlation with clinical outcomes.Results:Plasma biomarker and thyroglobulin data were available for 395 of 417 (94.7%) and 403 of 417 (96.6%) patients, respectively. Elevated baseline VEGFA was independently associated with poor prognosis for progression-free survival [PFS; HR = 1.82; 95% confidence interval (CI), 1.38–2.44; P = 0.0007], overall survival (HR = 2.13; 95% CI, 1.37–3.36; P = 0.013), and disease-control rate (DCR; OR = 0.30; P = 0.009). Elevated baseline thyroglobulin was independently associated with poor PFS (HR = 2.03; 95% CI, 1.52–2.71; P < 0.0001) and DCR (OR = 0.32; P = 0.01). Combined VEGFA/thyroglobulin signatures correlated with poor PFS (HR = 2.12; 95% CI, 1.57–2.87; P < 0.00001). Thyroglobulin decrease ≥30% from baseline was achieved by 76% and 14% of patients receiving sorafenib and placebo, respectively (P < 0.001). Patients with ≥30% thyroglobulin reduction had longer PFS than those without ≥30% reduction [HR (95% CI): sorafenib = 0.61 (0.40–0.94), P = 0.022; placebo = 0.49 (0.29–0.85), P = 0.009]. BRAF mutations were associated with better PFS; RAS mutations were associated with worse PFS, although neither was independently prognostic in multivariate models. No examined biomarker predicted sorafenib benefit.Conclusions:We identified biomarkers associated with poor prognosis in DTC, including elevated baseline VEGFA and thyroglobulin and the presence of RAS mutations. Serum thyroglobulin may be a biomarker of tumor response and progression.

The mutant IDH1 (mIDH1) inhibitor BAY1436032 demonstrated robust activity in preclinical AML models, supporting clinical evaluation. In the current dose-escalation study, BAY1436032 was orally administered to 27 mIDH1 AML subjects across 4 doses ranging from 300 to 1500 mg twice-daily. BAY1436032 exhibited a relatively short half-life and apparent non-linear pharmacokinetics after continuous dosing. Most subjects experienced only partial target inhibition as indicated by plasma R-2HG levels. BAY1436032 was safe and a maximum tolerated dose was not identified. The median treatment duration for all subjects was 3.0 months (0.49–8.5). The overall response rate was 15% (4/27; 1 CRp, 1 PR, 2 MLFS), with responding subjects experiencing a median treatment duration of 6.0 months (3.9–8.5) and robust R-2HG decreases. Thirty percent (8/27) achieved SD, with a median treatment duration of 5.5 months (3.1–7.0). Degree of R-2HG inhibition and clinical benefit did not correlate with dose. Although BAY1436032 was safe and modestly effective as monotherapy, the low overall response rate and incomplete target inhibition achieved at even the highest dose tested do not support further clinical development of this investigational agent in AML.

SUMMARYMutations affecting isocitrate dehydrogenase (IDH) enzymes are prevalent in glioma, leukemia, and other cancers. Although mutant IDH inhibitors are effective against leukemia, they appear less active in aggressive glioma, underscoring the need for alternative treatment strategies. Through a chemical synthetic lethality screen, we discovered that IDH1 mutant glioma cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate dehydrogenase (DHODH). We developed a genetically engineered mouse model of mutant IDH1-driven astrocytoma and used it and multiple patient-derived models to show that the brain-penetrant DHODH inhibitor BAY 2402234 displays monotherapy efficacy against IDH mutant gliomas. Mechanistically, this vulnerability selectively applies to de novo pyrimidine, but not purine, synthesis because glioma cells engage disparate programs to produce these nucleotide species and because IDH oncogenes increase DNA damage upon nucleotide pool imbalance. Our work outlines a tumor-selective, biomarker-guided therapeutic strategy that is poised for clinical translation.

Lymphoma diagnosis is complex, requiring a wide array of adjunctive tests to reach accurate diagnoses. We retrospectively examined the rates of concordance between referral and review lymphoma diagnoses on cases referred to St James’s Hospital, Dublin for multidisciplinary team review between 2013 and 2016. Frequency and cost of adjunctive diagnostic tests performed were also analysed. The overall discordance rate was 7.8% (14/179), compared with rates of 6%–48% in the published literature. 13 discordant cases required a change in clinical management following review of the referred diagnosis. Of all referred cases, 33.5% (60/179) required extra analyses to reach a final diagnosis, costing the reference laboratory €35463.40. We conclude that establishment of centralised haematopathology diagnostic networks would help reduce the rate of revision made to lymphoma diagnoses by providing specialist haematopathologist input and access to ancillary testing.

Mutations affecting isocitrate dehydrogenase (IDH) enzymes are prevalent in glioma, leukemia, and other cancers. Although mutant IDH inhibitors are effective against leukemia, they seem to be less active in aggressive glioma, underscoring the need for alternative treatment strategies. Through a chemical synthetic lethality screen, we discovered that IDH1-mutant glioma cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate dehydrogenase (DHODH). We developed a genetically engineered mouse model of mutant IDH1-driven astrocytoma and used it and multiple patient-derived models to show that the brain-penetrant DHODH inhibitor BAY 2402234 displays monotherapy efficacy against IDH-mutant gliomas. Mechanistically, this reflects an obligate dependence of glioma cells on the de novo pyrimidine synthesis pathway and mutant IDH's ability to sensitize to DNA damage upon nucleotide pool imbalance. Our work outlines a tumor-selective, biomarker-guided therapeutic strategy that is poised for clinical translation.

Background In the phase 3 GRID trial, regorafenib improved progression-free survival (PFS) independent of KIT mutations in exons 9 and 11. In this retrospective, exploratory analysis of the GRID trial, we investigated whether a more comprehensive KIT mutation analysis could identify mutations that impact treatment outcome with regorafenib and a regorafenib-induced mutation pattern. Methods Archived tumor samples, collected at any time prior to enrollment in GRID, were analyzed by Sanger sequencing (n = 102) and next-generation sequencing (FoundationONE; n = 47). Plasma samples collected at baseline were analyzed by BEAMing (n = 163) and SafeSEQ (n = 96). Results In archived tumor samples, 67% (68/102) had a KIT mutation; 61% (62/102) had primary KIT mutations (exons 9 and 11) and 12% (12/102) had secondary mutations (exons 13, 14, 17, and 18). At baseline, 81% of samples (78/96) had KIT mutations by SafeSEQ, including the M541L polymorphism (sole event in 6 patients). Coexisting mutations in other oncogenes were rare, as were mutations in PDGFR, KRAS, and BRAF. Regorafenib showed PFS benefit across all primary and secondary KIT mutational subgroups examined. Available patient-matched samples taken at baseline and end of treatment (n = 41; SafeSEQ), revealed heterogeneous KIT mutational changes with no specific mutation pattern emerging upon regorafenib treatment. Conclusion These data support the results of the GRID trial, and suggest that patients may benefit from regorafenib in the presence of KIT mutations and without the selection of particular mutation patterns that confer resistance. The study was not powered to address biomarker-related questions, and the results are exploratory and hypothesis-generating.

Purpose: BAY1436032, an inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), was active against multiple IDH1-R132X solid tumors in preclinical models. This first-in-human study was designed to determine the safety and pharmacokinetics of BAY1436032, and to evaluate its potential pharmacodynamics and antitumor effects. Patients and Methods: The study comprised of dose escalation and dose expansion cohorts. BAY1436032 tablets were orally administered twice daily on a continuous basis in subjects with mIDH1 solid tumors. Results: In dose escalation, 29 subjects with various tumor types were administered BAY1436032 across five doses (150–1,500 mg twice daily). BAY1432032 exhibited a relatively short half-life. Most evaluable subjects experienced target inhibition as indicated by a median maximal reduction of plasma R-2-hydroxyglutarate levels of 76%. BAY1436032 was well tolerated and an MTD was not identified. A dose of 1,500 mg twice daily was selected for dose expansion, where 52 subjects were treated in cohorts representing four different tumor types [lower grade glioma (LGG), glioblastoma, intrahepatic cholangiocarcinoma, and a basket cohort of other tumor types]. The best clinical outcomes were in subjects with LGG (n = 35), with an objective response rate of 11% (one complete response and three partial responses) and stable disease in 43%. As of August 2020, four of these subjects were in treatment for >2 years and still ongoing. Objective responses were observed only in LGG. Conclusions: BAY1436032 was well tolerated and showed evidence of target inhibition and durable objective responses in a small subset of subjects with LGG.

70–90% of lower-grade gliomas and secondary glioblastomas harbor gain-of-function mutations in isocitrate dehydrogenase 1 (IDH1), causing overproduction of the oncometabolite (R)-2-hydroxyglutarate [(R)-2HG]. Although inhibitors of mutant IDH enzymes are effective in other cancers, including leukemia, they have shown guarded efficacy in preclinical and clinical brain tumor studies, thus underscoring the need to identify additional therapeutic targets in IDH mutant glioma. We sought to identify tumor-specific metabolic vulnerabilities induced by IDH1 mutations that could be exploited therapeutically. To uncover such vulnerabilities, we conducted a chemical synthetic lethality screen using isogenic IDH1 mutant and IDH1 wild-type (WT) glioma cell lines and a novel metabolic inhibitor screening platform. We discovered that IDH1 mutant cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate dehydrogenase (DHODH). This vulnerability is specific because inhibitors of purine nucleotide metabolism did not score in our screen. We validated that the cytotoxicity of pyrimidine synthesis inhibitors is on-target and showed that IDH1 mutant patient-derived glioma stem-like cell lines are also hyperdependent on de novo pyrimidine nucleotide synthesis compared to IDH1 WT lines. To test pyrimidine synthesis dependence of IDH1 mutant gliomas in vivo, we used a brain-penetrent DHODH inhibitor currently undergoing evaluation in leukemia patients, BAY 2402234. We found that BAY 2402234 displays monotherapy activity against gliomas in an orthotopic xenograft model of IDH1 mutant glioma, with an effect size that compared favorably with radiotherapy. We also developed novel genetically engineered and allograft mouse models of mutant IDH1-driven anaplastic astrocytoma and showed that BAY 2402234 blocked growth of orthotopic astrocytoma allografts. Our findings bolster rationale to target DHODH in glioma, highlight BAY 2402234 as a clinical-stage drug that can be used to inhibit DHODH in brain tumors, and establish IDH1 mutations as predictive biomarkers of DHODH inhibitor efficacy.

Introduction: BAY2402234 is a potent and specific orally administered inhibitor of dihydroorotate dehydrogenase (DHODH) which showed anti-tumor activity in preclinical models of AML and is under clinical evaluation in myeloid malignancies (NCT03404726). Small cell lung cancer (SCLC) is a highly metastatic malignancy (the brain being a frequent metastatic site), which carries a dismal clinical prognosis. Previous preclinical research indicated that SCLC was particularly sensitive to DHODH inhibition, and in the current investigation the activity of BAY2402234 in this tumor indication was evaluated. Experimental Procedures: A variety of in vivo models derived from human SCLC samples were evaluated: (1) cell-line derived xenograft (CDX) subcutaneous models; (2) a CDX intracranial model; and (3) patient-derived xenograft (PDX) subcutaneous models. As is typical for SCLC, most of these models harbored mutations in both p53 and Rb1. BAY2402234 was administered orally either once daily or on an intermittent schedule (4 days on/3 days off). Standard-of-care (SoC) therapies were included in some experiments. Tumor tissue and plasma were collected for pharmacodynamic analyses. Results: In subcutaneous CDX models, BAY2402234 exhibited robust anti-tumor activity, including tumor regressions in some models. Strong anti-tumor activity was also observed in various subcutaneous PDX models, including activity in a model resistant to SoC therapy. In an intracranial tumor model, BAY2402234 significantly enhanced survival compared to the vehicle-treated cohort. Both dosing schedules tested were well-tolerated and highly active. Pharmacodynamic analyses to quantify the level of target inhibition observed in the various models are ongoing. Conclusions: The results of this investigation confirm and extend previous preclinical results and indicate that BAY2402234 may represent a novel treatment for SCLC, including patients with brain metastases. RESTRICTED Citation Format: Stefan Kaulfuss, Andreas Janzer, Gerhard Siemeister, Renan Borowicz, Katrin Jaensch, Katrin Gutberlet, Ricarda Schlenz, Andrea Triller, Ashley Eheim, Michael Jeffers, Sven Christian. Activity of DHODH inhibitor BAY2402234 in subcutaneous and intracranial models of SCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2077.

Purpose In the management of thyroid nodules, although the potential for malignancy exists, there is also the potential for overtreatment of subclinical disease. Although the TI-RADS (Thyroid Imaging-Reporting and Data System) system outlines a risk stratification score based on suspicious ultrasound findings, it has not been universally accepted. Many TI-RADS 2 or 3 patients proceed to fine needle aspiration biopsy (FNAB), potentially unnecessarily. The aim of the study was to identify whether lesions within a multinodular goiter (MNG) without suspicious features can be followed with ultrasound rather than biopsied as is recommended for single nodules. Methods Pathology records were retrospectively analysed for proven MNGs over a 5-year period. A total of 293 cases were identified. FNAB, prebiopsy ultrasound images, and reports were identified for each case. Images were reviewed and assessed for sonographically suspicious criteria guided by TI-RADS. Logistic regression was applied to determine if any sonographic features were associated with neoplasia. Odds ratios with 95% confidence intervals were calculated. Results Of 293 samples, 14 (4.7%) were neoplastic. Having no suspicious features conferred an average risk of 0.0339 (95% confidence interval: 0.02831-0.04087) of neoplasia. Risk of neoplasm significantly increased by having 1 and >1 suspicious feature ( P < .001). Regarding cytological results, of 237 patients with Thy-2 cytology, 159 were followed up and 8 had a neoplasm. Conclusion Ultrasound can be used to estimate risk of neoplasia in MNG. In the absence of suspicious radiological findings, follow-up with ultrasound rather than FNAB may be appropriate in patients who have a low clinical suspicion for neoplasia.

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin’s lymphoma. While many patients will be cured with Rituximab-CHOP, 30%–50% will either relapse or have disease refractory to treatment.1 The International Prognostic Index is not sufficiently accurate to stratify these patients into prognostic subgroups, thus gene expression profiling (GEP) and the identification of gene rearrangements (R) involving Myc , Bcl-2 and Bcl-6 are instead used for risk stratification. GEP or more commonly immunohistochemistry (IHC)-based algorithms are used to stratify patients according to their cell of origin (COO), broadly dividing them into germinal centre B (GCB), and non-GCB subgroups. The latter group incorporates the activated B-cell (ABC) subtype, which is associated with significantly worse outcomes when treated with standard chemotherapy regimens, as compared with the GCB subgroup.2 Double hit (DH) lymphomas are characterised by the presence of a Myc gene R with a concurrent Bcl-2 or Bcl-6 gene R, while triple hit (TH) lymphomas have all three. The rearrangement status of these lymphomas is reflected in the updated WHO classification of lymphoid neoplasms in 2017. DH/TH lymphomas account for 5%–10% of (morphologic) DLBCL.2 Interestingly, 80% of DH lymphomas have concurrent Myc and Bcl-2 R and are associated with the GCB subtype, while dual translocations of Myc and Bcl-6 are more commonly linked to the ABC phenotype.3 Overexpression of c-myc protein (defined as >40% positive neoplastic …

This phase I study evaluated the safety, tolerability, and pharmacokinetics of copanlisib, an intravenously administered pan-phosphatidylinositol 3-kinase inhibitor in patients with advanced solid tumors or non-Hodgkin's lymphoma. Copanlisib was well tolerated with a manageable safety profile, with anti-tumor activity in both advanced solid tumors and hematological malignancies., Background To evaluate the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of copanlisib, a phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors or non-Hodgkin's lymphoma (NHL). Patients and methods Phase I dose-escalation study including patients with advanced solid tumors or NHL, and a cohort of patients with type 2 diabetes mellitus. Patients received three weekly intravenous infusions of copanlisib per 28-day cycle over the dose range 0.1–1.2 mg/kg. Plasma copanlisib levels were analyzed for pharmacokinetics. Biomarker analysis included PIK3CA, KRAS, BRAF, and PTEN mutational status and PTEN immunohistochemistry. Whole-body [18F]-fluorodeoxyglucose positron emission tomography (18FDG-PET) was carried out at baseline and following the first dose to assess early pharmacodynamic effects. Plasma glucose and insulin levels were evaluated serially. Results Fifty-seven patients received treatment. The MTD was 0.8 mg/kg copanlisib. The most frequent treatment-related adverse events were nausea and transient hyperglycemia. Copanlisib exposure was dose-proportional with no accumulation; peak exposure positively correlated with transient hyperglycemia post-infusion. Sixteen of 20 patients treated at the MTD had reduced 18FDG-PET uptake; 7 (33%) had a reduction >25%. One patient achieved a complete response (CR; endometrial carcinoma exhibiting both PIK3CA and PTEN mutations and complete PTEN loss) and two had a partial response (PR; both metastatic breast cancer). Among the nine NHL patients, all six with follicular lymphoma (FL) responded (one CR and five PRs) and one patient with diffuse large B-cell lymphoma had a PR by investigator assessment; two patients with FL who achieved CR (per post hoc independent radiologic review) were on treatment >3 years. Conclusion Copanlisib, dosed intermittently on days 1, 8, and 15 of a 28-day cycle, was well tolerated and the MTD was determined to be 0.8 mg/kg. Copanlisib exhibited dose-proportional pharmacokinetics and promising anti-tumor activity, particularly in patients with NHL. ClinicalTrials.gov NCT00962611; https://clinicaltrials.gov/ct2/show/NCT00962611.

Purpose: The phase III DECISION trial (NCT00984282; EudraCT:2009-012007-25) established sorafenib efficacy in locally recurrent or metastatic, progressive, differentiated thyroid cancer (DTC) refractory to radioactive iodine. We conducted a retrospective, exploratory biomarker analysis of patients from DECISION. Experimental Design: Candidate biomarkers [15 baseline plasma proteins, baseline and during-treatment serum thyroglobulin, and relevant tumor mutations (BRAF, NRAS, HRAS, and KRAS)] were analyzed for correlation with clinical outcomes. Results: Plasma biomarker and thyroglobulin data were available for 395 of 417 (94.7%) and 403 of 417 (96.6%) patients, respectively. Elevated baseline VEGFA was independently associated with poor prognosis for progression-free survival [PFS; HR = 1.82; 95% confidence interval (CI), 1.38–2.44; P = 0.0007], overall survival (HR = 2.13; 95% CI, 1.37–3.36; P = 0.013), and disease-control rate (DCR; OR = 0.30; P = 0.009). Elevated baseline thyroglobulin was independently associated with poor PFS (HR = 2.03; 95% CI, 1.52–2.71; P < 0.0001) and DCR (OR = 0.32; P = 0.01). Combined VEGFA/thyroglobulin signatures correlated with poor PFS (HR = 2.12; 95% CI, 1.57–2.87; P < 0.00001). Thyroglobulin decrease ≥30% from baseline was achieved by 76% and 14% of patients receiving sorafenib and placebo, respectively (P < 0.001). Patients with ≥30% thyroglobulin reduction had longer PFS than those without ≥30% reduction [HR (95% CI): sorafenib = 0.61 (0.40–0.94), P = 0.022; placebo = 0.49 (0.29–0.85), P = 0.009]. BRAF mutations were associated with better PFS; RAS mutations were associated with worse PFS, although neither was independently prognostic in multivariate models. No examined biomarker predicted sorafenib benefit. Conclusions: We identified biomarkers associated with poor prognosis in DTC, including elevated baseline VEGFA and thyroglobulin and the presence of RAS mutations. Serum thyroglobulin may be a biomarker of tumor response and progression.

Pulmonary Nodular Lymphoid Hyperplasia (PNLH) is a rare benign pulmonary disorder characterized by a localized, reactive polyclonal lymphoproliferation. Although the radiological features of this disease have not been clearly defined, they usually consist of a solitary non-cavitatory pulmonary nodule. In this report, we describe two cases of histologically confirmed PNLH presenting as multiple bilateral cavitatory lesions on CT Thorax.

Sporadic Burkitt lymphoma (BL), characterised by translocation-associated C-MYC upregulation is a rare, aggressive lymphoma with a cure rate up to 90 % using the R-CODOX-M/R-IVAC (RCRI) protocol. RCRI is active in HIV-associated BL in combination with HAART. The WHO classification system defines lymphomas intermediate between DLBCL and BL, in which lymphomas with t(14;18)(q32;q21) and C-MYC-carrying translocation, i.e. ‘double-hit’ are included (BL-DH), and these patients are conventionally treated with RCRI. We describe the SJH experience of 25 patients with BL, BL + HIV and BL-DH treated with RCRI between 2002 and 2011. Twelve BL patients (8M/4F), median age 49.1 years (range 20–73 years); of whom 9 had extensive disease, including 8 with marrow and 2 with CNS involvement. Eleven patients remain in remission at 80.5 months (range 37–147 months) from completion of treatment and one died of progressive BL giving an OS of 91.6 % at 1 year with no late relapses. Eight patients with BL + HIV were treated (6M/2F) with a median age 40.25 years (range 24–64). Five remain in complete remission (CR) at 65 months (range 13–109 months), three patients died, two of progressive disease and one of treatment-associated hepatotoxicity in CR. Five patients with BL-DH were included; (3M/2F), age 47.8 years (range 42–55 years); and all patients died of progressive disease, 4 on RCRI therapy and a further patient despite an allogeneic transplantation. These results confirm that RCRI is an effective treatment in adults with BL and BL + HIV and remains the gold standard against which other regimens should be compared. We confirm the poor prognosis found in BL-DH, indicating new treatment approaches are needed for this sub-group which should be identified at diagnosis by FISH analysis.

Background: Approximately 40% of AML patients with IDH1 mutation respond to monotherapy with the IDH1 inhibitor ivosidenib with a median duration of response of 8.2 months, suggesting that IDH1 inhibitors should be rationally combined with other agents to improve efficacy. We have previously shown the synergistic activity of the mutant IDH1 (mIDH1) inhibitor BAY1436032 with azacitidine. We have also shown that the leukemogenic activity of the mIDH1 protein depends on PHD3 independent of R-2HG and its inhibition as a novel therapeutic strategy (Chaturvedi et al. 2018). Inhibition of Brd4 has been shown to induce rapid differentiation and death of IDH2 mutated AML mouse models (Chen et al., 2013). In the present study, we assessed the combination of either conventional chemotherapy, prolyl hydroxylase (PHD) inhibitor molidustat or bromodomain inhibitor JQ1 with BAY1436032 (BAY) in a preclinical patient-derived xenograft (PDX) model of mIDH1 AML. Methods and Results: Leukemic cells from an AML patient with mutated IDH1, NPM1, FLT3-TKD and NRAS were xenografted in immunocompromised mice. We investigated the effects of BAY in sequential (seq) or simultaneous (sim) combination with cytarabine plus doxorubicin in our mIDH1 PDX model. The control groups were treated with either vehicle, BAY (150 mg/kg once daily p.o. continuously), or chemotherapy, which consisted of cytarabine (50 mg/kg once daily days 1-5 i.v.) and doxorubicin (1 mg/kg once daily days 1-3 i.v.). The treatment was repeated once after 29 days. The test groups were treated with BAY and chemotherapy in the doses mentioned above either starting both drugs on day 1 (sim group) or starting chemotherapy on day 1 and BAY on day 6 (seq group). Treatment with BAY was stopped after 12 weeks. Leukemic cells in peripheral blood constantly increased in vehicle and chemotherapy-treated mice with median time to 50% engraftment (MT 50%) of 84 and 112 days respectively. After stop of treatment, the percentage of leukemic cells increased in the group receiving BAY1436032 (MT 50%: 252 days) and sequential combination (MT 50%: 280 days), however, the MT50% was not reached with the simultaneous treatment (P We hypothesized that combination therapy with BAY and molidustat may demonstrate superior anti-leukemic activity in comparison to single agents in the treatment of IDH1-mutant AML. mIDH1 PDX mice were treated with either vehicle, BAY at a dose of 150 mg/kg or molidustat at a dose of 10 mg/kg p.o. as monotherapy or in combination. The MT50% for Vehicle, Molidustat and BAY was 70, 70 and 182 days respectively,. However, the MT50% was significantly delayed (322 days) for the combination treatment (P Mutant IDH1 PDX mice were treated with either vehicle, BAY, BRD4 inhibitor JQ1 (50mg/kg i.p. once daily) or the combination of BAY and JQ1 for 12 weeks. JQ1 monotherapy showed a significant delay in leukemia engraftment compared to vehicle-treated mice in the first 12 weeks of treatment. During the treatment, the leukemic cells remained low in both BAY and combination treated mice but relapsed at the same time 4 weeks after the treatment had been stopped. Median survival for vehicle-treated mice was 139 days, 164 days for JQ1-treated mice, 220 days for BAY treated mice, and 242 days for the combination treatment (BAY vs combination; P=0.03). Conclusion: Similar to the combination treatment of BAY with azacitidine the concurrent administration of BAY with chemotherapy significantly improves efficacy of this combination compared to sequential administration. In addition, the combination of an IDH1 inhibitor with molidustat is a promising therapeutic approach, while the combination with the BRD4 inhibitor JQ1 did not improve the outcome compared to treatment with an IDH1 inhibitor alone. Our findings support ongoing and future clinical investigations and suggest that IDH1 inhibitors should be applied concurrently with chemotherapy. Disclosures Chaturvedi: Bayer Pharma AG, Berlin, Germany: Research Funding. Kaulfuss:Bayer Pharma AG, Berlin, Germany: Employment. Panknin:Bayer Pharma AG, Berlin, Germany: Employment. Wagner:Bayer Pharma AG, Berlin, Germany: Employment, Equity Ownership. Jeffers:Bayer Pharma AG, Whippany, NJ, USA: Employment. Haegebarth:Bayer Pharma AG, Berlin, Germany: Employment, Equity Ownership. Heuser:Synimmune: Research Funding; Bayer Pharma AG, Berlin: Research Funding.

This paper discusses the problems within autonomous robotic assembly workflows as they encounter a variable property of assembly parts or materials. This is shown through a case study with an industrial robot in an enclosed work cell and a simple assembly task with wooden sticks of variable lengths, designed as an adaptive feedback control system. To perform the study, the development of a virtual model for the persistent storage of material data and computation of next build-actions is required. Different sensing strategies are used to address issues of substantial, and minute, material variabilities of dimensional properties as they deviate from a predictive virtual model. Establishing communication strategies for a live-control pipeline as the infrastructure for this system allows the system to respond to pre-build scans of part dimensions, as well as update the virtual model when post-build scanning detected deviation. In the worst-case scenario—if preconditions were not met—the post-build scan would be unsuccessful and the system would self-terminate. Otherwise, deviations would update and influence future actions. This influence is what leads to the indeterminate nature of the resultant forms.

Summary Background Regorafenib inhibits VEGF receptors 1, 2, and 3 and PDGF receptors like other anti-angiogenic tyrosine-kinase inhibitors approved for treatment of advanced renal-cell cancer. Regorafenib also inhibits other potentially important angiogenic kinases like TIE2, activation of which is thought to be important in tumour escape mechanisms. This phase 2, open-label, non-randomised study assessed the safety and efficacy of the multikinase inhibitor regorafenib for treatment of renal-cell carcinoma. Methods Patients were recruited from 18 academic oncology centres across Europe and USA. Patients with previously untreated metastatic or unresectable clear-cell renal-cell carcinoma received oral regorafenib (160 mg per day) in repeating cycles of 3 weeks on, 1 week off until disease progression or until patients met the criteria for removal from study. The primary efficacy endpoint was the proportion of patients who achieved an objective overall response, assessed in all patients who were evaluable for response. The trial has finished. This trial is registered with ClinicalTrials.gov, number NCT00664326. Findings The study was done between April 30, 2008, and June 1, 2011. We screened 64 patients, of whom 49 received regorafenib. Median duration of treatment was 7·1 months (range 0·7–34·4, IQR 2·5–18·0) and at the time of data cutoff, six patients (12%) were still receiving treatment. 48 patients were assessable for tumour response. 19 patients (39·6%, 90% CI 27·7–52·5) had an objective response, all of which were partial responses. Drug-related adverse events occurred in 48 patients (98%) and drug-related serious adverse events in 17 (35%). Grade 3 drug-related adverse events were common, most frequently hand and foot skin reaction (16 patients, 33%), diarrhoea (five patients, 10%), renal failure (five patients, 10%), fatigue (four patients, 8%), and hypertension (three patients, 6%). Two patients had grade 4 treatment-related adverse events: two cardiac ischaemia or infarction, one hypomagnesaemia, and one pain in the chest or thorax. Four patients died during study treatment or within 30 days of last dose, of which two were deemed likely to be related to the study drug. Interpretation Regorafenib has antitumour activity as first-line treatment for metastatic or unresectable renal-cell carcinoma. The drug's safety profile requires close monitoring. Funding Bayer HealthCare Pharmaceuticals.

The objective of this study was to make an assessment of the utility of fine needle aspiration cytology (FNAC), in a “one-stop” symptomatic breast triple assessment clinic. Controversy surrounds the optimal tissue biopsy methodology in the diagnosis of symptomatic breast cancer and the identification of benign disease. FNAC in the context of a Rapid Assessment Breast Clinic (RABC) allows the same day diagnosis and early treatment of breast cancer, with the immediate reassurance and discharge of those with benign disease. We analyzed prospective data accrued at a RABC, over a 4-year period from 2004 to 2007. All patients were triple assessed, with FNACs performed on site by two consultant cytopathologists. Investigations were reported immediately, and clinical data were captured via a database using compulsory data field entry. There were 4487 attendances at our RABC, with 1572 FNACs were performed. The positive predictive value of FNAC with a C5 cancer diagnosis was 100%, 95.6% for a C4 report, with a complete sensitivity of 94%. The full specificity of correctly identified benign lesions was 77.4%, with a false negative rate of 3.85%. This enabled 66% of patients attending the RABC to receive a same day diagnosis of benign disease and discharge. FNAC is highly accurate in the diagnosis of symptomatic breast cancer in an RABC. FNAC allows accurate diagnosis of benign disease and immediate discharge of the majority of patients. In this era, when a large majority of patients have benign disease, we believe that FNAC provides an equivalent, if not better, method of evaluation of patients in a triple assessment RABC.

Dobson L, Conway C, Hanley A, Johnson A, Costello S, O’Grady A, Connolly Y, Magee H, O’Shea D, Jeffers M & Kay E (2010) Histopathology 57, 27–38 Image analysis as an adjunct to manual HER-2 immunohistochemical review: a diagnostic tool to standardize interpretation Aims: Accurate determination of HER-2 status is critical to identify patients for whom trastuzumab treatment will be of benefit. Although the recommended primary method of evaluation is immunohistochemistry, numerous reports of variability in interpretation have raised uncertainty about the reliability of results. Recent guidelines have suggested that image analysis could be an effective tool for achieving consistent interpretation, and this study aimed to assess whether this technology has potential as a diagnostic support tool. Methods and results: Across a cohort of 275 cases, image analysis could accurately classify HER-2 status, with 91% agreement between computer-aided classification and the pathology review. Assessment of the continuity of membranous immunoreactivity in addition to intensity of reactivity was critical to distinguish between negative and equivocal cases and enabled image analysis to report a lower referral rate of cases for confirmatory fluorescence in situ hybridization (FISH) testing. An excellent concordance rate of 95% was observed between FISH and the automated review across 136 informative cases. Conclusions: This study has validated that image analysis can robustly and accurately evaluate HER-2 status in immunohistochemically stained tissue. Based on these findings, image analysis has great potential as a diagnostic support tool for pathologists and biomedical scientists, and may significantly improve the standardization of HER-2 testing by providing a quantitative reference method for interpretation.

The human HDAC (histone deacetylase) family, a well-validated anticancer target, plays a key role in the control of gene expression through regulation of transcription. While HDACs can be subdivided into three main classes, the class I, class II and class III HDACs (sirtuins), it is presently unclear whether inhibiting multiple HDACs using pan-HDAC inhibitors, or targeting specific isoforms that show aberrant levels in tumours, will prove more effective as an anticancer strategy in the clinic. To address the above issues, we have tested a number of clinically relevant HDACis (HDAC inhibitors) against a panel of rhHDAC (recombinant human HDAC) isoforms. Eight rhHDACs were expressed using a baculoviral system, and a Fluor de Lys™ (Biomol International) HDAC assay was optimized for each purified isoform. The potency and selectivity of ten HDACs on class I isoforms (rhHDAC1, rhHDAC2, rhHDAC3 and rhHDAC8) and class II HDAC isoforms (rhHDAC4, rhHDAC6, rhHDAC7 and rhHDAC9) was determined. MS-275 was HDAC1-selective, MGCD0103 was HDAC1- and HDAC2-selective, apicidin was HDAC2- and HDAC3-selective and valproic acid was a specific inhibitor of class I HDACs. The hydroxamic acid-derived compounds (trichostatin A, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat) were potent pan-HDAC inhibitors. The growth-inhibitory effect of the HDACis on HeLa cells showed that both pan-HDAC and class-I-specific inhibitors inhibited cell growth. The results also showed that both pan-HDAC and class-I-specific inhibitor treatment resulted in increased acetylation of histones, but only pan-HDAC inhibitor treatment resulted in increased tubulin acetylation, which is in agreement with their activity towards the HDAC6 isoform.

Histone deacetylase inhibitors (HDACi) represent a promising new class of anticancer agents. In the current investigation, we examined the activity of the HDACi belinostat in preclinical models of prostate cancer. In vitro proliferation assays demonstrated that belinostat potently inhibited the growth of prostate cancer cell lines (IC(50) < 1.0 microM) and was cytotoxic to these cells. Washout experiments indicated that exposure to belinostat for relatively short periods of time (