INTRODUCTION {#s1}
============

Melanoma has one of the fastest increasing incidence rates of any cancer \[[@R1], [@R2]\]. According to 2014 estimates, there were 76,100 new cases of, and 9710 deaths from, malignant melanoma in the United States. Approved treatments for metastatic melanoma have only recently demonstrated significant activity. These treatments include ipilimumab (human cytotoxic T-lymphocyte antigen 4-blocking antibody), vemurafenib, dabrafenib (*BRAF* inhibitors), trametinib (MEK inhibitor), pembrolizumab (anti-programmed cell death 1 antibody), and nivolumab (an anti-PD1 receptor immune checkpoint inhibitor monoclonal antibody). Median overall survival with standard treatment is 7--15.9 months, and response rates range from 10.2% to 53% \[[@R3]--[@R8]\]. Unfortunately, some patients do not respond, and most still develop recurrent disease.

Angiogenesis---the formation of new blood vessels---is critical for tumor survival and progression \[[@R1], [@R2]\]. Genetic aberrations associated with angiogenic signaling pathways mediated by growth factors, including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF), have been correlated with progression in metastatic melanoma \[[@R1], [@R2]\].

Lenvatinib (E7080) is an orally active multikinase inhibitor of VEGF-receptor (VEGFR) 1--3, FGF-receptor (FGFR) 1--4, PDGF-receptor (PDGFR)-α, RET, and KIT proto-oncogenes \[[@R9]\]. In phase 1 studies, lenvatinib showed antitumor activity in solid-tumor patients at a maximum tolerated dose (MTD) of 25 mg/day \[[@R10], [@R11]\]. Temozolomide (TMZ) is an oral chemotherapeutic agent that shows evidence of response and similar efficacy to that of dacarbazine in melanoma, but it is also able to cross the blood--brain barrier, giving it a possible role in the treatment of melanoma patients with brain metastases \[[@R12]\]. TMZ is metabolized through nonenzymatic pH-dependent hydrolysis, and, therefore, has low potential for drug-drug interactions \[[@R13]\]. The combination of an alkylating agent and VEGF inhibitor has been previously proposed. In *in vitro* studies and *in vivo* xenograft models of melanoma, treatment with dacarbazine increased VEGF expression, providing a potential resistance mechanism to monotherapy \[[@R14], [@R15]\]. Preclinical data from a human melanoma xenograft study that evaluated a combination of lenvatinib and TMZ showed preliminary evidence of an additive efficacy (Eisai, Inc.; data on file).

We report here the phase 1b results of a phase 1/1b study conducted to determine the MTD and pharmacokinetic profile of lenvatinib when given once daily in combination with TMZ as treatment for advanced melanoma. The safety and tolerability of the combination, tumor response, and potential biomarkers of efficacy of this combination were also evaluated.

RESULTS {#s2}
=======

Patients {#s2_1}
--------

A total of 32 patients with metastatic melanoma were enrolled across the 3 dose levels (DLs): DL1, *n* = 6; DL2, *n* = 4; and DL3, *n* = 22. The demographics and baseline characteristics for the overall study population are summarized in Table [1](#T1){ref-type="table"}. The median age of patients was 57.5 years (range, 24--81). The majority of patients (65.6%) had an Eastern Cooperative Oncology Group (ECOG) performance score of 1, 62.5% were male, and 84% had received at least 1 prior chemotherapy regimen. Two patients, both in DL3, had previously received ipilimumab. The *BRAF*^*V600E*^ tumor mutation was present in 7 (44%) of 16 evaluable patients and the *NRAS* tumor mutation was present in 6 (50%) of 12 evaluable patients.

###### Baseline Patient Characteristics

  ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
  Category                                                            DL1\                                  DL2\                                  DL3\                                  Combined\
                                                                      Lenvatinib 20 mg + TMZ 100 mg/m^2^\   Lenvatinib 24 mg + TMZ 100 mg/m^2^\   Lenvatinib 24 mg + TMZ 150 mg/m^2^\   Total\
                                                                      (*n* = 6)                             (*n* = 4)                             (*n* = 22)                            (*N* = 32)
  ------------------------------------------------------------------- ------------------------------------- ------------------------------------- ------------------------------------- --------------
  **Age, years**

   Mean (SD)                                                          62.5 (9.71)                           57.0 (8.08)                           53.2 (13.97)                          55.4 (12.94)

   Median                                                             59.0                                  55.0                                  55.5                                  57.5

   Range (Min, Max)                                                   55, 81                                50, 68                                24, 79                                24, 81

  **Sex, *n* (%)**

   Male                                                               5 (83.3)                              3 (75.0)                              12 (54.5)                             20 (62.5)

   Female                                                             1 (16.7)                              1 (25.0)                              10 (45.5)                             12 (37.5)

  **Race, *n* (%)**

   Non-Hispanic White                                                 4 (66.7)                              4 (100)                               19 (86.4)                             27 (84.4)

   Hispanic                                                           1 (16.7)                              0                                     3 (13.6)                              4 (12.5)

   African-American                                                   1 (16.7)                              0                                     0                                     1 (3.1)

  **ECOG score^[a](#tfn_001){ref-type="table-fn"}^, *n* (%)**

   0                                                                  3 (50.0)                              2 (50.0)                              6 (27.3)                              11 (34.4)

   1                                                                  3 (50.0)                              2 (50.0)                              16 (72.7)                             21 (65.6)

  **Previous anticancer treatments, *n* (%)**

   Chemotherapy ≥ 1                                                   5 (83.3)                              3 (75.0)                              19 (86.4)                             27 (84.4)

   Radiotherapy                                                       3 (50.0)                              3 (75.0)                              9 (40.9)                              15 (46.9)

   Surgery                                                            6 (100)                               4 (100)                               22 (100)                              32 (100)

   Other anticancer treatment regimens                                3 (50.0)                              2 (50.0)                              13 (59.1)                             18 (56.3)

  **Previous chemotherapy regimens, *n* (%)**

   0                                                                  1 (16.7)                              1 (25.0)                              3 (13.6)                              5 (15.6)

   1                                                                  2 (33.3)                              2 (50.0)                              10 (45.5)                             14 (43.8)

   2                                                                  2 (33.3)                              0                                     4 (18.2)                              6 (18.8)

   ≥3                                                                 1 (16.7)                              1 (25.0)                              5 (22.7)                              7 (21.9)

  **Mutational status,^[a](#tfn_001){ref-type="table-fn"}^*n* (%)**

   *BRAF*                                                             NA                                    NA                                    7 (43.8)                              NA

   *NRAS*                                                             NA                                    NA                                    6 (50.0)                              NA
  ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

16 And 12 patient tumors were evaluable for *BRAF* and *NRAS* testing, respectively.

DL, dose level; ECOG, Eastern Cooperative Oncology Group; NA, not available; SD, standard deviation; TMZ, temozolomide.

Overall, 22 (68.8%) patients discontinued the study due to progressive disease (PD) or clinical deterioration (DL1, *n* = 4; DL2, *n* = 3; DL3, *n* = 15). Additionally, 5 patients withdrew consent (DL1, *n* = 1; DL3, *n* = 4), and 1 patient from each group discontinued due to adverse events (AEs) AEs (DL1) and physician\'s decision (DL2). Three patients (9.4%) died either during study treatment or within 30 days after last dose (DL1, *n* = 2; DL3, *n* = 2).

Dose-limiting toxicities and maximum tolerated dose {#s2_2}
---------------------------------------------------

One dose-limiting toxicity (DLT) (grade 3 proteinuria) occurred in DL1. The MTD was not reached because no patients experienced a DLT at the highest combination dose (DL3). Investigators chose not to escalate the lenvatinib dosage beyond 24 mg/day (the established MTD for lenvatinib) or TMZ dose beyond 150 mg/m^2^ (the conventional dose level when combined with other drugs).

Safety {#s2_3}
------

The safety population was comprised of all 32 patients receiving at least 1 dose of study drug. Fatigue (56%), hypertension (53%), and proteinuria (47%) were the most commonly observed study-drug-related toxicities (Table [2](#T2){ref-type="table"}). The most common National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0) grade 3 study-drug-related toxicities in the overall study population were asthenia (13%), hypertension (9%), fatigue (6%), hyponatremia (6%), and proteinuria (6%), with most grade 3 toxicities seen in DL3 (Table [2](#T2){ref-type="table"}). Only 1 grade 4 drug-related toxicity (DL3; myocardial infarction) occurred and was handled through dose adjustment. Overall, 31.3% of patients experienced only grade 1--2 toxicities. A total of 3 patients died during treatment or within 30 days of last dose. All 3 deaths appear to have been due to disease progression.

###### Adverse Events Occurring in ≥ 20% of Overall Patients and CTC Grade 3 Drug-related Adverse Events Occurring in at Least 2 Patients

  ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                DL1\                                  DL2\                                  DL3\                                  Combined\
                                                                                Lenvatinib 20 mg + TMZ 100 mg/m^2^\   Lenvatinib 24 mg + TMZ 100 mg/m^2^\   Lenvatinib 24 mg + TMZ 150 mg/m^2^\   Total\
                                                                                (*n* = 6)\                            (*n* = 4)\                            (*n* = 22)\                           (*N* = 32)\
                                                                                *n* (%)                               *n* (%)                               *n* (%)                               *n* (%)
  -------------------------------------------------------------------------------------- ------------------------------------- ------------------------------------- ------------------------------------- -------------
  **Patients with treatment-related all-grade AEs**                                      6 (100)                               4 (100)                               20 (90.9)                             30 (93.8)

  **≥20% All-grade drug-related TEAEs**

   Fatigue                                                                               4 (66.7)                              3 (75.0)                              11 (50.0)                             18 (56.3)

   Hypertension                                                                          5 (83.3)                              1 (25.0)                              11 (50.0)                             17 (53.1)

   Proteinuria                                                                           3 (50.0)                              1 (25.0)                              11 (50.0)                             15 (46.9)

   Hypothyroidism                                                                        3 (50.0)                              1 (25.0)                              10 (45.5)                             14 (43.8)

   Anorexia                                                                              3 (50.0)                              2 (50.0)                              9 (40.9)                              14 (43.8)

   Nausea                                                                                2 (33.3)                              1 (25.0)                              9 (40.9)                              12 (37.5)

   Vomiting                                                                              2 (33.3)                              0                                     10 (45.5)                             12 (37.5)

   Diarrhea                                                                              2 (33.3)                              1 (25.0)                              8 (36.4)                              11 (34.4)

   Thrombocytopenia                                                                      0                                     0                                     8 (36.4)                              8 (25.0)

   Asthenia                                                                              1 (16.7)                              1 (25.0)                              6 (27.3)                              8 (25.0)

   Blood thyroid stimulating hormone increased                                           0                                     1 (25.0)                              6 (27.3)                              7 (21.9)

  **Patients with CTC grade 3 drug-related TEAEs^[a](#tfn_002){ref-type="table-fn"}^**   2 (33.3)                              2 (50.0)                              9 (40.9)                              13 (40.6)

  CTC grade 3 drug-related TEAEs

   Asthenia                                                                              0                                     1 (25.0)                              3 (13.6)                              4 (12.5)

   Hypertension                                                                          1 (16.7)                              0                                     2 (9.1)                               3 (9.4)

   Fatigue                                                                               0                                     0                                     2 (9.1)                               2 (6.3)

   Hyponatremia                                                                          0                                     0                                     2 (9.1)                               2 (6.3)

   Proteinuria                                                                           1 (16.7)                              1 (25.0)                              0                                     2 (6.3)
  ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

Grade 4 drug-related TEAE occurred in 1 patient (myocardial infarction).

AEs, adverse events; CTC, common terminology criteria; DL, dose level; TEAE, treatment-emergent adverse event; TMZ, temozolomide.

Pharmacokinetics {#s2_4}
----------------

Overall, single-dose and repeat-dose PK parameters of lenvatinib were comparable across cycles and with concomitant TMZ administration ([Supplementary Table 1](#SD1){ref-type="supplementary-material"}). Lenvatinib area under the concentration-time curve extrapolation to time (AUC~(0--τ)),~ area under the curve from time 0 extrapolated to infinite time (AUC~(0--inf)~), and peak plasma concentration (C~max~) were similar across the 3 cohorts following single- and repeat-dose administration. Similarly, the median time to peak concentration (t~max~), terminal 1/2 life (t~1/2)~, and clearance after oral administration (CL/F) estimates for lenvatinib were independent of the dose of lenvatinib or TMZ regimen. Following administration of treatment on cycle 2 day 1, the median t~max~ ranged between 1 to 8 hours across the cohorts, and there was no apparent accumulation upon repeated administration of lenvatinib alone or in combination with TMZ (data not shown).

Tumor response and duration of treatment {#s2_5}
----------------------------------------

Patients in DL1 received a median of 3.0 (range 1.5) cycles of both lenvatinib and TMZ, patients in DL2 received a median of 3.0 (2.0, 4.0) cycles of lenvatinib and 2.5 (2.0, 4.0) cycles of TMZ, and patients in DL3 received a median of 4.0 (1.0, 7.0) cycles of lenvatinib and 3.5 (1.0, 7.0) cycles of TMZ. At the time of data cutoff, there were 4 partial responses (PRs) observed, with 3 patients still undergoing treatment; in an updated analysis, 2 out of those 3 patients additionally achieved PR (personal communication, D.S. Hong). A best response of PR was, therefore, observed in 6/32 (18.8%) patients, with 1 PR (16.7%) in DL1 and 5 PRs in DL3 (22.7%; Table [3](#T3){ref-type="table"}). All 6 patients who achieved PR received lenvatinib for at least 3 treatment cycles (range, 3--11 cycles). Stable disease (SD) ≥ 16 weeks was achieved by 9/32 (28.1%) patients; 1 patient each in DL1 and DL2, and 7 (31.8%) patients in DL3. Four (18.2%) patients in DL3 had durable SD. Median progression-free survival (PFS) in DL3 was 5.4 months.

###### Best Overall Tumor Responses

  -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
  Best Overall Tumor Response^[a](#tfn_003){ref-type="table-fn"}^   DL1\                                  DL2\                                  DL3\                                  Combined\
                                                                    Lenvatinib 20 mg + TMZ 100 mg/m^2^\   Lenvatinib 24 mg + TMZ 100 mg/m^2^\   Lenvatinib 24 mg + TMZ 150 mg/m^2^\   Total\
                                                                    (*n* = 6)\                            (*n* = 4)\                            (*n* = 22)\                           (*N* = 32)\
                                                                    *n* (%)                               *n* (%)                               *n* (%)                               *n* (%)
  ----------------------------------------------------------------- ------------------------------------- ------------------------------------- ------------------------------------- -------------
  Complete response                                                 0                                     0                                     0                                     0

  Partial response                                                  1 (16.7)                              0                                     5 (22.7)                              6 (18.8)

  Stable disease                                                    4 (66.7)                              2 (50.0)                              9 (40.9)                              15 (46.9)

  ≥16 Weeks                                                         1 (16.7)                              1 (16.7)                              7 (31.8)                              9 (28.1)

   ≥23 Weeks^[b](#tfn_004){ref-type="table-fn"}^                    0                                     0                                     4 (18.2)                              4 (12.5)

  Progressive disease                                               1 (16.7)                              1 (25.0)                              5 (22.7)                              7 (21.9)

  Unknown^[c](#tfn_005){ref-type="table-fn"}^                       0                                     1 (25.0)                              3 (13.6)                              4 (12.5)
  -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

DL, dose level; SD, stable disease; TMZ, temozolomide.

Responses evaluated based on RECIST 1.0 (Response Evaluation Criteria In Solid Tumors version 1.0). Responses for 3 patients were updated after the primary analysis because they were still on treatment at data cut-off: 2 Patients achieved partial responses, 1 patient achieved stable disease ≥23 weeks (personal communication, D.S. Hong).

Durable SD is defined as SD lasting ≥23 weeks.

Unknown -- not assessable or insufficient data.

Figure [1](#F1){ref-type="fig"} represents the maximum percentage change of target lesions from baseline in patients from DL3 stratified by *BRAF* and *NRAS* mutation status. Patients with wild type *BRAF* (BRAFWT) status (*n* = 7) seemed to have better overall response on treatment (*P* = 0.007). Two *BRAF*^WT^ patients achieved PR; 5 had SD ≥ 16 weeks (2 had durable \[ie, \> = 23 weeks\] SD). There was no significant correlation between *NRAS* mutation status and response (*n* = 5; *P* = 0.69).

![Patients with advanced/metastatic melanoma treated with the combination of lenvatinib and temozolomide\
\*3 Patients with PD and 2 patients with clinical deterioration were included in the waterfall arbitrarily at a 21% increase. Responses for 3 patients were updated after the primary analysis, since they were still on treatment at data cut-off: 2 Patients achieved partial responses, 1 patient achieved stable disease ≥23 weeks (personal communication, D.S. Hong).](oncotarget-06-43127-g001){#F1}

DISCUSSION {#s3}
==========

The MTD was not reached in this phase 1b combination treatment portion of the study because no patients experienced a DLT at the maximum administered dose of the combination treatment (DL3 once daily); however, the investigators felt it would have been inappropriate to further escalate either one of the drugs. The single DLT reported in this population was grade 3 proteinuria in DL1. The highest dose for further clinical evaluation of this combination was defined as lenvatinib 24 mg/day, days 1--28, plus TMZ 150 mg/m^2^, days 1--5.

The combination therapy of lenvatinib and TMZ generally had an acceptable toxicity profile in patients with advanced melanoma, and it was given at the highest level of DL3 without apparent worsening of either lenvatinib- or TMZ-related toxicities. The most common treatment-emergent adverse events (TEAEs) considered related to study drug by investigators included fatigue, hypertension, proteinuria, hypothyroidism, and anorexia. The incidences of several TEAEs, including hypothyroidism and thrombocytopenia (46.9% each), in this combination study were higher compared with those in a study of lenvatinib alone (15.6% and 13.0%, respectively). This difference may be due to the combination treatment (lenvatinib plus TMZ) or due to TMZ alone.

TMZ has a safety and efficacy profile similar to the current standard of care, dacarbazine. A benefit of adding TMZ to metastatic melanoma therapy may be its ability to cross the blood-brain barrier \[[@R12]\]. Single-agent TMZ has been associated with response rates of 0% to 29% in patients with metastatic melanoma \[[@R12]\]. In combination with interferon alpha, response rates of 13% to 23% have been reported \[[@R12]\]. An uncontrolled phase 2 study of TMZ in combination with sorafenib also demonstrated activity in TMZ-naïve patients with melanoma, including patients with brain metastases \[[@R16]\].

In the present study of TMZ and lenvatinib as a combination therapy, we observed a best overall response of PR in 18.8%, and SD ≥ 16 weeks in 28.1% of the overall population. In addition, 4 patients in DL3 experienced durable SD ≥ 23 weeks. Best overall response was not evaluable or censored in 4 patients. However, the response rates observed with TMZ and lenvatinib in the present study are lower than a 61% objective response rate (44 of 72 patients) observed in patients with melanoma receiving a combination of ipilimumab and nivolumab \[[@R17]\], and lower than a 31.7% objective response rate (38 or 120 patients) observed in a phase 3 trial of nivolumab in patients with metastatic melanoma whose disease had progressed after previous treatment with ipilimumab, or treatment with ipilimumab and a *BRAF* inhibitor if their tumors harbored a *BRAF* V600E mutation \[[@R18]\].

Overall, in our analysis of pharmacokinetic parameters, we found that the single-dose and repeat-dose pharmacokinetics of lenvatinib were comparable across cycles and with concomitant TMZ administration. Estimates of t~1/2,~ t~max~, and CL/F for lenvatinib were independent of the dose of lenvatinib or TMZ. The pharmacokinetics of lenvatinib 24 mg in combination with TMZ was comparable to that seen when lenvatinib was given as a monotherapy and there was no evidence for accumulation upon repeated administration of lenvatinib alone or in combination with TMZ.

Angiopoietins are ligands of the endothelial cell receptor soluble Tie-2 (sTie-2) and have crucial roles in tumor angiogenic switches \[[@R1]\]. In malignant melanoma, soluble angiopoietin-2 (sAng-2) levels are elevated and may function as part of an autocrine Ang-2/Tie2 growth loop. Circulating levels of sAng-2 have been correlated with tumor load, disease stage, and overall survival \[[@R19]\]. The relationship observed between maximum tumor shrinkage (MTS) and change in levels of Ang-2 in the current study suggests that this angiogenic pathway may be associated with the activity of lenvatinib.

The tumor gene mutation analyses performed in this study indicated that *BRAF~WT~* status appeared to correlate with better response to this combination treatment. No clear correlation between response and *NRAS* mutation status could be made. Due to the fairly small sample size and exploratory nature of these biomarker analyses, these findings should be further explored in larger ongoing studies of lenvatinib.

In conclusion, the combination of lenvatinib with TMZ had an acceptable toxicity profile and can be administered without increase in toxicity of either agent. This combination therapy demonstrated modest clinical activity in a population of patients with unresectable stage 3 or stage 4 melanoma. These results will be further confirmed in ongoing phase 2 studies of lenvatinib in advanced melanoma. Additional studies are also underway to further explore the potential role of lenvatinib in treatment of advanced or metastatic melanoma.

MATERIALS AND METHODS {#s4}
=====================

Patients {#s4_1}
--------

This was a phase 1/1b, open-label study (NCT00121680) conducted at the University of Texas MD Anderson Cancer Center and the Mary Crowley Cancer Research Center. The main inclusion criteria were: patients aged ≥ 18 years with a histological and/or cytological confirmed diagnosis of advanced or metastatic melanoma untreatable by standard therapies; melanoma lesions amenable to biopsy; adequate renal, hepatic, and hematologic parameters; and an ECOG performance status of 0 or 1. Patients who were intolerant of TMZ or any of its excipients, pregnant, required full-dose aspirin or chronic nonsteroidal anti-inflammatory drugs, or were untreated for or had unstable central nervous system metastases were excluded.

The study was conducted in accordance with World Medical Association Declaration of Helsinki and the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines. Prior to study participation, all participants provided written informed consent. The Mary Crowley Cancer Research Center and University of Texas MD Anderson Cancer Center Institutional Review Boards approved the study. A separate publication details results of the monotherapy portion of the phase 1 study of lenvatinib in solid tumors (including a melanoma population).

Study design {#s4_2}
------------

This phase 1b study utilized a standard "3+3" dose-escalation scheme to evaluate the MTD of lenvatinib in combination with TMZ. Patients were treated in sequential cohorts of escalating dosing of lenvatinib (continuous once daily) and TMZ (days 1--5) in a 28-day treatment cycle. The initial doses were lenvatinib 20 mg once daily with TMZ 100 mg/m^2^/day for days 1--5 (DL1). Subsequent doses were lenvatinib 24 mg with TMZ 100 mg/m^2^ (DL2) and lenvatinib 24 mg with TMZ 150 mg/m^2^ (DL3).

DLTs were assessed once the first 3 patients completed 1 treatment cycle. Any of the following events was defined as a DLT: any hematologic toxicity of grade 3 or higher; any nonhematologic toxicity of grade 3 or higher, with the exception of grade 3 hypertension that could be controlled (via intensification of single agent antihypertensive treatment or by adding a second antihypertensive); and any failure to administer ≥ 75% of the study drugs during cycle 1 due to treatment-related toxicities. The MTD was defined as the highest dose tolerated by a minimum of 5 out of the first 6 treated patients.

Procedures {#s4_3}
----------

Blood samples were collected on cycle 1, day 1 (C1D1) immediately prior to the first dose of lenvatinib and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 8, and 24 hours following administration on C1D1 and day 1 cycle 2. Additional samples were collected prior to lenvatinib administration on days 8, 15, and 22 of cycle 1, as well as on day 1 of cycles 3 and 4. T~max~, C~max~, C~trough~, AUC~0-t~, CL (total body clearance from plasma), Vss (volume of distribution at steady rate), and t~1/2~ were evaluated.

Pharmacodynamic assessments of lenvatinib were conducted based on serum samples collected prior to study drug administration and at 2 hours following administration on C1D1, as well as prior to administration on days 8, 15, and 22 of cycle 1. Serum samples were tested for angiogenesis-related markers (MDS Pharma/Clearstone Central Lab) and apoptosis-related (Pathway Diagnostics/Quest) markers. These angiogenesis-related markers were PDGF-homodimer BB, sTie-2 (receptor expressed by endothelial cells), angiopoietin-1 (Tie-2 ligand), soluble E-selectin (mediates leukocyte and tumor cell rolling), and soluble c-kit. The apoptosis-related markers assessed were cytochrome C (a measure of intrinsic apoptotic pathway activation) and M30 neoantigen (caspase-cleaved cytokeratin-18, also a terminal apoptotic product for epithelial-derived tumors). sTie-2, angiopoietin-1, PDGF-BB, soluble e-selectin, soluble c-kit, cytochrome C, and M30 were measured by enzyme-linked immunosorbent assay. PDGF-BB was assayed by Luminex Technology using Growth Factor Buffer Reagent and a Human Custom Multiplex Antibody Bead Kit from BioSource Invitrogen (Frederick, MD). Pretreatment (baseline) and posttreatment changes in levels of additional serum cytokine and angiogenic factors (CAF), including Ang-2, sVEGFR1-3, sTie-2, PDGF-AB, PDGF-BB, VEGFA, FGF4, VEGFD, hepatocyte growth factor, FMS-related tyrosine kinase 3 ligand (FLT3LG), and placental growth factor were evaluated. CAFs were measured in house by Eisai.

Safety assessments were performed in each cycle by physical examination, weekly blood pressure monitoring, periodic measurement of vital signs and electrocardiograms, ECOG performance status evaluation, and regular monitoring of hematology, blood chemistry, and urine values. All AEs and serious AEs were recorded.

Tumor assessments were conducted at baseline and approximately every 8 weeks during treatment. Responses were confirmed after ≥ 30 days using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0 \[[@R20]\]. Tumor responses were assessed by computed tomography, magnetic resonance imaging, or, in the case of skin lesions, photography and clinical examination. Tumor responses were classified as either complete response (CR), PR, SD, or progressive disease (PD). SD was further stratified as SD maintained for ≥ 7weeks and ≥ 16 weeks, and durable SD was defined as SD maintained for ≥ 23 weeks.

Tumor mutation analysis {#s4_4}
-----------------------

Paraffin-embedded tumor samples were macrodissected using a dissecting microscope and analyzed for *BRAF* and *NRAS* mutations at the Clinical Laboratory Improvement Amendments-certified Molecular Diagnostics Laboratory at MD Anderson using standard operating procedures.

Statistical analysis {#s4_5}
--------------------

Baseline and demographic variables including age, gender, race, height, weight, and ECOG performance score were summarized using descriptive statistics. Plasma concentrations of lenvatinib were analyzed and summarized using descriptive statistics for the following pharmacokinetic parameters: CL/F, AUC, C~max~, C~trough~, t~max~, and t~1/2~. Pearson and Spearman correlation coefficients were calculated between pharmacokinetic parameters and serum biomarkers at different time points compared with baseline to examine the correlation between drug exposure and biomarkers. Univariate and multivariate Cox proportional hazards models and log-rank tests were used to examine the relationship between PFS and baseline (and change from baseline) concentrations in angiogenesis and apoptosis biomarkers. Cumulative chi-square test was used to examine the correlation between mutation/serum biomarkers and best overall response. Pearson and Spearman correlation coefficients were also calculated between percent MTS (defined as percent change in sum of longest diameter from baseline to nadir using RECIST criteria) and serum biomarkers at different time points compared with baseline.

SUPPLEMENTARY DATA {#s5}
==================

We would like to thank all patients, as well as investigators and their teams, who participated and are participating in this study.

**CONFLICTS OF INTEREST**

David S. Hong, John Nemunaitis: Research funding, Eisai Inc. Kevin B. Kim: Honorarium and research funding, Eisai Inc. Min Ren, Lucy Xu, James P. O\'Brien: Employees of Eisai Inc. Razelle Kurzrock, Gerald S. Falchook, Corina Andresen, Jennifer Kwak, Goldy C. George, Ly M. Nguyen: Nothing to disclose.

**RESEARCH SUPPORT**

Medical editorial writing assistance was provided by Phase Five Communications and Oxford PharmaGenesis, Inc., and supported by Eisai, Inc.

The authors retained full editorial control over the manuscript.


A forensic artist has created an image of a mystery man found dead in a field more than two months ago.

Detectives struggling to identify his body have today released this striking picture in the hope someone recognises him.

The shock discovery of his body was made by a dog walker on the morning of February 3 in a field off Hollow Lane, Wincheap, near the A2 crossover.

An artist's impression of a man who was found dead in a field on February 3.

A post-mortem examination revealed the man died of natural causes.

Enquiries have been carried out to check he has not been reported missing elsewhere in the UK.

When his body was found, the man had on him a small black suitcase, an unregistered Oyster card and a book on clinical theology.

No identification was found and his fingerprints were not on file.

DS Gary Stamp said: "We would like to thank everyone who has been in touch with information about this case already.

"A forensic artist has digitally re-constructed how the man might have looked when alive and we are hoping that this detailed image might be recognisable to those who knew him."

Police taped off an alley near the field

The man is described as white and in his mid 50s to late 60s. He had short white hair and a short white beard.

He was of a slim to skinny build and was between 5ft 5in and 5ft 6in.

Anyone who recognises the man in the image, or has information they think would be useful, should contact police on 101 quoting SI/ZY/1363/17.


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The Last Remnant To Utilize SpeedTree

Everyone got all excited with the mention of Square-Enix's newest RPG next-gen project, The Last Remnant, and now there's one more reason to be excited.

Interactive Data Visualization has announced that their award-winning middleware, SpeedTreeRT, will be utilized in The Last Remnant. This addition will let developers create ultra-realistic trees and plants for the environment, which sounds somewhat basic on the surface, but there's plenty more to this than meets the eye. SpeedTree features more than 200 core species of plants and trees, plus "user-configurable and seamless LOD transitions" and "adjustable wind effects."

"Since it's able to render not only a large number, but a large variety of trees quickly, SpeedTree has really been an important tool for us in developing The Last Remnant," said Square Enix Chief Artist Kimihiko Miyamae.

The game is being powered by the Unreal Engine 3, which is yet another reason we think this game will be absolutely glorious when it finally arrives. SpeedTree is just another feather in S-E's cap at this point, but it's no real surprise. The company has been breaking new ground in video game visuals for years, so saying The Last Remnant should be gorgeous is hardly a stretch.


Synergistic interactions between differentiation-inducing agents in inhibiting the proliferation of HL-60 human myeloid leukaemia cells in clonogenic micro assays.
All-trans-retinoic acid, hexamethylene bisacetamide and 5-azacytidine are inducers of granulocytic differentiation of HL-60 human myeloid leukaemic cells, which eventually leads to inhibition of cell proliferation. The effect of graded concentrations of all-trans-retinoic acid (RA) (1 nM-1 microM), hexamethylene bisacetamide (HMBA) (0.5-4 mM) and/or 5-azacytidine (5azaC) (1 nM-1 mM), alone and in combination with each other on colony formation and growth of HL-60 cells was studied in agar capillary clonogenic micro assays in order to identify new potential therapeutic regimens for elderly patients with acute myeloid leukaemia. ED90 concentrations, inducing 90% inhibition of colony formation for RA, HMBA and 5azaC, were 128 nM, 2.7 mM and 40 microM, respectively. The drug interactions between these differentiating agents were analysed by Berenbaum's general algebraic solution. The combinations: RA + HMBA, 5azaC + HMBA and RA + 5azaC were significantly synergistic in inhibiting HL-60 colony formation. Their interaction indices were 0.62, 0.83, and 0.97, respectively, at a specific effect level of 15%. The addition of 1 mM HMBA to 100 nM 5azaC- and 1 nM RA-treated cultures significantly increased the colony-formation inhibition from only 2.6% and 7.0% to 46.4%, and 43.1%, respectively. Also, HMBA showed marked synergism with RA and 5azaC in inhibiting colony growth. The interaction indices (I) of HMBA + RA and HMBA + 5azaC were 0.013 and 0.009, respectively, at the same specific level of 15%. Moreover, the triple combination of RA + HMBA + 5azaC showed synergism in inhibiting both the colony formation (I = 0.7) and colony growth (I = 0.4) at the same specific level of 15%. Since RA, HMBA and 5azaC were effective when administered alone in phase I clinical trials of myeloid leukaemic patients, their synergistic combinations could provide shorter and less toxic courses of treatment in elderly myeloid leukaemic patients. I is less than 1, = 1 or greater than 1 in synergistic, additive or antagonistic interactions, respectively.


The El Dorado-based oil exploration and production company posted a net income of $129.4 million during the quarter compared with $402.6 million in the same period a year ago.

Excluding discontinued operations and other items that affect comparability of results between periods, the company had an income of $161.7 million during the quarter.

In the second half of 2013, the company separated its retail gasoline business from its exploration and production operations, creating Murphy USA Inc., an independent company.

Murphy Oil attributed the drop in profit to higher exploration expenses, higher costs of extraction in Malaysian oil fields and lower realized oil and natural gas sales prices for production from its Sarawak wells in Malaysia.

The company said "unfavorable effects in the U.S. from commodity contracts, and higher financing costs" also weighed on its financial results for the second quarter.

The company reported earnings per share of 72 cents, down from $2.12 a year ago and missing analysts estimates of $1.21.

Pavel Molchanov, an analyst for Raymond James and Associates, said Wednesday before Murphy Oil released its quarterly report that he expected the company to report earnings per share of $1.45.

"Following the company's [first quarter], we cut the production forecast for the second time this year," he said in an email. "Despite three quarters of disappointing dry holes and choppy production, full year production growth ... reflects new fields in Malaysia and sustained Eagle Ford expansion." Eagle Ford is a south Texas shale formation.

Murphy Oil released its financial results after markets closed Wednesday. Shares fell 51 cents to $66.72 on the New York Stock Exchange in average trading volume.

Murphy Oil took in $1.35 billion in revenue during the three months that ended June 30, compared with $1.33 billion during the same period last year.

"We continue to make progress on three fronts: profitable production and reserves growth, execution at [Eagle Ford] and lowering operating expenses," Roger Jenkins, president and chief executive officer, said in a statement. "Once again we will more than replace our production in 2014 and our overall operating expenses continue to trend down this year even with the initial start up of several fields."

The company said it spent $125 million to buy back shares of the company's common stock. Murphy Oil has repurchased about 18 million shares since 2012.

Murphy Oil will hold a conference call today at noon to discuss its financial results. The call can be accessed at (877) 329-7568 using pass code 9711325.It will also be available live online at http://ir.murphyoilcorp.com.


Transplacental flecainide therapy for fetal supraventricular tachycardia in a twin pregnancy.
We present the case of a twin pregnancy in which 1 fetus developed hydrops secondary to supraventricular tachycardia at 30 weeks' gestation. Transplacental flecainide administration successfully treated the condition without evidence of maternal or fetal side-effects. The case raises ethical and possibly legal issues that present when 1 fetus in a twin pregnancy develops a condition the management of which could cause complications to the other twin and/or the mother.


Q:

Problem with category conditional

I always seem to run into some problems with conditionals. The code in question is this:
{categories}
{if category_id != "305|325"}

Index version 1

{/if}

{if category_id == "305|325"}

Index version 2

{/if}
{/categories}

At the moment, it is always returning version 1 of the index, even when the category of the entry matches 305 or 325.

A:

If I'm not mistaken, for OR conditionals you must use one of the following:
{if category_id != 305 OR category_id != 325}

{if category_id != 305 || category_id != 325}

also, please double check that you don't need to use AND instead of OR. I've tripped myself up with that many times - especially when using negative comparison.
{if category_id != 305 AND category_id != 325}
     index 1 ---- the cat id is not 305 AND it is not 325
{if:else}
     index 2  --- all other cat ids
{/if}

OR...
{if category_id == 305 OR category_id == 325}
     index 2  ---- the cat id is 305 OR it is 325
{if:else}
     index 1 ---- all others
{/if}


Q:

Checking a comma separated string for a value within an binding

I want to create a visibility binding on an image. This image should show when a comma separated string from a calculated model contains a certain value.
The values to be checked could be: "Apple, Pear, Banana". Now I wanna set the visibility of the image to true if the string contains "Pear".
What I can do is:
@datasource.item.Fruits === "Pear" ? true : false;
The problem is that this will only trigger if the value is exactly "Pear" but not if there are multiple values.
I could try to include every possible combination in the binding but that seems to be a little bit overkill.
Anyone an idea to solve this?
Thanks

A:

First you will want to convert your comma separated string to an array by using the JavaScript split function, then you will want to use the JS indexOf function to look for your value inside this array. The result will be a binding that looks like this:
(@datasource.item.Fruits).split(‘,’).indexOf(‘Pear’) > -1

Make sure you include the () around the datasource item binding otherwise you can’t use the JS functions on it.


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# Copyright (C) 2015 KillerInstinct
#
# This program is free software: you can redistribute it and/or modify
# it under the terms of the GNU General Public License as published by
# the Free Software Foundation, either version 3 of the License, or
# (at your option) any later version.
#
# This program is distributed in the hope that it will be useful,
# but WITHOUT ANY WARRANTY; without even the implied warranty of
# MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE.  See the
# GNU General Public License for more details.
#
# You should have received a copy of the GNU General Public License
# along with this program.  If not, see <http://www.gnu.org/licenses/>.

from lib.cuckoo.common.abstracts import Signature

class ThemidaPacked(Signature):
    name = "packer_themida"
    description = "An executed process used known Themida API calls."
    severity = 3
    categories = ["packer", "anti-debug"]
    authors = ["KillerInstinct"]
    minimum = "1.2"
    evented = True
    ttp = ["T1045"]

    filter_apinames = set(["FindWindowA"])

    def __init__(self, *args, **kwargs):
        Signature.__init__(self, *args, **kwargs)
        self.ret = dict()

    def on_call(self, call, process):
        indicators = [
                "OLLYDBG",
                "GBDYLLO",
                "pediy06",
                "FilemonClass",
                "File Monitor - Sysinternals: www.sysinternals.com",
                "PROCMON_WINDOW_CLASS",
                "Process Monitor - Sysinternals: www.sysinternals.com",
                "RegmonClass",
                "Registry Monitor - Sysinternals: www.sysinternals.com",
                "18467-41",
        ]
        pid = str(process["process_id"])
        pname = process["process_name"]
        cname = self.get_argument(call, "ClassName")
        wname = self.get_argument(call, "WindowName")
        if pid not in self.ret.keys():
            self.ret[pid] = dict()
            self.ret[pid]["process"] = pname
            self.ret[pid]["apivalues"] = list()
        if cname and cname != "0" and cname in indicators:
            if cname not in self.ret[pid]["apivalues"]:
                self.ret[pid]["apivalues"].append(cname)
        if wname and wname != 0 and wname in indicators:
            if wname not in self.ret[pid]["apivalues"]:
                self.ret[pid]["apivalues"].append(wname)
        return None

    def on_complete(self):
        hit = False
        themidaprocs = list()
        if self.ret:
            for proc in self.ret.keys():
                if len(self.ret[proc]["apivalues"]) >= 8:
                    themidaprocs.append(self.ret[proc]["process"])

            if len(themidaprocs) > 0:
                hit = True
                procs = ", ".join(themidaprocs)
                self.description = "The following process appear to have been packed with Themida: " + procs

        return hit


WASHINGTON (Reuters) - Companies that share cyber data with the U.S. government in its fight against hackers would get broadened legal immunity, under a precedent-setting proposal likely to become part of a major spending bill being developed in Congress, sources close to the negotiations said on Tuesday.

A man types on a computer keyboard in Warsaw in this February 28, 2013 illustration file picture. REUTERS/Kacper Pempel/Files

If added to the $1.15 trillion spending package, the cyber-security proposal would amount to the first serious attempt by Congress to combat the rising threat of debilitating hacks from foreign nation-states and malicious actors that have hit a growing number of businesses and government agencies in recent years.

The spending bill must be approved within days to keep the U.S. government from shutting down and lawmakers were scrambling to attach a host of non-spending related policy riders to the fast-moving measure.

No agreement on the cyber immunity proposal has been finalized, sources cautioned. (reut.rs/1QqsJKz)

The proposal would broaden protections from privacy lawsuits to companies that voluntarily share cyber-threat data with the government through the Department of Homeland Security. That kind of data includes IP addresses and routing information that could be useful in spotting or blocking malicious intrusions and is meant to be scrubbed of personally identifiable information under the legislation.

Privacy advocates and some technology experts have said that more information sharing could mean more government surveillance by the National Security Agency and other spying agencies.

Information-sharing legislation has languished in Congress for years, but different versions easily passed both the Senate and House earlier this year. (reut.rs/1O3i1Ty)

According to an undated Obama administration memo seen by Reuters, the White House has been urging Congress to adopt language excluding “unnecessary prohibition” on direct sharing of data with the NSA or other military or intelligence agencies.

Some accused the administration of lobbying for changes to the legislation inconsistent with prior public statements.

The administration declined to comment on the specifics of congressional negotiations, but a senior official said the White House was hopeful lawmakers would “send cybersecurity legislation to the president’s desk as soon as possible.”


~ Just another WordPress.com site

Tag Archives: skeptic

Ok I may be a little late to the game with this one, but a fellow skeptic friend and I watched the 2006 documentary “Jesus Camp” recently. For those of you unaware it follows a few kids as they take part in ‘Kids On Fire School of Ministry’, a pentecostal summer camp run by Becky Fisher. At the camp they praise Jebus but also become motivated to ‘fight’ for God (I have no idea why he can’t do it on his own?) and become the next generation of evangelicals.

You know, a lot of people often throw around the term indoctrination and brainwashing in relation to parents and adults pushing their religious beliefs on children. But most religious parents, in the UK at least, are just nice people who are sincerely trying to imbibe the ideas and teachings that they believe give their life meaning and morality, into their progeny. Sincerity of course doesn’t make it any more right or wrong, or even their ideas more correct, but it seems rather more tolerable. Well, relatively speaking at least.

Someone who is completely intolerable is Becky Fisher. Towards the end of the film, she is asked by a radio commenter “Why kids?”. This is her response:

Anyone who does any work with kids knows the reason you go for kids is because whatever they learn by the time they are 7, 8, 9 years old is pretty well there for the rest of their life… I don’t think any child gets anything by choice. As I understood your question to me was ‘Do you feel it’s right for the fundamentalist to indoctrinate their children with their own belief?’ I guess fundamentally, yes I do, because every other religion is indoctrinating their kids. Hello! I would like to see more churches indoctrinating… You could call it brainwashing, but I am radical and passionate in teaching children their responsibility as christians, as God-fearing people, as Americans.

Don’t beat around the bush Becky, say what you really feel! Apart from the fact that Fisher believes it is ok to indoctrinate children at an age in their development when they do not have full comprehension of all available arguments, and when they are predisposed to believe adults and authority figures, there’s also something else inherently sad in her statement.

What does it say about your beliefs if you have to indoctrinate people into that way of thinking? It is almost as if she knows that her ideas don’t stand up to logic and reason…

The whole film just made me very, very sad. I did get a little chuckle when Ted Haggard made some comments about the acceptability of homosexuality, as ‘we don’t have to debate about what we should think about homosexual activity. It’s written in the Bible’. This from a man who was subsequently found to have been soliciting a male escort. The fun didn’t last though, soon Haggard turned his head to evolution. Woe. I think anyone can probably guess what an evangelical thinks of evolution, but the gist of it is that he doesn’t think public schools should tell students that they are animals created by natural selection. Boo hoo! More worryingly though, this is a man who used to speak to president Bush and his advisors every monday. Damn America, you scary!

Overall verdict of the film; it will make your head hurt and make you sad, if you have any sense, but it is a compelling watch. It also helped me to find some gems like this, after they showed a young man named Levi watching it at home:

And by gems I actually mean complete pieces of utter crap. In fact I think that may be an insult to fecal matter. I watched the whole thing and I swear by the end I was dribbling because of the inanity of it. I wouldn’t even know where to start to correct the multitude of errors in this video.

Giving it a go though, at an intuitive level their argument that because you can’t observe something, you cannot formulate any knowledge about it that would be anything other than belief; apart from completely ignoring the possibility of inferential evidence, doesn’t even work with their own philosophy. No one observed God create the earth.

Humans and dinosaurs co-existing?! Anything even remotely resembling animals from the Genus Homo do not appear in the fossil record until around 2,000,000, and modern Homo sapiens appear around 200,000 years ago. Dinosaurs existed 230 million years and are found in the fossil record up to 65 million years ago. The magnitude of the difference between the time of our existence and dinosaurs is immense, almost incomprehensible. Of course all of this is just belief. It is definitely not informed by stratigraphic evidence and radiometric dating. Definitely not.

Also the idea that because we don’t know what killed the dinosaurs; then we don’t know when they died is absurd. Imagine a pathologist who is unable to determine the cause of death of an individual. Does this mean that they can’t determine time of death despite evidences, such as onset of rigour mortis and body temperature, that are inconsequential of how the death was affected? The disappearance of dinosaurs from the fossil record occurs regardless of the method of their disappearance.

I love their explanation for why dinosaurs aren’t included in the bible though! The first english version of the bible was translated in 1611 (neglecting the fact that the Tyndale bible came earlier), however, the word dinosaur wasn’t invented until 1841. See, that’s why it’s not in the bible. Flawless logic! It has nothing to with the fact that the word dinosaur wasn’t invented until then because knowledge of dinosaurs didn’t exist until this point. And that isn’t why the authors of the bible, with their limited knowledge back then, didn’t include them in the holy book. Don’t be silly.

Anyway enough of this nonsense, I am off to drip feed bleach into the hippocampus and amygdala sections of my brain to make sure none of this stuff sticks.


NCAA FOOTBALL: Hackenberg, Nittany Lions seek strong finish

STATE COLLEGE — Christian Hackenberg’s season has mirrored that of Penn State overall. Some highs, some lows and a lot of memories in between.

But if the Nittany Lions freshman quarterback has indeed hit the wall during this roller-coaster season, he’s not showing it. In fact, he’s focused on finishing with an upswing — and that’s it.

“You’re going to face adversity throughout the season,” Hackenberg said. “That’s something I tried to keep on the back burner and just focus on doing everything I can do to help the team. The big thing for me is sending the seniors out right. They’ve done a lot for me and I have a lot of respect for the guys and I couldn’t thank them enough.”

Penn State (5-4) meets Purdue (1-8) on Saturday.

“It’s the same for all the underclassmen; we look at them with the same amount of respect,” Hackenberg added. “For me, it’s just time to buckle down and send the team out right.”

That could start vs. the Boilermakers this weekend. Securing and stashing Win No. 6, after all, won’t be as easy against Nebraska and Wisconsin — Penn State’s final two opponents.

Hackenberg has completed 178 of 306 passes for 2,187 yards. He’s also thrown eight interceptions and mishandled a few snaps. But it’s all been a part of the game as the Nittany Lions continue to build a new brand in the Bill O’Brien Era.

“I think that every freshman definitely hits that wall,” O’Brien said. “There’s been times when it’s been tough because we haven’t made plays or maybe made the play call we wanted to make. I think there’s other times that have been great times, like the Michigan and Illinois overtime wins. I think he made really great throws there at the end of both games.

“It’s an ever-evolving process and I think one of the things that’s great about Christian is that he’s very resilient.”

Hackenberg has passed for 13 scores this season, and opened the year 2-0.

“He’s smart, he has a tremendous work ethic and he’s 18 years old,” O’Brien said. “That’s not an excuse for anything; it just is what it is.

“I do think that over the next three weeks, you’ll see improvement and I think you’ll see Christian get better here.”

Offensive guard John Urschel concurs. Urschel, a fifth-year senior, has taken Hackenberg under his wing since June.

“Hack’s a different breed of guy,” he said. “He’s a true competitor. As a true freshman, he’s leading our offense. This guy is a leader and he really shows it day in and day out, and I’m really thankful we have him here.

“He makes mistakes here and there. Everybody does. But I don’t know how he handles everything he does.”

Hackenberg is second overall in Big Ten passing, and has handled the attention — that goes with being a quarterback at Penn State — quite well.

“As a quarterback, you have to understand everyone’s looking at you,” he said. “You have to bring the same type of intensity to the huddle each day at practice and then in the games be consistent. For me, luckily, it’s worked out pretty well. I wouldn’t say I’m the only leader.

“We have a lot of seniors out there we all rely on, and I rely on heavily, and they help me out.”

The feeling is mutual. And that’s why — despite some disheartening losses this season — there is still a wave of optimism around Happy Valley.


Q:

Canvas Pattern not repeating

I am making a Canvas Pattern using the following javascript:
//$('#canvas1').height($(document).height());
//console.log($('#canvas1').width($(document).width()));

var can = document.getElementById('canvas1');
var ctx = can.getContext('2d');

// set up a pattern
var pattern = document.createElement('canvas');
pattern.width = 80;
pattern.height = 80;
var pctx = pattern.getContext('2d');

pctx.beginPath();
pctx.lineWidth = "3";
pctx.strokeStyle = "red";
pctx.rect(74, 74, 3, 3);
pctx.stroke();

var pattern = ctx.createPattern(pattern, "repeat");
ctx.rect(0,0,800,800);
ctx.fillStyle = pattern;
ctx.fill();

The resulting pattern doesn't seem to repeat even when the ctx.rect values are defined as 800. The canvas is as follows:
<canvas id="canvas1"style="position:absolute;left:0;top:0;"></canvas>

How can I make it repeat throughout the height and width of current page. I know that I can set the height and width using jQuery and I tested that, but the pattern is still not repeating. Where am I going wrong?

A:

Well, I guess you got confused with .rect()'s parameters. It should be pctx.rect(3, 3, 74, 74).

var can = document.getElementById('canvas1');
var ctx = can.getContext('2d');

// set up a pattern
var pattern = document.createElement('canvas');
pattern.width = 80;
pattern.height = 80;
var pctx = pattern.getContext('2d');

pctx.beginPath();
pctx.lineWidth = "3";
pctx.strokeStyle = "red";
pctx.rect(3, 3, 74, 74);
pctx.stroke();

var _pattern = ctx.createPattern(pattern, "repeat");
ctx.rect(0, 0, can.width, can.height);
ctx.fillStyle = _pattern;
ctx.fill();
<canvas id="canvas1" width="320" height="320" style="border: 1px solid black; position: absolute; left: 0; top: 0;"></canvas>


/*
 * Copyright (C) 2018-2020 Intel Corporation
 *
 * SPDX-License-Identifier: MIT
 *
 */

#include "shared/source/memory_manager/internal_allocation_storage.h"
#include "shared/source/os_interface/os_context.h"
#include "shared/test/unit_test/helpers/debug_manager_state_restore.h"
#include "shared/test/unit_test/utilities/containers_tests_helpers.h"

#include "opencl/test/unit_test/fixtures/memory_allocator_fixture.h"
#include "opencl/test/unit_test/mocks/mock_allocation_properties.h"
#include "opencl/test/unit_test/mocks/mock_graphics_allocation.h"
#include "test.h"

struct InternalAllocationStorageTest : public MemoryAllocatorFixture,
                                       public ::testing::Test {
    using MemoryAllocatorFixture::TearDown;
    void SetUp() override {
        MemoryAllocatorFixture::SetUp();
        storage = csr->getInternalAllocationStorage();
    }
    InternalAllocationStorage *storage;
};

TEST_F(InternalAllocationStorageTest, givenDebugFlagThatDisablesAllocationReuseWhenStoreReusableAllocationIsCalledThenAllocationIsReleased) {
    DebugManagerStateRestore stateRestorer;
    DebugManager.flags.DisableResourceRecycling.set(true);

    auto allocation = memoryManager->allocateGraphicsMemoryWithProperties(MockAllocationProperties{csr->getRootDeviceIndex(), MemoryConstants::pageSize});

    storage->storeAllocation(std::unique_ptr<GraphicsAllocation>(allocation), REUSABLE_ALLOCATION);
    EXPECT_NE(allocation, csr->getAllocationsForReuse().peekHead());
    EXPECT_TRUE(csr->getAllocationsForReuse().peekIsEmpty());
}

TEST_F(InternalAllocationStorageTest, whenCleanAllocationListThenRemoveOnlyCompletedAllocations) {

    auto allocation = memoryManager->allocateGraphicsMemoryWithProperties(MockAllocationProperties{csr->getRootDeviceIndex(), MemoryConstants::pageSize});
    auto allocation2 = memoryManager->allocateGraphicsMemoryWithProperties(MockAllocationProperties{csr->getRootDeviceIndex(), MemoryConstants::pageSize});
    auto allocation3 = memoryManager->allocateGraphicsMemoryWithProperties(MockAllocationProperties{csr->getRootDeviceIndex(), MemoryConstants::pageSize});

    allocation->updateTaskCount(10, csr->getOsContext().getContextId());
    allocation2->updateTaskCount(5, csr->getOsContext().getContextId());
    allocation3->updateTaskCount(15, csr->getOsContext().getContextId());

    storage->storeAllocation(std::unique_ptr<GraphicsAllocation>(allocation), TEMPORARY_ALLOCATION);
    storage->storeAllocation(std::unique_ptr<GraphicsAllocation>(allocation2), TEMPORARY_ALLOCATION);
    storage->storeAllocation(std::unique_ptr<GraphicsAllocation>(allocation3), TEMPORARY_ALLOCATION);

    //head point to alloc 2, tail points to alloc3
    EXPECT_TRUE(csr->getTemporaryAllocations().peekContains(*allocation));
    EXPECT_TRUE(csr->getTemporaryAllocations().peekContains(*allocation2));
    EXPECT_TRUE(csr->getTemporaryAllocations().peekContains(*allocation3));
    EXPECT_EQ(-1, verifyDListOrder(csr->getTemporaryAllocations().peekHead(), allocation, allocation2, allocation3));

    //now remove element form the middle
    storage->cleanAllocationList(6, TEMPORARY_ALLOCATION);
    EXPECT_TRUE(csr->getTemporaryAllocations().peekContains(*allocation));
    EXPECT_FALSE(csr->getTemporaryAllocations().peekContains(*allocation2));
    EXPECT_TRUE(csr->getTemporaryAllocations().peekContains(*allocation3));
    EXPECT_EQ(-1, verifyDListOrder(csr->getTemporaryAllocations().peekHead(), allocation, allocation3));

    //now remove head
    storage->cleanAllocationList(11, TEMPORARY_ALLOCATION);
    EXPECT_FALSE(csr->getTemporaryAllocations().peekContains(*allocation));
    EXPECT_FALSE(csr->getTemporaryAllocations().peekContains(*allocation2));
    EXPECT_TRUE(csr->getTemporaryAllocations().peekContains(*allocation3));

    //now remove tail
    storage->cleanAllocationList(16, TEMPORARY_ALLOCATION);
    EXPECT_TRUE(csr->getTemporaryAllocations().peekIsEmpty());
}

TEST_F(InternalAllocationStorageTest, whenAllocationIsStoredAsReusableButIsStillUsedThenCannotBeObtained) {
    auto allocation = memoryManager->allocateGraphicsMemoryWithProperties(AllocationProperties{0, MemoryConstants::pageSize, GraphicsAllocation::AllocationType::BUFFER, mockDeviceBitfield});

    storage->storeAllocationWithTaskCount(std::unique_ptr<GraphicsAllocation>(allocation), REUSABLE_ALLOCATION, 2u);

    auto *hwTag = csr->getTagAddress();

    *hwTag = 1u;
    auto newAllocation = storage->obtainReusableAllocation(1, GraphicsAllocation::AllocationType::BUFFER);
    EXPECT_EQ(nullptr, newAllocation);
    storage->cleanAllocationList(2u, REUSABLE_ALLOCATION);
}

TEST_F(InternalAllocationStorageTest, whenAllocationIsStoredAsTemporaryAndIsStillUsedThenCanBeObtained) {
    auto allocation = memoryManager->allocateGraphicsMemoryWithProperties(AllocationProperties{0, MemoryConstants::pageSize, GraphicsAllocation::AllocationType::BUFFER, mockDeviceBitfield});

    storage->storeAllocationWithTaskCount(std::unique_ptr<GraphicsAllocation>(allocation), TEMPORARY_ALLOCATION, 2u);

    auto *hwTag = csr->getTagAddress();

    *hwTag = 1u;
    auto newAllocation = storage->obtainTemporaryAllocationWithPtr(1, allocation->getUnderlyingBuffer(), GraphicsAllocation::AllocationType::BUFFER);
    EXPECT_EQ(allocation, newAllocation.get());
    EXPECT_TRUE(csr->getTemporaryAllocations().peekIsEmpty());
    memoryManager->freeGraphicsMemory(newAllocation.release());
}

TEST_F(InternalAllocationStorageTest, givenTemporaryAllocationWhenAllocationIsObtainedThenItsTaskCountIsSetToNotReady) {
    const uint32_t initialTaskCount = 37u;
    const uint32_t contextId = csr->getOsContext().getContextId();

    auto allocation = memoryManager->allocateGraphicsMemoryWithProperties(AllocationProperties{0, MemoryConstants::pageSize, GraphicsAllocation::AllocationType::BUFFER, mockDeviceBitfield});
    storage->storeAllocationWithTaskCount(std::unique_ptr<GraphicsAllocation>(allocation), TEMPORARY_ALLOCATION, initialTaskCount);
    ASSERT_EQ(initialTaskCount, allocation->getTaskCount(contextId));

    auto newAllocation = storage->obtainTemporaryAllocationWithPtr(1, allocation->getUnderlyingBuffer(), GraphicsAllocation::AllocationType::BUFFER);
    EXPECT_EQ(allocation, newAllocation.get());
    EXPECT_EQ(CompletionStamp::notReady, allocation->getTaskCount(contextId));
    memoryManager->freeGraphicsMemory(newAllocation.release());
}

TEST_F(InternalAllocationStorageTest, whenObtainAllocationFromEmptyReuseListThenReturnNullptr) {
    auto allocation2 = storage->obtainReusableAllocation(1, GraphicsAllocation::AllocationType::BUFFER);
    EXPECT_EQ(nullptr, allocation2);
}

TEST_F(InternalAllocationStorageTest, whenCompletedAllocationIsStoredAsReusableAndThenCanBeObtained) {
    auto allocation = memoryManager->allocateGraphicsMemoryWithProperties(AllocationProperties{0, MemoryConstants::pageSize, GraphicsAllocation::AllocationType::BUFFER, mockDeviceBitfield});
    EXPECT_NE(nullptr, allocation);

    storage->storeAllocationWithTaskCount(std::unique_ptr<GraphicsAllocation>(allocation), REUSABLE_ALLOCATION, 2u);
    EXPECT_FALSE(csr->getAllocationsForReuse().peekIsEmpty());

    auto *hwTag = csr->getTagAddress();

    *hwTag = 2u;
    auto reusedAllocation = storage->obtainReusableAllocation(1, GraphicsAllocation::AllocationType::BUFFER).release();

    EXPECT_EQ(allocation, reusedAllocation);
    EXPECT_TRUE(csr->getAllocationsForReuse().peekIsEmpty());
    memoryManager->freeGraphicsMemory(allocation);
}

TEST_F(InternalAllocationStorageTest, whenNotUsedAllocationIsStoredAsReusableAndThenCanBeObtained) {

    auto allocation = memoryManager->allocateGraphicsMemoryWithProperties(AllocationProperties{0, MemoryConstants::pageSize, GraphicsAllocation::AllocationType::BUFFER, mockDeviceBitfield});
    EXPECT_NE(nullptr, allocation);
    EXPECT_FALSE(allocation->isUsed());
    EXPECT_EQ(0u, csr->peekTaskCount());
    *csr->getTagAddress() = 0; // initial hw tag for dll

    storage->storeAllocation(std::unique_ptr<GraphicsAllocation>(allocation), REUSABLE_ALLOCATION);
    EXPECT_EQ(0u, allocation->getTaskCount(csr->getOsContext().getContextId()));
    EXPECT_FALSE(csr->getAllocationsForReuse().peekIsEmpty());

    auto reusedAllocation = storage->obtainReusableAllocation(1, GraphicsAllocation::AllocationType::BUFFER).release();

    EXPECT_EQ(allocation, reusedAllocation);
    EXPECT_TRUE(csr->getAllocationsForReuse().peekIsEmpty());
    memoryManager->freeGraphicsMemory(allocation);
}

TEST_F(InternalAllocationStorageTest, whenObtainAllocationFromMidlleOfReusableListThenItIsDetachedFromLinkedList) {
    auto &reusableAllocations = csr->getAllocationsForReuse();
    EXPECT_TRUE(reusableAllocations.peekIsEmpty());

    auto allocation = memoryManager->allocateGraphicsMemoryWithProperties(AllocationProperties{0, 1, GraphicsAllocation::AllocationType::BUFFER, mockDeviceBitfield});
    auto allocation2 = memoryManager->allocateGraphicsMemoryWithProperties(AllocationProperties{0, 10000, GraphicsAllocation::AllocationType::BUFFER, mockDeviceBitfield});
    auto allocation3 = memoryManager->allocateGraphicsMemoryWithProperties(AllocationProperties{0, 1, GraphicsAllocation::AllocationType::BUFFER, mockDeviceBitfield});

    EXPECT_TRUE(reusableAllocations.peekIsEmpty());
    EXPECT_EQ(nullptr, allocation2->next);
    EXPECT_EQ(nullptr, allocation2->prev);

    storage->storeAllocation(std::unique_ptr<GraphicsAllocation>(allocation), REUSABLE_ALLOCATION);

    EXPECT_TRUE(reusableAllocations.peekContains(*allocation));
    EXPECT_FALSE(reusableAllocations.peekContains(*allocation2));
    EXPECT_FALSE(reusableAllocations.peekContains(*allocation3));
    EXPECT_EQ(nullptr, allocation2->next);
    EXPECT_EQ(nullptr, allocation2->prev);

    storage->storeAllocation(std::unique_ptr<GraphicsAllocation>(allocation2), REUSABLE_ALLOCATION);

    EXPECT_TRUE(reusableAllocations.peekContains(*allocation));
    EXPECT_TRUE(reusableAllocations.peekContains(*allocation2));
    EXPECT_FALSE(reusableAllocations.peekContains(*allocation3));
    EXPECT_EQ(nullptr, allocation2->next);
    EXPECT_EQ(allocation, allocation2->prev);

    storage->storeAllocation(std::unique_ptr<GraphicsAllocation>(allocation3), REUSABLE_ALLOCATION);

    EXPECT_TRUE(reusableAllocations.peekContains(*allocation));
    EXPECT_TRUE(reusableAllocations.peekContains(*allocation2));
    EXPECT_TRUE(reusableAllocations.peekContains(*allocation3));
    EXPECT_EQ(allocation3, allocation2->next);
    EXPECT_EQ(allocation, allocation2->prev);

    auto reusableAllocation = storage->obtainReusableAllocation(10000, GraphicsAllocation::AllocationType::BUFFER).release();
    EXPECT_EQ(reusableAllocation, allocation2);
    EXPECT_EQ(nullptr, allocation2->next);
    EXPECT_EQ(nullptr, allocation2->prev);

    EXPECT_EQ(nullptr, reusableAllocation->next);
    EXPECT_EQ(nullptr, reusableAllocation->prev);

    EXPECT_FALSE(reusableAllocations.peekContains(*reusableAllocation));
    EXPECT_TRUE(reusableAllocations.peekContains(*allocation));
    EXPECT_FALSE(reusableAllocations.peekContains(*allocation2));
    EXPECT_TRUE(reusableAllocations.peekContains(*allocation3));

    memoryManager->freeGraphicsMemory(allocation2);
    allocation->updateTaskCount(0u, csr->getOsContext().getContextId());
    allocation3->updateTaskCount(0u, csr->getOsContext().getContextId());
}

TEST_F(InternalAllocationStorageTest, givenAllocationWhenItIsPutOnReusableListWhenOtherAllocationTypeIsRequestedThenNullIsReturned) {
    EXPECT_TRUE(csr->getAllocationsForReuse().peekIsEmpty());

    auto allocation = memoryManager->allocateGraphicsMemoryWithProperties(AllocationProperties{0, MemoryConstants::pageSize, GraphicsAllocation::AllocationType::BUFFER, mockDeviceBitfield});
    storage->storeAllocation(std::unique_ptr<GraphicsAllocation>(allocation), REUSABLE_ALLOCATION);

    EXPECT_FALSE(csr->getAllocationsForReuse().peekIsEmpty());

    auto internalAllocation = storage->obtainReusableAllocation(1, GraphicsAllocation::AllocationType::INTERNAL_HEAP);
    EXPECT_EQ(nullptr, internalAllocation);
}

class WaitAtDeletionAllocation : public MockGraphicsAllocation {
  public:
    WaitAtDeletionAllocation(void *buffer, size_t sizeIn)
        : MockGraphicsAllocation(buffer, sizeIn) {
        inDestructor = false;
    }

    std::mutex mutex;
    std::atomic<bool> inDestructor;
    ~WaitAtDeletionAllocation() override {
        inDestructor = true;
        std::lock_guard<std::mutex> lock(mutex);
    }
};

TEST_F(InternalAllocationStorageTest, givenAllocationListWhenTwoThreadsCleanConcurrentlyThenBothThreadsCanAccessTheList) {
    auto allocation1 = new WaitAtDeletionAllocation(nullptr, 0);
    allocation1->updateTaskCount(1, csr->getOsContext().getContextId());
    storage->storeAllocation(std::unique_ptr<GraphicsAllocation>(allocation1), TEMPORARY_ALLOCATION);

    std::unique_lock<std::mutex> allocationDeletionLock(allocation1->mutex);

    auto allocation2 = memoryManager->allocateGraphicsMemoryWithProperties(MockAllocationProperties{csr->getRootDeviceIndex(), MemoryConstants::pageSize});
    allocation2->updateTaskCount(2, csr->getOsContext().getContextId());
    storage->storeAllocation(std::unique_ptr<GraphicsAllocation>(allocation2), TEMPORARY_ALLOCATION);

    std::mutex mutex;
    std::unique_lock<std::mutex> lock(mutex);

    std::thread thread1([&] {
        storage->cleanAllocationList(1, TEMPORARY_ALLOCATION);
    });

    std::thread thread2([&] {
        std::lock_guard<std::mutex> lock(mutex);
        storage->cleanAllocationList(2, TEMPORARY_ALLOCATION);
    });

    while (!allocation1->inDestructor)
        ;
    lock.unlock();
    allocationDeletionLock.unlock();

    thread1.join();
    thread2.join();

    EXPECT_TRUE(csr->getTemporaryAllocations().peekIsEmpty());
}


[Bronchoesophageal fistula and broncholithiasis].
Bronchoesophageal fistulas (BEF) in an adult, whether acquired or congenital, are uncommon but bronchoesophageal perforation secondary to broncholithiasis caused by calcified mediastinal adenopathy and leading to the formation of a fistulous tract is extremely rare. We present a case of acquired BEF in a 57-years-old women who presented cough with expectoration of broncholiths, hemoptysis and cough after swallowing liquid or solid hemoptysis and cough after swallowing liquid or solid foods. The chest film and computed tomographic scan showed calcified mediastinal adenopathy. Endoscopic examination of the esophagus revealed no mucosal abnormality. A bronchial esophageal fistula was identified at the level of the 1/3 midesophagus just below the carina in the esophagogram. The bronchoscopy showed a polypoid area located in the medial side of the right main bronchus. There was no evidence of neoplasm. The patient underwent excision of fistula and interposition of pleural bundle after completing a right posterolateral thoracotomy. The postoperative course was uneventful and the patient has been doing well on follow-up.