The importance of surgical margins in renal cell and urothelial carcinomas

This chapter reviews the prevalence, outcomes, and management of positive surgical margins for patients with either renal cell or urothelial carcinomas. Though renal cell carcinoma tends to be resistant to conventional radio- or chemotherapy, kidney cancer patients with positive surgical margins can often be managed with close surveillance with acceptable outcomes. On the other hand, urothelial tumors tend to be more aggressive, and positive surgical margins after radical cystectomy often requires adjuvant therapy. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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Clinicopathological significance of LAT1 and ASCT2 in patients with surgically resected esophageal squamous cell carcinoma

Background

Amino acid transporters are highly expressed in various human cancers. L-type amino acid transporter 1 (LAT1) and system alanine-serine-cysteine amino acid transporter-2 (ASCT2) play a crucial role in tumor progression and survival. However, the clinicopathological significance of these transporters in patients with esophageal squamous cell carcinoma (ESCC) remains unclear.

Methods

One hundred and fifty-seven patients with surgically resected ESCC were evaluated. Immunohistochemical analysis was performed for LAT1, ASCT2, CD98, Ki-67, and micro-vessel density (MVD), as determined by CD34 expression.

Results

LAT1 and ASCT2 were positively expressed in 59% (93/157) and 48% (76/157) of tumors respectively. LAT1 and ASCT2 expression significantly correlated with T factor, N factor, lymphatic permeation, vascular invasion, and CD98 expression. The 5-year survival rates of LAT1-high and -low and ASCT2-high and -low expressing patients were 62.0% and 69.6% (P < 0.05) and 59.6% and 70.1% (P = 0.068), respectively. The combined positive expression of LAT1 and ASCT2 was a significant prognostic factor in univariate analysis.

Conclusion

High expression of LAT1 and ASCT2 correlates with metastasis and invasion. Accordingly, these proteins could serve as prognostic biomarkers and therapeutic targets for treating patients with surgically resectable ESCC. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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Defining the possible therapeutic benefit of lymphadenectomy among patients undergoing hepatic resection for intrahepatic cholangiocarcinoma

Background

The aim of the study was to investigate the therapeutic role of lymphadenectomy (LND) in patients with intrahepatic cholangiocarcinoma.

Methods

826 patients who underwent liver resection were identified using the SEER database from 1988 to 2011. Two groups of patients were defined: 201 (24%) undergoing potentially therapeutic LND (group A, >3 lymph nodes (LN) removed), and 625 (76%) not receiving therapeutic LND (group B, ≤3 LNs removed). A propensity score analysis was performed to create a matched cohort of 402 patients (201 in either group). The survival benefit of therapeutic LND was also estimated using multivariate parametric analysis comparing two simulated cohorts of 826 patients.

Results

1-, 3-, and 5-year survival rates were 71%, 37%, and 27% for group A patients, and 73%, 37%, and 27% for matched group B patients (P = 0.656). When simulation analysis was performed, a moderate survival benefit of LND of 5.46 months was calculated (95%CI, 4.64–6.29). Considerable differences in LND survival benefit predictions were found according to patient's sex (males, 9.90 vs. females 1.16 months), age (≤60 years, 15 vs. >60 years, −1.34 months), and tumor size (>50 mm, 9.20 vs. ≤50 mm, −0.28).

Conclusions

LND therapeutic benefit among a subset of patients. Future work is required to investigate the role of routine LND among these patients. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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A qualitative study exploring health perceptions and factors influencing participation in health behaviors in colorectal cancer survivors

Abstract

Purpose

The purpose of the study was to explore colorectal cancer survivors' health perceptions following cessation of active treatment for cancer and to explore the factors influencing participation in health-promoting behaviors that may help reduce cardiovascular disease risk.

Methods

Face-to-face interviews were conducted with participants that had completed active treatment for cancer within the previous 2 years. Participants were colorectal cancer survivors (N = 24, men = 11, women = 13, M age = 69.38 years, SD = 4.19) recruited from a private hospital in Perth, Australia on the basis that they had existing morbidities that put them at increased risk of cardiovascular disease. Interview transcripts were analyzed using thematic analysis.

Results

Five main themes emerged: back to normal; the pleasures in life: 'is it worth it?'; beliefs about health behavior; skepticism of eating guidelines; and lack of motivation. The majority of participants felt they were in good health and had made a full recovery. Participants questioned whether it was worth changing their lifestyle given their life stage and referred to the desire to enjoy life. Lay health beliefs, skepticism of eating guidelines, and a lack of motivation were barriers to change.

Conclusions

Interventions should target lay beliefs and skepticism in relation to health behaviors in order to reinforce the importance and value of participating in health-related behavior.

Implications for Cancer Survivors

Findings may inform the development of effective, patient-centered interventions that target lay health beliefs and build motivation for health behavior change. Copyright © 2016 John Wiley & Sons, Ltd.

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Sarcopenia as a predictor of pulmonary complications after esophagectomy for thoracic esophageal cancer

Background and Objectives

Sarcopenia or loss of skeletal muscle mass has been identified as a poor prognostic factor for a wide variety of diseases and conditions. We investigated whether preoperative sarcopenia is associated with postoperative complications in patients undergoing esophagectomy for thoracic esophageal cancer.

Methods

We retrospectively reviewed the medical records of consecutive patients with thoracic esophageal cancer who underwent esophagectomy between September 2005 and July 2014 at Kyoto University Hospital. Skeletal muscle mass was assessed using preoperative computed tomographic scans by measuring the cross-sectional muscle area at the third lumbar vertebral level.

Results

Among the 199 eligible patients, 149 (75%) were classified as having sarcopenia. There was no difference in the incidence of overall complications between the groups (risk ratio [RR]: 1.10, 95% confidence interval [CI]: 0.80–1.53, P = 0.54). However, pulmonary complications were significantly more frequent in the sarcopenia group than in the nonsarcopenia group (RR: 2.63, 95% CI: 1.20–5.77, P = 0.007). Multivariate analyses demonstrated that sarcopenia was associated with a high adjusted risk of one or more pulmonary complications (odds ratio: 2.96, 95% CI: 1.14–7.69, P = 0.026).

Conclusions

Sarcopenia independently predicts pulmonary complications after esophagectomy for thoracic esophageal cancer. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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KIT exon 11 codons 557-558 deletion promotes GIST liver meta

Purpose:KIT mutations, the most prevalent genetic event in gastrointestinal stromal tumors (GISTs), are associated with malignant features and poor prognosis. Aggressive GISTs possess a high propensity to spread to the liver. This study aimed to explore the role of KIT mutations in GIST liver metastasis. Experimental Design:170 GISTs were used to determine the association between KIT mutations and liver metastasis. Immunohistochemistry was performed to assess the correlation of KIT mutations with CXCR4 and ETV1 expression. Genetic and pharmacological methods were used to study the regulation of CXCR4 and ETV1 by KIT mutations. Results:Codons 557 and 558 in KIT exon 11 were deletion hot spots in GISTs. KIT exon 11 deletions involving codons 557-558 were highly associated with liver metastasis. Overexpression of mutant KIT with exon 11 codons 557-558 deletion (KIT 557-558) increased GIST cell motility and liver metastasis. Mechanistically, overexpression of KIT 557-558 in GIST cells increased ETV1 and CXCR4 expression. CXCR4 knockdown counteracted KIT 557-558-mediated cell migration. Moreover, KIT 557-558-induced CXCR4 expression could be abolished by silencing ETV1. The chromatin immunoprecipitation assay showed that ETV1 directly bound to the CXCR4 promoter. After ERK inhibitor PD325901 treatment, the upregulation of ETV1 by KIT 557-558 was prevented. In addition, KIT exon 11 codons 557-558 deletion enhanced CXCL12-mediated GIST cell migration and invasion. Conclusions:KIT exon 11 557-558 deletion upregulates CXCR4 through increased binding of ETV1 to the CXCR4 promoter in GIST cells, which thus promotes liver metastasis. These findings highlighted the potential therapeutic targets for metastatic GISTs.

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Metabolomics of GBM

Purpose: We employed a metabolomics-based approach with the goal to better understand the molecular signatures of glioblastoma (GBM) cells and tissues, with an aim towards identifying potential targetable biomarkers for developing more effective and novel therapies. Experimental Design: We used liquid chromatography coupled with mass spectrometry (LC-MS/Q-TOF and LC-MS/QQQ) for the discovery and validation of metabolites from primary and established GBM cells, GBM tissues, and normal human astrocytes. Results: We identified tryptophan, methionine, kynurenine, and 5-methylthioadenosine as differentially regulated metabolites (DRMs) in GBM cells compared to normal human astrocytes (NHAs). Unlike NHAs, GBM cells depend on dietary methionine for proliferation, colony formation, survival, and to maintain a deregulated methylome (SAM:SAH ratio). In methylthioadenosine phosphorylase (MTAP) deficient GBM cells, expression of MTAP transgene did not alter methionine dependency, but compromised tumor growth in vivo. We discovered that a lack of the kynurenine metabolizing enzymes kynurenine monooxygenase and/or kynureninase promotes the accumulation of kynurenine, which triggers immune evasion in GBM cells. Insilico analysis of the identified DRMs mapped the activation of key oncogenic kinases that promotes tumorigenesis in GBM. We validated this result by demonstrating that the exogenous addition of DRMs to GBM cells in vitro, results in oncogene activation as well as the simultaneous downregulation of Ser/Thr phosphatase PP2A. Conclusions: We have connected a four-metabolite signature, implicated in the methionine and kynurenine pathways, to the promotion and maintenance of GBM. Together, our data suggest that these metabolites and their respective metabolic pathways serve as potential therapeutic targets for GBM.

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FGFR1 in head and neck squamous cell carcinoma

Purpose:FGFR1 (fibroblast growth factor receptor 1) is a promising therapeutic target in multiple tumors, including head and neck squamous cell carcinoma (HNSCC). However, resistance remains a major setback. In this study we have investigated the prognostic value of FGFR1 expression in HNSCC, the therapeutic relevance of targeting FGFR with AZD4547, and potential resistant mechanisms. Experimental Design:Immunohistochemistry and fluorescence in situ hybridization were applied on tissue microarrays to investigate FGFR1 protein expression and FGFR1 gene copy-numbers in 452 HNSCC. The sensitivity of HNSCC cell lines to AZD4547, either as single or combination treatment with the EGFR-inhibitor gefitinib, was assessed using long-term colony formation assays, short-term viability assays, and biochemical analysis. Results:FGFR1 protein overexpression occurred in 82% (36/44) of HPV-positive HNSCC and 75% (294/392) of HPV-negative HNSCC and relates with poor overall survival and disease-free survival in HPV-negative HNSCC (HR: 3.07; 95% CI: 1.74-6.90; P = 0.001, HR: 1.53; 95% CI: 1.04-2.39; P = 0.033). Moreover, the FGFR1 gene was amplified in 3% (3/110) of HPV-negative HNSCC. Treatment of the high FGFR1 expressing cell line CCL30 with AZD4547 reduced cell proliferation and FGFR signaling. Two FGFR-amplified cell lines, SCC147 and BICR16, were resistant to AZD4547 treatment due to EGFR signaling. Combined AZD4547 and gefitinib treatment synergistically inhibited proliferation of resistant cell lines. Conclusions Here we identify high FGFR1 expression as a candidate prognostic biomarker in HPV- negative HNSCC. We provide a rationale for treating FGFR1-expressing HNSCC with the FGFR inhibitor AZD4547 and for combining AZD4547 and gefitinib in FGFR inhibitor resistant HNSCC patients.

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MDM2 inhibition in adenoid cystic carcinoma

Purpose: There are no effective treatment options for patients with advanced adenoid cystic carcinoma (ACC). Here, we evaluated the effect of a new small molecule inhibitor of the MDM2-p53 interaction (MI-773) in preclinical models of ACC. Experimental Design: To evaluate the anti-tumor effect of MI-773, we administered it to mice harboring 3 different patient-derived xenograft (PDX) models of ACC expressing functional p53. The effect of MI-773 on MDM2, p53, phospho-p53 and p21 was examined by Western blots in 5 low passage primary human ACC cell lines and in MI-773-treated PDX tumors. Results: Single agent MI-773 caused tumor regression in the 3 PDX models of ACC studied here. For example, we observed a tumor growth inhibition (TGI) index of 127% in UM-PDX-HACC-5 tumors that was associated with an increase in the fraction of apoptotic cells (p=0.015). The number of p53-positive cells was increased in MI-773-treated PDX tumors (p<0.001), with a correspondent shift in p53 localization from the nucleus to the cytoplasm. Western blots demonstrated that MI-773 potently induced expression of p53 and its downstream targets p21, MDM2 and induced phosphorylation of p53 (serine 392) in low passage primary human ACC cells. Notably, MI-773 induced a dose-dependent increase in the fraction of apoptotic ACC cells and in the fraction of cells in the G1 phase of cell cycle (p<0.05). Conclusions: Collectively, these data demonstrate that therapeutic inhibition of the MDM2-p53 interaction with MI-773 activates downstream effectors of apoptosis and causes robust tumor regression in preclinical models of adenoid cystic carcinoma.

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Molecular profile and metabolic volume at staging in DLBCL.

Purpose:The prognostic impact of total metabolic tumor volume (TMTV) measured on pretreatment 18F-FDG PET/CT and its added value to molecular characteristics was investigated in patients with diffuse large B-cell lymphoma (DLBCL). Experimental Design:For 81 newly diagnosed DLBCL patients, treated with Rituximab and CHOP/CHOP-like regimen, TMTV was computed using the 41% SUVmax thresholding method. According to the gene expression profile, determined using DASL (cDNA-mediated Annealing, Selection, Ligation and extension) technology, a subset of 57 patients was classified in GCB or ABC subtypes and MYC or BCL2 overexpressed. Results:Median follow-up was 64 months. 5y-PFS and OS were 60% and 63% in the whole population. Median pre-therapy TMTV was 320 cm3 (25th-75th percentiles 106-668 cm3). With a 300cm3cut off, patients with high TMTV (n=43) had a 5 y-PFS and OS of 43% and 46% compared with 76% and 78% for patients with a low TMTV (p=0.0023, p=0.0047). ABC status, MYC or BCL2 overexpression and both overexpression ("dual expressor", DE) were significantly associated with a worse PFS and OS. TMTV combined with molecular data allowed a significant better risk sub-stratification of ABC/GCB patients, on PFS and OS. High TMTV individualized in molecular low risk patients a group with a poor outcome (MYC, PFS=51%, OS=55% BCL2, PFS=49%, OS=49% or DE PFS=50%, OS=50%) and a group with a good outcome (MYC, PFS=93%, OS=93% BCL2, PFS=86%, OS=86% or DE PFS=81%, OS=81%). Conclusions:The combination of molecular and imaging characteristics at diagnosis could lead to a more accurate selection of patients, in order to increase tailor therapy.

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ErbB2 Reactivates AR

Purpose: ErbB2 signaling appears to be increased and may enhance AR activity in a subset of CRPC, but agents targeting ErbB2 have not been effective. This study was undertaken to assess ErbB2 activity in abiraterone-resistant prostate cancer (PCa), and determine whether it may contribute to androgen receptor (AR) signaling in these tumors. Experimental Design: AR activity and ErbB2 signaling were examined in the radical prostatectomy specimens from a neoadjuvant clinical trial of leuprolide plus abiraterone, and in the specimens from abiraterone-resistant CRPC xenograft models. The effect of ErbB2 signaling on AR activity was determined in two CRPC cell lines. Moreover, the effect of combination treatment with abiraterone and an ErbB2 inhibitor was assessed in a CRPC xenograft model. Results: We found that ErbB2 signaling was elevated in residual tumor following abiraterone treatment in a subset of patients, and was associated with higher nuclear AR expression. In xenograft models, we similarly demonstrated that ErbB2 signaling was increased and associated with AR reactivation in abiraterone-resistant tumors. Mechanistically, we show that ErbB2 signaling and subsequent activation of the PI3K/AKT signaling stabilizes AR protein. Furthermore, concomitantly treating CRPC cells with abiraterone and an ErbB2 inhibitor, lapatinib, blocked AR reactivation and suppressed tumor progression. Conclusions: ErbB2 signaling is elevated in a subset of abiraterone-resistant prostate cancer patients and stabilizes AR protein. Combination therapy with abiraterone and ErbB2 antagonists may be effective for treating the subset of CRPC with elevated ErbB2 activity.

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The CTD2 Dashboard: A Platform to Explore Evidence-based Observations

The Cancer Genome Atlas (TCGA), TARGET, and other large-scale sequencing projects such as the International Cancer Genome Consortium (ICGC), have catalogued a vast number of genetic abnormalities in cancer. However, identifying these abnormalities is just one part of the puzzle.

Next, cancer researchers need to determine which changes drive cancer development, metastasis, and drug resistance, and how this information can be used to improve cancer care and early detection. The Cancer Target Discovery and Development (CTD²) Dashboard displays evidence-based conclusions on an interactive web interface for users to learn more about the biology of cancer.

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New Targeted Agents in Gynecologic Cancers: Synthetic Lethality, Homologous Recombination Deficiency, and PARP Inhibitors

Opinion statement

Inhibitors of poly (ADP-ribose) polymerase (PARP) have emerged as a new class of anti-cancer drugs, specifically for malignancies bearing aberrations of the homologous recombination pathway, like those with mutations in the BRCA 1 and BRCA 2 genes. Olaparib, a potent PARP1 and PARP2 inhibitor, has been shown to significantly increase progression-free survival (PFS) in women with recurrent ovarian cancer related to a germline BRCA mutation and is currently approved fourth-line treatment in these patients. PARP inhibitors (PARPi) target the genetic phenomenon known as synthetic lethality to exploit faulty DNA repair mechanisms. While ovarian cancer is enriched with a population of tumors with known homologous recombination defects, investigations are underway to help identify pathways in other gynecologic cancers that may demonstrate susceptibility to PARPi through synthetically lethal mechanisms. The ARIEL2 trial prospectively determined a predictive assay to identify patients with HRD. The future of cancer therapeutics will likely incorporate these HRD assays to determine the best treatment plan for patients. While the role of PARPi is less clear in non-ovarian gynecologic cancers, the discovery of a predictive assay for HRD may open the door for clinical trials in these other gynecologic cancers enriched with patients with HRD. Identification of patients with tumors deficient in homologous repair or have HRD-like behavior moves cancer treatment towards individualized therapies in order to maximize treatment effect and quality of life for women living with gynecologic cancers.

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Laparoscopic management for prenatally diagnosed choledochal cysts

Abstract

Purpose

The aim of this study was to validate our laparoscopic management strategy for asymptomatic and symptomatic patients with prenatally diagnosed choledochal cysts (CCs).

Methods

Thirteen prenatally diagnosed CC patients from 1997 to 2015 were included. Seven patients (1997–2008) underwent open surgery (OS group), and 6 (2009–2015) underwent laparoscopic surgery (LS group). In the asymptomatic patients, LS was performed when the patients weighed over 5 kg. When the patient had clinical manifestations, early LS was performed irrespective of body weight. A retrospective comparison was conducted between the LS and OS groups in terms of the operative time, blood loss, postoperative fasting period, hospital stay, and intra- and postoperative complications.

Results

There was no difference between the demographics of both groups. The operative time was significantly longer (380 vs. 288 min) and blood loss was significantly lower (4 vs. 30 mL) in the LS group. Additionally, the postoperative fasting period (3 vs. 6 days) and hospital stay (11 vs. 20 days) were significantly shorter in the LS group. Intraoperative events and early postoperative complications were not encountered in either group. Small bowel obstruction requiring surgery occurred in two patients, 10 and 13 years after OS, respectively.

Conclusions

LS is as safe and feasible as OS in small children with prenatally diagnosed CC, although sufficient pediatric laparoscopic expertise is mandatory.

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Randomized phase II study of axitinib versus physicians best alternative choice of therapy in patients with recurrent glioblastoma

Abstract

We conducted a randomized, non-comparative, multi center, phase II clinical trial in order to investigate the efficacy of axitinib, an oral small molecule tyrosine kinase inhibitor with high affinity and specificity for the vascular endothelial growth factor receptors, in patients with recurrent glioblastoma following prior treatment with radiation and temozolomide. Forty-four patients were randomly assigned to receive treatment with axitinib (5 mg BID starting dose; N = 22) or "physicians best alternative choice of therapy" that consisted of bevacizumab (N = 20) or lomustine (N = 2). Six-month progression-free survival served as the primary endpoint. The estimated 6-month progression-free survival rate was 34 % (95 % CI 14–54) for patients treated with axitinib and 28 % (95 % CI 8–48) with best alternative treatment; median overall survival was 29 and 17 weeks, respectively. Objective responses according to RANO criteria were documented in 28 % of patients treated with axitinib and 23 % of patients treated with best alternative therapy. A decrease in maximal uptake of 18F-fluoro-ethyl-tyrosine (18F-FET) by the glioblastoma on PET imaging was documented in 85 % of patients at the time of response on axitinib. Corticosteroid treatment could be stopped in four and tapered in seven out of the 15 patients who were treated with steroids at baseline in the axitinib cohort. Most frequent axitinib related grade ≥3 adverse events consisted of fatigue (9 %), diarrhea (9 %), and oral hyperesthesia (4.5 %). We conclude that axitinib has single-agent clinical activity and a manageable toxicity profile in patients with recurrent glioblastoma.

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Current Perspectives of Prophylaxis and Management of Acute Infective Endophthalmitis

Abstract

Endophthalmitis is an intraocular inflammatory condition which may or may not be caused by infective agents. Noninfectious (sterile) endophthalmitis may be attributable to various causes including postoperative retained soft lens matter or toxicity following introduction of other agents into the eye. Infectious endophthalmitis is further subdivided into endogenous and exogenous. In endogenous endophthalmitis there is hematogenous spread of organisms from a distant source of infection whereas in exogenous endophthalmitis direct microbial inoculation may occur usually following ocular surgery or penetrating eye injury with or without intraocular foreign bodies. Acute infective endophthalmitis is usually exogenous induced by inoculation of pathogens following ocular surgery, open-globe injury and intravitreal injections. More infrequently the infective source is internal and septicemia spreads to the eye resulting in endogenous endophthalmitis. Several risk factors have been implicated including immunosuppression, ocular surface abnormalities, poor surgical wound construction, complicated cataract surgery with vitreous loss and certain types of intraocular lens. Comprehensive guidelines and recommendations on prophylaxis and monitoring of surgical cases have been proposed to minimize the risk of acute endophthalmitis. Early diagnosis and prompt management of infective endophthalmitis employing appropriately selected intravitreal antibiotics are essential to optimize visual outcome.

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Resolving uncertainty in the spatial relationships between passive benzene exposure and risk of non-Hodgkin lymphoma

Publication date: Available online 2 March 2016
Source:Cancer Epidemiology
Author(s): Jeffrey M. Switchenko, Catherine Bulka, Kevin Ward, Jean L. Koff, A. Rana Bayakly, P. Barry Ryan, Lance A. Waller, Christopher R. Flowers
BackgroundBenzene is a known occupational carcinogen associated with increased risk of hematologic cancers, but the relationships between quantity of passive benzene exposure through residential proximity to toxic release sites, duration of exposure, lag time from exposure to cancer development, and lymphoma risk remain unclear.MethodsWe collected release data through the Environmental Protection Agency's Toxics Release Inventory (TRI) from 1989 to 2003, which included location of benzene release sites, years when release occurred, and amount of release. We also collected data on incident cases of non-Hodgkin lymphoma (NHL) from the Georgia Comprehensive Cancer Registry (GCCR) for the years 1999–2008. We constructed distance-decay surrogate exposure metrics and Poisson and negative binomial regression models of NHL incidence to quantify associations between passive exposure to benzene and NHL risk and examined the impact of amount, duration of exposure, and lag time on cancer development. Akaike's information criteria (AIC) were used to determine the scaling factors for benzene dispersion and exposure periods that best predicted NHL risk.ResultsUsing a range of scaling factors and exposure periods, we found that increased levels of passive benzene exposure were associated with higher risk of NHL. The best fitting model, with a scaling factor of 4 kilometers (km) and exposure period of 1989–1993, showed that higher exposure levels were associated with increased NHL risk (Level 4 (1.1–160kilograms (kg)) vs. Level 1: risk ratio 1.56 [1.44–1.68], Level 5 (>160kg) vs. Level 1: 1.60 [1.48–1.74]).ConclusionsHigher levels of passive benzene exposure are associated with increased NHL risk across various lag periods. Additional epidemiological studies are needed to refine these models and better quantify the expected total passive benzene exposure in areas surrounding release sites.



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Population pharmacokinetic/pharmacodynamic modeling of tumor growth kinetics in medullary thyroid cancer patients receiving cabozantinib

Nonlinear mixed effects models were developed to describe the relationship between cabozantinib exposure and target lesion tumor size in a phase III study of patients with progressive metastatic medullary thyroid cancer. These models used cabozantinib exposure estimates from a previously published population pharmacokinetic model for cabozantinib in cancer patients that was updated with data from healthy-volunteer studies. Semi-mechanistic models predict well for tumors with static, increasing, or decreasing growth over time, but they were not considered adequate for predicting tumor sizes in medullary thyroid cancer patients, among whom an early reduction in tumor size was followed by a late stabilization phase in those receiving cabozantinib. A semi-empirical tumor model adequately predicted tumor profiles that were assumed to have a net growth rate constant that was piecewise continuous in the regions of 0–110 and 110–280 days. Emax models relating average concentration to average change in tumor size predicted that an average concentration of 79 and 58 ng/ml, respectively, would yield 50% of the maximum possible tumor reduction during the first 110 days of dosing and during the subsequent 110–280 days of dosing. Simulations of tumor responses showed that daily doses of 60 mg or greater are expected to provide a similar tumor reduction. Both model evaluation of observed data and simulation results suggested that the two protocol-defined cabozantinib dose reductions from 140 to 100 mg/day and from 100 to 60 mg/day are not projected to result in a marked reduction in target lesion regrowth.

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Metastatic testicular cancer presenting with liver and kidney dysfunction treated with modified BEP chemotherapy combined with continuous hemodiafiltration and rasburicase

A 25-year-old man was admitted to our hospital complaining of right scrotal pain and upper abdominal pain. A computed tomographic scan indicated a right scrotal mass, a huge liver mass, and multiple lung masses, although there was no enlarged retroperitoneal lymph node swelling. Laboratory tests showed severe liver and kidney dysfunction and high levels of serum α-fetoprotein (11 997 ng/ml). Although needle biopsies of the testicular and liver masses were performed, the tissues were insufficient for a pathological diagnosis. As liver and kidney function worsened, we started chemotherapy with bleomycin, etoposide, and cisplatin (BEP chemotherapy), which was modified because of the liver and renal dysfunction. We also used continuous hemodiafiltration and rasburicase to prevent tumor lysis syndrome. After induction of chemotherapy, the liver and kidney dysfunction improved immediately and the high orchiectomy was performed on day 8 after chemotherapy. The pathological diagnosis was a yolk sac tumor. He underwent four courses of the BEP regimen and five courses of the TIN regimen (paclitaxel, ifosphamide, and nedaplatin), followed by the resection of liver metastases. There was no evidence of viable cells in the resected liver and no recurrence was evident at 1 year postoperatively.

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Synthesis and biological evaluation of 3-(4-fluorophenyl)-1H-pyrazole derivatives as androgen receptor antagonists

A novel series of 3-(4-fluorophenyl)-1H-pyrazole derivatives were synthesized and evaluated for their antiproliferative activity against two prostate cancer cell lines (LNCaP and PC-3) and androgen receptor target gene prostate-specific antigen (PSA) inhibitory activity in LNCaP cells. Several compounds showed potent antiproliferative activity against LNCaP cells and showed a promising PSA downregulation rate. Among these, compound 10e selectively inhibited LNCaP cell growth with an IC50 value of 18 μmol/l and showed a PSA downregulation rate of 46%, which was better than the lead compound T3.

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Efficacy and safety of vinorelbine in heavily pretreated recurrent/metastatic head and neck squamous cell carcinoma patients

The aim of this study was to evaluate the efficacy and tolerance of vinorelbine as a single agent in the treatment of recurrent/metastatic head and neck squamous cell carcinoma. Patients were treated with oral or intravenous vinorelbine according to the pluridisciplinary tumor board's decision. Efficacy and safety outcomes were analyzed retrospectively. Twenty-three patients were included in the study. Sixteen patients (69%) had received at least two previous lines of chemotherapy. The disease control rate was 19%. The median progression-free survival was 2.6 months and the median overall survival was 3.4 months. The rate of grade 3–4 side effects was low (13%). Only one patient discontinued treatment because of side effects. Vinorelbine seems to be a well-tolerated regimen in heavily pretreated patients. However, this regimen does not seem to be efficient enough to be recommended.

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Inhibition of nuclear factor κB transcription activity drives a synergistic effect of cisplatin and oridonin on HepG2 human hepatocellular carcinoma cells

Activation of nuclear factor κB (NF-κB) by cisplatin and other chemotherapeutics is responsible, at least in part, for the development of drug resistance in the treatment of hepatocellular carcinoma. Therefore, a combination of chemotherapeutics with NF-κB inhibitors could overcome resistance of cancer cells. Oridonin is a diterpenoid isolated from Rabdosia rubescens that can block the NF-κB signaling cascades. In this study, we investigated the synergistic effect of oridonin and cisplatin on human hepatocellular carcinoma HepG2 cells. Cell apoptosis and mitochondrial membrane potential loss were examined using Hoechst 33258 and rhodamine-123 staining, followed by flow cytometry, respectively. The expression of apoptosis-related proteins and NF-κB subunits was detected by real-time PCR and western blot. The activity of caspase 3 and 9 was measured using the Caspase Activity Kit. Electrophoretic mobility shift assay and the enzyme-linked immunosorbent assay-based kit were used to assess the DNA-binding activity of NF-κB. We found a synergistic antitumor effect between cisplatin and oridonin on HepG2 cells both in vitro and in vivo. In addition, the combination of cisplatin and oridonin synergistically induces apoptosis and regulates the expression and activity of several key apoptosis-related proteins. Furthermore, the combination treatment not only downregulates nuclear translocation of p50 and p65, but more significantly, decreases the transcription activity of all NF-κB subunits to a greater degree than either agent alone. Our results suggest that the synergistic effect between both agents is likely to be driven by the inhibition of transcription activity of NF-κB and the resulting increased apoptosis.

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Spontaneous regression of tumour and the role of microbial infection – possibilities for cancer treatment

This review deals with the role of microorganisms in spontaneous regression of a tumour. Spontaneous cancer regression is a phenomenon that has been described for many centuries. One of the most well known methods of inducing spontaneous regression of cancer is the application of Coley's toxin (heat-killed Streptococcus pyogenes and Serratia marcescens), which has been used for the successful treatment of sarcomas, carcinomas, lymphomas, myelomas and melanomas. In clinical practice, the use of Bacillus Calmette-Guérin vaccine for the treatment of superficial urinary bladder cancer is the most common instance of the application of microorganisms for the treatment of cancer. This review provides further information on other tested bacteria – Clostridium spp., Bifidobacterium spp., Lactobacillus spp. and Salmonella spp. – in this field of study. Among new age methods, bactofection, alternative gene therapy, combination bacteriolytic therapy and bacteria-directed enzyme prodrug therapy are some of the potential cancer treatment modalities that use microorganisms. We have also provided information about the interconnection among microorganisms, immune system response, and the possible mechanisms involved in the spontaneous regression of tumours.

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Simotinib as a modulator of P-glycoprotein: substrate, inhibitor, or inducer?

As a new antitumor drug, simotinib hydrochloride is prescribed for prolonged periods, often to patients with comorbidities. Therefore, the risk for developing drug resistance and drug–drug interactions between simotinib and other agents has to be taken into consideration. As P-glycoprotein (P-gp) is an efflux transporter, which plays a significant role in drug resistance and influences the pharmacological properties and toxicities of the drugs it interacts with, the interactions between simotinib and P-gp were investigated. Cytotoxicity was measured using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. Intracellular drug concentrations were detected by high-performance liquid chromatography, fluorescence-activated cell sorting and using a fluorescence reader. P-gp ATPase activity was measured using the Pgp-Glo assay, and intracellular pH was assessed using the fluorescent probe 2′,7′-bis(2-carboxyethyl)-5(6)-carboxyfluorescein acetoxymethyl. The expression and transcription of P-gp were detected by western blotting and the luciferase assay. Simotinib has no cross-resistance to P-gp substrates, and its efflux rate was independent of either the P-gp expression or the coadministered P-gp substrate. Simotinib reversed chemotherapeutic agent resistance in a short time by increasing the intracellular concentration of the chemotherapeutic agent and blocked rhodamine 123 efflux. Further studies demonstrated that simotinib inhibited P-gp activity by modulating its ATPase activity and the intracellular pH. Although simotinib induced P-gp expression after extended treatment, the induced expression of P-gp had little impact on drug resistance. Simotinib is not a substrate of P-gp. As a modulator, it functions mainly as an inhibitor of P-gp by modulating the intracellular pH and ATPase activity, although it also induces P-gp expression after extended treatment.

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The Use of a Brochure to Enable CAM-with-Chemotherapy Patient Education

Abstract

The majority of cancer patients receiving chemotherapy will consider taking complementary and alternative medicine (CAM) during their treatment. As biologically-active CAM may detrimentally interfere with chemotherapy treatment, cancer patients require evidence-based information on chemotherapy-CAM integration consequences. This study aimed to assess if the availability of a purpose-designed brochure within a cancer service aided doctors' discussions with their patients on CAM use and helped patients understand the effects of CAM during their chemotherapy treatment. Cancer care doctors consulting in an adult day unit completed a structured post-intervention feedback survey form (n = 17), and cancer patients receiving chemotherapy treatment were provided the brochure and completed the local health service consumer testing feedback form (n = 30). All cancer care doctors perceived a need for the brochure and recommended the brochure to their patients. All doctors thought the brochure made it easier for them to discuss CAM with their patients, and 59 % believed that it saved them time during patient consultations. Ninety percent of cancer patients reported the brochure had enough information to answer their CAM questions, and all patients thought the information was easy to read and understand. An evidence-based CAM-with-chemotherapy patient brochure was perceived to have enabled cancer care doctors to discuss CAM with their patients and to have answered patients' CAM questions.

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Live imaging of TAK1 activation in Lewis lung carcinoma 3LL cells implanted into syngeneic mice and treated with polyI:C

Abstract

TGF-β activated kinase 1 (TAK1) has been shown to play a crucial role in cell death, differentiation, and inflammation. Here, we live-imaged robust TAK1 activation in Lewis lung carcinoma 3LL cells implanted into the subcutaneous tissue of syngeneic C57BL/6 mice and treated with polyinosinic polycytidylic acid (PolyI:C). First, we developed and characterized a Förster resonance energy transfer (FRET)-based biosensor for TAK1 activity. The TAK1 biosensor, named Eevee-TAK1, responded to stress-inducing reagents such as anisomycin, tumor necrosis factor-α (TNF-α), and interleukin1-β (IL-1β). The anisomycin-induced increase in FRET was abolished by the TAK1 inhibitor (5z)-7-oxozeaenol. TAK1 activity in 3LL cells was markedly increased by PolyI:C in the presence of macrophages. 3LL cells expressing Eevee-TAK1 were implanted into mice and observed through imaging window by two-photon excitation microscopy. During the growth of tumor, the 3LL cells at the periphery of the tumor exhibited higher TAK1 activity than the 3LL cells locating at the center of the tumor, suggesting that cells at the periphery of the tumor mass were under stronger stress. PolyI:C injection, which is known to induce regression of the implanted tumors, induced marked and homogenous TAK1 activation within the tumor tissues. The effect of PolyI:C faded within four days. These observations suggest that Eevee-TAK1 is a versatile tool to monitor cellular stress in cancer tissues.

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Effectiveness and side-effects of peptide receptor radionuclide therapy for neuroendocrine neoplasms in Germany: A multi-institutional registry study with prospective follow-up

Publication date: May 2016
Source:European Journal of Cancer, Volume 58
Author(s): Dieter Hörsch, Samer Ezziddin, Alexander Haug, Klaus Friedrich Gratz, Simone Dunkelmann, Matthias Miederer, Mathias Schreckenberger, Bernd Joachim Krause, Frank M. Bengel, Peter Bartenstein, Hans-Jürgen Biersack, Gabriele Pöpperl, R.P. Baum
BackgroundMonocentric and retrospective studies indicate effectiveness of peptide receptor radionuclide therapy targeting somatostatin receptors of neuroendocrine neoplasms. We assessed overall and progression-free survival and adverse events of peptide receptor radionuclide therapy by a multi-institutional, board certified registry with prospective follow-up in five centres in Germany.MethodsA total of 450 patients were included and followed for a mean of 24.4 months. Most patients had progressive low- or intermediate grade neuroendocrine neoplasms and 73% were pretreated with at least one therapy. Primary neuroendocrine neoplasms were mainly derived of pancreas (38%), small bowel (30%), unknown primary (19%) or bronchial system (4%). Patients were treated with Lutetium-177 in 54%, with Yttrium-90 in 17% and with both radionuclides in 29%. Overall and progression-free survival was determined with Kaplan–Meier curves and uni-variate log rank test Cox models.FindingsMedian overall survival of all patients was 59 (95% confidence interval [CI] 49–68.9) months. Overall survival was significantly inferior in the patients treated with Yttrium-90 solely (hazard ratio, 3.22; 95% CI, 1.83–5.64) compared to any peptide receptor radionuclide therapy with Lutetium-177. Grade II (hazard ratio, 2.06; 95% CI, 0.79–5.32) and grade III (hazard ratio, 4.22; 95% CI, 1.41–12.06) neuroendocrine neoplasms had significantly worse overall survival than grade I neuroendocrine neoplasms. Patients with small neuroendocrine neoplasms of small bowel had significantly increased survival (hazard ratio, 0.39; 95% CI, 0.18–0.87) compared to neuroendocrine neoplasms of other locations. Median progression-free survival was 41 (35.9–46.1) months and significantly inferior in patients treated with Yttrium solely (hazard ratio, 2.7; 95% CI, 1.71–4.55). Complete remission was observed in 5.6% of patients, 22.4% had a partial remission, 47.3% were stable and 4% were progressive as best response. Adverse events of bone marrow and kidney function higher than grade III occurred in 0.2–1.5% of patients.InterpretationThese results indicate that peptide receptor radionuclide therapy is a highly effective therapy for patients with low to intermediate grade neuroendocrine neoplasms with minor adverse events.



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Long-term outcome of molecular subgroups of gastrointestinal stromal tumour patients treated with standard-dose imatinib in the BFR14 trial: The wild-type gastrointestinal stromal tumours are not a single group yet

Publication date: May 2016
Source:European Journal of Cancer, Volume 58
Author(s): Maria A. Pantaleo, Margherita Nannini




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The role of selected egzo- and endogenic agents on preinitiation process of bladder cancer

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Zinc as diagnostic marker of cancers

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Copper as diagnostic marker of cancers

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Copper transport system and response to ovarian cancer chemotherapy

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Iron as diagnostic marker of cancer

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Selenium as diagnostic marker of cancers

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Pharmacogenetics of FAC chemotherapy side effects in breast cancer patients

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Pathological complete response to neoadjuvant cisplatin in BRCA1-positive breast cancer patients

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RET gene mutations spectrum in patients with medullary thyroid carcinoma (MTC) from Great Poland region

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The curious case of a woman with two BRCA1 mutations in trans

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Factors influencing effective acquisition of primary care patients for cancer early diagnostics

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Micronutrient supplementation for cancer prevention

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Magnesium as a diagnostic marker of cancer

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