Human papillomavirus type 16 viral load is decreased following a therapeutic vaccination

Abstract

In the dose-escalation phase of a Phase I clinical trial in which six subjects each were vaccinated with PepCan at the 50, 100, 250, and 500 μg per peptide dose, the 50 μg dose showed the best histological regression rate. Ten additional subjects were vaccinated at this dose in the final dose phase. As with the dose-escalation phase, no dose-limiting toxicities were observed. Overall, the histological regression rates were 50 % at the 50 μg dose (7 of 14) and 100 μg dose (3 of 6), and 45 % overall (14 of 31). Of subjects in whom HPV type 16 (HPV 16) was detected at entry, it became undetectable in three subjects after vaccination, and the viral loads significantly decreased in nine subjects in whom HPV 16 infection was detected at entry and exit (p = 0.008). Immune profiling revealed increased T-helper type 1 cells after vaccinations (p = 0.02 and 0.0004 after 2 and 4 vaccinations, respectively). T-helper type 2 cells initially increased after two vaccinations (p = 0.01), but decreased below the baseline level after four vaccinations although not significantly. Pre-vaccination regulatory T cell levels were significantly lower in histological responders compared to non-responders (p = 0.03). Feasibility of testing plasma for multiplex cytokine/chemokine analysis and of performing proteomic analysis of PBMCs was examined for potentially identifying biomarkers in the future. While these analyses are feasible to perform, attention needs to be given to how soon the blood samples would be processed after phlebotomy. As sufficient safety of PepCan has been demonstrated, enrollment for the Phase II clinical trial has been opened.

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Time course and predictive factors for lung volume reduction following stereotactic ablative radiotherapy (SABR) of lung tumors

Stereotactic ablative volume reduction (SAVR) is a potential alternative to lung-volume reduction surgery in patients with severe emphysema and excessive surgical risk. Having previously observed a dose-volume...

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Human papillomavirus type 16 viral load is decreased following a therapeutic vaccination

Abstract

In the dose-escalation phase of a Phase I clinical trial in which six subjects each were vaccinated with PepCan at the 50, 100, 250, and 500 μg per peptide dose, the 50 μg dose showed the best histological regression rate. Ten additional subjects were vaccinated at this dose in the final dose phase. As with the dose-escalation phase, no dose-limiting toxicities were observed. Overall, the histological regression rates were 50 % at the 50 μg dose (7 of 14) and 100 μg dose (3 of 6), and 45 % overall (14 of 31). Of subjects in whom HPV type 16 (HPV 16) was detected at entry, it became undetectable in three subjects after vaccination, and the viral loads significantly decreased in nine subjects in whom HPV 16 infection was detected at entry and exit (p = 0.008). Immune profiling revealed increased T-helper type 1 cells after vaccinations (p = 0.02 and 0.0004 after 2 and 4 vaccinations, respectively). T-helper type 2 cells initially increased after two vaccinations (p = 0.01), but decreased below the baseline level after four vaccinations although not significantly. Pre-vaccination regulatory T cell levels were significantly lower in histological responders compared to non-responders (p = 0.03). Feasibility of testing plasma for multiplex cytokine/chemokine analysis and of performing proteomic analysis of PBMCs was examined for potentially identifying biomarkers in the future. While these analyses are feasible to perform, attention needs to be given to how soon the blood samples would be processed after phlebotomy. As sufficient safety of PepCan has been demonstrated, enrollment for the Phase II clinical trial has been opened.

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Indirect Treatment Comparison of Talimogene Laherparepvec Compared with Ipilimumab and Vemurafenib for the Treatment of Patients with Metastatic Melanoma

Abstract

Introduction

Few randomized controlled trials have compared new treatments for metastatic melanoma. We sought to examine the relative treatment effect of talimogene laherparepvec compared with ipilimumab and vemurafenib.

Methods

A systematic literature review of treatments for metastatic melanoma was undertaken but a valid network of evidence could not be established because of a lack of comparative data or studies with sufficient common comparators. A conventional adjusted indirect treatment comparison via network meta-analysis was, therefore, not feasible. Instead, a meta-analysis of absolute efficacy was undertaken, adjusting overall survival (OS) data for differences in prognostic factors between studies using a published algorithm.

Results

Four trials were included in the final indirect treatment comparison: two of ipilimumab, one of vemurafenib, and one of talimogene laherparepvec. Median OS for ipilimumab and vemurafenib increased significantly when adjustment was applied, demonstrating that variation in disease and patient characteristics was biasing OS estimates; adjusting for this made the survival data more comparable. For both ipilimumab and vemurafenib, the adjustments improved Kaplan–Meier OS curves; the observed talimogene laherparepvec OS curve remained above the adjusted OS curves for ipilimumab and vemurafenib, showing that long-term survival could differ from the observed medians.

Conclusion

Even with limited data, talimogene laherparepvec, ipilimumab, and vemurafenib could be compared following adjustments, thereby providing a more reliable understanding of the relative effect of treatment on survival in a more comparable patient population. The results of this analysis suggest that OS with talimogene laherparepvec is at least as good as with ipilimumab and vemurafenib and improvement was more pronounced in patients with no bone, brain, lung or other visceral metastases.

Funding

Amgen Inc.

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Issue Information

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Human papillomavirus type 16 viral load is decreased following a therapeutic vaccination

Abstract

In the dose-escalation phase of a Phase I clinical trial in which six subjects each were vaccinated with PepCan at the 50, 100, 250, and 500 μg per peptide dose, the 50 μg dose showed the best histological regression rate. Ten additional subjects were vaccinated at this dose in the final dose phase. As with the dose-escalation phase, no dose-limiting toxicities were observed. Overall, the histological regression rates were 50 % at the 50 μg dose (7 of 14) and 100 μg dose (3 of 6), and 45 % overall (14 of 31). Of subjects in whom HPV type 16 (HPV 16) was detected at entry, it became undetectable in three subjects after vaccination, and the viral loads significantly decreased in nine subjects in whom HPV 16 infection was detected at entry and exit (p = 0.008). Immune profiling revealed increased T-helper type 1 cells after vaccinations (p = 0.02 and 0.0004 after 2 and 4 vaccinations, respectively). T-helper type 2 cells initially increased after two vaccinations (p = 0.01), but decreased below the baseline level after four vaccinations although not significantly. Pre-vaccination regulatory T cell levels were significantly lower in histological responders compared to non-responders (p = 0.03). Feasibility of testing plasma for multiplex cytokine/chemokine analysis and of performing proteomic analysis of PBMCs was examined for potentially identifying biomarkers in the future. While these analyses are feasible to perform, attention needs to be given to how soon the blood samples would be processed after phlebotomy. As sufficient safety of PepCan has been demonstrated, enrollment for the Phase II clinical trial has been opened.

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Differences in cognitive function between patients with viral and alcoholic compensated liver cirrhosis

Abstract

As alcohol induces change in frontal cortex primarily involved in cognition, cognitive function may be different between viral and alcoholic liver cirrhosis (LC). This study aimed to determine the differences of cognitive function between viral and alcoholic compensated LC. From October 2011 to March 2013, 80 patients (viral: 37; alcohol: 43) with compensated LC were prospectively enrolled. Neuropsychological functions including attention, language, visuospatial, verbal memory, visual memory, and frontal/executive function were evaluated between two groups and compared with age-matched normal group (n = 1000). Cumulative incidence rate of overt hepatic encephalopathy (HE) was calculated. In the comparison with normal group, both two groups showed decreased memory function, frontal/executive function, and Korea-Mini Mental Status Examination. In the analysis of two groups, memory function by Verbal Learning Test (recognition: 20.1 ± 3.6 and 17.8 ± 4.8, p = 0.022), visuospatial function by Ray-Complex Figure Copy Test (recognition: 19.0 ± 2.6 and 17.3 ± 4.0, p = 0.043), frontal/executive function by Controlled Oral Ward Association (semantic: 17.1 ± 6.9 and 12.7 ± 6.9, p = 0.004), and the Korea-Mini Mental Status Examination (27.5 ± 1.9 and 26.2 ± 3.1, p = 0.03) showed low scores in alcoholic compensated LC patients. The 1-, 2-, and 3-year cumulative incidence rates of overt HE were 23 %, 26 %, and 26 % and 33 %, 43 %, and 49 % in the viral and alcoholic compensated LC group, respectively (p = 0.033). Impaired memory and frontal lobe executive functions and early development of overt HE were more common in patients with alcoholic LC. For patients with alcoholic LC, more integrated tests for early detection of minimal HE and intensive treatment should be considered to prevent overt HE.

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Atypical clinical and radiological course of a patient with Canavan disease

Abstract

Canavan disease (CD) is a rare metabolic disorder caused by aspartoacylase (ASPA) deficiency. It leads to severe neurological degeneration with spongiform brain degeneration. Accumulation of N-acetylaspartate (NAA) in brain and urine is specific to the disease and guides diagnosis. Magnetic resonance imaging (MRI) usually shows diffuse white matter abnormalities with involvement of the basal ganglia. Mild forms of the disease with a more favorable clinical course and radiological involvement of the basal ganglia without white matter abnormalities have also been reported. Here we report an atypical case of a girl aged nine years with CD. The disease started at the classical age of five months. Classical elevation of NAA in brain and urine was present and genetic analysis identified mutations in the ASPA gene. However, clinical evolution was milder than typical CD, with partial motor impairment and relatively well-preserved cognitive skills. MRI was also atypical with low white matter involvement and unusual topography and evolution of abnormalities in the basal ganglia.

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Chemically induced acute model of sarcosinemia in wistar rats

Abstract

In the present study, we developed an acute chemically induced model of sarcosinemia in Wistar rats. Wistar rats of 7, 14 and 21 postpartum days received sarcosine intraperitoneally in doses of 0.5 mmol/Kg of body weight three time a day at intervals of 3 h. Control animals received saline solution (NaCl 0.85 g%) in the same volume (10 mL/Kg of body weight). The animals were killed after 30 min, 1, 2, 3 or 6 h after the last injection and the brain and the blood were collected for sarcosine measurement. The results showed that plasma and brain sarcosine concentrations achieved levels three to four times higher than the normal levels and decreased in a time-dependent way, achieving normal levels after 6 hours. Considering that experimental animal models are useful to investigate the pathophysiology of human disorders, our model of sarcosinemia may be useful for the research of the mechanisms of neurological dysfunction caused by high tissue sarcosine levels.

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Intracerebroventricular administration of α-ketoisocaproic acid decreases brain-derived neurotrophic factor and nerve growth factor levels in brain of young rats

Abstract

Maple syrup urine disease (MSUD) is an inherited aminoacidopathy resulting from dysfunction of the branched-chain keto acid dehydrogenase complex, leading to accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine and valine as well as their corresponding transaminated branched-chain α-ketoacids. This disorder is clinically characterized by ketoacidosis, seizures, coma, psychomotor delay and mental retardation whose pathophysiology is not completely understood. Recent studies have shown that oxidative stress may be involved in neuropathology of MSUD. However, the effect of accumulating α-ketoacids in MSUD on neurotrophic factors has not been investigated. Thus, the objective of the present study was to evaluate the effects of acute intracerebroventricular administration of α-ketoisocaproic acid (KIC) on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in the brains of young male rats. Ours results showed that intracerebroventricular administration of KIC decreased BDNF levels in hippocampus, striatum and cerebral cortex, without induce a detectable change in pro-BDNF levels. Moreover, NGF levels in the hippocampus were reduced after intracerebroventricular administration of KIC. In conclusion, these data suggest that the effects of KIC on demyelination and memory processes may be mediated by reduced trophic support of BDNF and NGF. Moreover, lower levels of BDNF and NGF are consistent with the hypothesis that a deficit in this neurotrophic factor may contribute to the structural and functional alterations of brain underlying the psychopathology of MSUD, supporting the hypothesis of a neurodegenerative process in MSUD.

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Human papillomavirus infection and risk of breast cancer: a meta-analysis of case-control studies

Abstract

Background

Although systematic reviews (SR) report that human papillomavirus (HPV) increases the risk of breast cancer, there are still disputes regarding this association. In particular, it has been argued that the risk level differs depending on nationality, type of tissue, subtype of HPV, and publication year. Considering that the searching year of publication for the previous SRs was June 2013, a renewal meta-analysis needs to be conducted.

Methods

Using articles selected in the previous SRs, we compiled a list of references, cited articles, and related articles from the PubMed and Scopus databases. Of these, only publications with data from case-control studies on HPV DNA-positivity in tissues were chosen. Summary odds ratio (SOR) and 95 % confidence interval (CI) were calculated through meta-analysis. Meta-regression analysis was performed for nationality, types of tissue, subtype of HPV, and publication year.

Results

Twenty-two case-control studies were selected, and the total number of individuals in the case and control group was 1897 and 948, respectively. According to the meta-analysis about the 22 publications, HPV infection increased the risk of breast cancer (SOR = 4.02, 95 % CI: 2.42–6.68; I-squared = 44.7 %). Statistical significance was not found in meta-regression performed on the four variables of nationality, type of tissue, subtype of HPV, and publication year which some researchers think sources of heterogeneity.

Conclusions

The results of the present study supported the argument that HPV infection increases the risk of breast cancer. Age-matched case-control studies are in need in the future.

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Transthoracic needle aspiration biopsy for the cytologic diagnosis of subsolid lung nodules

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Preliminary estimates of SEER cancer incidence for 2013

BACKGROUND

This article presents a first look at rates and trends for cases in the Surveillance, Epidemiology, and End Results (SEER) program diagnosed through 2013 using the February 2015 submission, and a validation of rates and trends from the February 2014 submission using the subsequent November 2014 submission. To the authors' knowledge, this is the second time SEER has published trends based on the early February submission. Three new cancer sites were added: cervix, thyroid, and liver/ intrahepatic bile duct.

METHODS

A reporting delay model adjusted for the undercount of cases, which is substantially larger for the February than the subsequent November submission, was used. Joinpoint regression methodology was used to assess trends. Delay-adjusted rates and trends were checked to assess validity between the February and November 2014 submissions.

RESULTS

The validation of rates and trends from the February and November 2014 submissions demonstrated even better agreement than the previously reported comparison between the February and November 2013 submissions, thereby affording additional confidence that the delay-adjusted February submission data can be used to produce valid estimates of incidence trends. Trends for cases diagnosed through 2013 revealed more rapid declines in female colon and rectal cancer and prostate cancer. A plateau in female melanoma trends and a slowing of the increases in thyroid cancer and male liver/intrahepatic bile duct cancer trends were observed.

CONCLUSIONS

Analysis of early cancer data submissions can provide a preliminary indication of differences in incidence trends with an additional year of data. Although the delay adjustment correction adjusts for underreporting of cases, caution should be exercised when interpreting the results in this early submission. Cancer 2016. © 2016 American Cancer Society.

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Prognostic significance of 18F-FDG PET at diagnosis in patients with soft tissue sarcoma and bone sarcoma; systematic review and meta-analysis

Publication date: May 2016
Source:European Journal of Cancer, Volume 58
Author(s): Tadahiko Kubo, Taisuke Furuta, Muhammad P. Johan, Mitsuo Ochi
PurposeThe usefulness of ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) for the survival prognosis in soft tissue sarcoma (STS) and bone sarcoma (BS) is controversial. The objective of this systematic review was to provide an up-to-date and unprecedented summary of the prognostic value of ¹⁸F-FDG PET at diagnosis in STS and BS.MethodsStudies evaluating pre-treatment ¹⁸F-FDG PET for overall survival of STS and BS were systematically searched for in MEDLINE, EMBASE, and Web of Science. Comparative analyses of the pooled hazard ratios (HR) of overall survival were performed between patients with high and low maximum standardised uptake value (SUVmax). The quality of study designs was evaluated using the Newcastle-Ottawa scale (NOS) for quality assessment of cohort studies. P < 0.05 was defined as statistically significant.ResultsA total of six studies comprising 514 patients with STS and BS were considered for the meta-analysis. The pooled HR for overall survival was 1.22 (95% confidence interval: 1.03–1.46), suggesting that high SUVmax predicts a significantly shorter overall survival period than low SUVmax (P = 0.03). Additional subgroup analyses using patients with STS alone showed that high SUVmax might predict poorer overall survival than low SUVmax (P = 0.004), although only two studies consisting of 96 patients were included. The overall quality of the included studies evaluated by the NOS assessment was adequate.Conclusion¹⁸F-FDG PET at diagnosis provides a very useful predictive tool for patients with STS and BS.



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Thrombocytopenia and craniotomy for tumor: A National Surgical Quality Improvement Program analysis

BACKGROUND

To the authors' knowledge, the current study is the first national analysis of the association between preoperative platelet count and outcomes after craniotomy.

METHODS

Patients who underwent craniotomy for tumor were extracted from the prospective National Surgical Quality Improvement Program registry (2007-2014) and stratified by preoperative thrombocytopenia, defined as mild (125,000-149,000/μL), moderate (100,000-124,000/μL), severe (75,000-99,000/μL), or very severe (<75,000/μL). Cox proportional hazards analysis was used to evaluate the association between thrombocytopenia and 30-day mortality, and multivariable logistic regression with complications and unplanned reoperation. Covariates included patient age, sex, tumor histology, American Society of Anesthesiologists class, functional status, comorbidities, and surgical time.

RESULTS

A total of 14,852 patients were included in the current study and thrombocytopenia was classified as mild in 4.4% (646 patients), moderate in 2.0% (290 patients), severe in 0.7% (105 patients), or very severe in 0.4% (66 patients) of patients. The adjusted hazard of 30-day death was significantly higher for patients with moderate (6.6%; hazard ratio [HR], 2.13 [95% confidence interval (95% CI), 1.30-3.49; P =  0.003]), severe (10.5%; HR, 2.33 [95% CI, 1.18-4.60; P =  0.02]), and very severe (10.6%; HR, 3.65 [95% CI, 1.71-7.82; P =  0.001]) thrombocytopenia, compared with patients without thrombocytopenia (2.9%), with an increased effect size noted with greater thrombocytopenia. Likewise, when the platelet count was evaluated continuously, a higher platelet count was associated with a lower hazard of 30-day mortality (HR, 0.987 [95% CI, 0.981-0.993; P<.001]), developing any complication (odds ratio, 0.985 [95% CI, 0.981-0.988; P<.001]), and reoperation (odds ratio, 0.990 [95% CI, 0.983-0.994; P = .003]). Unplanned reoperation was due to intracranial hemorrhage in 53.3% of patients with moderate thrombocytopenia.

CONCLUSIONS

In this National Surgical Quality Improvement Program analysis, moderate and severe thrombocytopenia were associated with mortality and reoperation after craniotomy for tumor. Cancer 2016. © 2016 American Cancer Society.

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Using the galactose-α-1,3-galactose enzyme-linked immunosorbent assay to predict anaphylaxis in response to cetuximab

BACKGROUND

Cetuximab is a monoclonal antibody against epidermal growth factor receptor with activity against head and neck cancer and colorectal cancer. Anaphylaxis in response to cetuximab is a significant clinical problem in the Southeastern United States with a grade 3/4 infusion reaction rate of 14%. Previous retrospective data have suggested that the presence of preformed immunoglobulin E antibodies against galactose-α-1,3-galactose in serum can predict anaphylaxis in response to cetuximab.

METHODS

Sixty patients were prospectively screened as part of the entry criteria for a phase 2 study of neoadjuvant carboplatin, nab-paclitaxel, and cetuximab. Patients were recruited at 2 academic medical centers known to have high anaphylaxis rates: the University of North Carolina and Vanderbilt. Only patients with a negative laboratory result were treated on the clinical protocol.

RESULTS

No patient experienced anaphylaxis; the negative predictive value was thus 100%. Other than smoking history, the demographics were similar for assay-positive subjects and assay-negative subjects.

CONCLUSIONS

Subjects with a negative test result can be safely treated with cetuximab. Further research is required regarding the optimal cutoff for positivity and the positive predictive value. Cancer 2016. © 2016 American Cancer Society.

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Uveal melanoma: From diagnosis to treatment and the science in between

Melanomas of the choroid, ciliary body, and iris of the eye are collectively known as uveal melanomas. These cancers represent 5% of all melanoma diagnoses in the United States, and their age-adjusted risk is 5 per 1 million population. These less frequent melanomas are dissimilar to their more common cutaneous melanoma relative, with differing risk factors, primary treatment, anatomic spread, molecular changes, and responses to systemic therapy. Once uveal melanoma becomes metastatic, therapy options are limited and are often extrapolated from cutaneous melanoma therapies despite the routine exclusion of patients with uveal melanoma from clinical trials. Clinical trials directed at uveal melanoma have been completed or are in progress, and data from these well designed investigations will help guide future directions in this orphan disease. Cancer 2016. © 2016 American Cancer Society.

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Genetic anticipation in BRCA1/BRCA2 families after controlling for ascertainment bias and cohort effect

BACKGROUND

Genetic anticipation, the earlier onset of disease in successive generations, has been reported in hereditary breast and ovarian cancer syndrome (HBOC), but little is known about its underlying mechanisms. Ascertainment bias has been suggested as a reason in previous studies. Likewise, cohort effect, which may be caused by environmental factors, can be misinterpreted as genetic anticipation.

METHODS

The authors reviewed the pedigrees of 176 kindreds, segregating those with deleterious mutations in breast cancer genes 1 and 2 (BRCA1/BRCA2) who had at least 2 consecutive generations of the same cancer (breast or ovarian). By using mutation probabilities as analytical weights in weighted random-effect models, generational differences in the age at onset of breast/ovarian cancer were calculated. The analyses were further controlled for ascertainment bias by excluding probands and adjusting for birth-cohort effect in the anticipation models.

RESULTS

The mean age at the onset of breast cancer for the probands' generation was 41.9 years, which was 6.8 years and 9.8 years earlier than the parents' and grandparents' generations, respectively. The anticipation effect for breast cancer remained significant after excluding the probands. There was a birth-cohort effect: patients who were born in 1930s and 1940s had breast cancer 5.0 years and 7.6 years earlier than patients who were born before 1920. The difference in breast cancer age of onset across generations was no longer significant after adjusting for birth-cohort effect.

CONCLUSIONS

The observed anticipation effect was driven mainly by a decrease in age of onset across birth cohorts, underscoring the need for risk-reducing interventions that target changing environmental/lifestyle factors in BRCA1/BRCA2 carriers. Cancer 2016. © 2016 American Cancer Society.

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PLCε signaling in cancer

Abstract

Purpose

As one of the members of the PLC family, the phosphoinositide-specific phospholipase Cε (PLCε) has been shown to play pivotal roles in multiple signal pathways and control a variety of cellular functions. A number of studies have shown that aberrant regulation of PLCε was involved in various types of animal and human cancer. However, the role of PLCε in cancer remains elusive. In this review, we provide an overview of the PLCε, especially its roles in multiple signal pathways, and summarize the recent findings that highlight the roles of PLCε in carcinogenesis and cancer progression, making an avenue to provide a novel therapeutic strategy for the treatment of cancer.

Methods

A literature search mainly paying attention to the network of PLCε involved in tumorigenesis and development was performed in electronic databases.

Results

PLCε plays a key role in medicating the development and progression of human cancers with highest potency to be a target of cancer prevention and treatment.

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Systemic versus local responses in melanoma patients treated with talimogene laherparepvec from a multi-institutional phase II study

Abstract

Background

We previously reported that talimogene laherparepvec, an oncolytic herpes virus encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), resulted in an objective response rate of 26 % in patients with advanced melanoma in a phase II clinical trial. The response of individual lesions, however, was not reported. Since talimogene laherparepvec is thought to mediate anti-tumor activity through both direct tumor cytolysis and induction of systemic tumor-specific immunity, we sought to determine the independent response rate in virus-injected and non-injected lesions.

Methods

Fifty patients with stage IIIC or IV melanoma were treated with talimogene laherparepvec in a multi-institutional single-arm open-label phase II clinical trial. In this study patients were treated until a complete response was achieved, all accessible tumors disappeared, clinically significant disease progression, or unacceptable toxicity. This report is a post hoc analysis of the systemic effects of talimogene laherparepvec in injected lesions and two types of uninjected lesions—non-visceral lesions and visceral lesions.

Results

Eleven of 23 patients (47.8 %) had a ≥ 30 % reduction in the total burden of uninjected non-visceral lesions, and 2 of 12 patients (16.7 %) had a ≥ 30 % reduction in the total burden of visceral lesions. Among 128 evaluable lesions directly injected with talimogene laherparepvec, 86 (67.2 %) decreased in size by ≥ 30 % and 59 (46.1 %) completely resolved. Of 146 uninjected non-visceral lesions, 60 (41.1 %) decreased in size by ≥ 30 %, the majority of which (44 [30.1 %]) completely resolved. Of 32 visceral lesions, 4 (12.5 %) decreased in size by ≥ 30 %, and 3 (9.4 %) completely resolved. The median time to lesion response was shortest for lesions that were directly injected (18.4 weeks), followed by uninjected non-visceral lesions (23.1 weeks) and visceral lesions (51.3 weeks), consistent with initiation of a delayed regional and systemic anti-tumor immune response to talimogene laherparepvec.

Conclusions

These results support a regional and systemic effect of talimogene laherparepvec immunotherapy in patients with advanced melanoma.

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Immune monitoring technology primer: immunoprofiling of antigen-stimulated blood

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Phase I study with ONCOS-102 for the treatment of solid tumors – an evaluation of clinical response and exploratory analyses of immune markers

Abstract

Background

We conducted a phase I study with a granulocyte macrophage colony stimulating factor (GMCSF)-expressing oncolytic adenovirus, ONCOS-102, in patients with solid tumors refractory to available treatments. The objectives of the study were to determine the optimal dose for further use and to assess the safety, tolerability and adverse event (AE) profile of ONCOS-102. Further, the response rate and overall survival were evaluated as well as preliminary evidence of disease control. As an exploratory endpoint, the effect of ONCOS 102 on biological correlates was examined.

Methods

The study was conducted using a classic 3 + 3 dose escalation study design involving 12 patients. Patients were repeatedly treated intratumorally with ONCOS-102 plus daily low-dose oral cyclophosphamide (CPO). Tumor response was evaluated with diagnostic positron emission tomography (PET) and computed tomography (CT). Tumor biopsies were collected at baseline and after treatment initiation for analysis of immunological correlates. Peripheral blood mononuclear cells (PBMCs) were collected at baseline and during the study to assess antigen specificity of CD8+ T cells by interferon gamma (IFNγ) enzyme linked immunospot assay (ELISPOT).

Results

No dose limiting toxicity (DLT) or maximum tolerated dose (MTD) was identified for ONCOS-102. Four out of ten (40 %) evaluable patients had disease control based on PET/CT scan at 3 months and median overall survival was 9.3 months. A short-term increase in systemic pro-inflammatory cytokines and a prominent infiltration of TILs to tumors was seen post-treatment in 11 out of 12 patients. Two patients showed marked infiltration of CD8+ T cells to tumors and concomitant systemic induction of tumor-specific CD8+ T cells. Interestingly, high expression levels of genes associated with activated T_H1 cells and T_H1 type immune profile were observed in the post-treatment biopsies of these two patients.

Conclusions

ONCOS-102 is safe and well tolerated at the tested doses. All three examined doses may be used in further development. There was evidence of antitumor immunity and signals of clinical efficacy. Importantly, treatment resulted in infiltration of CD8+ T cells to tumors and up-regulation of PD-L1, highlighting the potential of ONCOS-102 as an immunosensitizing agent for combinatory therapies with checkpoint inhibitors.

Trial registration

NCT01598129. Registered 19/04/2012

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A role for pre-mNK cells in tumor progression

Abstract

The innate and adaptive immune systems have evolved together to fight infection and cancerous tissues. The innate immune system emerges first with the adaptive immune system following, both ostensibly being bridged by dendritic cells (DC). Recently cells have emerged that possess characteristics of both innate and adaptive immune cell qualities, termed interferon-producing killer dendritic cells (IKDCs). These cells have an indistinct origin that is not well understood. They appear to have more NK cell attributes than DC but purportedly can regulate the immune system similar to immunoregulatory NK cells. Because of this, they have been renamed pre-mNK cells (pre-mature NK cells). We argue in this commentary that pre-mNK cells may contribute to cancer recurrence.

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From bench to bedside a comprehensive review of pancreatic cancer immunotherapy

Abstract

The incidence of pancreatic cancer has been increasing while its 5-year survival rate has not changed in decades. In the era of personalized medicine, immunotherapy has emerged as a promising treatment modality in a variety of malignancies, including pancreatic cancer. This review will discuss the unique pancreatic tumor microenvironment, including the cells and receptors that transform the pancreas from its normal architecture into a complex mix of suppressor immune cells and dense extracellular matrix that allows for the unrestricted growth of cancer cells. Next, we will highlight the recently completed immunotherapy clinical trials in pancreatic cancer. Finally, we will explore the on-going immunotherapy clinical trials and future directions of this engaging and changing field.

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Immunodynamics: a cancer immunotherapy trials network review of immune monitoring in immuno-oncology clinical trials

Abstract

The efficacy of PD-1/PD-L1 targeted therapies in addition to anti-CTLA-4 solidifies immunotherapy as a modality to add to the anticancer arsenal. Despite raising the bar of clinical efficacy, immunologically targeted agents raise new challenges to conventional drug development paradigms by highlighting the limited relevance of assessing standard pharmacokinetics (PK) and pharmacodynamics (PD). Specifically, systemic and intratumoral immune effects have not consistently correlated with standard relationships between systemic dose, toxicity, and efficacy for cytotoxic therapies. Hence, PK and PD paradigms remain inadequate to guide the selection of doses and schedules, both starting and recommended Phase 2 for immunotherapies. The promise of harnessing the immune response against cancer must also be considered in light of unique and potentially serious toxicities. Refining immune endpoints to better inform clinical trial design represents a high priority challenge. The Cancer Immunotherapy Trials Network investigators review the immunodynamic effects of specific classes of immunotherapeutic agents to focus immune assessment modalities and sites, both systemic and importantly intratumoral, which are critical to the success of the rapidly growing field of immuno-oncology.

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Systemic inflammation in a melanoma patient treated with immune checkpoint inhibitors—an autopsy study

Abstract

Background

Immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have been recently approved for treatment of patients with metastatic melanoma and non-small cell lung cancer (NSCLC). Despite important clinical benefits, these therapies are associated with a diverse spectrum of immune-related adverse events (irAEs) that are typically transient, but occasionally severe or even fatal.

Case presentation

This autopsy case illustrates that clinically overt irAEs may represent only a fraction of the total spectrum of immune-related organ pathology in patients treated with immune checkpoint inhibitors. We report a comprehensive analysis of systemic irAE pathology based on the autopsy of a 35-year-old female patient with metastatic melanoma treated first with ipilimumab and then nivolumab. The clinical course was characterized by a mixed tumor response with regression of skin and lung metastases and fatal progression of metastatic disease in the small bowel, peritoneum and brain. During therapy with ipilimumab, radiographic features of immune-related pneumonitis were noted. The autopsy examination established a sarcoid-like granulomatous reaction of the lung, pulmonary fibrosis and diffuse alveolar damage. Importantly, a clinically unapparent but histologically striking systemic inflammation involving the heart, central nervous system, liver and bone marrow was identified. Severe immune-related end-organ damage due to lymphocytic myocarditis was found.

Conclusions

Autopsy studies are an important measure of quality control and may identify clinically unapparent irAEs in patients treated with immunotherapy. Pathologists and clinicians need to be aware of the broad spectrum of irAEs for timely management of treatment-related morbidity.

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A Study of the Possible Harmful Effects of Cosmetic Beauty Products on Human Health

Abstract

The origins of the usage of different substances in beauty, skin, body, hair, and nails care products can be found in ancient times. To achieve better quality and enhance their effects, some additives such as preservatives, stabilizers, mineral pigments, dye, and shine were added to these products. Some of these substances may also have allergic, irritating, and harmful effects on human health. The aim of this study was the optimization of the potentiometric stripping analysis (PSA) for the purpose of determining the content of heavy metals (lead, cadmium, zinc), in some commercial cosmetic beauty products (lipsticks, lip glosses, eye shadows, and henna hair dye). In addition, in order to monitor the potential adverse effects of henna dye on hair quality, as well as the total body burden of heavy metals (Pb, Cd), the paper analyzed hair samples before and after henna dye treatment. Beauty products used for cosmetic purposes can have adverse effects to human health due to the fact that they contain lead, a highly toxic metal. The lead content in the tested samples varied depending on the additives used along with the method of production. The cosmetic products that were analyzed in this study contained a certain amount of zinc, which is an essential element, although its content above the prescribed limit may lead to side effects. Highly toxic metal, cadmium, was not detected in the tested samples. The presence of these metals in cosmetic products certainly indicate that it is necessary to monitor and determinate the content of toxic heavy metals in these products, especially because they are in direct contact with skin or mucous membranes and are often used in daily life.

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Characterization of Selenoprotein M and Its Response to Selenium Deficiency in Chicken Brain

Abstract

Selenoprotein M (SelM) may function as thiol disulfide oxidoreductase that participates in the formation of disulfide bonds and can be implicated in calcium responses. SelM may have a functional role in catalyzing free radicals and has been associated with Alzheimer's disease (AD). However, studies of SelM in chicken remain very limited. In this study, two groups of day-old broiler chicks (n = 40/group) were fed a corn-soy basal diet (BD, 13 μg Se/kg) and BD supplemented with Se (as sodium selenite) at 0.3 mg/kg. The brain was collected at 14, 21, 28, and 42 days of age. We performed a sequence analysis and predicted the structure and function of SelM. We also investigated the effects of Se deficiency on the expression of Selt, Selw, and Selm and the Se status in the chicken brain. The results show that Se deficiency induced the lower (P < 0.05) Se content, glutathione peroxidase (GPx), and catalase (CAT) activities; increased (P < 0.05) malondialdehyde (MDA) content; and reduced (P < 0.05) the expression of Selm messenger RNA (mRNA) and protein abundance of SelM in the brain. However, there were no significant brain Selt and Selw mRNA levels by dietary Se deficiency in chicks. The different regulations of these three redox (Rdx) protein expressions by Se deficiency represent a novel finding of the present study. Our results demonstrated that SelM may have an important role in protecting against oxidative damage in the brain of chicken, which might shed light on the role of SelM in human neurodegenerative disease. More studies are needed to confirm our conclusion.

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Blood Pressure Decreases Following Lead Treatment Cessation: Highest NO Bioavailability Involved

Abstract

Although lead is known to induce arterial hypertension and vascular damage, it is not clear if after cessation of lead treatment, the increase of blood pressure is sustained and the vascular function is different from untreated rats. Therefore, we aimed to evaluate the systolic blood pressure during and following lead-treatment discontinuance and the possible vascular alterations involved with it. Rats received lead acetate (100 mg/L) in the drinking water or distilled water for 14 days. After 14 days, lead acetate solution was substituted by water distilled for more 28 days, as control group. Systolic blood pressure (SBP) was measured weekly by tail plethysmography, and the vascular reactivity to phenylephrine in isolated aortic rings was evaluated at end of treatment time. The increase in SBP induced by lead was reversed after stopping exposure, and it was accompanied by a reduction on vasoconstrictor response to phenylephrine. L-NAME treatment increased the phenylephrine response in both groups, but its effect was greater in lead group. Our findings provide evidence that the increased modulation by NO on contractile response to phenylephrine could be a compensatory mechanism that might contribute to decrease blood pressure after lead treatment cessation.

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Urinary Magnesium, Calcium, and Phosphorus to Creatinine Ratios of Healthy Elementary School Lebanese Children

Abstract

Urinary magnesium (Mg), calcium (Ca), and phosphorus (P) excretions are known to vary greatly between populations due to dietary habits, physical activity, mineral content of water, climate, genetics, and race. Thus, it is essential to determine the normal values in each population in order to assess the status as well as to diagnose any possible abnormality of metabolisms especially hypercalciuria. A study was conducted to determine urinary Mg/creatinine (Cr), Ca/Cr, and P/Cr ratios of healthy Lebanese elementary schoolchildren. Using a multi-stage cluster sampling at district, school, and class levels, a sample of 1403 children (781 boys and 622 girls), from 26 different schools, was selected. Non-fasting morning urine samples and anthropometric data were collected and analyzed. The mean Mg/Cr, Ca/Cr, and P/Cr ratios were 0.122 ± 0.075 mg/mg (0.568 ± 0.348 mM/mM), 0.084 ± 0.101 mg/mg (0.237 ± 0.286 mM/mM), and 0.692 ± 0.417 mg/mg (2.527 ± 1.524 mM/mM), respectively, with no significant difference between boys and girls (P = 0.706, 0.161, and 0.604; respectively). The 95th percentile of Mg/Cr, Ca/Cr, and P/Cr ratios fluctuated with age, showing a sharp decrease in Ca/Cr and P/Cr at the age of 10. The mean Mg/Cr, Ca/Cr, and P/Cr ratios were comparable to those of similar age groups in other populations. The 95th percentiles of Mg/Cr, Ca/Cr, and P/Cr ratios were 0.26 mg/mg (1.23 mM/mM), 0.27 mg/mg (0.76 mM/mM), and 1.48 mg/mg (5.40 mM/mM), respectively. These values can be used as cutoffs to detect abnormalities in these three minerals' metabolisms among healthy Lebanese children.

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cAMP/PKA Signaling Pathway Induces Apoptosis by Inhibited NF-κB in Aluminum Chloride-Treated Lymphocytes In Vitro

Abstract

To explore the apoptosis mechanism in lymphocytes of rats induced by aluminum chloride (AlCl₃) by activating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway, the splenic lymphocytes of rats were cultured and exposed to different concentrations of AlCl₃ for 24 h. The final concentrations of AlCl₃ (AlCl₃ · 6H₂O) in supernatant were 0 (control group, CG), 0.3 mmol/L (low-dose group, LG), 0.6 mmol/L (mid-dose group, MG), and 1.2 mmol/L (high-dose group, HG), respectively. Lymphocytes Apoptosis rate, intracellular cAMP content, PKA, survivin, B cell lymphoma/leukemia-2 (Bcl-2) and Bcl-2-associated X protein (Bax) mRNA expressions, and the mRNA and protein expressions of nuclear factor-κ-gene binding (NF-κB, p65) were detected, respectively. The results showed that apoptosis index of lymphocytes, cAMP content in intracellular and PKA mRNA expression were significantly upregulated, whereas NF-κB and survivin mRNA expressions, nuclear NF-κB (p65) protein expression, and the ratio of Bcl-2 and Bax mRNA expression were downregulated in the AlCl₃-treated groups compared with those in CG. The results indicated that the activated cAMP/PKA signaling pathway induces apoptosis by inhibited NF-κB in AlCl₃-treated lymphocytes in vitro.

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Mechanisms of Intracellular Calcium Homeostasis in MC3T3-E1 Cells and Bone Tissues of Sprague-Dawley Rats Exposed to Fluoride

Abstract

Calcium homeostasis of osteoblasts (OBs) has an important role in the physiology and pathology of bone tissue. In order to study the mechanisms of intracellular calcium homeostasis, MC3T3-E1 cells and Sprague-Dawley rats were treated with different concentrations of fluoride. Then, we examined intracellular-free calcium ion ([Ca²⁺]i) in MC3T3-E1 cells as well as mRNA and protein levels of Cav1.2, the main subunit of L-type voltage-dependent calcium channels (VDCCs), Na⁺/Ca²⁺ exchange carriers (NCS), and plasma membrane Ca²⁺-ATPase (PMCA), inositol 1,4,5-trisphosphate receptor (IP3R) channels, sarco/endoplasmic reticulum calcium ATPase 2b (SERCA2b)/ATP2A2 in vitro, and rat bone tissues in vivo. Our results showed that [Ca²⁺]i of fluoride-treated OBs increased in a concentration-dependent manner with an increase in the concentration of fluoride. We also found that the low dose of fluoride led to high expression levels of Cav1.2, NCS-1, and PMCA and low expression levels of IP3R and SERCA2b/ATP2A2, while the high dose of fluoride induced an increase in SERCA2b/ATP2A2 levels and decrease in Cav1.2, PMCA, NCS-1, and IP3R levels. These results demonstrate that calcium channels and calcium pumps of plasma and endoplasmic reticulum (ER) membranes keep intracellular calcium homeostasis by regulating Cav1.2, NCS-1, PMCA, IP3R, and SERCA2b/ATP2A2 expression.

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Effects of Excess Fluoride and Iodide on Thyroid Function and Morphology

Abstract

Exposure to high levels of iodide in Cangzhou, Shandong Province, China has been associated with increased incidence of thyroid disease; however, whether fluoride can affect the thyroid remains controversial. To investigate the effects of excess fluoride, we evaluated thyroid gland structure and function in rats exposed to fluoride and iodide, either alone or in combination. Five-week-old Wistar rats (n = 160 total) were randomly divided into eight groups: three groups that were given excess fluoride (15, 30, or 60 ppm F); one group given excess iodide (1200 μg/L I); three groups given excess iodide plus fluoride (1200 μg/L I plus 15, 30, or 60 ppm F); and one control group. The serum concentrations of the thyroid hormones TT₃ and TT₄ on day 150 were significantly reduced for certain fluoride groups; however, no significant differences were observed in concentrations for the pituitary hormone TSH among any groups. Hematoxylin and eosin staining revealed that iodide causes an increase in the areas of the colloid lumens and a decrease in the diameters of epithelial cells and nuclei; however, fluoride causes an increase in nuclear diameters. The damage to follicular epithelial cells upon fluoride or iodide treatment was easily observed by transmission electron microscopy, but the effects were most dramatic upon treatment with both fluoride and iodide. These results suggest that iodide causes the most damage but that fluoride can promote specific changes in the function and morphology of the thyroid, either alone or in combination with iodide.

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Sodium Para-aminosalicylic Acid Protected Primary Cultured Basal Ganglia Neurons of Rat from Manganese-Induced Oxidative Impairment and Changes of Amino Acid Neurotransmitters

Abstract

Manganese (Mn), an essential trace metal for protein synthesis and particularly neurotransmitter metabolism, preferentially accumulates in basal ganglia. However, excessive Mn accumulation may cause neurotoxicity referred to as manganism. Sodium para-aminosalicylic acid (PAS-Na) has been used to treat manganism with unclear molecular mechanisms. Thus, we aim to explore whether PAS-Na can inhibit Mn-induced neuronal injury in basal ganglia in vitro. We exposed basal ganglia neurons with 50 μM manganese chloride (MnCl₂) for 24 h and then replaced with 50, 150, and 450 μM PAS-Na treatment for another 24 h. MnCl₂ significantly decreased cell viability but increased leakage rate of lactate dehydrogenase and DNA damage (as shown by increasing percentage of DNA tail and Olive tail moment). Mechanically, Mn reduced glutathione peroxidase and catalase activity and interrupted amino acid neurotransmitter balance. However, PAS-Na treatment reversed the aforementioned Mn-induced toxic effects. Taken together, these results showed that PAS-Na could protect basal ganglia neurons from Mn-induced neurotoxicity.

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Time course and predictive factors for lung volume reduction following stereotactic ablative radiotherapy (SABR) of lung tumors

Abstract

Background

Stereotactic ablative volume reduction (SAVR) is a potential alternative to lung-volume reduction surgery in patients with severe emphysema and excessive surgical risk. Having previously observed a dose-volume response for localized lobar volume reduction after stereotactic ablative radiotherapy (SABR) for lung tumors, we investigated the time course and factors associated with volume reduction.

Methods

We retrospectively identified 70 eligible patients receiving lung tumor SABR during 2007-2013. We correlated lobar volume reduction (relative to total, bilateral lung volume [TLV]) with volume receiving high biologically effective doses (V_XXBED3) and other pre-treatment factors in all patients, and measured the time course of volume changes on 3-month interval CT scans in patients with large V_60BED3 (n = 21, V_60BED3 ≥4.1 % TLV).

Results

Median CT follow-up was 15 months. Median volume reduction of treated lobes was 4.5 % of TLV (range 0.01–13.0 %), or ~9 % of ipsilateral lung volume (ILV); median expansion of non-target adjacent lobes was 2.2 % TLV (−4.6–9.9 %; ~4 % ILV). Treated lobe volume reduction was significantly greater with larger V_XXBED3 (XX = 20–100 Gy, R ²  = 0.52–0.55, p < 0.0001) and smaller with lower pre-treatment FEV1% (R ²  = 0.11, p = 0.005) in a multivariable linear model. Maximum volume reduction was reached by ~12 months and persisted.

Conclusions

We identified a multivariable model for lobar volume reduction after SABR incorporating dose-volume and pre-treatment FEV1% and characterized its time course.

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Different Array CGH profiles within hereditary breast cancer tumors associated to BRCA1 expression and overall survival

Abstract

Background

Array CGH analysis of breast tumors has contributed to the identification of different genomic profiles in these tumors. Loss of DNA repair by BRCA1 functional deficiency in breast cancer has been proposed as a relevant contribution to breast cancer progression for tumors with no germline mutation. Identifying the genomic alterations taking place in BRCA1 not expressing tumors will lead us to a better understanding of the cellular functions affected in this heterogeneous disease. Moreover, specific genomic alterations may contribute to the identification of potential therapeutic targets and offer a more personalized treatment to breast cancer patients.

Methods

Forty seven tumors from hereditary breast cancer cases, previously analyzed for BRCA1 expression, and screened for germline BRCA1 and 2 mutations, were analyzed by Array based Comparative Genomic Hybridization (aCGH) using Agilent 4x44K arrays. Overall survival was established for tumors in different clusters using Log-rank (Mantel-Cox) Test. Gene lists obtained from aCGH analysis were analyzed for Gene Ontology enrichment using GOrilla and DAVID tools.

Results

Genomic profiling of the tumors showed specific alterations associated to BRCA1 or 2 mutation status, and BRCA1 expression in the tumors, affecting relevant cellular processes. Similar cellular functions were found affected in BRCA1 not expressing and BRCA1 or 2 mutated tumors. Hierarchical clustering classified hereditary breast tumors in four major, groups according to the type and amount of genomic alterations, showing one group with a significantly poor overall survival (p = 0.0221). Within this cluster, deletion of PLEKHO1, GDF11, DARC, DAG1 and CD63 may be associated to the worse outcome of the patients.

Conclusions

These results support the fact that BRCA1 lack of expression in tumors should be used as a marker for BRCAness and to select these patients for synthetic lethality approaches such as treatment with PARP inhibitors. In addition, the identification of specific alterations in breast tumors associated with poor survival, immune response or with a BRCAness phenotype will allow the use of a more personalized treatment in these patients.

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MiR-29c regulates the expression of miR-34c and miR-449a by targeting DNA methyltransferase 3a and 3b in nasopharyngeal carcinoma

Abstract

Background

Nasopharyngeal carcinoma (NPC) is prevalent in South East Asia and Southern China particularly, despite the reported 5-year survival ratio is relative higher than other deadly cancers such as liver, renal, pancreas cancer, the lethality is characterized by high metastatic potential in the early stage and high recurrence rate after radiation treatment. MicroRNA-29c was found to be down-regulated in the serum as well as in the tissue of nasopharyngeal carcinoma tissue.

Methods

In this study, we found accidentally that the transfection of pre-miR-29c or miR-29c mimics significantly increases the expression level of miR-34c and miR-449a but doesn't affect that of miR-222 using real-time quantitative PCR in nasopharyngeal carcinoma cell lines. To explore the molecular mechanism of the regulatory role, the cells are treated with 5-Aza-2-deoxycytidine (5-Aza-CdR) treatment and the level of miR-34c and miR-449a but not miR-222 accumulated by the treatment. DNA methyltransferase 3a, 3b were down-regulated by the 5-Aza-CdR treatment with western blot and real-time quantitative PCR.

Results

We found that pre-miR-29c or miR-29c mimics significantly increases the expression level of miR-34c and miR-449a. We further found DNA methyltransferase 3a and 3b are the target gene of miR-29c. Restoration of miR-29c in NPC cells down-regulated DNA methyltransferase 3a, 3b, but not DNA methyltransferase T1.

Conclusions

The regulation of miR-29c/DNMTs/miR-34c\449a is an important molecular axis of NPC development and targeting DNMTs or restoring of miR-29c might be a promising therapy strategy for the prevention of NPC.

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Evaluation of the role of remission status in a heterogeneous limited disease small-cell lung cancer patient cohort treated with definitive chemoradiotherapy

Abstract

Background

The role of remission status in limited disease (LD) small-cell lung cancer (SCLC) patients treated with definitive chemoradiotherapy (CRT) remains to be finally clarified.

Methods

Individual data from 184 patients treated with definitive CRT concurrently or sequentially were retrospectively reviewed. Kaplan-Meier analysis as well as univariate and multivariate Cox regression models were used to describe survival within patient subgroups defined by remission status.

Results

71 (39 %) patients were treated in the concurrent, 113 (61 %) in the sequential CRT mode. Prophylactic cranial irradiation (PCI) was applied in 71 (39 %) patients. 37 (20 %) patients developed local, while 89 (48 %) distant recurrence. 58 (32 %) patients developed metachronous brain metastases. Complete, partial remission and non-response (defined as stable and progressive disease) were documented in 65 (35 %), 77 (42 %), and 37 (20 %) patients, respectively. In complete responders median overall survival was 21.8 months (95CI: 18.6 – 25) versus 14.9 (95 % CI: 11.7 – 18.2) (p = 0.041, log-rank test) and 11.5 months (95 % CI: 8.9 – 15.0) (p < 0.001, log-rank test) in partial and non-responders, respectively. The same effect was documented for the time to progression and distant metastasis-free survival. In the multivariate analysis achievement of complete remission as a variable shows a trend for the prolonged time to progression (p = 0.1, HR 1.48) and distant metastasis-free survival (p = 0.06, HR 1.63) compared to partial responders and was highly significant compared to non-responders.

Conclusion

In this treated heterogeneous LD SCLC patient cohort complete remission was associated with longer time to progression, distant metastasis-free and overall survival compared to the non- and especially partial responders.

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Efficacy and safety of Vinflunine for advanced or metastatic urothelial carcinoma in routine practice based on the French multi-centre CURVE study

Abstract

Background

To retrospectively assess the efficacy and safety of Vinflunine (VFL) under routine conditions and identify overall survival (OS) prognostic factors.

Methods

Twenty centres participated in the retrospective study (minimum 4 patients undergoing VFL treatment for advanced/metastatic UC after platinum-based regimen progression. Primary endpoint was OS. Secondary endpoints: progression-free survival (PFS), radiological response rate (RR) RECIST criteria and toxicity (CTC NCI v3).

Results

These centres enrolled 134 patients. Prior chemotherapy (CT) lines (≥1 palliative): 1 and ≥2 in 69 % and 26 % of patients, respectively. Performance status (PS): 0, 1, 2 in 25 %, 46 % and 23 % of patients. Median OS = 8.2 months [6.5–9.4], PFS = 4.2 months and RR 22 %, median number of 5 cycles. In risk groups based on 0–3 presence of adverse prognostic factors (PS ≥1, haemoglobin ≤10 g/dl and liver metastasis), median OS: 13.2, 9.9, 3.6, and 2.4 months (P < .0001), respectively; 3.3 months (1.9–5.6) in PS ≥ 2 subgroup.

Conclusion

This study reflects routine UC management and confirmed VFL patient efficacy. The drug is safe with gastro-intestinal and haematological prophylaxis. Analysis of prognostic factors for OS is consistent with pivotal trials.

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Dynamic changes of alkaline phosphatase are strongly associated with PSA-decline and predict best clinical benefit earlier than PSA-changes under therapy with abiraterone acetate in bone metastatic castration resistant prostate cancer

Abstract

Background

Significant progress in treatment of metastatic castration resistant prostate cancer (mCRPC) has been made. Biomarkers to tailor therapy are scarce. To facilitate decision-making we evaluated dynamic changes of alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and prostate specific antigen (PSA) under therapy with Abiraterone.

Methods

Men with bone mCRPC (bmCRPC) on Abiraterone 12/2009-01/2014 were analyzed. Dynamic ALP-, LDH- and PSA-changes were analyzed as predictors of best clinical benefit and overall survival (OS) with logistic-regression, Cox-regression and Kaplan-Meier-analysis.

Results

Thirty-nine pre- and 45 post-chemotherapy patients with a median follow up of 14.0 months were analyzed. ALP-Bouncing can be observed very early during therapy with Abiraterone. ALP-Bouncing is defined as rapidly rising ALP-levels independent of baseline ALP during the first 2–4 weeks of Abiraterone-therapy with subsequent equally marked decline to pretreatment levels or better within 8 weeks of therapy, preceding potentially delayed PSA-decline. In univariate analysis failure of PSA-reduction ≥50 % and failure of ALP-Bouncing were the strongest predictors of progressive disease (p = 0.003 and 0.021). Rising ALP at 12 weeks, no PSA-reduction ≥50 % and no ALP-Bouncing were strongest predictors of poor OS, (all p < 0.001). Kaplan-Meier-analysis showed worse OS for rising ALP at 12 weeks, no PSA-reduction ≥50 % and no ALP-Bouncing (p < 0.001). In subgroup-analysis of oligosymptomatic patients all parameters remained significant predictors of poor OS, with no PSA-reduction ≥50 % and rising ALP at 12 weeks being the strongest (p < 0.001). In multivariate analysis PSA-reduction ≥50 % remained an independent predictor of OS for the whole cohort and for the oligosymptomatic subgroup (both p = 0.014). No patient with ALP-Bouncing had PD for best clinical benefit. Patients with rising ALP at 12 weeks had no further benefit of Abiraterone.

Conclusions

Dynamic changes of ALP, LDH and PSA during Abiraterone-therapy are associated with best clinical benefit and OS in bmCRPC. ALP-Bouncing occurring earlier than PSA-changes as well as prior to equivocal imaging results and rising ALP at 12 weeks under Abiraterone may help to decide whether to discontinue Abiraterone. An external validation of these findings on a prospective cohort is planned.

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Relevance of miR-21 in regulation of tumor suppressor gene PTEN in human cervical cancer cells

Abstract

Background

Expression of the microRNA miR-21 has been found to be altered in almost all types of cancers and it has been classified as an oncogenic microRNA or oncomir. Due to the critical functions of its target proteins in various signaling pathways, miR-21 is an attractive target for genetic and pharmacological modulation in various cancers. Cervical cancer is the second most common cause of death from cancer in women worldwide and persistent HPV infection is the main etiologic agent. This malignancy merits special attention for the development of new treatment strategies. In the present study we analyze the role of miR-21 in cervical cancer cells.

Methods

To identify the downstream cellular target genes of upstream miR-21, we silenced endogenous miR-21 expression in a cervical intraepithelial neoplasia-derived cell lines using siRNAs. The effect of miR-21 on gene expression was assessed in cervical cancer cells transfected with the siRNA expression plasmid pSIMIR21. We identified the tumor suppressor gene PTEN as a target of miR-21 and determined the mechanism of its regulation throughout reporter construct plasmids. Using this model, we analyzed the expression of miR-21 and PTEN as well as functional effects such as autophagy and apoptosis induction.

Results

In SiHa cells, there was an inverse correlation between miR-21 expression and PTEN mRNA level as well as PTEN protein expression in cervical cancer cells. Transfection with the pSIMIR21 plasmid increased luciferase reporter activity in construct plasmids containing the PTEN-3′-UTR microRNA response elements MRE21-1 and MRE21-2. The role of miR-21 in cell proliferation was also analyzed in SiHa and HeLa cells transfected with the pSIMIR21 plasmid, and tumor cells exhibited markedly reduced cell proliferation along with autophagy and apoptosis induction.

Conclusions

We conclude that miR-21 post-transcriptionally down-regulates the expression of PTEN to promote cell proliferation and cervical cancer cell survival. Therefore, it may be a potential therapeutic target in gene therapy for cervical cancer.

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Prise en charge des sarcomes des tissus mous des membres par radiothérapie externe

Publication date: Available online 14 March 2016
Source:Cancer/Radiothérapie
Author(s): L. Moureau-Zabotto, M. Delannes, C. Le Péchoux, M.P. Sunyach, G. Kantor, P. Sargos, J. Thariat, C. Llacer-Moscardo




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Breast Cancer Patients’ Preferences for Adjuvant Radiotherapy Post Lumpectomy: Whole Breast Irradiation vs. Partial Breast Irradiation—Single Institutional Study

Abstract

This study was conducted to elucidate patients with early breast cancer preference for standard whole breast irradiation (WBI) or partial breast irradiation (PBI) following lumpectomy, as well as identify important factors for patients when making their treatment decisions. Based on relevant literature and ASTRO consensus statement guidelines, an educational tool and questionnaire were developed. Consenting, eligible women reviewed the educational tool and completed the trade-off questionnaire. Descriptive statistics were calculated, as well as chi-squares and a logistic regression model. Of the 90 patients who completed the study, 62 % preferred WBI, 30 % preferred PBI, 4 % required more information, and 3 % had no preferences. Of the patients who chose WBI, 58 % preferred hypofractionated RT, whereas 25 % preferred the conventional RT regimen. The majority of patients rated recurrence rate [WBI = 55/55 (100 %), PBI = 26/26 (100 %)] and survival [WBI = 54/55 (98 %), PBI = 26/26 (100 %)] as important factors contributing to their choice of treatment preference. Financial factors [WBI = 21/55 (38 %), PBI = 14/26 (53 %)] and convenience [WBI = 36/54 (67 %), PBI = 18/26 (69 %)] were rated as important less frequently. Significantly, more patients who preferred WBI also rated standard method of treatment as important when compared to patients who preferred PBI [WBI = 52/54 (96 %), PBI = 16/26 (61 %), χ ² = 16.63, p = 0.001]. The majority of patients with early breast cancer who were surveyed for this study preferred WBI as an adjuvant treatment post lumpectomy, yet there was a sizeable minority who preferred PBI. This was associated with the importance patients place on standard treatment. These results will help medical professionals treat patients according to patient values.

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Pediatric Phase I Ipilimumab

Purpose: Ipilimumab is a first-in-class immune checkpoint inhibitor approved for treatment of metastatic melanoma but not studied in children until this phase I protocol.

Experimental Design: This study examined safety, pharmacokinetics, and immunogenicity, and immune correlates of ipilimumab administered to subjects ≤21 years old with recurrent or progressive solid tumors. Dose escalation cohorts received 1, 3, 5, or 10 mg/m² intravenously every 3 weeks in a 3 + 3 design. Response was assessed after 6 weeks and 12 weeks, and then every 3 months. Treatment was continued until disease progression or unacceptable toxicity.

Results: Thirty-three patients received 72 doses of ipilimumab. Patients enrolled had melanoma (n = 12), sarcoma (n = 17), or other refractory solid tumors (n = 4). Immune-related adverse events included pancreatitis, pneumonitis, colitis, endocrinopathies, and transaminitis with dose-limiting toxicities observed at 5 and 10 mg/kg dose levels. Pharmacokinetics revealed a half-life of 8 to 15 days. At day 21, subjects had increased levels of cycling T cells, but no change in regulatory T-cell populations. Six subjects had confirmed stable disease for 4 to 10 cycles (melanoma, osteosarcoma, clear cell sarcoma, and synovial sarcoma).

Conclusions: Ipilimumab was safely administered to pediatric patients using management algorithms for immune-related toxicities. The spectrum of immune-related adverse events is similar to those described in adults; however, many of the pediatric toxicities were evident after a single dose. Although no objective tumor regressions were observed with ipilimumab as a single agent, subjects with immune-related toxicities had an increased overall survival compared with those who showed no evidence of breaking tolerance. Clin Cancer Res; 22(6); 1364–70. ©2015 AACR.

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Pharmacogenetic Associations of AI-Mediated Lipid Changes

Purpose: Aromatase inhibitors can exert unfavorable effects on lipid profiles; however, previous studies have reported inconsistent results. We describe the association of single-nucleotide polymorphisms (SNP) in candidate genes with lipid profiles in women treated with adjuvant aromatase inhibitors.

Experimental Design: We conducted a prospective observational study to test the associations between SNPs in candidate genes in estrogen signaling and aromatase inhibitor metabolism pathways with fasting lipid profiles during the first 3 months of aromatase inhibitor therapy in postmenopausal women with early breast cancer randomized to adjuvant letrozole or exemestane. We performed genetic association analysis and multivariable linear regressions using dominant, recessive, and additive models.

Results: A total of 303 women had complete genetic and lipid data and were evaluable for analysis. In letrozole-treated patients, SNPs in CYP19A1, including rs4646, rs10046, rs700518, rs749292, rs2289106, rs3759811, and rs4775936 were significantly associated with decreases in triglycerides by 20.2 mg/dL and 39.3 mg/dL (P < 0.00053), respectively, and with variable changes in high-density lipoprotein (HDL-C) from decreases by 4.2 mg/dL to increases by 9.8 mg/dL (P < 0.00053).

Conclusions: Variants in CYP19A1 are associated with decreases in triglycerides and variable changes in HDL-C in postmenopausal women on adjuvant aromatase inhibitors. Future studies are needed to validate these findings, and to identify breast cancer survivors who are at higher risk for cardiovascular disease with aromatase inhibitor therapy. Clin Cancer Res; 22(6); 1395–402. ©2015 AACR.

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HLA-B*57:01 Associated with Pazopanib Hepatotoxicity

Purpose: Pazopanib is an effective treatment for advanced renal cell carcinoma and soft-tissue sarcoma. Transaminase elevations have been commonly observed in pazopanib-treated patients. We conducted pharmacogenetic analyses to explore mechanistic insight into pazopanib-induced liver injury.

Experimental Design: The discovery analysis tested association between four-digit HLA alleles and alanine aminotransferase (ALT) elevation in pazopanib-treated patients with cancer from eight clinical trials (N = 1,188). We conducted confirmatory analysis using an independent dataset of pazopanib-treated patients from 23 additional trials (N = 1,002). Genome-wide association study (GWAS) for transaminase elevations was also conducted.

Results: The discovery study identified an association between HLA-B*57:01 carriage and ALT elevation [P = 5.0 x 10^–5 for maximum on-treatment ALT (MaxALT); P = 4.8 x 10^–4 for time to ALT > 3x upper limit of normal (ULN) event; P = 4.1 x 10^–5 for time to ALT > 5x ULN event] that is significant after adjustment for number of HLA alleles tested. We confirmed these associations with time to ALT elevation event (P = 8.1 x 10^–4 for ALT > 3x ULN, P = 9.8 x 10^–3 for ALT > 5x ULN) in an independent dataset. In the combined data, HLA-B*57:01 carriage was associated with ALT elevation (P = 4.3 x 10^–5 for MaxALT, P = 5.1 x 10^–6 for time to ALT > 3xULN event, P = 5.8 x 10^–6 for time to ALT > 5x ULN event). In HLA-B*57:01 carriers and noncarriers, frequency of ALT > 3x ULN was 31% and 19%, respectively, and frequency of ALT > 5x ULN was 18% and 10%, respectively. GWAS revealed a possible borderline association, which requires further evaluation.

Conclusions: These data indicate that HLA-B*57:01 carriage confers higher risk of ALT elevation in patients receiving pazopanib and provide novel insight implicating an immune-mediated mechanism for pazopanib-associated hepatotoxicity in some patients. Clin Cancer Res; 22(6); 1371–7. ©2015 AACR.

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Galeterone for Metastatic Castration-Resistant Prostate Cancer

Purpose: Galeterone is a selective, multitargeted agent that inhibits CYP17, antagonizes the androgen receptor (AR), and reduces AR expression in prostate cancer cells by causing an increase in AR protein degradation. These open-label phase I and II studies [Androgen Receptor Modulation Optimized for Response-1 (ARMOR1) and ARMOR2 part 1] evaluated the efficacy and safety of galeterone in patients with treatment-naive nonmetastatic or metastatic castration-resistant prostate cancer (CRPC) and established a dose for further study.

Experimental Design: In ARMOR1, 49 patients received increasing doses (650–2,600 mg) of galeterone in capsule formulation; 28 patients in ARMOR2 part 1 received increasing doses (1,700–3,400 mg) of galeterone in tablet formulation for 12 weeks. Patients were evaluated biweekly for safety and efficacy, and pharmacokinetic parameters were assessed.

Results: In ARMOR1, across all doses, 49.0% (24/49) achieved a ≥30% decline in prostate-specific antigen (PSA; PSA30) and 22.4% (11/49) demonstrated a ≥50% PSA decline (PSA50). In ARMOR2 part 1, across all doses, PSA30 was 64.0% (16/25) and PSA50 was 48.0% (12/25). In the 2,550-mg dose cohort, PSA30 was 72.7% (8/11) and PSA50 was 54.5% (6/11). Galeterone was well tolerated; the most common adverse events were fatigue, increased liver enzymes, gastrointestinal events, and pruritus. Most were mild or moderate in severity and required no action and there were no apparent mineralocorticoid excess (AME) events.

Conclusions: The efficacy and safety from ARMOR1 and ARMOR2 part 1 and the pharmacokinetic results support the galeterone tablet dose of 2,550 mg/d for further study. Galeterone was well tolerated and demonstrated pharmacodynamic changes consistent with its selective, multifunctional AR signaling inhibition. Clin Cancer Res; 22(6); 1356–63. ©2015 AACR.

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Nesvacumab for Advanced Solid Tumors

Purpose: Nesvacumab (REGN910) is a fully human immunoglobulin G1 (IgG1) monoclonal antibody that specifically binds and inactivates the Tie2 receptor ligand Ang2 with high affinity, but shows no binding to Ang1. The main objectives of this trial were to determine the safety, tolerability, dose-limiting toxicities (DLT), and recommended phase II dose (RP2D) of nesvacumab.

Experimental Design: Nesvacumab was administered intravenously every two weeks with dose escalations from 1 to 20 mg/kg in patients with advanced solid tumors.

Results: A total of 47 patients were treated with nesvacumab. No patients in the dose escalation phase experienced DLTs, therefore a maximum tolerated dose (MTD) was not reached. The most common nesvacumab-related adverse events were fatigue (23.4%), peripheral edema (21.3%), decreased appetite, and diarrhea (each 10.6%; all grade ≤ 2). Nesvacumab was characterized by linear kinetics and had a terminal half-life of 6.35 to 9.66 days in a dose-independent manner. Best response by RECIST 1.1 in 43 evaluable patients included 1 partial response (adrenocortical carcinoma) of 24 weeks duration. Two patients with hepatocellular carcinoma had stable disease (SD) > 16 weeks, with tumor regression and >50% decrease in α-fetoprotein. Analyses of putative angiogenesis biomarkers in serum and tumor biopsies were uninformative for treatment duration.

Conclusions: Nesvacumab safety profile was acceptable at all dose levels tested. Preliminary antitumor activity was observed in patients with treatment-refractory advanced solid tumors. On the basis of cumulative safety, antitumor activity, pharmacokinetic and pharmacodynamic data, the 20 mg/kg dose was determined to be the RP2D. Clin Cancer Res; 22(6); 1348–55. ©2015 AACR.

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Fluorescent Image-Guided Surgery with an Anti-PSCA Diabody

Purpose: The inability to visualize cancer during prostatectomy contributes to positive margins, cancer recurrence, and surgical side effects. A molecularly targeted fluorescent probe offers the potential for real-time intraoperative imaging. The goal of this study was to develop a probe for image-guided prostate cancer surgery.

Experimental Design: An antibody fragment (cys-diabody, cDb) against prostate stem cell antigen (PSCA) was conjugated to a far-red fluorophore, Cy5. The integrity and binding of the probe to PSCA was confirmed by gel electrophoresis, size exclusion, and flow cytometry, respectively. Subcutaneous models of PSCA-expressing xenografts were used to assess the biodistribution and in vivo kinetics, whereas an invasive intramuscular model was utilized to explore the performance of Cy5-cDb–mediated fluorescence guidance in representative surgical scenarios. Finally, a prospective, randomized study comparing surgical resection with and without fluorescent guidance was performed to determine whether this probe could reduce the incidence of positive margins.

Results: Cy5-cDb demonstrated excellent purity, stability, and specific binding to PSCA. In vivo imaging showed maximal signal-to-background ratios at 6 hours. In mice carrying PSCA⁺ and negative (–) dual xenografts, the mean fluorescence ratio of PSCA^+/– tumors was 4.4:1. In surgical resection experiments, residual tumors <1 mm that were missed on white light surgery were identified and resected using fluorescence guidance, which reduced the incidence of positive surgical margins (0/8) compared with white light surgery alone (7/7).

Conclusions: Fluorescently labeled cDb enables real-time in vivo imaging of prostate cancer xenografts in mice, and facilitates more complete tumor removal than conventional white light surgery alone. Clin Cancer Res; 22(6); 1403–12. ©2015 AACR.

See related commentary by van Leeuwen and van der Poel, p. 1304

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Surrogate Endpoints in Melanoma That Correlate with OS

Purpose: Surrogate endpoints are needed that correlate with overall survival (OS). We analyzed individual patient tumor data from a phase III trial of vemurafenib versus dacarbazine (BRIM3) to identify criteria for tumor measures that correlated with OS. Correlates were validated using a separate data set from a phase II trial of vemurafenib (BRIM2).

Experimental Design: Deidentified tumor measurements and OS data from BRIM3 and from BRIM2 were analyzed. Target tumor measurement data and nontarget tumor data were available from pretreatment, weeks 6,12, and every 9 weeks thereafter. In the BRIM3 data set, associations of OS with both early tumor response (first 12 weeks) and time to progression (TTP) were assessed. Different definitions of response and progression were explored. Findings were validated using the BRIM2 data set.

Results: Thresholds of early response were explored ranging from any degree of tumor shrinkage to 100% tumor shrinkage. Correlation was weak at all thresholds tested. TTP, however, was more strongly correlated with OS. The strongest correlation was seen when progression was defined as ≥50% increase in the sum of tumor diameters or appearance of new tumors. This was confirmed by similar analyses in the BRIM2 cohort.

Conclusions: TTP defined as ≥50% increase in the sum of tumor diameters or appearance of new tumors was more strongly associated with OS than early tumor shrinkage in melanoma patients treated with RAF inhibitor. In future trials, consideration should be given to replacing response rate with TTP or PFS as preferable clinical endpoints in early-phase studies. Clin Cancer Res; 22(6); 1341–7. ©2015 AACR.

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ERR{alpha} Is a Marker of Tamoxifen Response in TNBC

Purpose: Estrogen-related receptor alpha (ERRα) signaling has recently been implicated in breast cancer. We investigated the clinical value of ERRα in randomized cohorts of tamoxifen-treated and adjuvant-untreated patients.

Experimental Design: Cox proportional hazards regression was used to evaluate the significance of associations between ERRα gene expression levels and patient DMFS in a previously published microarray dataset representing 2,000 breast tumor cases derived from multiple medical centers worldwide. The 912 tumors used for immunostaining were from a tamoxifen-randomized primary breast cancer trial conducted in Stockholm, Sweden, during 1976–1990. Mouse model was used to study the effect of tamoxifen treatment on lung colonization of MDA-MB-231 control cells and MDA-MB-231 cells with stable knockdown of ERRα. The phenotypic effects associated with ERRα modulation were studied using immunoblotting analyses and wound-healing assay.

Results: We found that in ER-negative and triple-negative breast cancer (TNBC) adjuvant-untreated patients, ERRα expression indicated worse prognosis and correlated with poor outcome predictors. However, in tamoxifen-treated patients, an improved outcome was observed with high ERRα gene and protein expression. Reduced ERRα expression was oncogenic in the presence of tamoxifen, measured by in vitro proliferation and migration assays and in vivo metastasis studies.

Conclusions: Taken together, these data show that ERRα expression predicts response to tamoxifen treatment, and ERRα could be a biomarker of tamoxifen sensitivity and a prognostic factor in TNBC. Clin Cancer Res; 22(6); 1421–31. ©2015 AACR.

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