Subsequent primary malignancies and acute myelogenous leukemia transformation among myelodysplastic syndrome patients treated with or without lenalidomide

Abstract

The few studies that have examined rates of acute myeloid leukemia (AML) transformation in lenalidomide-treated myelodysplastic syndrome (MDS) patients have been limited to deletion 5q MDS. The association between lenalidomide and subsequent primary malignancies (SPMs) in MDS patients has not been evaluated previously. We conducted a retrospective cohort study to evaluate the risk of both SPM and AML in association with lenalidomide. A cohort of MDS patients (n = 1248) treated between 2004 and 2012 at Moffitt Cancer Center were identified, and incident cases of SPM and AML transformation were ascertained. Using a nested case–control design, MDS controls were 1:1 matched to SPM (n = 41) and AML (n = 150) cases, on age and date of MDS diagnosis, gender, follow-up time, IPSS, and del (5q). Associations between lenalidomide and (1) SPM incidence and (2) AML transformation were estimated with hazards ratios (HR) and 95% confidence intervals (CIs) in the cohort and odds ratios (OR) in the case–control analysis. SPM incidence did not differ significantly between cohort MDS patients treated with (0.7 per 100 person-years) or without lenalidomide (1.4 per 100 person-years) (HR = 1.04, 95% CI = 0.40–2.74), whereas a significantly reduced SPM risk was observed in the case–control sample (OR = 0.03, 95% CI = <0.01–0.63). Lenalidomide was not associated with AML transformation in the cohort analysis (HR = 0.75, 95% CI = 0.44–1.27) or in the case–control analyses (OR = 1.16, 95% CI = 0.52–2.56), after adjustment for potential confounders. Lenalidomide was not associated with increased risk of SPM or AML transformation in a large cohort of MDS patients mostly including nondeletion 5q MDS.

In a retrospective cohort study of myelodysplastic syndrome (MDS) patients (n = 1248), conducted at Moffitt Cancer Center, lenalidomide was not associated with subsequent primary malignancies (SPMs) incidence in the MDS cohort (HR = 1.04, 95% CI = 0.40–2.74), whereas a significantly reduced SPM risk was observed in the case–control sample (OR = 0.03, 95% CI = <0.01–0.63). Lenalidomide was not associated with acute myeloid leukemia (AML) transformation in the cohort analysis (HR = 0.75, 95% CI = 0.44–1.27) or in the case–control analyses (OR = 1.16, 95% CI = 0.52–2.56), after adjustment for potential confounders. In conclusion, lenalidomide was not associated with increased risk of SPM or AML transformation in a large cohort of MDS patients mostly including nondeletion 5q MDS.

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Lapatinib-Related Rash and Breast Cancer Outcome in the ALTTO Phase III Randomized Trial

Background: Previously we have shown that early development of rash is associated with a higher chance of achieving pathological complete response to neoadjuvant lapatinib. In the current analysis, we investigate its impact on survival in the ALTTO phase III adjuvant trial.

Methods: In ALTTO, patients with human epidermal growth factor receptor 2 (HER2)–positive early breast cancer were randomly assigned to adjuvant trastuzumab, lapatinib, their sequence, or their combination for a total duration of one year. We evaluated whether the development of early lapatinib-related rash (ie, within 6 weeks) is associated with disease-free (DFS) and overall survival (OS). Landmark analysis at eight weeks and time-dependent analysis were tested in a multivariable model stratifying on trial's stratification factors. All statistical tests were two-sided.

Results: Out of 6098 lapatinib-treated patients, 3973(65.2%) were included in the landmark analysis, of whom 1389 (35.0%) had developed early rash. After median follow-up of 4.5 years, the development of early rash was associated with a trend of improved DFS (multivariable: hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.73 to 1.03, P = .10) and statistically significantly improved OS (multivariable: HR = 0.63, 95% CI = 0.48 to 0.82, P < .001) compared with subjects without early rash. Compared with patients randomly assigned to trastuzumab (n = 2051), patients who were randomly assigned to trastuzumab/lapatinib combination and developed early rash (n = 692) had superior DFS (multivariable: HR = 0.72, 95% CI = 0.55 to 0.92, P = .01) and OS (multivariable: HR = 0.59, 95% CI = 0.39 to 0.90, P = .01). Time-dependent analysis suggests that the occurrence of rash is predictive of lapatinib benefit, both when given in combination or sequential to trastuzumab.

Conclusions: Our results indicate that early development of rash identifies patients who derive superior benefit from lapatinib-based therapy.

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Pixantronerituximab versus gemcitabinerituximab in relapsed/refractory aggressive non-Hodgkin lymphoma

Future Oncology Ahead of Print.


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Induction chemotherapy for head and neck cancer: is there still a role?

Future Oncology Ahead of Print.


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Conformal radiotherapy as a bridge to liver transplantation for hepatocellular carcinoma: is it safe?

Future Oncology Ahead of Print.


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Pixantronerituximab versus gemcitabinerituximab in relapsed/refractory aggressive non-Hodgkin lymphoma

Future Oncology Ahead of Print.


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Induction chemotherapy for head and neck cancer: is there still a role?

Future Oncology Ahead of Print.


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Conformal radiotherapy as a bridge to liver transplantation for hepatocellular carcinoma: is it safe?

Future Oncology Ahead of Print.


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Luteal versus follicular phase surgical oophorectomy plus tamoxifen in premenopausal women with metastatic hormone receptor-positive breast cancer

Publication date: June 2016
Source:European Journal of Cancer, Volume 60
Author(s): Richard R. Love, Syed Mozammel Hossain, Md. Margub Hussain, Mohammad Golam Mostafa, Adriano V. Laudico, Stephen Sixto S. Siguan, Clement Adebamowo, Jing-zhong Sun, Fei Fei, Zhi-Ming Shao, Yunjiang Liu, Syed Md. Akram Hussain, Baoning Zhang, Lin Cheng, Sonar Panigaro, Fardiana Walta, Jiang Hong Chuan, Maria Rica Mirasol-Lumague, Cheng-Har Yip, Narciso S. Navarro, Chiun-sheng Huang, Yen-shen Lu, Tahmina Ferdousy, Reza Salim, Chameli Akhter, Shamsun Nahar, Gemma Uy, Gregory S. Young, Erinn M. Hade, David Jarjoura
PurposeIn premenopausal women with metastatic hormone receptor-positive breast cancer, hormonal therapy is the first-line therapy. Gonadotropin-releasing hormone analogue + tamoxifen therapies have been found to be more effective. The pattern of recurrence risk over time after primary surgery suggests that peri-operative factors impact recurrence. Secondary analyses of an adjuvant trial suggested that the luteal phase timing of surgical oophorectomy in the menstrual cycle simultaneous with primary breast surgery favourably influenced long-term outcomes.MethodsTwo hundred forty-nine premenopausal women with incurable or metastatic hormone receptor-positive breast cancer entered a trial in which they were randomised to historical mid-luteal or mid-follicular phase surgical oophorectomy followed by oral tamoxifen treatment. Kaplan–Meier methods, the log-rank test, and multivariable Cox regression models were used to assess overall and progression-free survival (PFS) in the two randomised groups and by hormone-confirmed menstrual cycle phase.ResultsOverall survival (OS) and PFS were not demonstrated to be different in the two randomised groups. In a secondary analysis, OS appeared worse in luteal phase surgery patients with progesterone levels <2 ng/ml (anovulatory patients; adjusted hazard ratio 1.46, 95% confidence interval [CI]: 0.89–2.41, p = 0.14) compared with those in luteal phase with progesterone level of 2 ng/ml or higher. Median OS was 2 years (95% CI: 1.7–2.3) and OS at 4 years was 26%.ConclusionsThe history-based timing of surgical oophorectomy in the menstrual cycle did not influence outcomes in this trial of metastatic patients.ClinicalTrials.gov number NCT00293540.



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Results of the Belgian expanded access program of eribulin in the treatment of metastatic breast cancer closely mirror those of the pivotal phase III trial

Publication date: June 2016
Source:European Journal of Cancer, Volume 60
Author(s): Philippe Aftimos, Laura Polastro, Lieveke Ameye, Christiane Jungels, Jalal Vakili, Marianne Paesmans, Joanne van den Eerenbeemt, Alfino Buttice, Andrea Gombos, Dominique de Valeriola, Thierry Gil, Martine Piccart-Gebhart, Ahmad Awada
BackgroundEribulin is a non-taxane microtubule dynamics inhibitor that showed a survival benefit versus treatment of physician's choice in a phase III trial enrolling patients with metastatic breast cancer (MBC).MethodsThe E7389-G000-398 trial was designed to provide eribulin to MBC patients pre-treated with anthracylines, taxanes and capecitabine. Patient characteristics, efficacy and safety data were collected prospectively. Efficacy and survival analyses were performed using retrospectively collected data of patients treated at a single institution.ResultsOne hundred fifty-four patients were enrolled and the median number of previous lines of chemotherapy was 4. The most frequent adverse events were fatigue/asthenia (74%), alopecia (55%), peripheral neuropathy (46%) and neutropenia (43%). Objective response rate (ORR) was 24% in the evaluable population and 14% in patients pre-treated with both taxanes and vinorelbine. In patients with oestrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)– MBC, response rate was 29% and 21% with triple-negative disease. Activity was minimal in HER2+ MBC treated with eribulin monotherapy (14% ORR). Median progression-free survival was 3.2 months. Median overall survival was 11.3 months; 77% of patients were alive at 6 months and 43% at 12 months.ConclusionEribulin was active in MBC patients with a high tumour burden and predominant visceral disease. Safety profile was similar to what was reported in the phase III trials. Prophylactic granulocyte colony-stimulating factor administration allowed optimal dose intensity and could have contributed to the recorded response rate. Activity is sustained after treatment with taxanes and vinorelbine. The recently investigated combination of eribulin and trastuzumab should lead to higher activity in HER2-positive MBC.



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Differential gene expression in porcine SK6 cells infected with wild-type and SAP domain-mutant foot-and-mouth disease virus

Abstract

Foot-and-mouth disease virus (FMDV) is the causative agent of a highly contagious disease in livestock. The viral proteinase L^pro of FMDV is involved in pathogenicity, and mutation of the L^pro SAP domain reduces FMDV pathogenicity in pigs. To determine the gene expression profiles associated with decreased pathogenicity in porcine cells, we performed transcriptome analysis using next-generation sequencing technology and compared differentially expressed genes in SK6 cells infected with FMDV containing L^pro with either a wild-type or mutated version of the SAP domain. This analysis yielded 1,853 genes that exhibited a ≥ 2-fold change in expression and was validated by real-time quantitative PCR detection of several differentially expressed genes. Many of the differentially expressed genes correlated with antiviral responses corresponded to genes associated with transcription factors, immune regulation, cytokine production, inflammatory response, and apoptosis. Alterations in gene expression profiles may be responsible for the variations in pathogenicity observed between the two FMDV variants. Our results provided genes of interest for the further study of antiviral pathways and pathogenic mechanisms related to FMDV L^pro.

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A Shared Commitment for Accelerating Progress with the Cancer Moonshot

We're coming off an exciting week for the cancer research community and the ongoing efforts behind the Vice President's National Cancer Moonshot Initiative.

The big event, which took place in New Orleans, was the annual meeting of the American Association for Cancer Research (AACR), which featured many oral and poster presentations of promising results, from basic research studies to late-stage clinical trials.

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Is cervical screening preventing adenocarcinoma and adenosquamous carcinoma of the cervix?

Abstract

Whilst the incidence of squamous carcinoma of the cervix has declined in countries with organised screening, adenocarcinoma has become more common. Cervical screening by cytology often fails to prevent adenocarcinoma. Using prospectively recorded cervical screening data in England and Wales we conducted a population based case-control study to examine whether cervical screening leads to early diagnosis and down staging of adenocarcinoma. Conditional logistic regression modelling was carried out to provide odds ratios (OR) and 95% confidence intervals on 12,418 women with cervical cancer diagnosed between ages 30-69 and 24,453 age-matched controls. Of women with adenocarcinoma of the cervix, 44.3% were up to date with screening and 14.6% were non-attenders. The overall OR comparing women up to date with screening with non-attenders was 0.46(95%CI:0.39-0.55) for adenocarcinoma. The odds were significantly decreased (OR: 0.22, 95%CI:0.15-0.33) in up to date women with stage 2 or worse adenocarcinoma, but not for women with stage1A adenocarcinoma 0.71(95%CI:0.46-1.09). The odds of stage 1A adenocarcinoma was double among lapsed attenders (OR: 2.35, 95%CI:1.52-3.62) compared with non-attenders. Relative to women with no negative cytology within seven years of diagnosis, women with stage1A adenocarcinoma were very unlikely to be detected within 3 years of a negative cytology test (OR: 0.08, 95%CI:0.05-0.13), however the odds doubled 3-5 years after a negative test (OR: 2.30, 95%CI:1.67-3.18). ORs associated with up to date screening were smaller for squamous and adenosquamous cervical carcinoma. Although cytology screening is inefficient at preventing adenocarcinomas, invasive adenocarcinomas are detected earlier than they would be in the absence of screening, substantially preventing stage 2 and worse adenocarcinomas. This article is protected by copyright. All rights reserved.

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Tumor Growth Attenuating Effect of Celastrol In Systemic Malignancies

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Underutilization of gene expression profiling for early-stage breast cancer in California

Abstract

Purpose

To describe the utilization of gene expression profiling (GEP) among California breast cancer patients, identify predictors of use of GEP, and evaluate how utilization of GEP influenced treatment of early-stage breast cancer.

Methods

All women diagnosed with hormone-receptor-positive, node-negative breast cancer reported to the California Cancer Registry between January 2008 and December 2010 were linked to Oncotype DX (ODX) assay results.

Results

Overall, 26.7 % of 23,789 eligible patients underwent the assay during the study period. Women age 65 or older were much less likely than women under age 50 to be tested (15.1 vs. 41.4 %, p < 0.001). Black women were slightly less likely and Asian women were slightly more likely than non-Hispanic white women to undergo GEP with the ODX assay (22.2 and 28.9 vs. 26.9 %, respectively, p < 0.001). Patients residing in low SES census tracts had the lowest use of the test (8.9 %), with the proportion increasing with higher SES category. Women with Medicaid health insurance were less likely than other women to be tested (17.7 vs. 27.5 %, p < 0.001). Receipt of adjuvant chemotherapy (ACT) was associated with the ODX recurrence score, although only 63 % of patients whose recurrence scores indicated a high benefit received ACT. Of patients not tested, 15 % received ACT.

Conclusions

Nearly three-fourths of eligible breast cancer patients in California during the 3-year period 2008 through 2010 did not undergo GEP. As a result, it is likely that many women unnecessarily received ACT and suffered associated morbidity. In addition, some high-risk women who would have benefited most from ACT were not identified.

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In situ clinical evidence that zinc levels are decreased in breast invasive ductal carcinoma

Abstract

Purpose

Altered zinc levels in malignant cells versus their normal cells have important implications in the development and progression of several cancers. Prostate, pancreatic, and hepatocellular carcinomas exhibit consistent marked zinc decrease in situ in the malignant cells, and other cancers (such as kidney, lung, and thyroid) also exhibit decreased tissue zinc levels. However, zinc levels are increased in breast cancer tissue compared to breast normal tissue, and the contemporary dominant view is that zinc is increased in invasive ductal carcinoma. This has important implications regarding the role and effects of zinc in breast malignancy compared to other cancers, which caused us to initiate this study to either confirm or challenge the contemporary view of an increased zinc level in the invasive ductal malignant cells.

Methods

We employed dithizone staining of breast tissue sections and tissue cores to determine the relative in situ cellular zinc levels specifically in the invasive ductal malignant cells as compared to normal ductal epithelium. This approach had not been employed in any of the reported breast studies.

Results

The results revealed that the zinc levels are consistently and markedly decreased in the ductal malignant cells as compared with higher prominent zinc levels in the normal ductal epithelium. Decreased zinc is evident in Grade 1 well-differentiated malignancy and in Grade 2 and Grade 3 carcinomas. Among the twenty-five cancer cases in this study, none exhibited increased zinc in the invasive ductal carcinoma compared to the zinc level in the normal ductal epithelium.

Conclusions

The decreased zinc levels in breast invasive ductal carcinoma is consistent with prostate, pancreatic, and liver carcinomas in which the decrease in zinc is a required event in the development of malignancy to prevent cytotoxicity that would result from the higher zinc levels in the normal cells. This new understanding requires a redirection in elucidating the mechanisms and factors regarding the regulation of zinc in breast cancer, its potential translational applications as possible biomarkers, and for treatment of breast invasive ductal carcinoma.

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Variants of EVER1 and EVER2 ( TMC6 and TMC8 ) and human papillomavirus status in patients with mucosal squamous cell carcinoma of the head and neck

Abstract

Purpose

There is a growing association of human papillomavirus (HPV) with some cases of mucosal squamous cell carcinoma of the head and neck (HNSCC), particularly of the oropharynx. Persistent oral HPV infection is believed to increase the likelihood of malignancy, and it is possible that host genetic factors can determine susceptibility to persistent HPV infection. Polymorphisms in the two EV genes (EVER1 and EVER2, also known as transmembrane channel protein (TMC) 6 and 8) have been identified as strong candidate genes, since a small number of critical mutations in these genes have been shown to cause profound and florid skin HPV infections, and some of them have been linked to susceptibility to cervical cancer.

Methods

We sought to determine whether there was a difference in the frequency of single nucleotide polymorphisms (SNPs) in EVER1 (rs2613516, rs12449858) and EVER2 (rs7205422, rs12452890) between HNSCC patients with HPV-positive and HPV-negative tumors, and healthy controls. We used logistic regression to analyze SNPs in 219 patients with histologically confirmed primary SCC of the oropharynx, oral cavity, hypopharynx, or larynx, and 321 healthy controls.

Results

We did not find any associations with the EVER1/EVER2 SNPs and HPV status or being a HNSCC case or a control.

Conclusions

The present data do not provide evidence for a role of genetic variations in EVER1 or EVER2 for HPV status of mucosal HNSCC or between HNSCC patients and controls.

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Protein Biomarkers for Breast Cancer Risk Are Specifically Correlated with Local Steroid Hormones in Nipple Aspirate Fluid

Abstract

The local endocrine environment of the breast may have stronger relations to breast cancer risk than systemic hormones. Nipple aspiration fluid (NAF) provides a window into this milieu. We hypothesized that the correlations between proteins and steroid hormones in NAF are stronger, and specific relationships may reveal links to breast cancer risk. NAF and blood samples were obtained simultaneously from 54 healthy women and from the contralateral unaffected breast of 60 breast cancer patients. The abundance of five proteins, superoxide dismutase (SOD1), C-reactive protein (CRP), chitinase-3-like protein 1 (YKL40), cathepsin D (CatD), and basic fibroblast growth factor (bFGF) in NAF was measured using ELISA. The NAF and serum concentrations of estradiol, estrone, progesterone, androstenedione, testosterone, and dehydroepiandrostrerone (DHEA) were measured using ELISA or RIA. The correlations between proteins and hormones revealed that NAF proteins correlated with each other: SOD1 with CRP (R = 0.276, P = 0.033) and CatD (R = 0.340, P = 0.0036), and bFGF with CRP (R = 0.343, P = 0.0021). NAF proteins displayed significant correlations with NAF steroids, but not with serum steroids: SOD1 with DHEA (R = 0.333, P = 0.019), YKL40 with testosterone (R = 0.389, P = 0.0012), and bFGF negatively correlated with testosterone (R = −0.339, P = 0.015). The regulation of YKL40 and bFGF by testosterone was confirmed in breast cancer cell lines. In summary, NAF proteins were more strongly related to local hormone levels than to systematic hormone levels. Some proteins were specifically correlated with different NAF steroids, suggesting that these steroids may contribute to breast cancer risk through different mechanisms.

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Fitness outcomes from a randomised controlled trial of exercise training for men with prostate cancer: the ENGAGE study

Abstract

Purpose

The main purpose of this study was to investigate the effects of a 12-week, clinician-referred, community-based exercise training program with supervised and unsupervised sessions for men with prostate cancer. The secondary purpose was to determine whether androgen deprivation therapy (ADT) modified responses to exercise training.

Methods

Secondary analysis was undertaken on data from a multicentre cluster randomised controlled trial in which 15 clinicians were randomly assigned to refer eligible patients to an exercise training intervention (n = 8) or to provide usual care (n = 7). Data from 119 patients (intervention n = 53, control n = 66) were available for this analysis. Outcome measures included fitness and physical function, anthropometrics, resting heart rate, and blood pressure.

Results

Compared to the control condition, men in the intervention significantly improved their 6-min walk distance (M _diff = 49.98 m, p _adj = 0.001), leg strength (M _diff = 21.82 kg, p _adj = 0.001), chest strength (M _diff = 6.91 kg, p _adj = 0.001), 30-s sit-to-stand result (M _diff = 3.38 reps, p _adj = 0.001), and reach distance (M _diff = 4.8 cm, p _adj = 0.024). A significant difference (unadjusted for multiplicity) in favour of men in the intervention was also found for resting heart rate (M _diff = −3.76 beats/min, p = 0.034). ADT did not modify responses to exercise training.

Conclusions

Men with prostate cancer who act upon clinician referrals to community-based exercise training programs can improve their strength, physical functioning, and, potentially, cardiovascular health, irrespective of whether or not they are treated with ADT.

Implications for Cancer Survivors

Clinicians should inform men with prostate cancer about the benefits of exercise and refer them to appropriately qualified exercise practitioners and suitable community-based programs.

Trial registration

Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12610000609055

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Differential response to ablative ionizing radiation in genetically distinct non-small cell lung cancer cells

Volume 17, Issue 4, April 2016, pages 390-399<br/>10.1080/15384047.2016.1139241<br/>Ayman Oweida

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A triad of telomerase androgen receptor and early growth response 1 in prostate cancer cells

Volume 17, Issue 4, April 2016, pages 439-448<br/>10.1080/15384047.2016.1156255<br/>Sheeba Jacob

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Ganetespib radiosensitization for liver cancer therapy

Volume 17, Issue 4, April 2016, pages 457-466<br/>10.1080/15384047.2016.1156258<br/>Sivarajan T. Chettiar

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Targeting blockage of STAT3 inhibits hepatitis B virus-related hepatocellular carcinoma

Volume 17, Issue 4, April 2016, pages 449-456<br/>10.1080/15384047.2016.1156257<br/>Yinli Yang

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Identifying cancer origin using circulating tumor cells

Volume 17, Issue 4, April 2016, pages 430-438<br/>10.1080/15384047.2016.1141839<br/>Si-Hong Lu

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Role of miR-27a miR-181a and miR-20b in gastric cancer hypoxia-induced chemoresistance

Volume 17, Issue 4, April 2016, pages 400-406<br/>10.1080/15384047.2016.1139244<br/>Katia Danza

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Identification of fungal pathogens in a patient with acute myelogenic leukemia using a pathogen detection array technology

Volume 17, Issue 4, April 2016, pages 339-345<br/>10.1080/15384047.2015.1121349<br/>Sagarika Banerjee

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Evaluation of the radiotherapy management of ocular surface squamous neoplasia in a high HIV prevalence setting- a retrospective review

Abstract

Background

This article evaluates a single institute's radiotherapy management of OSSN, a previously regarded as rare malignancy, for possible future development of strategies to clearly define the role of adjuvant radiotherapy in improving treatment outcomes.

Materials and methods

A retrospective review of 153 patients treated from January 2003 to December 2009.

Results

There was no difference in OSSN prevalence by gender (male to female ratio 1.07). Of 80/153 patients tested 79 (98.8 %) were HIV positive. Most patients (62.9 %) had prior orbital exenteration. Moderately and poorly differentiated grade (82.3 %) was associated with significantly higher stage and incidence of positive regional lymph nodes. External beam therapy dose mostly used was 60Gy in 30 fractions at 200 cGy per fraction in 5 fractions per week (34.8 %). ⁹⁰Strontium therapy was given to 13.5 % (60Gy in 6 fractions at 10Gy per fraction weekly). Favourable response (complete and partial) was seen in about 80 % of patients associated with higher total doses. Regional lymph node positivity was associated with poorer outcome.

Conclusion

Adjuvant radiotherapy could have an important role in the management of patients presenting with locally advanced OSSN who are mostly HIV positive in developing countries. Prospective studies to evaluate the role of radiotherapy with or without chemotherapy in the management of OSSN in these settings are warranted.

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CAR T Cell Therapy in Acute Lymphoblastic Leukemia and Potential for Chronic Lymphocytic Leukemia

Opinion statement

Adoptive transfer of autologous T cells engineered to express a chimeric antigen receptor (CAR) represents a powerful targeted immunotherapy that has shown great promise in some of the most refractory leukemias. CAR-modified T cells directed against CD19 have led the way, setting a high standard with remission rates as high as 90 % in clinical trials for relapsed/refractory acute lymphoblastic leukemia (ALL). Yet, the first demonstration of efficacy was in another disease, chronic lymphocytic leukemia (CLL), in which CD19-targeted CAR T cells eradicated bulky, highly refractory disease. Despite early encouraging results, clinical trials in CLL have yielded lower response rates, revealing disease-specific differences in response in this form of immunotherapy. Ongoing research focused on identifying and overcoming these limitations, promises to improve response rates. Beyond the induction of remission, the transformative impact of engineered T cell therapy lies in its potential for long-term disease control. With longer follow-up and durable T cell persistence now reported, we are closer to answering the question of whether sustained remissions are possible with CAR T cell monotherapy. As might be expected with a highly effective therapy using a single mechanism of action, escape pathways have emerged. Combinatorial approaches are needed to anticipate and prevent this mode of relapse. Lastly, toxicity management is vital to ensure the safety of this exciting cancer immunotherapy.

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SABR vs. Limited Resection for Non-small Cell Lung Cancer: Are We Closer to an Answer?

Opinion statement

Lobectomy is currently the guideline-recognized gold standard for the treatment of early-stage non-small cell lung cancer (ES-NSCLC) in patients who are surgical candidates. In patients who are not medically fit for surgery, stereotactic ablative radiotherapy (SABR) is the treatment of choice with good reported rates of local control and overall survival. For patients at high risk for lobectomy, sublobar resection (SLR) may achieve similar outcomes as lobectomy, especially for peripheral tumors ≤2 cm. While there are merits to both SLR and SABR for these high-risk patients, evidence is conflicting on which may be preferred in the context of clinical and cost-effectiveness outcomes. For SABR, a histologic diagnosis is preferred prior to treatment. However, some individuals may be at high risk for biopsy, and a likelihood-of-malignancy probability threshold of >85 % has been proposed as reasonable to proceed with SABR in a positron emission tomography (PET)-positive lesion without histology. Increased risks of SABR are noted in ultra-central tumors and in patients recently treated with anti-VEGF therapy. Co-existing interstitial lung disease can cause increased treatment-related toxicity in both SABR and surgery. Toxicity is generally well tolerated for SABR and SLR, though treatment-related mortality may be higher in surgery. Ongoing comparative effectiveness research, especially through randomized control trials, is crucial in further delineating the roles of SLR and SABR in the treatment of ES-NSCLC.

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Radioembolization as a Treatment Strategy for Metastatic Colorectal Cancer to the Liver: What Can We Learn from the SIRFLOX Trial?

Opinion statement

In the setting of liver metastases from colorectal cancer (CRC), radioembolization with yttrium-90 has been used to treat chemotherapy refractory disease with a growing interest to establish its efficacy in prospective trials combined with first- and second-line chemotherapy. SIRFLOX is an ongoing, multi-center, phase 3 randomized trial comparing first-line chemotherapy alone or in combination with yttrium-90 radioembolization in patients with CRC who have isolated liver metastases or liver-dominant metastases. Preliminary results from SIRFLOX demonstrate that radioembolization combined with first-line chemotherapy is safe and feasible. There was no significant difference in median overall progression-free survival (PFS) between the combined radioembolization-chemotherapy and chemotherapy-only arms (10.7 versus 10.2 months). Although the trial did not meet its primary endpoint of improved median PFS, there was a significant increase in the median hepatic PFS (20.5 versus 12.6 months; p = 0.02) favoring the combination arm. Thus, combining radioembolization with chemotherapy in the first-line setting may be most effective for liver-limited metastatic CRC. Since radioembolization targets liver disease, it is plausible that the trial failed to achieve an improvement in PFS given that 40 % of the SIRFLOX population had extra-hepatic disease. It is also possible that the overall median PFS may be a poor surrogate endpoint, and other endpoints like overall survival still needs to be delineated in this setting. In addition, it is crucial to document improvement or delay in time to deterioration in quality of life symptom endpoints in this population. SIRFLOX is the first of three prospective studies that assess the efficacy of adding radioembolization to first-line chemotherapy, and the combined data from these trials will provide the necessary power for an overall survival analysis. The final results of SIRFLOX will be eagerly awaited to determine if the increased hepatic PFS in preliminary data will translate to increased overall survival benefit.

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Start Today: What Will You Do to Be More Physically Active?

By Colleen Doyle, MS, RD

My husband and I once had a 101-year-old neighbor named Arlie. One day, after driving my husband to work, I arrived home – at 7:30 a.m. – and Arlie was out raking the leaves in our front yard.

On garbage day, after the garbage trucks had been up and down the street, Arlie used to wheel ours and all the other neighbors' empty garbage cans back up to our houses.

If there was anyone who could ever convince me that being active could help you live long and well, it was Arlie.  My father is another one – but more on that in a bit.

Today, the American Cancer Society is part of an event to release the newly revised National Physical Activity Plan. The first National Plan was released in 2010, after the creation of the country's first National Physical Activity Guidelines for Americans in 2008.

This plan is based on a vision: that one day, all Americans will be physically active, and they will live, work and play in environments that encourage and support regular physical activity.

This is important to the mission of the American Cancer Society, because physical activity reduces the risk of a variety of cancers, and may reduce the risk of recurrence and improve survival, as well.

Currently, only 50% of adults meet minimum physical activity recommendations.  Among youth, in 2012, about 25% of those ages 12 to 15  met recommended levels and in 2013, only 27% of high school students did, according to Cancer Prevention & Early Detection Facts & Figures 2015-2016. Reduced leisure time, increased amounts of time spent sitting, increased reliance on cars for transportation, and increased availability of electronic entertainment and communications media all contribute to lower levels of physical activity.

Research suggests that the way we build our communities  impacts our ability to be physically active. A lack of sidewalks, parks, and recreation facilities is associated with greater levels of obesity compared to neighborhoods that make it easier for the people who live there to walk and be active. To get more people  living a physically active life, we need more policies, programs and initiatives that reduce barriers to being active.

And that is what the new plan is all about.  It is a is a comprehensive set of policies, programs, and initiatives designed to help all people in the U.S. increase their physical activity. The plan calls on 9 different groups to play a leading role:

• Business and Industry
• Community Recreation
• Fitness and Parks
• Education
• Faith-based Settings
• Health Care
• Mass Media
• Public Health
• Sport
• Transportation, Land Use and Community Design

We need all of these sectors to work together to make it possible for everyone in the country to be more physically active.

The new plan also outlines things each of these sectors can do to address the substantial disparities in physical activity that exist across groups based on gender, age, race, ethnicity, socioeconomic status, physical, cognitive or sensory ability, and geography.

The goal of the National Physical Activity Plan is to increase physical activity in the U.S. population. For the plan to succeed, many people and groups will need to play a role in implementing it. As an individual, you can speak up: speak up at your workplace for more opportunities to be active during the day; speak up at your kids' schools for regular physical education and recess; speak up to your city council for sidewalks, bike lanes, and safe parks for your family to enjoy.

I mentioned my father – that he is another one who has convinced me that living a physically active life is key to longevity and good health.  He is 84 years old, and is a runner.  He recently said to me that "all of this eating right and exercising is making me BORING.  All my friends – they sit around talking about all of the medications they are on.  I don't take any!  I feel like I don't have anything to talk to them about!"  Way to go, Dad.

What will you do, starting today, to increase your own physical activity, and to help make it easier for others to be more active?

Doyle is managing director of nutrition and physical activity for the American Cancer Society. 

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Impact of Gleason pattern 5 including tertiary pattern 5 on outcomes of salvage treatment for biochemical recurrence in pT2-3N0M0 prostate cancer

Abstract

Background

Gleason pattern 5 (GP5), including tertiary GP5, at radical prostatectomy has reportedly been associated with poorer clinical outcome. However, it is undetermined how tertiary GP5 is handled in the new Gleason grade grouping starting in 2016, and its prognostic value in patients undergoing salvage treatment for postoperative biochemical recurrence (BCR) remains unclear.

Methods

We retrospectively reviewed 116 patients with pT2-3N0M0 prostate cancer (PC) who received salvage treatment for BCR after radical prostatectomy between 2003 and 2014. The primary endpoint was failure of salvage treatment, defined as a single prostate-specific antigen (PSA) value ≥0.2 ng/ml after PSA nadir following salvage treatment. Associations of various clinicopathological factors, including GP5, with failure-free survival were assessed. Cox proportional hazards model was used for multivariate analysis.

Results

Patients received salvage treatment with either radiotherapy (n = 48), androgen-deprivation therapy (n = 61), or both (n = 7) for BCR. Twenty-three patients (19.8 %) experienced failure of salvage treatment, with a median follow-up period of 79 months. Univariate analysis associated GP5, Gleason score-based parameters, lymphovascular invasion, and PSA doubling time <6 months with poorer failure-free survival. Receiver operating characteristic curve analyses identified the area under the curve for GP5 (0.654) as the largest among those parameters (P = 0.0060). Multivariate analysis demonstrated that GP5 was the only independent predictor of poor outcome.

Conclusions

The presence of GP5 is an independent predictor of poor prognosis in patients with pT2-3N0M0 PC undergoing salvage treatment for BCR after radical prostatectomy. GP5 may thus be a more useful marker than conventional Gleason score in this setting.

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Local Injection of Bone Mesenchymal Stem Cells and Fibrin Glue Promotes the Repair of Bone Atrophic Nonunion In Vivo

Abstract

Introduction

This study aimed to evaluate the efficacy of local injection of bone mesenchymal stem cells (BMSCs) and fibrin glue in the treatment of atrophic nonunion in an animal model.

Methods

Thirty-six male Lewis rats were randomly assigned into three groups: Group A (control group), Group B (atrophic nonunion group), and Group C (experimental group). All the rats underwent femoral osteotomy of the right hind limb, and stabilized with a custom-designed external fixator. Atrophic nonunion of the rats in Group B and C was induced by cauterization of the periosteum and bone marrow removal, and repaired by injection of fibrin glue and BMSCs-seeded fibrin glue, respectively. The surgically treated femurs were assessed by radiographic and histological analysis, and biomechanical test.

Results

During the follow-up period, the external fixator maintained correct placement and all the femurs retained normal positioning. Eight weeks postoperatively, atrophic nonunion was detected in Group B, with the presence of fibrous connective tissue in the osteotomy gap. The femurs in Group C demonstrated complete bony bridging of the osteotomy gap, with the formation of plenty of woven bone.

Conclusion

The repair of bone atrophic nonunion can be promoted through local injection of BMSCs and fibrin glue.

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Whole brain radiotherapy with adjuvant or concomitant boost in brain metastasis: dosimetric comparison between helical and volumetric IMRT technique

To compare and evaluate the possible advantages related to the use of VMAT and helical IMRT and two different modalities of boost delivering, adjuvant stereotactic boost (SRS) or simultaneous integrated boost ...

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Pyomyositis at the surgical site in a patient with chronic myeloid leukemia: a case report and literature review

Abstract

Background

Pyomyositis is a rare, subacute, deep pyogenic infection of the muscle tissue. This disease has been previously described in patients that were immunocompromised due to a hematological malignancy.

Case Presentation

A 68-year-old man with a history of chronic myeloid leukemia was treated with imatinib. He was diagnosed with ascending colon cancer and underwent curative surgery. His postoperative course was uneventful, and he was healthy at 6 months after surgery, allowing for reinitiation of imatinib therapy. After the reinitiation of therapy, a computed tomography (CT) scan revealed a mass shadow in the right iliopsoas muscle. This lesion was clinically diagnosed as recurrent colon cancer with an abscess, which was resected surgically. A pathological examination uncovered both edema and inflammation. Two months after the second surgery, imatinib therapy was reinitiated; however, he again developed painful swelling and erythema in his right thigh. A CT scan revealed a similar shadow as described previously. He was then diagnosed with pyomyositis; he underwent incisional drainage and was administered linezolid. Following the treatment for pyomyositis, there was no cancer recurrence or evidence of any recurrent pyomyositis.

Conclusions

Findings from this case suggest that both undergoing surgery and receiving imatinib therapy may modulate an individual's immune response, whereby the surgical site becomes more prone to infection and may predispose an individual to pyomyositis. The case report is followed by a discussion of the literature regarding this disease, including potential risk factors and the underlying pathogenesis.

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Sentinel node biopsy during thoracolaparoscopic esophagectomy for advanced esophageal cancer

Abstract

Background

Omitting extensive lymph node dissection could reduce esophagectomy morbidity in patients without lymph node metastases. Sentinel node biopsy may identify abdominal or thoracic lymph node metastases, thereby differentiating treatment. Feasibility of this approach was investigated in Western European esophageal cancer patients with advanced disease, without lymph node metastases at diagnostic work-up.

Methods

The sentinel node biopsy was performed in eight esophageal cancer patients with cT1-3N0 disease. One day pre-operatively, Tc-99m-labeled nanocolloid was endoscopically injected around the tumor. Lymphoscintigraphy was performed 1 and 3 h after injection. All patients underwent robotic thoracolaparoscopic esophagectomy with two-field lymph node dissection. Intraoperatively, sentinel nodes were detected by gamma probe. The resection specimen was analyzed for remaining activity by scintigraphy and gamma probe.

Results

Visualization rates of lymphoscintigraphy 1 and 3 h after tracer injection were 88 and 100 %, respectively. Intraoperative identification rate was 38 %. Postoperative identification was possible in all patients using the gamma probe to analyze the resection specimen. In 5/8 patients, lymph node metastases were found at histopathology, none of which was detected by the sentinel node biopsy. No adverse events related to the sentinel node biopsy were observed.

Conclusions

In our advanced esophageal cancer patients who underwent thoracolaparoscopic esophagectomy, the sentinel node biopsy did not predict lymph node status. Probably the real sentinel node could not be identified due to localization adjacent to the primary tumor or bypassing due to metastatic tumor involvement. Therefore, we consider the sentinel node biopsy not feasible in advanced esophageal cancer.

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Transverse carcinoma after Miles operation: a case in which preoperative evaluation was assisted by computed tomographic colonography

Abstract

Background

There were only few case reports in which CTC was performed in patients with colostomy.

Case Presentation

A 68-year-old man was admitted with right abdominal pain and bloody stool that had been present for 2 weeks prior to admission. His medical history included abdominoperineal rectal resection with permanent sigmoid stoma (Miles operation). Colonoscopy showed a sub-occlusive tumor in the transverse colon but provided no information about the proximal colon. Thus, computed tomographic colonography (CTC) was planned to assist our examination of the proximal colon under sigmoid colostomy. CTC revealed the apple core sign in the hepatic flexure, without any evident tumor in the proximal colon. Therefore, we performed transverse colectomy and lymph node dissection, preserving a part of the ascending colon and Bauhin valve.

Conclusion

CTC examination can be an effective means of preoperatively evaluating the proximal colon in patients with occlusive tumor. Further, CTC examination was technically feasible through a sigmoid stoma.

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Surgery methods and soft tissue extension are the potential risk factors of local recurrence in giant cell tumor of bone

Abstract

Background

Various treatments of giant cell tumor of bone (GCTB) included in curettages and resections and with adjuvant are exerted, but the best treatment is controversial. The aim of the study was the identification of individual risk factors after various treatments in GCTB.

Methods

A total of 179 patients treated for GCTB between 1998 and 2010 were concluded in the retrospective study. All patients were treated with intralesional curettage, extensive curettage, or wide resection. Mean follow-up was 60.2 ± 18.7 months (36~112 months). Age, gender, tumor location, Campanacci grade, soft tissue extension, pathological features, and surgical methods were performed to univariate Kaplan-Meier survival analysis and multivariate Cox regression analysis.

Results

The local recurrence rates of intralesional curettage (41.9 %) and extensive curettage (19.0 %) were significantly higher than that of wide resection (7.7 %). The higher risk of local recurrence was found for soft tissue extension (hazard = 7.921, 95 % CI 1.107~56.671), compared with no statistical significances between gender, location, Campanacci grade, pathologic fracture, and local recurrences, which were shown by Kaplan-Meier analysis. However, recurrence-free survival (RFS) of patients younger than 30 was significantly lower than that of patients older than 30. The RFS of pathologic fracture patients with soft tissue extension was significantly lower than that of pathologic fracture patients without soft tissue extension. Multivariate Cox regression analysis indicated that the independent variable that contributed to recurrence-free survival was soft tissue extension and surgical methods. The RFS of extensive curettage had no statistically significant difference with wide resection and was significantly higher than that of intralesional curettage. Use of high-speed burring and bone cement significantly decreased the local recurrence rate.

Conclusions

Age (below 30 years), gender, tumor location, Campanacci grade, and pathologic fracture have no statistically significant influence on local recurrences. Soft tissue extension and intralesional curettage of surgical methods increased the RFS. The results of the present study suggested that compared with curettage and wide section, treatment of GCTB by extensive curettage could provide the favorable local control and functional recovery.

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Totally laparoscopic gastrectomy using intracorporeally stapler or hand-sewn anastomosis for gastric cancer: a single-center experience of 478 consecutive cases and outcomes

Abstract

Background

Totally laparoscopic gastrectomy (TLG) using intracorporeal anastomosis has gradually become mature thanks to the advancements of laparoscopic surgical instruments and the accumulation of operative experience. The goal of this study is to review our institution's experience with TLG for the treatment of gastric cancer.

Methods

A retrospective study was conducted to examine the short-term outcomes of TLG using intracorporeally stapler or hand-sewn anastomosis performed at Sir Run Run Shaw Hospital between March 2007 and June 2015. The details of intracorporeal anastomosis were described, and the clinicopathological data, surgical outcomes, and postoperative complications were evaluated.

Results

Four hundred seventy-eight patients were included in the study. Generally speaking, the patients could be divided into stapler or hand-sewn groups according to whether intracorporeal anastomosis was performed by only hand-sewn technique (n = 97) or only stapling devices (n = 381). For overall patients, the mean operation time and anastomotic time were 225.7 and 30.0 min, respectively. Postoperative complications were observed in 65 patients. All of the patients recovered well without perioperative death by conservative or surgical management.

Conclusions

TLG using intracorporeally stapler or hand-sewn anastomosis is a reasonable option for the treatment of gastric cancer, with early data showing acceptable perioperative outcomes.

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Whole brain radiotherapy with adjuvant or concomitant boost in brain metastasis: dosimetric comparison between helical and volumetric IMRT technique

Abstract

Background

To compare and evaluate the possible advantages related to the use of VMAT and helical IMRT and two different modalities of boost delivering, adjuvant stereotactic boost (SRS) or simultaneous integrated boost (SIB), in the treatment of brain metastasis (BM) in RPA classes I-II patients.

Methods

Ten patients were treated with helical IMRT, 5 of them with SRS after whole brain radiotherapy (WBRT) and 5 with SIB. MRI co-registration with planning CT was mandatory and prescribed doses were 30 Gy in 10 fractions (fr) for WBRT and 15Gy/1fr or 45Gy/10fr in SRS or SIB, respectively. For each patient, 4 "treatment plans" (VMAT SRS and SIB, helical IMRT SRS and SIB) were calculated and accepted if PTV boost was included in 95 % isodose and dose constraints of the main organs at risk were respected without major deviations. Homogeneity Index (HI), Conformal Index (CI) and Conformal Number (CN) were considered to compare the different plans. Moreover, time of treatment delivery was calculated and considered in the analysis.

Results

Volume of brain metastasis ranged between 1.43 and 51.01 cc (mean 12.89 ± 6.37 ml) and 3 patients had double lesions. V95% resulted over 95 % in the average for each kind of technique, but the "target coverage" was inadequate for VMAT planning with two sites. The HI resulted close to the ideal value of zero in all cases; VMAT-SIB, VMAT-SRS, Helical IMRT-SIB and Helical IMRT-SRS showed mean CI of 2.15, 2.10, 2.44 and 1.66, respectively (optimal range: 1.5–2.0). Helical IMRT-SRS was related to the best and reliable finding of CN (0.66). The mean of treatment time was 210 s, 467 s, 440 s, 1598 s, respectively, for VMAT-SIB, VMAT-SRS, Helical IMRT-SIB and Helical IMRT-SRS.

Conclusions

This dosimetric comparison show that helical IMRT obtain better target coverage and respect of CI and CN; VMAT could be acceptable in solitary metastasis. SIB modality can be considered as a good choice for clinical and logistic compliance; literature's preliminary data are confirming also a radiobiological benefit for SIB. Helical IMRT-SRS seems less effective for the long time of treatment compared to other techniques.

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Clinicopathological characteristics of cancer associated with Crohns disease

Abstract

Purpose

We examined the clinicopathological characteristics and prognosis of patients with cancer associated with Crohn's disease (CD).

Methods

The subjects of this study were patients with cancer confirmed in a resected specimen of bowel, who were treated at our institution between September, 1974 and December, 2014.

Results

We analyzed 34 patients (26 men, 8 women, median age at cancer diagnosis 43.5 years, duration of illness 18 years) and found that the number of those with CD complicated with cancer began to drastically increase after 2005. The site of onset of cancer was in an anorectal lesion in 24 (70.6 %) patients. In 17 (50 %) patients, the cancer was diagnosed before surgery; in 3 patients (8.8 %), it was based on pathological findings during surgery; and in 14 patients (41.2 %), it was based on postoperative pathological findings. Mucinous carcinoma was the dominant histological type, seen in 15 patients (44.1 %), while the special type of signet-ring cell carcinoma was found in 4 patients. The cumulative overall 5 year survival rate was 46.2 %.

Conclusion

In this group of Japanese CD patients, an anorectal lesion was the most frequent site of origin of cancer. As cancer was diagnosed preoperatively in only 50 % of these patients, the overall prognosis was poor, with a cumulative 5 year survival rate of just 46.2 %.

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Ethanolic Extract of Bark from Salix aegyptiaca Ameliorates 12-dimethylhydrazine-induced Colon Carcinogenesis in Mice by Reducing Oxidative Stress.

Ethanolic Extract of Bark from Salix aegyptiaca Ameliorates 1,2-dimethylhydrazine-induced Colon Carcinogenesis in Mice by Reducing Oxidative Stress.

Nutr Cancer. 2016 Apr;68(3):495-506

Authors: Bounaama A, Enayat S, Ceyhan MS, Moulahoum H, Djerdjouri B, Banerjee S

Abstract
We have previously shown that ethanolic extract from bark (EEB) of Salix aegyptiaca (Musk Willow) can inhibit proliferation and motility and induce apoptosis in colon cancer cells. Tandem mass spectrometry revealed EEB to be rich in catechin, catechol, and salicin. The present study investigated the chemopreventive effect of HPLC-fingerprinted EEB on 1,2-dimethylhydrazine (DMH)-induced aberrant crypt foci (ACF) formation in mice. DMH (20 mg/kg body weight) was weekly injected subcutaneously to mice for the first 2 weeks. EEB (100 and 400 mg/kg body weight) was provided orally from the 7th to 14th week, after which colon tissues were evaluated histologically and biochemically. DMH treatment induced high number of ACF; EEB significantly reduced the number and multiplicity of ACF, along with a restoration in goblet cells and mucin accumulation. EEB supplementation improved the markers of inflammation (myeloperoxidase and neutrophil infiltration) and oxidative stress. More importantly, EEB amplified apoptosis of neoplastic cells in the colon mucosa of DMH-treated mice. It also lowered levels of markers for early transformation events such as EGFR, nuclear β-catenin, and COX-2 in colon cancer cell lines HT-29 and HCT-116. The innocuity of EEB (up to 1600 mg/kg) to mice reinforces its potential as a chemopreventive agent.

PMID: 27093594 [PubMed - as supplied by publisher]

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Linkage of E2F1 transcriptional network and cell proliferation with respiratory chain activity in breast cancer cells

Summary

Mitochondria are multifunctional organelles; they have been implicated in various aspects of tumorigenesis. In this study, we investigated a novel role of the basal electron transport chain (ETC) activity in cell proliferation by inhibiting mitochondrial replication and transcription (mtR/T) using pharmacological and genetic interventions, which depleted mitochondrial DNA/RNA, thereby inducing ETC deficiency. Interestingly, mtR/T inhibition did not decrease ATP levels despite deficiency in ETC activity in different cell types, including MDA-MB-231 breast cancer cells, but it severely impeded cell cycle progression, specifically progression during G2 and/or M phases in the cancer cells. Under these conditions, the expression of a group of cell cycle regulators was downregulated without affecting growth signaling pathway. Further analysis suggested that the transcriptional network organized by E2F1 was significantly affected because of the downregulation of E2F1 in response to ETC deficiency, which eventually resulted in the suppression of cell proliferation. Thus, in this study, the E2F1-mediated ETC-dependent mechanism has emerged as the regulatory mechanism of cell cycle progression. In addition to E2F1, FOXM1 and BMYB were also downregulated, which contributed specifically to the defects in G2 and/or M phase progression. Thus, ETC-deficient cancer cells lost their growing ability, including their tumorigenic potential in vivo. ETC deficiency abolished the production of reactive oxygen species (ROS) from the mitochondria and a mitochondria-targeted antioxidant mimicked the deficiency, thereby suggesting that ETC activity signaled through ROS production. In conclusion, this novel coupling between ETC activity and cell cycle progression may be an important mechanism for coordinating cell proliferation and metabolism.

This article is protected by copyright. All rights reserved.

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miR-199a-5p Regulates β1 Integrin through Ets-1 to Suppress Invasion in Breast Cancer

Abstract

Increasing evidences reveal that miR-199a-5p is actively involved in tumor invasion and metastasis as well as in the decline of breast cancer tissues. In this research, overexpression of miR-199a-5p weakened motility and invasion of breast cancer cells MCF-7 and MDA-MB-231. Upregulation of Ets-1 increased breast cancer cell invasion, but the mechanism by which miR-199a-5p modulates activation of Ets-1 in breast cancer was not clarified. We investigated the relationship between miR-199a-5p and Ets-1 on the basis of 158 primary breast cancer case specimens, and the results showed that Ets-1 expression was inversely correlated with endogenous miR-199a-5p. Overexpression of miR-199a-5p reduced the mRNA and protein levels of Ets-1 in MCF-7 and MDA-MB-231 cells, whereas anti-miR-199a-5p elevated Ets-1. siRNA-mediated Ets-1 knockdown phenocopied the inhibition invasion of miR-199a-5p in vitro. Moreover, luciferase reporter assay revealed that miR-199a-5p directly targeted 3'-UTR of Ets-1 mRNA. This research discovered that miR-199a-5p could descend the levels of β1 integrin by targeting 3'-UTR of Ets-1 to alleviate the invasion of breast cancer via FAK/Src/Akt/mTOR signaling pathway. Our results provide insight into the regulation of β1 integrin through miR-199a-5p-mediated Ets-1 silence and help in designing new therapeutic strategies to inhibit signal pathways induced by miR-199a-5p in breast cancer invasion.

This article is protected by copyright. All rights reserved.

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A phase Ia/Ib clinical trial of metronomic chemotherapy based on a mathematical model of oral vinorelbine in metastatic non-small cell lung cancer and malignant pleural mesothelioma: rationale and study protocol

Abstract

Background

Metronomic oral vinorelbine is effective in metastatic NSCLC and malignant pleural mesothelioma, but all the studies published thus far were based upon a variety of empirical and possibly suboptimal schedules, with inconsistent results. Mathematical modelling showed by simulation that a new metronomic protocol could lead to a better safety and efficacy profile.

Design

This phase Ia/Ib trial was designed to confirm safety (phase Ia) and evaluate efficacy (phase Ib) of a new metronomic oral vinorelbine schedule. Patients with metastatic NSCLC or malignant pleural mesothelioma in whom standard treatments failed and who exhibited ECOG performance status 0–2 and adequate organ function will be eligible. Our mathematical PK-PD model suggested an alternative weekly D1, D2 and D4 schedule (named Vinorelbine Theoretical Protocol) with a respective dose of 60, 30 and 60 mg. Trial recruitment will be two-staged, as 12 patients are planned to participate in phase Ia to confirm safety and consolidate the calibration of the model parameters. Depending on the phase Ia results and after a favourable decision from a consultative committee, the extension phase (phase Ib) will be an efficacy study including 20 patients who will receive the Optimal Vinorelbine Theoretical Protocol. The primary endpoint is the tolerance (assessed by CTC v4.0) for the phase Ia and the objective response according to RECIST 1.1 for phase Ib.

An ancillary study on circulating angiogenesis biomarkers will be a subproject of the trial.

Discussion

This ongoing trial is the first to prospectively test a mathematically optimized schedule in metronomic chemotherapy. As such, this trial can be considered as a proof-of-concept study demonstrating the feasibility to run a computational-driven protocol to ensure an optimal efficacy/toxicity balance in patients with cancer.

Trial registration

EudraCT N°: 2015-000138-31

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Synergistic Dual Drug Liposomes in Multiple Myeloma

Here, we report the synthesis and evaluation of dual drug loaded nanoparticles as an effective means to deliver carfilzomib and doxorubicin to multiple myeloma tumor cells at their optimal synergistic ratio. First, various molar ratios of carfilzomib to doxorubicin were screened against multiple myeloma cell lines to determine the molar ratio that elicited the greatest synergy using the Chou-Talalay method. The therapeutic agents were then incorporated into liposomes at the optimal synergistic ratio of 1:1 to yield dual drug loaded nanoparticles with a narrow size range of 115 nm and high reproducibility. Our results demonstrated that the dual drug loaded liposomes exhibited synergy in vitro and were more efficacious in inhibiting tumor growth in vivo than a combination of free drugs, while at the same time reducing systemic toxicity. Taken together, this study presents the synthesis and pre-clinical evaluation of dual drug loaded liposomes containing carfilzomib and doxorubicin for enhanced therapeutic efficacy to improve patient outcome in multiple myeloma.

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AMG 337 inhibits growth of MET-dependent cancer models

The MET receptor tyrosine kinase is involved in cell growth, survival, and invasion. Clinical studies with small-molecule MET inhibitors have shown the role of biomarkers in identifying patients most likely to benefit from MET-targeted therapy. AMG 337 is an oral, small-molecule, ATP-competitive, highly selective inhibitor of the MET receptor. Herein, we describe AMG 337 preclinical activity and mechanism of action in MET-dependent tumor models. These studies suggest MET is the only therapeutic target for AMG 337. In an unbiased tumor cell line proliferation screen (260 cell lines), a closely related analogue of AMG 337, Compound 5, exhibited activity in 2 of 260 cell lines; both were <i>MET</i>-amplified. Additional studies examining the effects of AMG 337 on the proliferation of a limited panel of cell lines with varying <i>MET</i> copy numbers revealed that high-level focal <i>MET</i> amplification (>12 copies), was required to confer <i>MET</i> oncogene addiction and AMG 337 sensitivity. One <i>MET</i>-amplified cell line, H1573 (>12 copies), was AMG 337-insensitive, possibly because of a downstream G12A KRAS mutation. Mechanism-of-action studies in sensitive <i>MET</i>-amplified cell lines demonstrated that AMG 337 inhibited MET and adaptor protein Gab-1 phosphorylation, subsequently blocking the downstream PI3K and MAPK pathways. AMG 337 exhibited potency in pharmacodynamic assays evaluating MET signaling in tumor xenograft models; >90% inhibition of Gab-1 phosphorylation was observed at 0.75 mg/kg. These findings describe the preclinical activity and mechanism of action of AMG 337 in MET-dependent tumor models and indicate its potential as a novel therapeutic for the treatment of MET-dependent tumors.

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Genome and immune profiling of inflammatory breast cancer

Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer that remains poorly understood at the molecular level. Comprehensive tumor profiling was performed to understand clinically actionable alterations in IBC. Targeted-next-generation sequencing and IHC were performed to identify activated pathways in IBC tumor tissues. siRNA studies examined the impact of IBC genomic variants in cellular models. IBC tumor tissues were further characterized for immune infiltration and immune checkpoint expression by IHC. Genomic analysis identified recurrent alterations in core biological pathways including activating and targetable variants in HER/PI3K/mTOR signaling. High rates of activating HER3 point mutations were discovered in IBC tumors. Cell line studies confirmed a role for mutant HER3 in IBC cell proliferation. Immunological analysis revealed a subset of IBC tumors associated with high CD8+/PD-L1+ lymphocyte infiltration. Immune infiltration positively correlated with an NGS-based estimate of neo-antigen exposure derived from the somatic mutation rate and mutant allele frequency, iScore. Additionally, DNA mismatch repair alterations, which may contribute to higher iScores, occurred at greater frequency in tumors with higher immune infiltration. Our study identifies genomic alterations that mechanistically contribute to oncogenic signaling in IBC and provides a genetic basis for the selection of clinically relevant targeted and combination therapeutic strategies. Furthermore, an NGS-based estimate of neo-antigen exposure developed in this study (iScore) may be a useful biomarker to predict immune infiltration in IBC and other cancers. The iScore may be associated with greater levels of response to immunotherapies such as PD-L1/PD-1 targeted therapies.

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