JNK modulates EGFR/HER2 targeted therapy acquired resistance

Resistance limits the effectiveness of receptor tyrosine kinase (RTK)-targeted therapies. Combination therapies targeting resistance mechanisms can considerably improve response, but will require an improved understanding of when particular combinations will be effective. One common form of resistance is bypass signaling, wherein RTKs not targeted by an inhibitor can direct reactivation of pathways essential for survival. While this mechanism of resistance is well appreciated, it is unclear which downstream signaling events are responsible. Here, we apply a combined experimental- and statistical modeling-based approach to identify a set of pathway reactivation essential for RTK-mediated bypass resistance. Differences in the downstream pathway activation provided by particular RTKs lead to qualitative differences in the capacity of each receptor to drive therapeutic resistance. We identify and validate that the JNK pathway is activated during and strongly modulates bypass resistance. These results identify effective therapeutic combinations that block bypass-mediated resistance and provide a basic understanding of this network-level change in kinase dependence that will inform the design of prognostic assays for identifying effective therapeutic combinations in individual patients.

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{alpha}v{beta}6 integrin activates androgen receptor

Androgen receptor signaling fuels prostate cancer and is a major therapeutic target. However, mechanisms of resistance to therapeutic androgen ablation are not well understood. Here, using a prostate cancer mouse model, Ptenpc-/-, carrying a prostate epithelial-specific Pten deletion, we show that the αvβ6 integrin is required for tumor growth in vivo of castrated as well as of non-castrated mice. We describe a novel signaling pathway that couples the αvβ6 integrin cell surface receptor to androgen receptor via activation of JNK1 and causes increased nuclear localization and activity of androgen receptor. This downstream kinase activation by αvβ6 is specific for JNK1 with no involvement of p38 or ERK kinase. In addition, differential phosphorylation of Akt is not observed under these conditions, nor is cell morphology affected by αvβ6 expression. This pathway, which is specific for αvβ6, since is not regulated by a different αv containing integrin, αvβ3, promotes up-regulation of survivin which in turn supports anchorage-independent growth of αvβ6 expressing cells. Consistently, both αvβ6 and survivin are significantly increased in prostatic adenocarcinoma, but are not detected in normal prostatic epithelium. Neither XIAP nor bcl-2 is affected by αvβ6 expression. In conclusion, we show that αvβ6 expression is required for prostate cancer progression including castrate resistant prostate cancer; mechanistically, by promoting activation of JNK1, the αvβ6 integrin causes androgen receptor nuclear accumulation and increased activity in the absence of androgen, and consequent up-regulation of survivin. These preclinical results pave the way for further clinical development of αvβ6 antagonists for prostate cancer therapy.

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Calcium-sensing receptor and breast cancer

Parathyroid hormone-related protein (PTHrP) contributes to the development and metastatic progression of breast cancer by promoting hypercalcemia, but it is not known how PTHrP is upregulated during breast tumorigenesis. Here we report a central role in this process for CaSR, a calcium-sensing receptor which enables cellular responses to changes in extracellular calcium, through studies of CaSR-PTHrP interactions in the MMTV-PymT transgenic mouse model of breast cancer and in human breast cancer cells. CaSR activation stimulated PTHrP production by breast cancer cells in vitro and in vivo. Tissue-specific disruption of the CaSR gene in mammary epithelial cells in MMTV-PymT mice inhibited tumor cell proliferation and tumor outgrowth. CaSR signaling promoted the proliferation of human breast cancer cell lines and tumor cells cultured from MMTV-PyMT mice. Further, CaSR activation inhibited cell death triggered by high extracellular concentrations of calcium. These antiproliferative effects appeared to be mediated by nuclear actions of PTHrP that decreased p27kip1 levels and prevented nuclear accumulation of the pro-apoptotic factor AIF. Taken together, our findings suggest CaSR-PTHrP interactions as a locus for the development of therapeutic agents to limit metastasis to bone and other microenvironments where elevated PTHrP and extracellular calcium have been causally implicated.

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Human papillomavirus oncoprotein E6 upregulates c-Met through p53 downregulation

Publication date: September 2016
Source:European Journal of Cancer, Volume 65
Author(s): Guoqing Qian, Dongsheng Wang, Kelly R. Magliocca, Zhongliang Hu, Sreenivas Nannapaneni, Sungjin Kim, Zhengjia Chen, Shi-Yong Sun, Dong M. Shin, Nabil F. Saba, Zhuo G. Chen
PurposeHuman papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) carries a distinct clinical behaviour. c-Met oncogene is an important driver for tumour progression and its relationship with HPV in OPSCC was explored in the present study.Experimental designKnockdown of HPV oncogene E6 or p53 alone and in combination was performed to examine their effects on c-Met expression by Western blot and quantitative real-time polymerase chain reaction. The effects of c-Met inhibition on cell proliferation, migration, and colony formation were examined in HPV-positive head and neck squamous cell carcinoma (HNSCC) cells. Retrospectively collected OPSCC patient specimens (N = 78) were stained for c-Met by immunohistochemistry and the staining levels were correlated with HPV status and patient outcomes.ResultsE6 knockdown decreased c-Met protein and mRNA expression in HPV-positive HNSCC cells, which was partially abolished by the elimination of p53. Reducing c-Met decreased cell proliferation, migration, and colony formation in HPV-positive HNSCC cells. In OPSCC patient samples, high c-Met expression was associated with HPV-positive status (OR = 4.11, 95%CI: 1.16–14.55, P = 0.028) and tumour stage (OR = 0.27, 95%CI: 0.08–0.93, P = 0.039) by multivariable analysis. In T3/T4 stage patients, high c-Met expression was associated with HPV positivity and low p53 levels, supporting an axis of E6-p53-c-Met regulation. Furthermore, high c-Met expression was marginally associated with poor disease-free survival in HPV-positive patients.ConclusionsOur results suggest that c-Met may serve as a novel target for treating HPV-associated OPSCC. The data also demonstrate that HPV E6 upregulates c-Met expression partially through p53 downregulation.



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Rapid and objective CT scan prognostic scoring identifies metastatic patients with long-term clinical benefit on anti-PD-1/-L1 therapy

Publication date: September 2016
Source:European Journal of Cancer, Volume 65
Author(s): Laurent Dercle, Samy Ammari, Stéphane Champiat, Christophe Massard, Charles Ferté, Lokmane Taihi, Romain-David Seban, Sandrine Aspeslagh, Linda Mahjoubi, Nyam Kamsu-Kom, Caroline Robert, Aurélien Marabelle, Martin Schlumberger, Jean-Charles Soria, Sophie Postel-Vinay
BackgroundDrugs targeting programmed death receptor-1 (PD-1) and its ligand PD-L1 have shown activity in multiple malignancies. Considering their novel mechanism of action, whether traditional prognostic scores also apply to patients treated with these drugs is unknown. We investigated whether a baseline 3-point (pt) computed tomography (CT) scan (PS3-CT) score and a 7-pt prognostic (PS7) score allowed identifying long-term survivors on anti-PD-1/-L1 therapy.Materials and methodsWe reviewed 251 consecutive patients enrolled in phase I trials evaluating anti-PD-1/-L1 agents between 26th December 2011 and 7th September 2015. PS3-CT was calculated using high tumour burden (TB1D-RECIST > 9 cm), low skeletal muscle index (SMI < 53 cm² m⁻²) and non-pulmonary visceral metastases (NPVM) (1 pt each). PS7 was calculated by adding lower performance status, decreased serum albumin, increased serum lactate dehydrogenase and more than two distant metastases (1 pt each). Effect on overall survival (OS) of each parameter was tested using Kaplan–Meier and multivariable Cox analyses.ResultsPS3-CT was a significant independent predictor of OS (hazard ratio [HR] = 1.39 [95% confidence interval {CI} = 1.07–1.81], p = 0.01) when compared to the Royal Marsden Hospital, Barbot and American Joint Committee on Cancer scores. High TB (n = 78), low SMI (n = 55) and NPVM (n = 146) were associated with poorer survival (p < 0.01). High TB and low SMI were independent predictors of OS (respective HR of death: 2.00 [95% CI = 1.38–2.88], p < 0.01 and 1.75 [95% CI = 1.15–2.66], p < 0.01). PS7 was a significant predictor of OS (HR = 1.40 [95% CI = 1.25–1.56], p < 0.01).ConclusionObjective and rapid-risk scoring based on three CT scan parameters allows identifying patients with prolonged OS on anti-PD-1/-L1 therapy, independently from conventional clinical–biological prognostic scores.



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Progression-free survival as a surrogate for overall survival in first-line chemotherapy for advanced pancreatic cancer

Publication date: September 2016
Source:European Journal of Cancer, Volume 65
Author(s): Tsuyoshi Hamada, Yousuke Nakai, Hiroyuki Isayama, Hideo Yasunaga, Hiroki Matsui, Naminatsu Takahara, Suguru Mizuno, Hirofumi Kogure, Saburo Matsubara, Natsuyo Yamamoto, Minoru Tada, Kazuhiko Koike
BackgroundOverall survival (OS), as the primary end-point in first-line chemotherapy trials, requires a prolonged follow-up time and may be confounded by subsequent regimens. This study aimed to evaluate the correlation between OS and surrogate end-points (progression-free survival [PFS], response rate and disease control rate), and to identify a potential surrogate for OS in advanced pancreatic cancer.MethodsBased on an electronic search, we identified randomized controlled phase II and III trials of first-line chemotherapy for advanced pancreatic cancer. Correlation analyses were performed between surrogate end-points and OS, and between improvements in surrogates and those in OS.ResultsFifty trials (II/II–III/III, 17/2/31) with 111 treatment arms were identified, and 15,906 patients were analysed. PFS was most strongly correlated with OS (correlation coefficient, 0.76). Weighted linear regression models revealed the greatest determinant coefficient of 0.84 between the hazard ratio (HR) of the experimental arms compared with the control arms of PFS and that of OS. The approximate equation was log HROS = 0.01 + 0.77 × log HRPFS, indicating that risk reduction of OS via chemotherapy would translate into a 77% risk reduction of PFS. The surrogacy of PFS for OS was robust throughout our subgroup analyses: e.g., biologic versus non-biologic regimens, locally advanced versus metastatic disease.ConclusionsThe surrogacy of PFS for OS in pancreatic cancer was validated. Therefore, the use of PFS as the primary end-point in clinical trials could facilitate the early introduction of new effective chemotherapy regimens into clinical practice.



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Erratum

Future Oncology Ahead of Print.


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Lung adenocarcinoma may be a more susceptive subtype to a dendritic cell-based cancer vaccine than other subtypes of non-small cell lung cancers: a multicenter retrospective analysis

Abstract

Objective

The J-SICT DC Vaccine Study Group provides dendritic cell (DC) vaccines for compassionate use under unified cell production and patient treatment regimens. We previously reported beneficial effects of DC vaccines on the overall survival of 62 patients with advanced non-small cell lung cancer (NSCLC) in a single-center analysis. Here, we extended analysis to 260 patients with NSCLC who were treated at six centers.

Methods

Of the 337 patients who met the inclusion criteria, we analyzed 260 patients who received ≥5 peptide-pulsed DC vaccinations once every 2 weeks.

Results

The mean survival time (MST) from diagnosis was 33.0 months (95 % confidence interval [CI]: 27.9–39.2), and that from time of first vaccination was 13.8 months (95 % CI 11.4–16.8). An erythema reaction at the injection site that was ≥30 mm in diameter was correlated most strongly with overall survival from the first vaccine (≥30 vs. < 30 mm: MST 20.4 vs. 8.8 months, P < 0.001). We reported a similar finding in our previous analysis of patients with advanced pancreatic cancer. Interestingly, although such findings were common between patients with adenocarcinoma and those with other subtypes, the former group experienced significantly prolonged overall survival and a higher response rate for erythema (56.3 vs. 37.3 %, respectively, P = 0.014).

Conclusions

This is the first multicenter study that suggests a possible clinical benefit of DC vaccines for patients with advanced NSCLC, especially those with adenocarcinoma. These findings suggest a specific potential responder population for DC vaccines and warrant further investigation in well-controlled prospective randomized trials.

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Lung adenocarcinoma may be a more susceptive subtype to a dendritic cell-based cancer vaccine than other subtypes of non-small cell lung cancers: a multicenter retrospective analysis

Abstract

Objective

The J-SICT DC Vaccine Study Group provides dendritic cell (DC) vaccines for compassionate use under unified cell production and patient treatment regimens. We previously reported beneficial effects of DC vaccines on the overall survival of 62 patients with advanced non-small cell lung cancer (NSCLC) in a single-center analysis. Here, we extended analysis to 260 patients with NSCLC who were treated at six centers.

Methods

Of the 337 patients who met the inclusion criteria, we analyzed 260 patients who received ≥5 peptide-pulsed DC vaccinations once every 2 weeks.

Results

The mean survival time (MST) from diagnosis was 33.0 months (95 % confidence interval [CI]: 27.9–39.2), and that from time of first vaccination was 13.8 months (95 % CI 11.4–16.8). An erythema reaction at the injection site that was ≥30 mm in diameter was correlated most strongly with overall survival from the first vaccine (≥30 vs. < 30 mm: MST 20.4 vs. 8.8 months, P < 0.001). We reported a similar finding in our previous analysis of patients with advanced pancreatic cancer. Interestingly, although such findings were common between patients with adenocarcinoma and those with other subtypes, the former group experienced significantly prolonged overall survival and a higher response rate for erythema (56.3 vs. 37.3 %, respectively, P = 0.014).

Conclusions

This is the first multicenter study that suggests a possible clinical benefit of DC vaccines for patients with advanced NSCLC, especially those with adenocarcinoma. These findings suggest a specific potential responder population for DC vaccines and warrant further investigation in well-controlled prospective randomized trials.

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Downregulation of proinflammatory cytokines in HTLV-1-infected T cells by Resveratrol

Abstract

Background

Human T-cell leukemia virus (HTLV-1) is a lymphotropic retrovirus associated to adult T cell leukemia (ATL) and to non-neoplastic inflammatory conditions affecting the central nervous system, lung or skin. The inflammatory disorders associated to HTLV-1 are mediated by different proinflammatory cytokines as IL-1α, IL-6, TNF-α. The release and the role of IL-17 is still debated. Aims of this study were to analyze IL-17 induction by HTLV-1 infection and to determine whether resveratrol (RES) is able to down regulate the pathway of cytokines production either in HTLV-1 chronically infected MT-2 cell line or in human CD4+ cells infected in vitro with HTLV-1.

Methods

MT-2 and HTLV-1 infected CD4+ cells were analyzed for proinflammatory cytokine production before or after RES treatment. The concentrations of IL-17, IL-1α, IL-6, and TNF-α were measured in cell culture supernatants by ELISA and SearchLight™ technology. The IL-17 mRNA expression was evaluated by RT-PCR. NF-kB activation was detected by non-radioactive, Electro Mobility Shift Assay (EMSA). HTLV-1 RNA expression was detected by Real-time-PCR (RQ-PCR).

Results

We found that RES is capable of inducing a dose-dependent inhibition of IL-1α, IL-6 and TNF-α production in vitro and can down regulate the expression of IL-17 at both mRNA and protein levels in HTLV-1 infected cells. This effect was associated with a dose-dependent inhibition of the of the nuclear factor kappa-B (NF-kB) activity. Conversely, RES did not apparently affect HTLV-1 proliferation.

Conclusions

These results support the anti-inflammatory properties of RES, suggesting that it might be a useful therapeutic agent for the treatment of HTLV-1 related inflammatory diseases.

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Ulcerative colitis associated with nephrotic syndrome after treatment with mesalazine developed into rectal carcinoma: a case study

Abstract

Background

Previous studies reported that nephrotic syndrome is associated with ulcerative colitis (UC) patients treated with mesalazine. Dysplasia associated with UC often develops into colorectal carcinoma.

Case presentation

A 17-year-old man was referred to our hospital, complaining of diarrhea and bloody stool. Total colonoscopy (TC) was performed and total-type UC was diagnosed. After treatment with mesalazine for 5 years, a low-grade dysplasia (LGD) was detected in the rectum by histological analysis of a biopsy sample. One month later, he complained of dyspnea and edema. He was diagnosed with nephrotic syndrome and administered steroid and immunosuppressant treatment: cyclosporine and mizoribine. Eight years after LGD was detected, he complained of abdominal distension and pain. Stenosis of the upper rectum by an advanced rectal carcinoma was detected. Abdominal computed tomography showed a rectal tumor with multiple lymph node metastases. Transverse colostomy was performed surgically, followed by two cycles of modified FOLFOX6 and panitumumab. He safely underwent a total proctocolectomy with a stapled ileal pouch anal-canal anastomosis, total mesorectal and bilateral pelvic lymph node dissection, and temporary loop ileostomy. Metastases were observed in 25 lymph nodes microscopically. The pathological stage of rectal carcinoma was pT3N2bM1a. After one cycle of modified FOLFOX6 postoperatively, he was discharged from the hospital.

Conclusions

A patient with UC associated with nephrotic syndrome was treated with mesalazine. LGD developed into an advanced rectal carcinoma after an 8-year interval. The use of immunosuppressants for the treatment of nephrotic syndrome might affect the development of rectal carcinoma.

Trial registration

Trial registration: Case report registration #1626

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Prostate Cancer in African American Men: The Effect of Androgens and microRNAs on Epidermal Growth Factor Signaling

Abstract

Prostate cancer (PC) is one of the leading causes of mortality amongst elderly men in the USA and is second only to lung cancer. African Americans (AA) are at an increased risk of developing PC and are more likely to die from the disease in comparison to Caucasian Americans (CA). Chromosomal alterations or genetic differences between AA and CA may account for the variances observed in PC progression. Importantly, mutations in the androgen receptor (AR) or the epidermal growth factor receptor (EGFR) may contribute to the disparity. Current studies are investigating the role of small nucleotide polymorphisms (SNPs) and microRNAs (miRNAs), which affect protein translation of the receptors by regulation of the 3′ untranslated region (UTR), which may enhance the progression of PC. However, these genetic differences have not been fully explored in prostates between the two ethnic groups. This review will highlight the current studies on the EGFR signaling pathway as well as the involvement of SNPs and miRNAs and relate them to variances observed in PC of AA and CA men. With an understanding of these differences, specific preventive and therapeutic strategies may be developed to target personalized medicine for prostate carcinogenesis.

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Controversies in the Therapy of Brain Metastases: Shifting Paradigms in an Era of Effective Systemic Therapy and Longer-Term Survivorship

Opinion statement

With the development of therapies that improve extracranial disease control and increase long-term survival of patients with metastatic cancer, effective treatment of brain metastases while minimizing toxicities is becoming increasingly important. An expanding arsenal that includes surgical resection, whole brain radiation therapy, radiosurgery, and targeted systemic therapy provides multiple treatment options. However, significant controversies still exist surrounding appropriate use of each modality in various clinical scenarios and patient populations in the context of cancer care strategies that control systemic disease for increasingly longer periods of time. While whole brain radiotherapy alone is still a reasonable and standard option for patients with multiple metastases, several randomized trials have now revealed that survival is maintained in patients treated with radiosurgery or surgery alone, without upfront whole brain radiotherapy, for up to four brain metastases. Indeed, recent data even suggest that patients with up to 10 metastases can be treated with radiosurgery alone without a survival detriment. In an era of dramatic advances in targeted and immune therapies that control systemic disease and improve survival but may not penetrate the brain, more consideration should be given to brain metastasis-directed treatments that minimize long-term neurocognitive deficits, while keeping in mind that salvage brain therapies will likely be more frequently required. Less toxic therapies now also allow for concurrent delivery of systemic therapy with radiosurgery to brain metastases, such that treatment of both extracranial and intracranial disease can be expedited, and potential synergies between radiotherapy and agents with central nervous system penetration can be harnessed.

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Incidence and survival time trends for Spanish children and adolescents with leukaemia from 1983 to 2007

Abstract

Objective

We have analysed incidence and survival trends of children and adolescents with leukaemia registered in Spanish population-based cancer registries during the period 1983–2007.

Methods

Childhood and adolescent leukaemia cases were drawn from the 11 Spanish population-based cancer registries. For survival, registries with data for the period 1991–2005 and follow-up until 31-12-2010 were included. Overall incidence trends were evaluated using joinpoint analysis. Observed survival rates were estimated using Kaplan–Meier, and trends were tested using the log-rank test.

Results

Based on 2606 cases (2274 children and 332 adolescents), the overall age-adjusted incidence rate (ASRw) of leukaemia was 47.9 cases per million child-years in children and 23.8 in adolescents. The ASRw of leukaemia increased with an annual percentage change of 9.6 % (95 % CI: 2.2–17.6) until 1990 followed by a stabilisation of rates. In adolescents, incidence did not increase. Five-year survival increased from 66 % in 1991–1995 to 76 % in 2001–2005. By age, survival was dramatically lower in infants (0) and adolescents (15−19) than in the other age groups and no improvement was observed. In both children and adolescents, differences in 5-year survival rates among major subgroups of leukaemias were significant.

Conclusions

The increasing incidence trends observed in childhood leukaemias during the study period were confined to the beginning of the period. Remarkable improvements in survival have been observed in Spanish children with leukaemias. However, this improvement was not observed in infants and adolescents.

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From glioblastoma to endothelial cells through extracellular vesicles: messages for angiogenesis

Abstract

Glioblastoma has one of the highest mortality rates among cancers, and it is the most common and malignant form of brain cancer. Among the typical features of glioblastoma tumors, there is an aberrant vascularization: all gliomas are among the most vascularized/angiogenic tumors. In recent years, it has become clear that glioblastoma cells can secrete extracellular vesicles which are spherical and membrane-enclosed particles released, in vitro or in vivo, by both normal and tumor cells; they are involved in the regulation of both physiological and pathological processes; among the latter, cancer is the most widely studied. Extracellular vesicles from tumor cells convey messages to other tumor cells, but also to normal stromal cells in order to create a microenvironment that supports cancer growth and progression and are implicated in drug resistance, escape from immunosurveillance and from apoptosis, as well as in metastasis formation; they are also involved in angiogenesis stimulation, inducing endothelial cells proliferation, and other pro-angiogenic activities. To this aim, the present paper assesses in detail the extracellular vesicles phenomenon in the human glioblastoma cell line U251 and evaluates extracellular vesicles ability to promote the processes required to achieve the formation of new blood vessels in human brain microvascular endothelial cells, highlighting that they stimulate proliferation, motility, and tube formation in a dose-response manner. Moreover, a molecular characterization shows that extracellular vesicles are fully equipped for angiogenesis stimulation in terms of proteolytic enzymes (gelatinases and plasminogen activators), pro-angiogenic growth factors (VEGF and TGFβ), and the promoting-angiogenic CXCR4 chemokine receptor.

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Molecular mechanisms of action of quercetin in cancer: recent advances

Abstract

In the last few decades, the scientific community has discovered an immense potential of natural compounds in the treatment of dreadful diseases such as cancer. Besides the availability of a variety of natural bioactive molecules, efficacious cancer therapy still needs to be developed. So, to design an efficacious cancer treatment strategy, it is essential to understand the interactions of natural molecules with their respective cellular targets. Quercetin (Quer) is a naturally occurring flavonol present in many commonly consumed food items. It governs numerous intracellular targets, including the proteins involved in apoptosis, cell cycle, detoxification, antioxidant replication, and angiogenesis. The weight of available synergistic studies vigorously fortifies the utilization of Quer as a chemoprevention drug. This extensive review covers various therapeutic interactions of Quer with their recognized cellular targets involved in cancer treatment.

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Cytokeratin-19 fragment in the diagnosis of bladder carcinoma

Abstract

The results of previous studies evaluated the accuracy of serum, and urinary measurements of cytokeratin-19 fragment (CYFRA 21-1) for the diagnosis of bladder cancer were inconsistent. We read with great interest the recent systematic review of diagnostic accuracy of CYFRA 21-1 for bladder cancer by Huang et al. The systematic analysis demonstrated that the pooled sensitivities and specificities for serum and urine CYFRA 21-1 were 0.42 (95 % confidence interval (CI), 0.33–0.51), 0.82 (95 % CI, 0.70–0.90), 0.94 (95 % CI, 0.90–0.96), and 0.80 (95 % CI, 0.73–0.86), respectively. Areas under the summary receiver-operating-characteristic curves for serum and urine CYFRA 21-1 were 0.88 (95 % CI, 0.85–0.91) and 0.87 (95%CI, 0.84–0.90), respectively. The authors considered that both serum and urine CYFRA 21-1 served as efficient indexes for bladder-cancer diagnosis. We congratulate and applaud their important work, but several important issues should be noted.

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Breast cancer epidemic in the early twenty-first century: evaluation of risk factors, cumulative questionnaires and recommendations for preventive measures

Abstract

Rapidly increasing incidence of breast cancer is a new social challenge resulting from a spectrum of internal and external risk factors which appear to be well accepted as an attribute of the early twenty-first century, being, however, new for female sub-populations compared to the past. These include altered socio-economical conditions such as occupational exposure, rotating shift work, specific environmental factors (increased pollution and environmental toxicity, altered dietary habits, quality and composition of meal) as well as consequently shifted and/or adapted physiologic factors such as lower age at menarche, late age of first full-term pregnancy, if any, shorter periods of breastfeeding and later menopause. Consolidated expert statements suggest that over 50 % of all breast cancer cases may be potentially prevented by risk reduction strategy such as regulation of modifiable risk factors. Currently available risk assessment models may estimate potential breast cancer predisposition, in general; however, they are not able to predict the disease manifestation individually. Further, current deficits in risk assessment and effective breast cancer prevention have been recently investigated and summarised as follows: gaps in risk estimation, preventive therapy, lifestyle prevention, understanding of the biology of breast cancer risk and implementation of known preventive measures. This paper overviews the most relevant risk factors, provides recommendations for improved risk assessment and proposes an extended questionnaire for effective preventive measures.

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Controversies in the Therapy of Brain Metastases: Shifting Paradigms in an Era of Effective Systemic Therapy and Longer-Term Survivorship

Opinion statement

With the development of therapies that improve extracranial disease control and increase long-term survival of patients with metastatic cancer, effective treatment of brain metastases while minimizing toxicities is becoming increasingly important. An expanding arsenal that includes surgical resection, whole brain radiation therapy, radiosurgery, and targeted systemic therapy provides multiple treatment options. However, significant controversies still exist surrounding appropriate use of each modality in various clinical scenarios and patient populations in the context of cancer care strategies that control systemic disease for increasingly longer periods of time. While whole brain radiotherapy alone is still a reasonable and standard option for patients with multiple metastases, several randomized trials have now revealed that survival is maintained in patients treated with radiosurgery or surgery alone, without upfront whole brain radiotherapy, for up to four brain metastases. Indeed, recent data even suggest that patients with up to 10 metastases can be treated with radiosurgery alone without a survival detriment. In an era of dramatic advances in targeted and immune therapies that control systemic disease and improve survival but may not penetrate the brain, more consideration should be given to brain metastasis-directed treatments that minimize long-term neurocognitive deficits, while keeping in mind that salvage brain therapies will likely be more frequently required. Less toxic therapies now also allow for concurrent delivery of systemic therapy with radiosurgery to brain metastases, such that treatment of both extracranial and intracranial disease can be expedited, and potential synergies between radiotherapy and agents with central nervous system penetration can be harnessed.

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From glioblastoma to endothelial cells through extracellular vesicles: messages for angiogenesis

Abstract

Glioblastoma has one of the highest mortality rates among cancers, and it is the most common and malignant form of brain cancer. Among the typical features of glioblastoma tumors, there is an aberrant vascularization: all gliomas are among the most vascularized/angiogenic tumors. In recent years, it has become clear that glioblastoma cells can secrete extracellular vesicles which are spherical and membrane-enclosed particles released, in vitro or in vivo, by both normal and tumor cells; they are involved in the regulation of both physiological and pathological processes; among the latter, cancer is the most widely studied. Extracellular vesicles from tumor cells convey messages to other tumor cells, but also to normal stromal cells in order to create a microenvironment that supports cancer growth and progression and are implicated in drug resistance, escape from immunosurveillance and from apoptosis, as well as in metastasis formation; they are also involved in angiogenesis stimulation, inducing endothelial cells proliferation, and other pro-angiogenic activities. To this aim, the present paper assesses in detail the extracellular vesicles phenomenon in the human glioblastoma cell line U251 and evaluates extracellular vesicles ability to promote the processes required to achieve the formation of new blood vessels in human brain microvascular endothelial cells, highlighting that they stimulate proliferation, motility, and tube formation in a dose-response manner. Moreover, a molecular characterization shows that extracellular vesicles are fully equipped for angiogenesis stimulation in terms of proteolytic enzymes (gelatinases and plasminogen activators), pro-angiogenic growth factors (VEGF and TGFβ), and the promoting-angiogenic CXCR4 chemokine receptor.

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Molecular mechanisms of action of quercetin in cancer: recent advances

Abstract

In the last few decades, the scientific community has discovered an immense potential of natural compounds in the treatment of dreadful diseases such as cancer. Besides the availability of a variety of natural bioactive molecules, efficacious cancer therapy still needs to be developed. So, to design an efficacious cancer treatment strategy, it is essential to understand the interactions of natural molecules with their respective cellular targets. Quercetin (Quer) is a naturally occurring flavonol present in many commonly consumed food items. It governs numerous intracellular targets, including the proteins involved in apoptosis, cell cycle, detoxification, antioxidant replication, and angiogenesis. The weight of available synergistic studies vigorously fortifies the utilization of Quer as a chemoprevention drug. This extensive review covers various therapeutic interactions of Quer with their recognized cellular targets involved in cancer treatment.

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Breast cancer epidemic in the early twenty-first century: evaluation of risk factors, cumulative questionnaires and recommendations for preventive measures

Abstract

Rapidly increasing incidence of breast cancer is a new social challenge resulting from a spectrum of internal and external risk factors which appear to be well accepted as an attribute of the early twenty-first century, being, however, new for female sub-populations compared to the past. These include altered socio-economical conditions such as occupational exposure, rotating shift work, specific environmental factors (increased pollution and environmental toxicity, altered dietary habits, quality and composition of meal) as well as consequently shifted and/or adapted physiologic factors such as lower age at menarche, late age of first full-term pregnancy, if any, shorter periods of breastfeeding and later menopause. Consolidated expert statements suggest that over 50 % of all breast cancer cases may be potentially prevented by risk reduction strategy such as regulation of modifiable risk factors. Currently available risk assessment models may estimate potential breast cancer predisposition, in general; however, they are not able to predict the disease manifestation individually. Further, current deficits in risk assessment and effective breast cancer prevention have been recently investigated and summarised as follows: gaps in risk estimation, preventive therapy, lifestyle prevention, understanding of the biology of breast cancer risk and implementation of known preventive measures. This paper overviews the most relevant risk factors, provides recommendations for improved risk assessment and proposes an extended questionnaire for effective preventive measures.

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A randomized cross-over trial to detect differences in arm volume after low- and heavy-load resistance exercise among patients receiving adjuvant chemotherapy for breast cancer at risk for arm lymphedema: study protocol

Abstract

Background

In an effort to reduce the risk of breast cancer-related arm lymphedema, patients are commonly advised to avoid heavy lifting, impacting activities of daily living and resistance exercise prescription. This advice lacks evidence, with no prospective studies investigating arm volume changes after resistance exercise with heavy loads in this population. The purpose of this study is to determine acute changes in arm volume after a session of low- and heavy-load resistance exercise among women undergoing adjuvant chemotherapy for breast cancer at risk for arm lymphedema.

Methods/Design

This is a randomized cross-over trial. Participants: Women receiving adjuvant chemotherapy for breast cancer who have undergone axillary lymph node dissection will be recruited from rehabilitation centers in the Copenhagen area. Intervention: Participants will be randomly assigned to engage in a low- (two sets of 15–20 repetition maximum) and heavy-load (three sets of 5–8 repetition maximum) upper-extremity resistance exercise session with a one week wash-out period between sessions. Outcome: Changes in extracellular fluid (L-Dex score) and arm volume (ml) will be assessed using bioimpedance spectroscopy and dual-energy x-ray absorptiometry, respectively. Symptom severity related to arm lymphedema will be determined using a visual analogue scale (heaviness, swelling, pain, tightness). Measurements will be taken immediately pre- and post-exercise, and 24- and 72-hours post-exercise. Sample size: A sample size of 20 participants was calculated based on changes in L-Dex scores between baseline and 72-hours post exercise sessions.

Discussion

Findings from this study are relevant for exercise prescription guidelines, as well as recommendations regarding participating in activities of daily living for women following surgery for breast cancer and who may be at risk of developing arm lymphedema.

Trial registration

Current Controlled Trials ISRCTN97332727. Registered 12 February 2015.

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Free/Total Serum Prostate-Specific Antigen Ratio in Women with Colorectal Cancer Has Prognostic Significance

Abstract

Purpose

The presence of prostate-specific antigen (PSA) in colon cancer tissues has been shown, but its clinical significance has not been known yet in colorectal cancer patients. We investigated the prognostic significance of percent free PSA value (free PSA/total PSA × 100) in female patients with colorectal cancer.

Methods

The serum concentrations of total and free PSA were measured by solid-phase two-site immunoradiometric assay in 184 patients.

Results

The cancer-specific survival (CSS) of patients with percent free PSA value ≥35 was significantly better compared to that of patients with percent free PSA value <35 (CSS rate was 82.9 and 55.5 %, respectively; log-rank x² = 8135, p = 0.004). In multivariate Cox analysis, this percent free PSA threshold value had independent prognostic significance (relative risk 0.27, 95 % confidence interval 0.11–0.64, p = 0.003).

Conclusion

Percent free PSA value, calculated by serum total and free PSA levels, has prognostic significance in women with colorectal cancer. The studies with larger patient series, utilizing ultrasensitive PSA assays whose lowest detection limit is lower, are required for a clearer understanding of this issue.

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Expression analysis of three miRNAs, miR-26a, miR-29b and miR-519d, in relation to MMP - 2 expression level in non-small cell lung cancer patients: a pilot study

Abstract

Lung cancer is the most common cause of death in men and second only to breast cancer in women. MicroRNAs (miRNAs) are involved in tumorigenesis and function as oncogenes or tumor suppressor genes. Among other genes, miRNAs regulate matrix metalloproteinases (MMPs), the proteolytic enzymes playing a significant role in the degradation of extracellular matrix, enhancing tumor invasion and metastasis. The aim of the study was to evaluate the expression levels of selected miRNAs: miR-26a, miR-29b and miR-519d, and their target gene, matrix metalloproteinase-2 (MMP-2) in patients with non-small cell lung cancer (NSCLC). The results were correlated with tumor staging, NSCLC histopathological subtypes and patients' demographical features to assess the possible diagnostic/prognostic value of the studied miRNAs and MMP-2. Total RNA was isolated from 38 NSCLC tissue samples, and the expression analysis was performed using TaqMan^® probes in qPCR assay. The results indicated underexpression of selected miRNAs and overexpression of MMP-2. The decrease in miRNA-29b expression was statistically significant and differentiated NSCLC histopathological subtypes. Additionally, statistically significant negative correlation was found between MMP-2 expression and its regulatory miR-26a. There are very few studies reporting miRNA-MMPs analysis on mRNA level in lung cancer, and no similar reports are available from Polish population. The results of our pilot study indicated the diagnostic potential of miR-29b and MMP-2, an inverse association between miR-26a and MMP-2, and proved the role of MMP-2 and the studied miRNAs in lung carcinogenesis. Further studies are needed to verify their potential usefulness for the treatment of lung cancer.

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Analysis of the benefit of sequential cranial radiotherapy in patients with EGFR mutant non-small cell lung cancer and brain metastasis

Abstract

Although cranial radiotherapy is considered the standard treatment for brain metastasis (BM), EGFR tyrosine kinase inhibitors (TKIs) have shown promising activity in EGFR mutant non-small cell lung cancer (NSCLC) patients with BM. However, the efficacy of sequential cranial radiotherapy in patients with EGFR mutant NSCLC who are treated with EGFR TKIs remains to be determined. Patients with NSCLC who harbored an EGFR mutation and whose BM had been treated with EGFR TKIs were retrospectively reviewed. The clinical outcomes of patients treated with EGFR TKIs alone and those treated with cranial radiotherapy followed by EGFR TKIs (additive therapy) were compared. Of the 573 patients with NSCLC with BM who harbored an EGFR mutation and had received EGFR TKIs, 121 (21.1 %) had BM at the time of initial diagnosis. Fifty-nine (49 %) patients were treated with additive therapy, whereas 62 (51 %) patients were treated only with EGFR TKIs. No significant differences were observed between the additive therapy group and the EGFR TKI alone group regarding intracranial progression-free survival (PFS) (16.6 vs 21.0 months, p = 0.492) or extracranial PFS (12.9 vs 15.0 months, p = 0.770). The 3-year survival rates were similar in both groups (71.9 vs 68.2 %, p = 0.675). Additive therapy consisting of cranial radiotherapy followed by EGFR TKI treatment did not improve OS or intracranial PFS compared with EGFR TKI treatment alone in EGFR mutant NSCLC patients with BM. Further prospective studies are needed to determine the precise benefits of sequential cranial radiotherapy in EGFR mutant NSCLC treated with EGFR TKIs.

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Head and neck margin reduction with ART: robustness of treatment plans against anatomy changes

Publication date: Available online 21 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): S. van Kranen, O. Hamming-Vrieze, A.L. Wolf, E. Damen, M. van Herk, J.-J. Sonke
PurposeTo investigate loss of target coverage from anatomy changes in head-and-neck cancer(HNC) patients as function of applied safety margins and to verify a CBCT based adaptive strategy with an average patient anatomy to overcome possible target underdosage.Methods& Materials: For 19 oropharyngeal cancer patients, VMAT treatments plans(2 arcs, SIB, 70/54.25Gy, 35 fractions) were automatically optimized with uniform CTV to PTV margins of 5, 3 and 0mm. B-spline CBCT-to-CT deformable registration was applied to allow recalculating the dose on modified CTs(planning CT deformed to daily CBCT following online positioning) and dose accumulation in the planning CT. Patients with deviations in primary or elective CTV-coverage >2Gy(ΔD99%) were identified as candidates for adaptive replanning. For these patients, a single adaptive intervention was simulated with an average anatomy from the first 10 fractions.ResultsMargin reduction from 5→3→0mm generally led to OAR sparing of ∼1Gy/mm(Dmean). CTV shrinkage was mainly seen in the elective volumes(up to 10%), likely related to weight-loss. Despite online repositioning, substantial systematic errors were present(>3mm) in lymph-node CTV, the parotid glands and the larynx. Nevertheless, average increase in OAR dose was small: max 1.2Gy(parotid glands, Dmean) for all applied margins. Loss of CTV-coverage >2Gy was found in 1, 3 and 7 of 73 CTVs respectively. Adaptive intervention in 0mm plans substantially improved coverage: in 5 of 7 CTVs(in 6 patients) to less than 2Gy of initially planned.ConclusionVMAT HNC treatment plans with 5mm margins are robust for anatomy changes and show modest increase in OAR dose. Margin reduction improves OAR sparing with ∼1Gy/mm at the expense of target coverage in a subgroup of patients. Patients at risk of CTV-underdosage>2Gy in 0mm plans may be identified early in treatment using dose accumulation. A single intervention with an average anatomy derived from CBCT effectively mitigates discrepancies.



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18F-fluorodeoxyglucose-positron emission tomography can quantify and predict esophageal injury during radiation therapy

Publication date: Available online 21 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Joshua S. Niedzielski, Jinzhong Yang, Zhongxing Liao, Daniel R. Gomez, Francesco Stingo, Radhe Mohan, Mary K. Martel, Tina M. Briere, Laurence E. Court
We investigated the use of mid-treatment FDG-PET as an objective quantification of radiation esophagitis for NSCLC patients undergoing chemoradiotherapy. FDG-PET uptake was normalized to low-dose regions of the esophagus to create localized radiation response metrics. We found normalized PET uptake was highly correlated to esophagitis grade, both during the PET study, and by treatment completion. In addition, PET uptake can predict eventual esophagitis from patients who are asymptomatic during the mid-treatment PET scan.



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Stereotactic Body Radiotherapy Delivery in a Genetically Engineered Mouse Model of Lung Cancer

Publication date: Available online 21 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Shisuo Du, Virginia Lockamy, Lin Zhou, Christine Xue, Justin LeBlanc, Shonna Glenn, Gaurav Shukla, Yan Yu, Adam P. Dicker, Bo Lu
PurposeTo implement clinical stereotactic body radiotherapy (SBRT) using a small animal radiation research platform (SARRP) in a genetically engineered mouse model of lung cancer.Methods and MaterialsA murine model of multi-nodular Kras-driven spontaneous lung tumors was utilized for this stiudy. High resolution cone-beam computed tomography (CBCT) imaging was used to identify and target peripheral tumor nodules wheras off-target lung nodules in the contralateral lung were utilized as a non-irradiated control. CBCT imaging helps to localize tumors, facilitate high-precision irradiation, and monitor tumor growth. SBRT planning, prescription dose and dose limits to normal tissue follow the guidelines set by RTOG protocols. Pathologic changes in the irradiated tumors were investigated using immunohistochemistry.ResultsThe image-guided radiation delivery using the SARRP system effectively localized and treated lung cancer with precision in a genetically engineered mouse model of lung cancer. Immunohistochemical data confirmed the precise delivery of SBRT to the targeted lung nodules. 60 Gy delivered in three weekly fractions markedly reduce proliferation index, Ki-67 and increased apoptosis per staining for cleaved caspase-3 in irradiated lung nodules.ConclusionsIt is feasible to use the SARRP platform to perform dosimetric planning and delivery of SBRT in mice with lung cancer. This allows for preclinical studies that provide rationale for clinical trials involving SBRT, especially in the setting of being combined with immunotherapeutics.

Teaser

This work demonstrates the feasibility of using human SBRT protocols to deliver image-guided SBRT treatments in rodent models utilizing a small animal irradiator. The use of genetically engineered mice with Kras-driven spontaneous lung tumors that closely mimic human NSCLC is a unique preclinical model for SBRT. We have demonstrated that SBRT can be precisely delivered to murine lung peripheral tumors while sparing on adjacent tissues and OARs. In addition, we validated biological effects from SBRT in irradiated tissues. This novel platform provides new research opportunities that investigate the combination of SBRT with other therapeutic agents.


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Effect of the Maximum Dose on White Matter Fiber Bundles Utilizing Longitudinal Diffusion Tensor Imaging

Publication date: Available online 21 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Tong Zhu, Christopher H. Chapman, Christina Tsien, Michelle Kim, Daniel E. Spratt, Theodore S. Lawrence, Yue Cao
PurposePrevious efforts to decrease neurocognitive effects of radiation focused on sparing isolated cortical structures. We hypothesize that understanding temporal, spatial and dosimetric patterns of radiation damage of whole brain white matter (WBWM) after partial brain irradiation might also be important. Therefore, we carried out a study to develop the methodology to assess radiotherapy-induced damage to WBWM bundles.MethodsAn atlas-based, automated WM tractography analysis was implemented to quantify longitudinal changes in indices of diffusion tensor imaging (DTI) of 22 major WM fibers in 33 patients with predominantly low-grade/benign brain tumors treated by radiotherapy. Six DTI scans per patient were performed from pre-RT to 18 months post-RT. The DTI indices and planned doses (maximum and mean doses) were mapped onto profiles of each of 22 WM bundles. A multivariate linear regression was performed to determine the main dose effect as well as the influence of other clinical factors on longitudinal percentage changes in axial and radial diffusivity (AD and RD) from pre-RT.ResultsOf 22 fiber bundles, AD/RD changes in 12 bundles were affected significantly by doses (P<0.05), as the effect was progressive over time. In nine elongated tracts, decreased AD/RD was significantly related to maximum doses received, consistent with a serial-structure. In individual bundles, AD changes were up to 11.5% at the maximum dose locations 18 months post-RT. The dose effect on WM was greater in older females than younger males.ConclusionOur study demonstrates for the first time that the maximum dose to the elongated WM bundles causes post-radiotherapy damage in WM. Validation and correlative studies are necessary to determine the ability and impact of sparing these bundles on preserving neurocognitive function post-radiotherapy.

Teaser

Neurocognitive function is supported by white matter (WM) fiber bundles in the neural network. WM bundles are highly susceptible to radiation damage. In this study, we found that elongated WM fiber bundles responded to the received maximum dose rather than the mean dose, much like a typical serial-structure. These findings provide a new framework on how to spare dose for critical functional networks to preserve cognitive function.


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Effectiveness of four outreach modalities to patients overdue for cervical cancer screening in the primary care setting: a randomized trial

Abstract

Purpose

Papanicolaou (Pap) testing has dramatically decreased cervical cancer incidence in the USA, but only 83 % of women screen according to guidelines. Our study aimed to examine the real-world effectiveness of various outreach methods in engaging patients who are overdue for cervical cancer screening.

Methods

In total, 1,100 patients at an urban federally qualified health center overdue for Pap testing were randomized to receive usual care (control), letter outreach, email outreach, telephone outreach, or multimodal (letter/email/telephone) outreach over a period of 3 months. Eighteen months after randomization, medical records were used to determine whether and when each patient had obtained a Pap.

Results

Compared to patients receiving usual care, patients in the multimodal (36 vs. 21 %, AOR 2.3, 95 % CI 1.4, 3.6) and telephone (29 vs. 21 %, AOR 1.7, 95 % CI 1.1, 2.8) outreach groups were significantly more likely to receive cervical cancer screening during the follow-up period. Intervention effects were similar among older and younger patients. Telephone, multimodal, and letter outreach resulted in significantly lower median time to screening among patients who did screen (119, 122, and 157 days, respectively) in those groups as compared to the usual care group (270 days).

Conclusions

This is the first study to perform a direct, randomized comparison of four distinct cervical cancer outreach intervention modalities with a control usual care group, ensuring comparability across intervention methods. In an urban primary care setting, a multimodal outreach strategy was most effective at increasing the proportion of overdue patients who undergo cervical screening and decreasing time to screening.

Clinical Trials Registry

ClinicalTrials.gov; Registration Number: NCT02427399; http://ift.tt/2ahbHkF.

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Six-gene metastasis signature for HCC prognosis

Purpose: The dismal outcome of hepatocellular carcinoma (HCC) is largely attributed to its early recurrence and venous metastases. We aimed to develop a metastasis-related model to predict HCC prognosis. Experimental Design: Using microarrays, sequencing and RT-PCR, we measured the expression of mRNAs and lncRNAs in a training set of 94 well-defined low-risk (LRM) and high-risk metastatic (HRM) HCC patients from a Shanghai cohort. We refined a metastasis signature and established a corresponding model using logistic regression analysis. The validation set consisted of 567 HCC patients from four-center cohorts. Survival analysis was performed according to the metastasis model. Results: Using relative expression of tumor to para-tumor tissues, we refined the metastasis signature of 5 mRNAs and 1 lncRNA. A generalized linear model was further established to predict the probability of metastasis (MP). Using MP cutoff of 0.7 to separate LRM and HRM in Shanghai cohort, the specificity and sensitivity of the model were 96% (95% confidence interval, CI: 85~99%) and 74% (95% CI: 58~86%), respectively. Furthermore, HRM patients showed a significantly shorter overall and recurrence-free survival in validation cohorts (p < 0.05 for each cohort). Early HCC patients also have a poorer outcome for multi-center HRM patients. Lastly, Cox regression analysis indicated that continuous MP was an independent risk factor and associated with the recurrence and survival of HCC patients after resection (Hazard ratio: 2.98 to 16.6, p < 0.05). Conclusions: We developed an applicable six-gene metastasis signature, which is robust and reproducible in multi-center cohorts for HCC prognosis.

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KLF4/MSI2 Signaling in PDA progression

Purpose: Musashi 2 (MSI2) is reported to be a potential oncoprotein in cases of leukemia and several solid tumors. However, its expression, function, and regulation in pancreatic ductal adenocarcinoma (PDAC) cases have yet to be demonstrated. Therefore, in the present study, we investigated the clinical significance and biologic effects of MSI2 expression in PDAC cases and sought to delineate the clinical significance of the newly identified Krüppel-like factor 4 (KLF4)/MSI2 regulatory pathway. Experimental Design: MSI2 expression and its association with multiple clinicopathologic characteristics in human PDAC specimens were analyzed immunohistochemically. The biologic functions of MSI2 regarding PDAC cell growth, migration, invasion, and metastasis were studied using gain- and loss-of-function assays both in vitro and in vivo. Regulation of MSI2 expression by KLF4 was examined in several cancer cell lines, and the underlying mechanisms were studied using molecular biologic methods. Results: MSI2 expression was markedly increased in both PDAC cell lines and human PDAC specimens, and high MSI2 expression was associated with poor prognosis for PDAC. Forced MSI2 expression promoted PDAC proliferation, migration, and invasion in vitro and growth and metastasis in vivo, whereas knockdown of MSI2 expression did the opposite. Transcriptional inhibition of MSI2 expression by KLF4 occurred in multiple PDAC cell lines as well as mouse models of PDAC. Conclusions: Lost expression of KLF4, a transcriptional repressor of MSI2, results in overexpression of MSI2 in PDACs, which may be a biomarker for accurate prognosis. A dysregulated KLF4/MSI2 signaling pathway promotes PDAC progression and metastasis.

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CYLD downregulates Livin and synergistically improves gemcitabine chemosensitivity and decreases migratory/invasive potential in bladder cancer: the effect is autophagy-associated

Abstract

Although GC (gemcitabine and cisplatin) chemotherapy remains an effective method for treating bladder cancer (BCa), chemoresistance is a major obstacle in chemotherapy. In this study, we determined whether gemcitabine resistance correlates with migratory/invasive potential in BCa and whether this relationship is regulated by the cylindromatosis (CYLD)-Livin module. First, we independently investigated the correlation of CYLD/Livin and gemcitabine resistance with the potential for tumor migration and invasiveness. Second, we found that co-transfected CYLD and Livin dramatically improved sensitivity to gemcitabine chemotherapy and decreased migration/invasion potential. Next, we determined that CYLD may regulate Livin by the NF-κB-dependent pathway. We also found that CYLD overexpression and Livin knockdown might improve gemcitabine chemosensitivity by decreasing autophagy and increasing apoptosis in BCa cells. Finally, the effects of CYLD-Livin on tumor growth in vivo were evaluated. Our study demonstrates that CYLD-Livin might represent a potential therapeutic for chemoresistant BCa.

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4.1N is involved in a flotillin-1/β-catenin/Wnt pathway and suppresses cell proliferation and migration in non-small cell lung cancer cell lines

Abstract

The membrane-cytoskeletal protein 4.1N has recently been proposed as a tumor suppressor in a number of cancers of epithelial origin, including non-small-cell lung cancer (NSCLC). However, the molecular mechanism associated with 4.1N tumor suppression remains has not been thoroughly characterized. In this study, 4.1N was shown to directly interact with the lipid raft marker flotillin-1 through its FERM and U2 domains in several different NSCLC cell lines using immunoprecipitation, co-immunoprecipitation and pull-down assays. Moreover, 4.1N silencing/overexpression experiments in paired 95C/95D cells that are of homologous origin but varying endogenous 4.1N expression (high expression in 95C cells, low expression in 95D cells) indicated that 4.1N is involved in the suppression of cell proliferation and migration through a flotillin-1/β-catenin/Wnt pathway. Taken together, the findings of this study help to elucidate the novel tumor suppressor role of 4.1N in NSCLC.

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Molecular targets of gambogic acid in cancer: recent trends and advancements

Abstract

Natural compounds have been known as biosafety agents for their significant clinical and biological activity against dreadful diseases, including cancer, cardiovascular, and neurodegenerative disorders. Gambogic acid (GA), a naturally occurring xanthone-based moiety, reported from Garcinia hanburyi tree, is known to perform numerous intracellular and extracellular actions, including programmed cell death, autophagy, cell cycle arrest, antiangiogenesis, antimetastatic, and anti-inflammatory activities. In addition, GA-based synergistic approaches have been proven to enhance the healing strength of existing chemotherapeutic agents along with lesser side effects. The present review uncovers the bio-therapeutic potential of gambogic acid along with the possible mechanistic interactions of GA with its recognized cellular targets.

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ZNRF3 is downregulated in papillary thyroid carcinoma and suppresses the proliferation and invasion of papillary thyroid cancer cells

Abstract

Zinc and ring finger 3 (ZNRF3) is a transmembrane E3 ubiquitin ligase that has emerged as an important regulator of cancer development; however, its cancer-related function remains controversial. Here, we investigated the possible role of ZNRF3 in thyroid carcinoma (TC). We found that ZNRF3 is downregulated in papillary thyroid carcinoma (PTC) compared to normal thyroid tissues and inversely correlated with the degree of cell differentiation. Overexpression of ZNRF3 significantly suppressed cell malignant behaviors, including cell proliferation, migration, and invasion in vitro, as well as tumor growth in vivo. Consistent with recent studies showing that ZNRF3 is involved in the Wnt/β-catenin pathway, ZNRF3 overexpression negatively regulated β-catenin activation, modulating PTC cell behaviors. Clinical specimens revealed a significant inverse correlation between ZNRF3 and β-catenin mRNA levels. Taken together, these results provide insight into a potential tumor suppressor role of ZNRF3 in PTC progression, and may have potential clinical relevance for the prognosis and treatment of PTC.

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Erratum to: TMPRSS2:ERG fusion gene occurs less frequently in Chinese patients with prostate cancer

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Silencing of TGIF attenuates the tumorigenicity of A549 cells in vitro and in vivo

Abstract

The aim of this study was to investigate the effects of the silencing of the TG-interacting factor (TGIF) on the tumorigenicity of A549 cells in vitro and in vivo. Stable TGIF-silenced A549 cells were established by infecting shRNA lentiviral particles. Western blotting analysis was used to detect the expression of proteins. Cell cycle was detected by flow cytometry. Soft agar assay and tumor formation assay in nude mice were applied. The silencing of TGIF inhibited A549 cell proliferation, colony formation in vitro, growth of tumor xenograft in vivo, and arrested the cell cycle in the G1 phase. The expression of CDK4, cyclin D1, and phospho-Rb was markedly decreased in the A549-shTGIF cells compared with the A549-shcon cells, and p21 was markedly increased in the A549-shTGIF cells compared with the A549-shcon cells. A lower level of β-Catenin protein expression was observed in the A549-shTGIF cells than that in the A549-shcon cells. The silencing of TGIF attenuates the tumorigenicity of A549 cells in vitro and in vivo.

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The alpha-fetoprotein (AFP) third domain: a search for AFP interaction sites of cell cycle proteins

Abstract

The carboxy-terminal third domain of alpha-fetoprotein (AFP-3D) is known to harbor binding and/or interaction sites for hydrophobic ligands, receptors, and binding proteins. Such reports have established that AFP-3D consists of amino acid (AA) sequence stretches on the AFP polypeptide that engages in protein-to-protein interactions with various ligands and receptors. Using a computer software program specifically designed for such interactions, the present report identified AA sequence fragments on AFP-3D that could potentially interact with a variety of cell cycle proteins. The cell cycle proteins identified were (1) cyclins, (2) cyclin-dependent kinases, (3) cell cycle-associated proteins (inhibitors, checkpoints, initiators), and (4) ubiquitin ligases. Following detection of the AFP-3D to cell cycle protein interaction sites, the computer-derived AFP localization AA sequences were compared and aligned with previously reported hydrophobic ligand and receptor interaction sites on AFP-3D. A literature survey of the association of cell cycle proteins with AFP showed both positive relationships and correlations. Previous reports of experimental AFP-derived peptides effects on various cell cycle proteins served to confirm and verify the present computer cell cycle protein identifications. Cell cycle protein interactions with AFP-CD peptides have been reported in cultured MCF-7 breast cancer cells subjected to mRNA microarray analysis. After 7 days in culture with MCF-7 cells, the AFP-derived peptides were shown to downregulate cyclin E, SKP2, checkpoint suppressors, cyclin-dependent kinases, and ubiquitin ligases that modulate cyclin E/CdK2 transition from the G1 to the S-phase of the cell cycle. Thus, the experimental data on AFP-CD interaction with cell cycle proteins were consistent with the "in silico" findings.

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MiR-541-3p reverses cancer progression by directly targeting TGIF2 in non-small cell lung cancer

Abstract

Lung cancer remains a leading cause of cancer-associated mortality worldwide, and non-small lung cancer (NSCLC) is responsible for over 80 % of lung cancer-related deaths. Identifying novel molecular biomarker that can inhibit the progression of lung cancer will facilitate the development of new treatment strategies. Herein, we demonstrated that miR-541-3p is a tumor-suppressor microRNA (miRNA) in NSCLC progression. We found that expression of miR-541-3p was decreased obviously in NSCLC tissues and plasma. Down-regulation of miR-541-3p was associated with TNM stage and postoperative survival. Overexpression of miR-541-3p inhibited the growth and metastasis of NSCLC cells. The TGIF2 was a direct target of miR-541-3p and promoted the growth and metastasis of NSCLC cells. Further study showed that TGIF2 could reverse the inhibitory effect of miR-541-3p on growth and metastasis of NSCLC cells. Taken together, our data highlight the pivotal role of miR-541-3p in the progression of NSCLC. Thus, miR-541-3p may be a potential prognostic marker and of treatment relevance for NSCLC progression intervention.

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Profiling of mRNA and long non-coding RNA of urothelial cancer in recipients after renal transplantation

Abstract

The molecular mechanism and signal transduction pathways involved in urothelial cancer (UC) after renal transplantation (RTx) remain unknown. In this study, we investigated the profiling of messenger RNA (mRNA) and long non-coding RNA (lncRNA) in RTx recipients with UC. The mRNA and lncRNA of six pairs of UC and corresponding normal urothelial tissues in RTx recipients were profiled using Arraystar Human lncRNA Microarray V3.0, which is designed for the global profiling of 26,109 coding transcripts and 30,586 lncRNAs. Quantitative real-time PCR (qRT-PCR) was used to validate the differentially expressed mRNAs and lncRNAs. Molecular function classification and biological process classification for the differentially expressed mRNAs were analyzed with Gene Ontology. The key pathways that were associated with UC after RTx were analyzed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Compared to normal urothelial tissues, 1597 mRNAs were upregulated and 1032 mRNAs were downregulated in UC; 2107 lncRNAs were upregulated and 1794 lncRNAs were downregulated (greater than twofold). Further qRT-PCR analysis of mRNA and lncRNA expression showed well consistency with the data of microarray analysis. The expression of matrix metalloprotease (MMP)-3, MMP-10, MMP-12, and MMP-13 was significantly increased, while the expression of CD36 was decreased in UC after RTx. Co-expression analysis of lncRNAs and their nearby coding genes showed that lncRNAs may play critical roles in regulating nearby genes in the carcinogenesis of UC. Our results also suggest that peroxisome proliferator-activated receptor (PPAR) signaling may be involved in UC after RTx. Moreover, several cytokines and their receptors were also significantly upregulated in UC after RTx, suggesting that cytokines might be modulated and participated in the carcinogenesis of UC after RTx. We analyzed the potential molecular mechanism and pathways involved in the UC of RTx recipients. Our results revealed that several key regulatory pathways and lncRNAs play critical roles in the carcinogenesis of UC, and suggest that UC in RTx recipients may be more likely to invade and metastasis. However, the detailed functional analysis of these mechanisms should be further performed in the future.

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MiRNAs-mediated cisplatin resistance in breast cancer

Abstract

Cisplatin is a widely used chemotherapeutic agent in breast cancer treatments with inevitable rapidly acquired resistance or intrinsically resistance. Enormous evidence points to the bioprocesses of resistant formation consisting of diverse miRNAs direct and indirect actions on relevant encoding genes. In this report, we overview detailed information on the miRNAs effect on cisplatin-induced resistance, including alterations in cell survival, modification of DNA damage response, changes in cellular uptake or efflux of the drug, altered DNA methylation, and perturbations in the miRNA biogenesis pathway. This will provide potential miRNA-targeted strategies for the treatment of breast cancer therapy and requires further clinical application.

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Highlights from the first International ecancer Conference on Oncology and Radiotherapy, 6–7 May 2016, Santiago, Chile

Leonardo Carmona Reimann and Beatriz Amendola

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Leukemic blasts are present at low levels in spinal fluid in one-third of childhood acute lymphoblastic leukemia cases

Abstract

Background

Central nervous system (CNS) involvement is associated with relapse in childhood acute lymphoblastic leukemia (ALL) and is a diagnostic challenge.

Procedure

In a Nordic/Baltic prospective study, we assessed centralized flow cytometry (FCM) of locally fixed cerebrospinal fluid (CSF) samples versus local conventional cytospin-based cytology (CC) for detecting leukemic cells and evaluating kinetics of elimination of leukemic cells in CSF.

Results

Among 300 patients with newly diagnosed ALL, 87 (29%) had CSF involvement by FCM, while CC was positive in 30 (10%) of 299 patients with available CC data (P < 0.001). Patients with FCM+/CC+ had higher CSF leukemic blast counts compared to patients positive by FCM only (medians: 0.10 vs. 0.017 leukemic blasts/μl, P = 0.006). Patients positive by FCM had higher white blood cell counts in peripheral blood than patients negative by FCM (medians: 45 × 10⁹/l vs. 10 × 10⁹/l, P < 0.001), were younger (medians: 3 years vs. 4 years, P = 0.03), and more frequently had T-cell ALL (18/87 vs. 16/213, P = 0.001). At treatment day 15, five of 52 patients (10%) who had CSF positive by FCM at diagnosis remained so despite at least two doses of weekly intrathecal chemotherapy.

Conclusions

Longer follow-up is needed to clarify whether FCM positivity has prognostic significance and is an indicator for intensified CNS-directed therapy.

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Maintenance therapy of childhood acute lymphoblastic leukemia revisited—Should drug doses be adjusted by white blood cell, neutrophil, or lymphocyte counts?

Abstract

Background

6-Mercaptopurine (6MP) and methotrexate (MTX) based maintenance therapy is a critical phase of childhood acute lymphoblastic leukemia treatment. Wide interindividual variations in drug disposition warrant frequent doses adjustments, but there is a lack of international consensus on dose adjustment guidelines.

Procedure

To identify relapse predictors, we collected 28,255 data sets on drug doses and blood counts (median: 47/patient) and analyzed erythrocyte (Ery) levels of cytotoxic 6MP/MTX metabolites in 9,182 blood samples (median: 14 samples/patient) from 532 children on MTX/6MP maintenance therapy targeted to a white blood cell count (WBC) of 1.5–3.5 × 10⁹/l.

Results

After a median follow-up of 13.8 years for patients in remission, stepwise Cox regression analysis did not find age, average doses of 6MP and MTX, hemoglobin, absolute lymphocyte counts, thrombocyte counts, or Ery levels of 6-thioguanine nucleotides or MTX (including its polyglutamates) to be significant relapse predictors. The parameters significantly associated with risk of relapse (N = 83) were male sex (hazard ratio [HR] 2.0 [1.3–3.1], P = 0.003), WBC at diagnosis (HR = 1.04 per 10 × 10⁹/l rise [1.00–1.09], P = 0.048), the absolute neutrophil count (ANC; HR = 1.7 per 10⁹/l rise [1.3–2.4], P = 0.0007), and Ery thiopurine methyltransferase activity (HR = 2.7 per IU/ml rise [1.1–6.7], P = 0.03). WBC was significantly related to ANC (Spearman correlation coefficient, r_s = 0.77; P < 0.001), and only a borderline significant risk factor for relapse (HR = 1.28 [95% CI: 1.00–1.64], P = 0.046) when ANC was excluded from the Cox model.

Conclusions

This study indicates that a low neutrophil count is likely to be the best hematological target for dose adjustments of maintenance therapy.

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Long-term trajectories of self-reported cognitive function in a cohort of older survivors of breast cancer: CALGB 369901 (Alliance)

BACKGROUND

The number of survivors of breast cancer aged ≥65 years ("older") is growing, but to the authors' knowledge, little is known regarding the cognitive outcomes of these individuals.

METHODS

A cohort of cognitively intact older survivors with nonmetastatic, invasive breast cancer was recruited from 78 sites from 2004 through 2011; approximately 83.7% of the survivors (1280 survivors) completed baseline assessments. Follow-up data were collected at 6 months and annually for up to 7 years (median, 4.1 years). Cognitive function was self-reported using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30); scores ranged from 0 to 100, with a higher score indicating better function. Group-based trajectory modeling determined trajectories; women were assigned to a trajectory group based on the highest predicted probability of membership. Multinomial logistic regression evaluated the association between receipt of chemotherapy (with or without hormonal treatment) and trajectory group.

RESULTS

Survivors were aged 65 to 91 years; approximately 41% received chemotherapy. There were 3 cognitive trajectories: "maintained high" (42.3% of survivors); "phase shift" (50.1% of survivors), with scores slightly below but parallel to maintained high; and "accelerated decline" (7.6% of survivors), with the lowest baseline scores and greatest decline (from 71.7 [standard deviation, 19.8] to 58.3 [standard deviation, 21.9]). The adjusted odds of being in the accelerated decline group (vs the maintained high group) were 2.1 times higher (95% confidence interval, 1.3-3.5) for survivors who received chemotherapy (with or without hormonal therapy) versus those treated with hormonal therapy alone. Greater comorbidity and frailty also were found to be associated with accelerated decline.

CONCLUSIONS

Trajectory group analysis demonstrated that the majority of older survivors maintained good long-term self-reported cognitive function, and that only a small subset who were exposed to chemotherapy manifested accelerated cognitive decline. Future research is needed to determine factors that place some older survivors at risk of experiencing cognitive decline. Cancer 2016. 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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The effect of referral for genetic counseling on genetic testing and surgical prevention in women at high risk for ovarian cancer: Results from a randomized controlled trial

BACKGROUND

Guidelines recommend genetic counseling and testing for women who have a pedigree suggestive of an inherited susceptibility for ovarian cancer. The authors evaluated the effect of referral to genetic counseling on genetic testing and prophylactic oophorectomy in a randomized controlled trial.

METHODS

Data from an electronic mammography reporting system identified 12,919 women with a pedigree that included breast cancer, of whom 625 were identified who had a high risk for inherited susceptibility to ovarian cancer using a risk-assessment questionnaire. Of these, 458 women provided informed consent and were randomized 1:1 to intervention consisting of a genetic counseling referral (n = 228) or standard clinical care (n = 230).

RESULTS

Participants were predominantly aged 45 to 65 years, and 30% and 20% reported a personal history of breast cancer or a family history of ovarian cancer, respectively. Eighty-five percent of women in the intervention group participated in a genetic counseling session. Genetic testing was reported by 74 (33%) and 20 (9%) women in the intervention and control arms (P < .005), respectively. Five women in the intervention arm and 2 in the control arm were identified as germline mutation carriers. Ten women in the intervention arm and 3 in the control arm underwent prophylactic bilateral salpingo-oophorectomy (P < .05).

CONCLUSIONS

Routine referral of women at high risk for ovarian cancer to genetic counseling promotes genetic testing and prophylactic surgery. The findings from the current randomized controlled trial demonstrate the value of implementing strategies that target women at high risk for ovarian cancer to ensure they are offered access to recommended care. CA Cancer J Clin 2016. © 2016 American Cancer Society, Inc.

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Endoscopic ultrasound-guided FNA of pelvic lesions: A Large single-center experience

BACKGROUND

Pelvic endoscopic ultrasound-guided fine-needle aspiration (PEUS-FNA) of rectal or perirectal lesions is safe, minimally invasive, and well tolerated. It provides valuable information, which can greatly influence patient management. Herein, the authors present what to their knowledge is the largest series to date of PEUS-FNA.

METHODS

PEUS-FNA specimens were retrieved from the archives of the study institution from January 2001 to March 2015. Only patients with solid pelvic lesions were examined. The cytopathology findings, immunohistochemistry, corresponding histology, and clinical data were collected. For analysis of accuracy, atypical or suspicious results were classified as "negative." The sensitivity and specificity of PEUS-FNA were calculated in a subset of patients with available surgical pathology.

RESULTS

A total of 127 cases meeting the current study criteria were obtained from patients who underwent PEUS-FNA at the study institution between January 2001 and March 2015. The mean age of the patients was 60 years, and 53% were female. Pelvic lesions were comprised of 72% masses and 28% lymph nodes, with a mean mass diameter of 27.38 mm (range, 5-100 mm). PEUS-FNA was positive for malignancy in 45% of cases, atypical/suspicious in 4.7% of cases, and negative for malignancy in 50.3% of cases. Surgical pathology was available for 44 patients. PEUS-FNA demonstrated 89.3% sensitivity, 100% specificity, a diagnostic accuracy of 93.2%, a positive predictive value of 100%, and a negative predictive value of 84.2%. No complications were noted.

CONCLUSIONS

PEUS-FNA is safe and effective for the investigation of pelvic lesions. Cancer Cytopathol 2016. © 2016 American Cancer Society.

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Incidence and survival time trends for Spanish children and adolescents with leukaemia from 1983 to 2007

Abstract

Objective

We have analysed incidence and survival trends of children and adolescents with leukaemia registered in Spanish population-based cancer registries during the period 1983–2007.

Methods

Childhood and adolescent leukaemia cases were drawn from the 11 Spanish population-based cancer registries. For survival, registries with data for the period 1991–2005 and follow-up until 31-12-2010 were included. Overall incidence trends were evaluated using joinpoint analysis. Observed survival rates were estimated using Kaplan–Meier, and trends were tested using the log-rank test.

Results

Based on 2606 cases (2274 children and 332 adolescents), the overall age-adjusted incidence rate (ASRw) of leukaemia was 47.9 cases per million child-years in children and 23.8 in adolescents. The ASRw of leukaemia increased with an annual percentage change of 9.6 % (95 % CI: 2.2–17.6) until 1990 followed by a stabilisation of rates. In adolescents, incidence did not increase. Five-year survival increased from 66 % in 1991–1995 to 76 % in 2001–2005. By age, survival was dramatically lower in infants (0) and adolescents (15−19) than in the other age groups and no improvement was observed. In both children and adolescents, differences in 5-year survival rates among major subgroups of leukaemias were significant.

Conclusions

The increasing incidence trends observed in childhood leukaemias during the study period were confined to the beginning of the period. Remarkable improvements in survival have been observed in Spanish children with leukaemias. However, this improvement was not observed in infants and adolescents.

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