Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Τρίτη 24 Μαΐου 2016
Effectiveness of a Survivorship Program: An Assessment of Patients With Breast Cancer in a Community Setting [Care Delivery]
Purpose:
This study assesses the effectiveness of a single institution's breast cancer survivorship program on patient perceptions, quality of life (QOL), and compliance with National Comprehensive Cancer Network (NCCN) guidelines for follow-up.
Methods:Sampled patients completed all their breast cancer treatment at a single tertiary center. Surveys designed to evaluate QOL were obtained, and retrospective medical record review was conducted to assess NCCN compliance. Survivorship clinic (SC) attendees and nonattendees were matched for age and disease stage for comparison of the outcomes (QOL, NCCN compliance, and overall effectiveness).
Results:SC patients (n = 63) tended to perceive their concerns in various categories to be addressed more adequately than did nonattendees (n = 54), with significant differences in the areas of practical concerns (P = .03) and late-term adverse effects (P = .03). There was a significant difference in compliance with three NCCN guidelines (history and physical every 3 to 6 months, annual mammography, and a pelvic examination if on tamoxifen) between survivorship attendees and nonattendees (P < .001, P = .02, and P < .001, respectively). Women who attended an SC used other survivorship support resources more often.
Conclusion:Survivorship programs can be time and resource consuming, but our study is one of the first to show that a survivorship program effectively changes patient behavior in important ways. Patients who attended an SC were more likely to be compliant with NCCN-recommended follow-up and to use other survivorship resources and felt their concerns were better addressed. These measures can be used to help us improve our survivorship services and by other institutions to measure the quality and effectiveness of their programs.
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Pathways Clinical Decision Support for Appropriate Use of Key Biomarkers [Care Delivery]
Purpose:
Breast cancer diagnostics have the ability to predict disease recurrence and the benefit of chemotherapy. This study measures the use of a diagnostic assay, Oncotype DX, when embedded in a breast cancer decision support algorithm and, on the basis of the assay results, the use of chemotherapy in the adjuvant setting.
Methods:UPMC CancerCenter retrospectively reviewed patients with estrogen receptor–positive, human epidermal growth factor receptor 2 (HER2)Neu–negative disease with zero to three positive nodes navigated in the Via Pathways decision support portal during a 12-month period. The breast algorithm prompted input of the assay recurrence score (RS) and then recommended hormonal therapy alone (HT) for low RS, or chemotherapy followed by HT for high RS. The patient's RS was correlated with the treatment decision.
Results:During this time period, 643 patients had ER-positive, HER2Neu-negative disease with zero to three positive nodes. Of those, 596 (92.7%) had diagnostic testing to determine chemotherapy plus HT versus HT alone, and 47 had chemotherapy followed by HT without an RS. For node-negative patients classified with low or high RS, pathway treatment adherence rates were 99.7% and 96.6%, respectively; node-positive patients had 95.7% and 87.5% adherence rates, respectively.
Conclusion:This analysis demonstrates the use of a clinical pathway to measure the adoption of a diagnostic test, the Oncotype DX breast assay, and the use of the appropriate therapy on the basis of the RS. As more diagnostics are established to aid in the personalized treatment of diseases, pathways may be important in maintaining clinician awareness of the appropriate disease presentations where these tests should be used, measuring usage of these tests, and tracking the treatment decisions on the basis of test results.
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Lower Patient Ratings of Physician Communication Are Associated With Unmet Need for Symptom Management in Patients With Lung and Colorectal Cancer [Care Delivery]
Purpose:
Little is known about factors associated with unmet needs for symptom management in patients with cancer.
Methods:Patients with a new diagnosis of lung and colorectal cancer from the diverse nationally representative Cancer Care Outcomes Research and Surveillance cohort completed a survey approximately 5 months after diagnosis (N = 5,422). We estimated the prevalence of unmet need for symptom management, defined as patients who report that they wanted help for at least one common symptom (pain, fatigue, depression, nausea/vomiting, cough, dyspnea, diarrhea) during the 4 weeks before the survey but did not receive it. We identified patient factors associated with unmet need by using logistic regression with random effects to account for clustering within study sites.
Results:Overall, 15% (791 of 5,422) of patients had at least one unmet need for symptom management. Adjusting for sociodemographic and clinical factors, African American race, being uninsured or poor, having early-stage lung cancer, and the presence of moderate to severe symptoms were associated with unmet need (all P < .05). Furthermore, patients who rated their physician's communication score < 80 (on a 0 to 100 scale) had adjusted rates of an unmet need for symptom management that were more than twice as high as patients who rated their physicians with a perfect communication score (23.1% v 10.0%; P < .001).
Conclusion:A significant minority of patients with newly diagnosed lung and colorectal cancer report unmet needs for symptom management. Interventions to improve symptom management should consider the importance of physician communication to the patient's experience of disease.
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Cross-Sectional Data That Explore the Relationship Between Outpatients Quality of Life and Preferences for Quality Improvement in Oncology Settings [Focus on Quality]
Purpose:
This cross-sectional study assessed the association between oncology outpatients' quality improvement preferences and health-related quality of life (HRQoL). Implementation of specific initiatives preferred by patients with lower HRQoL may be a strategic approach to enhancing care for potentially vulnerable patients.
Methods:English-speaking adults were recruited from five outpatient chemotherapy clinics located in New South Wales, Australia. Using touch screen devices, participants selected up to 25 initiatives that would improve their experiences and completed the Functional Assessment of Cancer Therapy-General (FACT-G) survey. The logistic odds of selecting an initiative according to FACT-G scores were calculated to determine whether preferences were associated with HRQoL after controlling for potential confounders.
Results:Of the 411 eligible outpatients approached to participate, 263 (64%) completed surveys. Commonly selected initiatives were up-to-date information on treatment and condition progress (19.8%), access to or information on financial assistance (18.3%), and reduced clinic wait times (17.5%). For those with relatively lower FACT-G scores, the adjusted odds of selecting five initiatives illustrated an increasing trend: convenient appointment scheduling systems (+23% [P = .002]), reduced wait times (+15% [P = .01]), information on medical emergencies (+14% [P = .04]), access to or information on financial assistance (+15% [P = .009]), help to maintain daily living activities (+18% [P = .007]).
Conclusion:Two areas of improvement were commonly selected: easily accessible health services and information and support for self-management. Although the results suggest an association between a few quality improvement preferences and HRQoL, a wider spectrum of patient characteristics must be considered when targeting quality improvement to patient subgroups.
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Quality of Patient-Provider Communication Among Cancer Survivors: Findings From a Nationally Representative Sample [Care Delivery]
Purpose:
Although patient-provider communication is an essential component of health care delivery, little is known about the quality of these discussions among patients with cancer.
Methods:Data are from the 2011 Medical Expenditure Panel Survey Experiences with Cancer survey among 1,202 adult cancer survivors. We evaluated discussions with any provider after a cancer diagnosis about: (1) follow-up care; (2) late or long-term treatment effects; (3) lifestyle recommendations, such as diet, exercise, and quitting smoking; and (4) emotional or social needs. Using a response scale ranging from "did not discuss" to "discussed in detail," a summary score was constructed to define communication quality as high, medium, or low. Patient factors associated with the quality of provider discussions were examined using multivariable polytomous logistic regression analyses.
Results:At the time of the survey, approximately one half of the patients (46%) were either within 1 year (24.1%) or between 1 and 5 years (22.0%) of treatment. More than one third of cancer survivors reported that they did not receive detailed communication about follow-up care, and more than one half reported that they did not receive detailed communication regarding late or long-term effects, lifestyle recommendations, or emotional and social needs. Only 24% reported high-quality communication for all four elements, indicating that the vast majority experienced suboptimal communication. In multivariable analysis, survivors reporting a high communication quality with providers included those who were within 1 year of treatment, between the ages of 18 and 64 years, non-Hispanic black or other ethnicity, and married.
Conclusion:Study findings demonstrate gaps in the communication quality experienced by cancer survivors in the United States and help identify survivors for targeted interventions.
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Use of Gene Expression Profiling and Chemotherapy in Early-Stage Breast Cancer: A Study of Linked Electronic Medical Records, Cancer Registry Data, and Genomic Data Across Two Health Care Systems [Care Delivery]
Purpose:
The 21-gene recurrence score (RS) identifies patients with breast cancer who derive little benefit from chemotherapy; it may reduce unwarranted variability in the use of chemotherapy. We tested whether the use of RS seems to guide chemotherapy receipt across different cancer care settings.
Methods:We developed a retrospective cohort of patients with breast cancer by using electronic medical record data from Stanford University (hereafter University) and Palo Alto Medical Foundation (hereafter Community) linked with demographic and staging data from the California Cancer Registry and RS results from the testing laboratory (Genomic Health Inc., Redwood City, CA). Multivariable analysis was performed to identify predictors of RS and chemotherapy use.
Results:In all, 10,125 patients with breast cancer were diagnosed in the University or Community systems from 2005 to 2011; 2,418 (23.9%) met RS guidelines criteria, of whom 15.6% received RS. RS was less often used for patients with involved lymph nodes, higher tumor grade, and age < 40 or ≥ 65 years. Among RS recipients, chemotherapy receipt was associated with a higher score (intermediate v low: odds ratio, 3.66; 95% CI, 1.94 to 6.91). A total of 293 patients (10.6%) received care in both health care systems (hereafter dual use); although receipt of RS was associated with dual use (v University: odds ratio, 1.73; 95% CI, 1.18 to 2.55), there was no difference in use of chemotherapy after RS by health care setting.
Conclusion:Although there was greater use of RS for patients who sought care in more than one health care setting, use of chemotherapy followed RS guidance in University and Community health care systems. These results suggest that precision medicine may help optimize cancer treatment across health care settings.
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Incorporating a 3-dimensional printer into the management of early-stage cervical cancer
We used a 3-dimensional (3D) printer to create anatomical replicas of real lesions and tested its application in cervical cancer. Our study patient decided to undergo radical hysterectomy after seeing her 3D model which was then used to plan and simulate this surgery. Using 3D printers to create patient-specific 3D tumor models may aid cervical cancer patients make treatment decisions. This technology will lead to better surgical and oncological outcomes for cervical cancer patients. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.
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Systemic inflammatory markers as prognostic factors in stage IIA colorectal cancer
Background
The aim of this study was to evaluate systemic inflammatory markers as prognostic factors in patients with stage IIA colorectal cancer.
Methods
Among the patients who underwent curative resection for colorectal cancer at Seoul National University Hospital between 2002 and 2010, 1,035 who were classified as postoperative pathologic stage IIA (T3N0M0) were included. Systemic inflammatory markers, such as the neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (dNLR), platelet-to-lymphocyte ratio (PLR), prognostic nutritional index (PNI), and serum fibrinogen level, were retrospectively reviewed. The patients were divided into two groups according to the cut-off values of the systemic inflammatory markers after receiver operating characteristic (ROC) curve analysis. Survival analysis was performed to identify factors associated with disease-free survival (DFS) and overall survival (OS).
Results
Age, American Society of Anesthesiologists (ASA) score, tumor location, number of harvested lymph nodes, venous invasion, perineural invasion, adjuvant treatment and PNI (HR = 1.534, 95%CI: 1.065–2.211, P = 0.022; HR = 1.915, 95%CI: 1.286–2.852, P = 0.001 for DFS and OS, respectively) were independent significant prognostic factors for both DFS and OS.
Conclusions
PNI can be a prognostic marker in stage IIA colorectal cancer. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.
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Prognosis of T1 synovial sarcoma depends upon surgery by oncologic surgeons
Background
The prognosis of early stage synovial sarcomas is not well-defined since long-term follow-up is lacking in most studies. The optimal use of surgery, radiation, and chemotherapy needs to be clarified for this group.
Methods
From 1994 to 2012, 63 patients were treated for localized synovial sarcoma with T1 (<5 cm) tumors. There were 27 males and 36 females. Mean follow-up was 85 months (range 13–210).
Results
At 10 years, local recurrence-free survival was 82% (95% confidence interval [CI] 67–97%), and distant recurrence-free survival was 95% (95%CI 89–100%). Two patients developed metastases after 10 years. Local recurrence was associated with lack of re-excision and treatment by non-oncologic surgeons. Microscopic residual tumor was found in 43% of re-excised specimens. Metastasis was associated with local recurrence, tumor size ≥3 cm, and treatment by non-oncologic surgeons. Radiation and chemotherapy treatment did not have a significant effect in this patient cohort.
Conclusions
Early stage synovial sarcomas with T1 tumors have a relatively favorable prognosis but the potential for late relapse, and long-term follow-up beyond 10 years is recommended. Re-excision of the tumor bed and definitive treatment by trained oncologic surgeons may decrease the risk of local recurrence and metastasis. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.
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Clinicopathological features of colloid adenocarcinoma of the lung: A report of six cases
Objectives
Colloid adenocarcinoma of the lung (CA) is a rare neoplasm that is associated with abundant mucin, which destroys alveoli. We evaluated the clinicopathological features of CA.
Methods
A total of 4,648 patients underwent surgical resection of primary lung cancer at our institution from 2002 to 2014. We analyzed the clinicopathological features of CA in six (0.13%) of these patients.
Results
All patients were asymptomatic. The median age was 60.5 years. The median tumor size was 2.4 cm. All tumors appeared as solitary solid nodules on computed tomography (CT). Four of the six showed intense 18F-fluorodeoxyglucose positron emission tomography (18F-FDG–PET) accumulation, and the remaining two showed weak 18F-FDG accumulation. All patients underwent lobectomy with systematic lymph node dissection. Histologically, CAs presented with various degrees of a non-mucinous component in addition to abundant mucin. Only one patient with pN2 had recurrence.
Conclusions
On CT, CA appears a solitary solid nodule. Further, FDG–PET findings present various 18F-FDG accumulations. Lobectomy with systematic lymph node dissection is an appropriate procedure in view of lymph node metastasis. Since the definitive diagnosis of CA of the lung is difficult, further immunohistochemical and genetic analyses are needed. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.
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FAK inhibition in mutant KRAS lung adenocarcinoma
Purpose: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide due to limited availability of effective therapeutic options. For instance, there are no effective strategies for NSCLCs that harbor mutant KRAS, the most commonly mutated oncogene in NSCLC. Thus, our purpose was to make progress toward the generation of a novel therapeutic strategy for NSCLC. Experimental Design: we characterized the effects of suppressing focal adhesion kinase (FAK) by RNA interference (RNAi), CRISPR/CAS9 gene editing or pharmacologic approaches in NSCLC cells and in tumor xenografts. In addition, we tested the effects of suppressing FAK in association with ionizing radiations, a standard of care treatment modality. Results: FAK is a critical requirement of mutant KRAS NSCLC cells. With functional experiments, we also found that, in mutant KRAS NSCLC cells, FAK inhibition resulted in persistent DNA damage and susceptibility to exposure to ionizing radiation (IR). Accordingly, administration of IR to FAK null tumor xenografts causes a profound antitumor effect in vivo. Conclusions: FAK is a novel regulator of DNA damage repair in mutant KRAS NSCLC and its pharmacologic inhibition leads to radiosensitizing effects that could be beneficial in cancer therapy. Our results provide a framework for the rationale clinical testing of FAK inhibitors in NSCLC patients.
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CANCER PREVENTION AND INTERCEPTION
At several recent, internationally attended scientific meetings, including the American Association for Cancer Research (AACR)'s "Shaping the Future of Cancer Prevention: A Roadmap for Integrative Cancer Science and Public Health" summit in Leesburg (VA) and the AACR Annual Meeting in New Orleans, the focus on cancer prevention to reduce cancer deaths was extensively discussed with renewed attention and emphasis. Cancer prevention should be actively proposed even to healthy individuals, and not just to individuals with high cancer risk. We discuss evaluation of a high cancer risk versus the relatively low risk for side effects of chemopreventive agents. The concept of cancer interception, which is halting transformed cells from becoming malignant cancers, should be adopted for cancer prevention. Potential prevention/interception actions include: adopting healthy life style and avoiding carcinogens, repressing inflammation and pathological angiogenesis, controlling metabolism, correcting insulin resistance and other metabolic alterations. Current drugs with limited toxicity that can be repurposed to reduce cancer incidence. Aspirin is now being recommended for prevention of colorectal cancer and prevents other neoplasms as well. Metformin and beta blockers could be valuable for reducing pancreatic and breast cancer onset. Based on the evaluation of cancer risk, we here call for personalized approaches for cancer prevention and preventive interception and we envisage a list of measures and potential guidelines for preventive and interceptive strategies to reduce cancer burden. Investment into translational research to bring these approaches into public health policies and in the clinic is urgently needed.
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Biomarkers in HCC Treated With Sorafenib Plus Erlotinib
Purpose: Sorafenib is the current standard therapy for advanced HCC, but validated biomarkers predicting clinical outcomes are lacking. This study aimed to identify biomarkers predicting prognosis and/or response to sorafenib, with or without erlotinib, in HCC patients from the phase 3 SEARCH trial. Experimental Design: 720 patients were randomized to receive oral sorafenib 400 mg BID plus erlotinib 150 mg QD or placebo. Fifteen growth factors relevant to the treatment regimen and/or to HCC were measured in baseline plasma samples. Results: Baseline plasma biomarkers were measured in 494 (69%) patients (sorafenib plus erlotinib, n=243; sorafenib plus placebo, n=251). Treatment arm-independent analyses showed that elevated HGF (HR, 1.687 [high vs low expression]; endpoint multiplicity adjusted [e-adj] P=0.0001) and elevated plasma VEGF-A (HR, 1.386; e-adj P=0..0377) were significantly associated with poor OS in multivariate analyses, and low plasma KIT (HR, 0.75 [high vs low]; P=0.0233; e-adj P=0.2793) tended to correlate with poorer OS. High plasma VEGF-C independently correlated with longer TTP (HR, 0.633; e-adj P=0.0010) and trended toward associating with improved disease control rate (univariate:OR, 2.047; P=0.030; e-adj P=0.420). In 67% of evaluable patients (339/494), a multimarker signature of HGF, VEGF-A, KIT, epigen, and VEGF-C correlated with improved median OS in multivariate analysis (HR, 0.150; P<0.00001). No biomarker predicted efficacy from erlotinib. Conclusions: Baseline plasma HGF, VEGF-A, KIT, and VEGF-C correlated with clinical outcomes in HCC patients treated with sorafenib with or without erlotinib. These biomarkers plus epigen constituted a multimarker signature for improved OS.
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Viroimmunotherapy for Renal Cell Carcinoma
Purpose:In addition to their direct cytopathic effects, oncolytic viruses are capable of priming anti-tumor immune responses. However, strategies to enhance the immunotherapeutic potential of these agents are lacking. Here, we investigated the ability of the multi-tyrosine kinase inhibitor and first-line metastatic renal cell carcinoma (RCC) agent, sunitinib, to augment the anti-tumor immune response generated by oncolytic reovirus. Experimental Design:In vitro, oncolysis and chemokine production were assessed in a panel of human and murine RCC cell lines following exposure to reovirus, sunitinib or their combination. In vivo, the RENCA syngeneic murine model of RCC was employed to determine therapeutic and tumor-specific immune responses following treatment with reovirus (intra-tumoral), sunitinib or their combination. Parallel investigations employing the KLN205 syngeneic murine model of lung squamous cell carcinoma (NSCLC) were conducted for further validation Results:Reovirus mediated oncolysis and chemokine production was observed following RCC infection. Reovirus monotherapy reduced tumor burden and was capable of generating a systemic adaptive anti-tumor immune response evidenced by increased numbers of tumor-specific CD8+ IFN- producing cells. Co-administration of sunitinib with reovirus further reduced tumor burden resulting in improved survival, decreased accumulation of immune suppressor cells and the establishment of protective immunity upon tumor re-challenge. Similar results were observed for KLN205 tumor bearing mice, highlighting the potential broad applicability of this approach. ConclusionsThe ability to repurpose sunitinib for augmentation of reovirus' immunotherapeutic efficacy positions this novel combination therapy as an attractive strategy ready for clinical testing against a range of histologies, including RCC and NSCLC.
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Tyrosine Kinases in Renal Cell Carcinoma
Purpose: Targeted therapies in renal cell carcinoma (RCC) are limited by acquired resistance. Novel therapeutic targets are needed to combat resistance and, ideally, target the unique biology of RCC subtypes. Experimental Design: Tyrosine kinases provide critical oncogenic signaling and their inhibition has significantly impacted cancer care. In order to describe a landscape of tyrosine kinase activity in RCC that could inform novel therapeutic strategies, we performed a mass spectrometry-based system-wide survey of tyrosine phosphorylation in 10 RCC cell lines as well as 15 clear cell and 15 papillary RCC human tumors. To prioritize identified tyrosine kinases for further analysis, a 63 tyrosine kinase inhibitor (TKI) drug screen was performed. Results: Among the cell lines, 28 unique tyrosine phosphosites were identified across 19 kinases and phosphatases including EGFR, MET, JAK2, and FAK in nearly all samples. Multiple FAK TKIs decreased cell viability by at least 50% and inhibited RCC cell line adhesion, invasion, and proliferation. Among the tumors, 49 unique tyrosine phosphosites were identified across 44 kinases and phosphatases. FAK pY576/7 was found in all tumors and many cell lines, while DDR1 pY792/6 was preferentially enriched in the papillary RCC tumors. Both tyrosine kinases are capable of transmitting signals from the extracellular matrix and emerged as novel RCC therapeutic targets. Conclusions: Tyrosine kinase profiling informs novel therapeutic strategies in RCC and highlights the unique biology amongst kidney cancer subtypes.
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Parkinson’s disease and colorectal cancer risk—A nested case control study
Publication date: August 2016
Source:Cancer Epidemiology, Volume 43
Author(s): Ben Boursi, Ronac Mamtani, Kevin Haynes, Yu-Xiao Yang
BackgroundA pro-inflammatory gut microbiota was described in both Parkinson's disease and colorectal cancer (CRC) and recently α-synuclein was demonstrated in the enteric nervous system. We sought to evaluate the association between Parkinson's disease and CRC.MethodsWe conducted a nested case-control study using a large primary-care database. Cases were defined as all individuals with CRC. Up to 4 controls were matched with each case based on age, sex, practice-site and duration of follow-up. The primary exposure of interest was diagnosis of Parkinson's disease prior to CRC as well as disease duration, and Parkinson's specific therapies. The primary analysis was a conditional logistic-regression to estimate odds ratios (ORs) and 95% confidence interval (95%CI).ResultsThe study included 22,093 CRC cases and 85,833 matched controls. Past medical history of Parkinson's disease >1 year before index-date was associated with lower CRC risk (OR 0.74, 95%CI 0.59–0.94). The inverse association was more prominent among females compared to males (0.64, 95%CI 0.42–0.96 and 0.8, 95%CI 0.60–1.07, respectively). While patients who received no therapy or therapy with dopamine agonists had a non-significant decrease in cancer risk, patients who were treated with dopamine had a non-significant elevated cancer risk.ConclusionParkinson's disease is inversely associated with CRC risk.
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Human papillomavirus not detected in esophageal adenocarcinoma tumor specimens-Letter
Publication date: Available online 24 May 2016
Source:Cancer Epidemiology
Author(s): Shanmugarajah Rajendra, Bin Wang
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Physicochemical and structure-activity properties of piroxicam—a mini review
Abstract
The neutral bidentate ligand coordinated to the metal ion through pyridyl-N and carbonyl of the amide moiety causes protonation/deprotonation equilibria (tautomerism) of piroxicam. The penetration of piroxicam through blood–brain barrier (BBB) may be by redox chemical delivery system linking it to the lipophilic dihydropyridine carrier creating a complex with carboxylic acid that transverses the BBB. The complex is enzymatically oxidized to the conic pyridinium salt. Subsequent cleavage of the drug from the pyridinium carrier leads to sustained drug delivery in the brain parenchyma. Brain uptake of piroxicam may be positively correlated with lipid solubility at high doses or negatively correlated with hydrogen bonding or due to damage to meninges.
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UGT1A1 gene polymorphism is associated with toxicity and clinical efficacy of irinotecan-based chemotherapy in patients with advanced colorectal cancer
Abstract
Objectives
To investigate the relationship between uridine diphosphate glucoronosyltransferase 1A1 (UGT1A1)*28/*6 and toxicity and clinical efficacy of irinotecan-based chemotherapy in patients with advanced colorectal cancer (CRC) in Xinjiang Uygur and Han population.
Methods
A total of 183 patients (Uygur, 114; Han, 69) with advanced CRC who received the irinotecan-based chemotherapy were enrolled in this retrospective analysis. Polymerase chain reaction amplification and direct sequencing method were used for UGT1A1*28 and UGT1A1*6 polymorphism detection. The patients were followed up to analyze the relationship between different genotypes with adverse reactions and the clinical outcome of irinotecan-based chemotherapy.
Results
Significant differences were found in genotype frequencies of UGT1A1*28 and UGT1A1*28/*6 between Uygur and Han (P = 0.02 and P = 0.002). Uygur and Han patients carrying wild UGT1A1*28 and *6 genotypes appeared to have significantly lower diarrhea incidence (I/II and III/IV) than those carrying mutant genotypes (all P < 0.05). In Uygur patients, UGT1A1*28 genotypes were related with objective response rate and disease control rate (P < 0.05). Compared with *1 allele *1/*1, *1 allele *1/*28*1/*28 mutant of UGT1A1*28 was associated with shorter OS in both Uygur and Han ethnicities (all P < 0.05). Compared with double allele variants (DW), single allele variants (SV), and double allele variants (DV) of UGT1A1*28/*6 were associated with shorter overall survival (OS) in Uygur and Han (all P < 0.05). Cox regression analysis revealed factors significantly influencing OS, including UGT1A1*28, UGT1A1*6, combined genotypes and chemotherapy line in Ugyur, and only combined genotypes in Han (all P < 0.05).
Conclusion
UGT1A1 gene polymorphism predicts irinotecan-related adverse reactions in advanced CRC patients of Xinjiang Uygur and Han nationality; UGT1A1 gene polymorphism is correlated with efficacy and prognosis in Uygur nationality, but only related to prognosis in Han nationality in irinotecan-based chemotherapy.
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Educational differences in likelihood of attributing breast symptoms to cancer: A vignette-based study
Abstract
Background
Stage at diagnosis of breast cancer varies by socio-economic status (SES), with lower SES associated with poorer survival. We investigated associations between SES (indexed by education), and the likelihood of attributing breast symptoms to breast cancer.
Method
We conducted an online survey with 961 women (47-92 years) with variable educational levels. Two vignettes depicted familiar and unfamiliar breast changes (axillary lump and nipple rash). Without making breast cancer explicit, women were asked 'What do you think this […..] could be?' After the attribution question, women were asked to indicate their level of agreement with a cancer avoidance statement ('I would not want to know if I have breast cancer').
Results
Women were more likely to mention cancer as a possible cause of an axillary lump (64%) compared with nipple rash (30%). In multivariable analysis, low and mid education were independently associated with being less likely to attribute a nipple rash to cancer (OR 0.51, 0.36-0.73 and OR 0.55, 0.40-0.77, respectively). For axillary lump, low education was associated with lower likelihood of mentioning cancer as a possible cause (OR 0.58, 0.41-0.83). Although cancer avoidance was also associated with lower education, the association between education and lower likelihood of making a cancer attribution was independent.
Conclusion
Lower education was associated with lower likelihood of making cancer attributions for both symptoms, also after adjustment for cancer avoidance. Lower likelihood of considering cancer may delay symptomatic presentation and contribute to educational differences in stage at diagnosis.
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P21 and p27 Immunoexpression in Upper Urinary Tract Urothelial Carcinomas
Abstract
p21 and p27 are members of cyclin-dependent kinase family, which function as tumor suppressors and they are involved in development and progression of several malignancies. We investigated their expression in upper urinary tract urothelial carcinoma (UUTUC). Radical nephroureterectomy materials of 34 patients were assessed by immunohistochemistry to evaluate expression of p21 and p27 in UUTUC. Results were correlated with various clinicopathological variables as age, gender, tumor grade and stage, tumor architecture, multifocality, subsequent bladder carcinoma development and clinical outcome.
p21 and p27 expression was observed in 52.9 % (n = 18) and 88.2 % (n = 30), respectively. A total of 21 tumors (61.7 %) showed either total loss of p21 expression (n = 16, 47 %) or lower expression (n = 5, 14.7 %). No correlation was found between p21 expression and clinicopathologic variables. Cases showing total loss or lower p27 expression (11.7 % and <25.6 %, respectively) (n = 19, 55.8 %) constituted 67.6 % (n = 23) of the cases totally. This loss or lower p27 expression correlated with a shorter overall survival in both univariate and multivariate analysis (p = 0.039 and p = 0.037, respectively). None of the noninvasive tumors (papillary and nodular tumors) showed loss of p27 (p = 0.016) while 33.3 % of invasive ones showed p27 loss. Noninvasive tumor architecture also correlated with subsequent bladder carcinoma development (p = 0.032) while invasive tumor architecture correlated with advanced stage (T3 and T4) (p = 0.003). p27 is widely expressed in UUTUC, while p21 expression is observed in half of the cases. Loss of p27 expression correlated with tumor architecture and overall survival in UUTUC. However, further research is needed to assess their role in UUTUC.
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An observational study to examine changes in metabolic syndrome components in patients with breast cancer receiving neoadjuvant or adjuvant chemotherapy
BACKGROUND
The authors sought to determine the effect of chemotherapy on the development of metabolic syndrome (MetS) in premenopausal and postmenopausal women undergoing (neo)adjuvant therapy for early-stage breast cancer.
METHODS
A total of 86 women with early-stage (AJCC stage I-III) breast cancer who were free from clinically diagnosed MetS (defined as 3 of 5 components of MetS) were prospectively tested for the presence of the 5 components of MetS within 1 week before initiating and after completing (neo)adjuvant chemotherapy. The 5 components of MetS measured were waist circumference; blood pressure; and fasting levels of blood glucose, triglycerides, and high-density lipoprotein cholesterol. Anthropometrics (body weight, percentage body fat, fat mass), lipid profile (total cholesterol, low-density lipoprotein cholesterol), glucose metabolism (insulin, homeostatic model assessment of insulin resistance, glycated hemoglobin), and inflammation (C-reactive protein) also were examined before initiating and after completing treatment.
RESULTS
The current study included 46 premenopausal and 40 postmenopausal women. All individual MetS components and the overall MetS score were found to be statistically significantly increased (P<.01) after chemotherapy. Body weight, percentage body fat, fat mass, lipids, glucose metabolism, and inflammation also were found to be statistically significantly increased (P<.01).
CONCLUSIONS
A 12-week to 18-week course of chemotherapy appears to statistically significantly increase MetS and related anthropometrics, biomarkers of glucose metabolism, and inflammation in patients with early-stage breast cancer with no preexisting MetS. Lifestyle interventions such as diet and exercise may be preventive approaches for use during chemotherapy to reduce the onset of MetS in patients with breast cancer. Cancer 2016. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.
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Predicting advanced neoplasia at colonoscopy in a diverse population with the National Cancer Institute colorectal cancer risk-assessment tool
BACKGROUND
Tailoring screening to colorectal cancer (CRC) risk could improve screening effectiveness. Most CRCs arise from advanced neoplasia (AN) that dwells for years. To date, no available colorectal neoplasia risk score has been validated externally in a diverse population. The authors explored whether the National Cancer Institute (NCI) CRC risk-assessment tool, which was developed to predict future CRC risk, could predict current AN prevalence in a diverse population, thereby allowing its use in risk stratification for screening.
METHODS
This was a prospective examination of the relation between predicted 10-year CRC risk and the prevalence of AN, defined as advanced or multiple (≥3 adenomatous, ≥5 serrated) adenomatous or sessile serrated polyps, in individuals undergoing screening colonoscopy.
RESULTS
Among 509 screenees (50% women; median age, 58 years; 61% white, 5% black, 10% Hispanic, and 24% Asian), 58 (11%) had AN. The prevalence of AN increased progressively from 6% in the lowest risk-score quintile to 17% in the highest risk-score quintile (P = .002). Risk-score distributions in individuals with versus without AN differed significantly (median, 1.38 [0.90-1.87] vs 1.02 [0.62-1.57], respectively; P = .003), with substantial overlap. The discriminatory accuracy of the tool was modest, with areas under the curve of 0.61 (95% confidence interval [CI], 0.54-0.69) overall, 0.59 (95% CI, 0.49-0.70) for women, and 0.63 (95% CI, 0.53-0.73) for men. The results did not change substantively when the analysis was restricted to adenomatous lesions or to screening procedures without any additional incidental indication.
CONCLUSIONS
The NCI CRC risk-assessment tool displays modest discriminatory accuracy in predicting AN at screening colonoscopy in a diverse population. This tool may aid shared decision-making in clinical practice. Cancer 2016. © 2016 American Cancer Society.
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Parental preparedness for late effects and long-term quality of life in survivors of childhood cancer
BACKGROUND
Parents of children with cancer desire information regarding the late effects of treatment. In the current study, the authors assessed parents' preparedness for late effects at least 5 years after their child's diagnosis.
METHODS
A cross-sectional survey was conducted of all eligible parents of children with cancer between April 2004 and September 2005 at Dana-Farber/Boston Children's Cancer and Blood Disorders Center within 1 year of diagnosis, and a follow-up questionnaire was administered at least 5 years later.
RESULTS
Approximately 66% of parents of children who were still living, and who were able to be contacted, completed the follow-up questionnaire (91 of 138 parents). Approximately 77% of respondents (70 of 91 respondents) were parents of disease-free survivors and 23% (21 of 91 respondents) were parents of children with recurrent disease. The majority of parents believed they were well prepared for their child's oncology treatment (87%), but fewer felt prepared for future limitations experienced by their children (70%; P = .003 using the McNemar test) or for life after cancer (62%; P<.001). On bivariable analysis among parents of disease-free survivors, parents were more likely to believe themselves to be prepared for future limitations when they also reported that communication with the oncologist helped to address worries regarding the future (odds ratio, 4.50; P = .01). At the time of diagnosis, both parents and physicians underestimated a child's risk of future limitations; 45% of parents and 39% of clinicians predicted future limitations in physical abilities, intelligence, or quality of life, but at the time of the follow-up questionnaire >5 years later, 72% of children experienced limitations in at least 1 domain.
CONCLUSIONS
Parents believe themselves to be less prepared for survivorship than for treatment. High-quality communication may help parents to feel more prepared for life after cancer therapy. Cancer 2016. © 2016 American Cancer Society.
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Second-opinion interpretations of neuroimaging studies by oncologic neuroradiologists can help reduce errors in cancer care
BACKGROUND
The purpose of this study was to investigate the utility and clinical impact of second-opinion interpretations of outside neuroimaging studies by oncologic neuroradiologists at a National Cancer Institute–designated cancer center.
METHODS
We performed a retrospective analysis of initial outside and second-opinion radiology reports from 300 computed tomography and magnetic resonance imaging studies and identified cases with discrepancies between the two reports. An adult neuro-oncologist, pediatric neuro-oncologist, and head and neck surgeon reviewed each pair of discrepant reports based on their area of expertise, patient age, and the type of study performed. The clinicians were blinded to the origin of each report and recorded whether the differences in the reports would have led to a change in patient management and/or disease staging. Histopathologic analysis, clinical assessment, and/or minimum 3-month imaging follow-up served as the reference standards to establish which of the 2 reports was correct.
RESULTS
Among the 283 cases that met our study criteria, there were 55 neuroimaging studies with disagreements (19%) between the initial outside report and second-opinion interpretation. Patient management and/or disease stage would have been altered in 42 of 283 cases (15%) based on report differences as determined by the 2 neuro-oncologists and the surgeon participating in the study. Sufficient follow-up was available in 35 of 42 cases (83%). The second-opinion interpretation was correct 100% of the time (35/35).
CONCLUSION
Second-opinion interpretations of neuroimaging studies by subspecialized oncologic neuroradiologists provide added value by reducing error and optimizing the care of cancer patients. Cancer 2016. © 2016 American Cancer Society.
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PMH 9907: Long-term outcomes of a randomized phase 3 study of short-term bicalutamide hormone therapy and dose-escalated external-beam radiation therapy for localized prostate cancer
BACKGROUND
The role of hormone therapy (HT) with dose-escalated external-beam radiotherapy (DE-EBRT) in the treatment of intermediate-risk prostate cancer (IRPC) remains controversial. The authors report the long-term outcome of a phase 3 study of DE-EBRT with or without HT for patients with localized prostate cancer (LPC).
METHODS
From 1999 to 2006, 252 of an intended 338 patients with LPC were randomized to receive DE-EBRT with or without 5 months of neoadjuvant and concurrent bicalutamide 150 mg once daily. The study was closed early because of contemporary concerns surrounding bicalutamide. The primary outcome was biochemical failure (BF) incidence, and the secondary endpoints were overall survival (OS), local control (LC), and quality of life. The BF and OS rates were estimated using the cumulative incidence function and Kaplan-Meier methods and were compared using the Gray test and the log-rank test.
RESULTS
Eleven patients were excluded the from analysis. Characteristics were well balanced in each treatment arm. Ninety-five percent of patients had IRPC. The prescribed dose increased from 75.6 grays (Gy) in 42 fractions to 78 Gy in 39 fractions over the period. At a median follow-up of 9.1 years, 98 BFs occurred, with no significant effect of HT versus no HT on the BF rate (40% vs 47%; P = .32), the OS rate (82% vs 86%; P = .37), the LC rate (52% vs 48 %; P = .32) or quality of life, in the patients who completed the questionnaires. Dose escalation to 75.6 Gy versus >75.6 Gy reduced the BF rate by 26% (P = .004).
CONCLUSIONS
For patients who predominantly have IRPC, the addition of HT to DE-EBRT did not significantly affect BF, OS, or LC. Bicalutamide appeared to be well tolerated. The conclusions from the study are limited by incomplete recruitment. Cancer 2016. © 2016 American Cancer Society.
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Early impact of Medicare accountable care organizations on cancer surgery outcomes
BACKGROUND
Accountable care organizations (ACOs) were established to improve care and outcomes for beneficiaries requiring highly coordinated, complex care. The objective of this study was to evaluate the association between hospital ACO participation and the outcomes of major surgical oncology procedures.
METHODS
This was a retrospective cohort study of Medicare beneficiaries older than 65 years who were undergoing a major surgical resection for colorectal, bladder, esophageal, kidney, liver, ovarian, pancreatic, lung, or prostate cancer from 2011 through 2013. A difference-in-differences analysis was implemented to compare the postimplementation period (January 2013 through December 2013) with the baseline period (January 2011 through December 2012) to assess the impact of hospital ACO participation on 30-day mortality, complications, readmissions, and length of stay (LOS).
RESULTS
Among 384,519 patients undergoing major cancer surgery at 106 ACO hospitals and 2561 control hospitals, this study found a 30-day mortality rate of 3.4%, a readmission rate of 12.5%, a complication rate of 43.8%, and a prolonged LOS rate of 10.0% in control hospitals and similar rates in ACO hospitals. Secular trends were noted, with reductions in perioperative adverse events in control hospitals between the baseline and postimplementation periods: mortality (percentage-point reduction, 0.1%; P = .19), readmissions (percentage-point reduction, 0.4%; P = .001), complications (percentage-point reduction, 1.0%; P < .001), and prolonged LOS (percentage-point reduction, 1.1%; P < .001). After accounting for these secular trends, this study identified no significant effect of hospital participation in an ACO on the frequency of perioperative outcomes (difference-in-differences estimator P values, .24-.72).
CONCLUSIONS
Early hospital participation in the Medicare Shared Savings Program ACO program was not associated with greater reductions in adverse perioperative outcomes for patients undergoing major cancer surgery in comparison with control hospitals. Cancer 2016. © 2016 American Cancer Society.
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Glycogen synthase kinase-3β antagonizes ROS-induced hepatocellular carcinoma cell death through suppression of the apoptosis signal-regulating kinase 1
Abstract
Glycogen synthase kinase-3β (GSK-3β), a multifunctional kinase, is an important regulator of cancer cell survival. Apoptosis signal-regulating kinase 1 (ASK1) is also a key factor for controlling several cellular events including the cell cycle, senescence, and apoptosis, in response to reactive oxygen species (ROS). The role of GSK-3β regulating the activity and protein level of ASK1 in the cancer cells remains largely unexplored. In this study, we showed that GSK-3β inhibits ROS-induced hepatocellular carcinoma cell death by suppressing ASK1. We first found that ectopic expression of GSK-3β suppressed hydrogen peroxide (H2O2)-induced cell death in HepG2 cells and knockdown of endogenous GSK-3β expression exhibited opposite effects. Moreover, GSK-3β expression clearly inhibited H2O2-induced phosphorylation of ASK1 in HepG2 cells, in association with a decrease in ASK1 protein level. Further exploration revealed that GSK-3β induced ubiquitination and proteasome-dependent degradation of ASK1 via inhibition of ubiquitin-specific protease USP9X. Our results thus suggest that GSK-3β is a key factor involved in ASK1 activation and ROS-induced cell death.
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Cancers, Vol. 8, Pages 53: Letter to the Editor Re: Ogawa, Y. Cancers 2016, 8, 28
We read with interest the recently published paper by Dr. Ogawa "Paradigm Shift in Radiation Biology/Radiation Oncology—Exploitation of the H2O2 Effect" for Radiotherapy Using Low-LET (Linear Energy Transfer) Radiation such as X-rays and High-Energy Electrons".[...]
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Improving outcomes in cancer diagnosis, prevention and control: barriers, facilitators and the need for health literacy in Ibadan Nigeria
Abstract
Background
Cancers constitute a significant public health problem in Nigeria. Breast, cervix and prostate cancers are leading causes of cancer-related deaths. Changing diets, lifestyles, HIV/AIDS and macro-structural factors contribute to cancer morbidity and mortality. Poor health information linking cancer risk to individual behaviors, environmental pollutants and structural barriers undermine prevention/control efforts. Studies suggest increasing health literacy and empowering individuals to take preventive action will improve outcomes and mitigate impact on a weak health system.
Methods
We obtained qualitative data from 80 men, women, and young adults in 11 focus groups to assess beliefs, risk-perceptions, preventive behaviors and perceptions of barriers and facilitators to cancer control in Ibadan, Nigeria and conducted thematic analysis.
Results
Participants demonstrated awareness of cancers and mentioned several risk factors related to individual behaviors and the environment. Nonetheless, myths and misconceptions as well as micro, meso and macro level barriers impede prevention and control efforts.
Conclusion
Developing and implementing comprehensive context-relevant health literacy interventions in community settings are urgently needed. Copyright © 2016 John Wiley & Sons, Ltd.
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Resilience of internal medicine house staff and its association with distress and empathy in an oncology setting
Abstract
Context
Resilience is a beneficial trait for resident physicians who are exposed to adversity through their work with patients. Inpatient hematology–oncology produces vicarious trauma for physicians in training. Physician distress and empathy influence patient care and may be associated with respectively lower and greater levels of resilience.
Methods
We collected measures of resilience (Connor–Davidson Resilience Scale), distress (Impact of Events Scale – Revised), and rotation-specific information (e.g., number of death encounters, death stress, and meaning) at the end of a routine hematology–oncology ward rotation. Empathy (Interpersonal Reactivity Index) was measured both before and after the rotation.
Results
Fifty-six out of 96 residents completed the study with an overall response rate of 58%. Resilience was negatively correlated with distress (r = −0.306, p = 0.023) but not with empathy (r = 0.172, p = 0.204) and nor with change in empathy over the course of the rotation (r = −0.122, p = 0.374). When separated by sex, male resilience was negatively correlated with distress (r = −0.389, p = 0.04), but female resilience was not. Resident distress levels were in a clinically significant (76%) or posttraumatic stress disorder range (17%), and resident empathy decreased during the rotation (p = 0.018). Resilience levels were similar in those who reported that death events were the most stressful experiences of the rotation and those who derived a sense of meaning from working with dying patients.
Conclusions
Resident physicians experienced clinically relevant distress and a decrease in empathy. Resilient resident physicians were less likely to experience distress. This study provides evidence for the salutary effects of resilience on physician distress. Copyright © 2016 John Wiley & Sons, Ltd.
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The use of varenicline to treat nicotine dependence among patients with cancer
Abstract
Background
Continuing to smoke after a cancer diagnosis can adversely influence the prognosis for patients with cancer. However, remarkably few studies have carefully examined the use of first-line FDA-approved medications for nicotine dependence in patients with cancer. This study evaluated the feasibility, safety, and effect on cessation of varenicline for smoking cessation in patients with cancer.
Methods
Data from 132 treatment-seeking smokers who received 12 weeks of open-label varenicline and five brief behavioral counseling sessions were used to evaluate the feasibility, safety, and impact on cessation of varenicline. The effects of abstinence on cognitive function and affect were also explored.
Results
Of 459 patients screened, 306 were eligible for the study (66.7%) and 132 entered treatment (43.1%). Retention was 84.1% over 12 weeks. The rate of biochemically verified abstinence at week 12 was 40.2%. Expected side effects were reported (e.g. sleep problems, nausea), but there were no reports of elevated depressed mood, suicidal thoughts, or cardiovascular events. Abstinence was associated with improved cognitive function and reduced negative affect over time (p < 0.05).
Conclusions
Although many patients with cancer who smoke did not enroll in treatment, the side effect profile of varenicline and its effect on short-term cessation converge with what is seen in the general population. Further, as with the general population, abstinence while taking varenicline may lead to improved cognitive function and reduced negative affect. The present data support the use of varenicline to help patients with cancer to quit smoking. Copyright © 2016 John Wiley & Sons, Ltd.
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The present and the future of the RAS pathway: From function and genomics to inhibition.
The present and the future of the RAS pathway: From function and genomics to inhibition.
Cancer Biol Ther. 2016 May 21;:0
Authors: Gil-Bazo I, Sweet-Cordero A, Vicent S
Abstract
This meeting report summarizes the highlights of the II International Frontiers in Oncology meeting "The present and future of the RAS pathway: from function and genomics to inhibition" (RAS Frontiers) organized by the Center for Applied Medical Research (CIMA; Pamplona, SPAIN), the Clinic of the University of Navarra (CUN; Pamplona, SPAIN) and the Stanford Cancer Institute (SCI; Stanford University, CA, USA) in Pamplona (October 5-7, 2015). The RAS Frontiers meeting gathered together scientists from all over the world and featured the latest advances in the study of the RAS pathway covering aspects from basic research to translational and clinical investigation. Among the topics presented were novel mouse models that recapitulate human carcinogenesis and serve as preclinical platforms for drug testing, cutting-edge approaches for the identification of novel vulnerabilities and regulators of the RAS pathway, as well as current inhibitory strategies for the treatment of human RAS-driven cancers.
PMID: 27212457 [PubMed - as supplied by publisher]
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The 5q deletion size in myeloid malignancies is correlated to additional chromosomal aberrations and to TP53 mutations
Abstract
Deletions in the long arm of chromosome 5 (del(5q)) are recurrent abnormalities in myeloid malignancies. We analyzed del(5q) and accompanying molecular mutations in MDS, MPN and MDS/MPN cases. A high del(5q) frequency was revealed in MDS (1869/11398 cases; 16%), followed by MDS/MPN (37/1107; 3%) and MPN (97/6373; 2%). To investigate potential associations of the del(5q) size with the respective phenotypes, we applied array CGH analyses in selected cohorts of 61 MDS, 22 MDS/MPN and 23 MPN cases. The size varied between 16-119 Mb with no differences between the entities. However, MPN and MDS/MPN cases with del(5q) sole showed a significantly smaller del(5q) than cases with additional aberrations. Sequence analyses of 27 genes revealed ≥1 mutation in 91% of patients. The highest mutation frequencies in the total cohort were observed for TP53 (31%), JAK2 (23%) and DNMT3A (18%). The molecular mutation patterns in the del(5q) cohorts were different between the entities but resembled known patterns of cohorts not selected for del(5q). Further, TP53 mutations were significantly more frequent in cases with a larger deletion size (p=0.003). The results suggest a correlation of large del(5q) with TP53 mutations and with additional chromosomal aberrations possibly contributing to more severe courses of these cases. This article is protected by copyright. All rights reserved.
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Cytogenetic and Molecular Profile of Endometrial Stromal Sarcoma
Abstract
Recent cytogenetic and molecular investigations have improved our understanding of endometrial stromal tumors, including sarcomas (ESS), and helped redefine their classification into more pathogenetically meaningful categories. Since much more can be gained through such studies, we add information on another 22 ESS examined by karyotyping, PCR analysis, expression array analysis, and transcriptome sequencing. In spite of the known preference for certain pathogenetic pathways, we found considerable genetic heterogeneity in high-grade (HG) as well as in low-grade (LG) ESS. Not all HG tumors showed a YWHAE-NUTM chimeric transcript and as many as six LGESS showed no hitherto known ESS-related fusions. Among the transcripts identified by transcriptome sequencing and verified by Sanger sequencing, new variants of ZC3H7-BCOR and its reciprocal BCOR-ZC3H7 were identified as was involvement of the CREBBP and MLLT4 genes (both well known leukemia-related genes) in two new fusions. FISH analysis identified a known EPC1-PHF1 fusion which led to the identification of a new variant at the molecular level. The fact that around 70 genes were found differentially expressed, by microarray analysis, when comparing LGESS showing ESS-related fusions with LGESS without such transcripts, underscores the biochemical importance of the observed genetic heterogeneity and hints that new subgroups/entities in LGESS still remain undiscovered. This article is protected by copyright. All rights reserved.
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Copy Number Changes of Clinically Actionable Genes in Melanoma, Non-Small Cell Lung Cancer and Colorectal Cancer – A Survey Across 822 Routine Diagnostic Cases
Abstract
Targeted deep massive parallel sequencing has been implemented in routine molecular diagnostics for high-throughput genetic profiling of formalin-fixed paraffin-embedded (FFPE) cancer samples. This approach is widely used to interrogate simple somatic mutations but experience with the analysis of copy number variations (CNV) is limited. Here, we retrospectively analyzed CNV in 822 cancer cases (135 melanoma, 468 non-small cell lung cancers (NSCLC), 219 colorectal cancers (CRC)). We observed a decreasing frequency of CNV in clinically actionable genes from melanoma to NSCLC to CRC. The overall cohort displayed 168 (20%) amplifications in 17 druggable targets. The majority of BRAF mutant melanomas (57%) showed co-occurring CNV in other genes, mainly affecting CDKN2A. Subsets showed clustered deletions in ABL1, NOTCH1, RET or STK11, GNA11, and JAK3. Most NRAS mutant melanomas (77%) harbored CNVs in other genes with CDKN2A and FGFR3 being most frequently affected. Five BRAF/NRASwt tumors had co-amplifications of KDR, KIT, PDGFRA and another six mutated KIT. Among NSCLC, we identified 14 EGFRamp (with ten EGFRmut) and eight KRASamp (with seven KRASmut). KRASmut tumors displayed frequent amplifications of MYC (n=10) and MDM2 (n=5). Fifteen KRAS/EGFR/BRAFwt tumors had MET mutations/amplifications. In CRC, amplified IGF2 was most prevalent (n=13) followed by MYC (n=9). Two cases showed amplified KRAS wildtype alleles. Five KRAS mutant tumors showed either amplifications of NRAS (n=2) or EGFR (n=3). In conclusion we demonstrate that our approach i) facilitates detection of CNV, ii) enables detection of known CNV patterns, and iii) uncovers new CNV of clinically actionable genes in FFPE tissue samples across cancers. This article is protected by copyright. All rights reserved.
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Secondary EWSR1 Gene Abnormalities in SMARCB1-Deficient Tumors with 22q11-12 Regional Deletions: Potential Pitfalls in Interpreting EWSR1 FISH Results
ABSTRACT
SMARCB1 inactivation occurs in a variety of tumors, being caused by various genetic mechanisms. Since SMARCB1 and EWSR1 genes are located close to each other on at the chromosome 22, larger SMARCB1 deletions may encompass the EWSR1 locus. Herein, we report four cases with SMARCB1-deletions showing concurrent EWSR1 gene abnormalities by FISH, which lead initially to misinterpretations as EWSR1-rearranged tumors. Our study group included various morphologies: a poorly differentiated chordoma, an extrarenal rhabdoid tumor, a myoepithelial carcinoma, and a proximal-type epithelioid sarcoma. All cases showed loss of SMARCB1 (INI1) by immunohistochemistry and displayed characteristic histologic features for the diagnoses. The SMARCB1 FISH revealed homozygous or heterozygous deletions in three and one case, respectively. The co-hybridized EWSR1 probes demonstrated either unbalanced split signals or heterozygous deletion in two cases each. The former suggested bona fide rearrangement, while the latter resembled an unbalanced translocation. However, all the FISH patterns were quite complex and distinct from the simple and uniform split signals seen in typical EWSR1 rearrangements. We conclude that in the context of 22q11-12 regional alterations present in SMARCB1-deleted tumors, simultaneous EWSR1 involvement may be misinterpreted as equivalent to EWSR1 rearrangement. A detailed clinicopathologic correlation and supplementing the EWSR1 FISH assay with complementary methodology is mandatory for correct diagnosis. This article is protected by copyright. All rights reserved.
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ADCs with potent DNA alkylating agents
The promise of tumor-selective delivery of cytotoxic agents in the form of antibody-drug conjugates (ADCs) has now been realized, evidenced by the approval of two ADCs, both of which incorporate highly cytotoxic tubulin-interacting agents, for cancer therapy. An ongoing challenge remains in identifying potent agents with alternative mechanisms of cell killing that can provide ADCs with high therapeutic indices and favorable tolerability. Here we describe the development of a new class of potent DNA alkylating agents that meets these objectives. Through chemical design, we changed the mechanism of action of our novel DNA crosslinking agent to a mono-functional DNA alkylator. This modification, coupled with linker optimization, generated ADCs that were well tolerated in mice and demonstrated robust antitumor activity in multiple tumor models at doses 1.5 - 3.5% of maximally tolerated levels. These properties underscore the considerable potential of these purpose-created, unique DNA-interacting conjugates for broadening the clinical application of ADC technology.
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Suppression of pancreatic cancer by miR-192
Pancreatic ductal adenocarcinoma (PDAC) is characterized by very early metastasis, suggesting the hypothesis that metastasis-associated changes may occur prior to actual tumor formation. In this study, we identified miR-192 as an epigenetically regulated suppressor gene with predictive value in this disease. miR-192 was downregulated by promoter methylation in both PDAC and chronic pancreatitis (CP), the latter of which is a major risk factor for development of PDAC. Functional studies in vitro and in vivo in mouse models of PDAC showed that overexpression of miR-192 was sufficient to reduce cell proliferation and invasion. Mechanistic analyses correlated changes in miR-192 promoter methylation and expression with epithelial-mesenchymal transition (EMT). Cell proliferation and invasion were linked to altered expression of the miR-192 target gene SERPINE1 that is encoding the protein plasminogen activator inhibitor-1 (PAI-1), an established regulator of these properties in PDAC cells. Notably, our data suggested that invasive capacity was altered even before neoplastic transformation occurred, as triggered by miR-192 downregulation. Overall, our results highlighted a role for miR-192 in explaining the early metastatic behavior of PDAC and suggested its relevance as a target to develop for early diagnostics and therapy.
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STAT3/IRF1 sensitizes cervical cancer for chemotherapy
Neoadjuvant radio/chemotherapy regimens can markedly improve cervical cancer outcome in a subset of patients, while other patients show poor responses but may encounter severe adverse effects. Thus, there is a strong need for predictive biomarkers to improve clinical management of cervical cancer patients. STAT3 is considered as a critical anti-apoptotic factor in various malignancies. We therefore investigated STAT3 activation during cervical carcinogenesis and its impact on the response of cervical cancer cells to chemotherapeutic drugs. Tyr705-phosphorylated STAT3 increased from low-grade cervical intraepithelial neoplasia (CIN1) to pre-cancerous CIN3 lesions. Notably, pTyr705-STAT3 activation significantly declined from CIN3 to invasive cancer, also when compared in the same clinical biopsy. pTyr705-STAT3 was also low or absent in cultured human cervical cancer cell lines consistent with the in vivo expression data. Unexpectedly, IL-6-type cytokine signaling inducing STAT3 activation rendered cervical cancer cells significantly more susceptible to chemotherapeutic drugs, i.e. cisplatin or etoposide. This chemosensitization was STAT3-dependent and we identified interferon regulatory factor-1 (IRF1) as the STAT3-inducible mediator required for cell death enhancement. In line with these data, pTyr705-STAT3 significantly correlated with nuclear IRF1 expression in cervical cancer in vivo. Importantly, high IRF1 expression in pre-treatment cervical cancer biopsy cells was associated with a significantly better response to neoadjuvant radio/chemotherapy of the patients. In summary, our study has identified a key role of the STAT3/IRF1 pathway for chemosensitization in cervical cancer. Our results suggest that pre-therapeutic IRF1 expression should be evaluated as a novel predictive biomarker for neoadjuvant radio/chemotherapy responses.
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RhoGAPs can act as Oncogenes in Basal-like Breast Cancer
The basal-like breast cancer (BLBC) subtype accounts for a disproportionately high percentage of overall breast cancer mortality. The current therapeutic options for BLBC need improvement; hence, elucidating signaling pathways that drive BLBC growth may identify novel targets for the development of effective therapies. Rho GTPases have previously been implicated in promoting tumor cell proliferation and metastasis. These proteins are inactivated by Rho-selective GTPase-activating proteins (RhoGAPs), which have generally been presumed to act as tumor suppressors. Surprisingly, RNA-Seq analysis of the Rho GTPase signaling transcriptome revealed high expression of several RhoGAP genes in BLBC tumors, raising the possibility that these genes may be oncogenic. To evaluate this, we examined the roles of two of these RhoGAPs, ArhGAP11A (also known as MP-GAP) and RacGAP1 (also known as MgcRacGAP), in promoting BLBC. Both proteins were highly expressed in human BLBC cell lines, and knockdown of either gene resulted in significant defects in the proliferation of these cells. Knockdown of ArhGAP11A caused CDKN1B/p27-mediated arrest in the G1 phase of the cell cycle, whereas depletion of RacGAP1 inhibited growth through the combined effects of cytokinesis failure, CDKN1A/p21-mediated RB1 inhibition, and the onset of senescence. Random migration was suppressed or enhanced by the knockdown of ArhGAP11A or RacGAP1, respectively. Cell spreading and levels of GTP-bound RhoA were increased upon depletion of either GAP. We have established that, via the suppression of RhoA, ArhGAP11A and RacGAP1 are both critical drivers of BLBC growth, and propose that RhoGAPs can act as oncogenes in cancer.
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T cell clonotype change with sipuleucel-T treatment
Sipuleucel-T is an autologous cellular therapy for asymptomatic, or minimally symptomatic, metastatic castrate-resistant prostate cancer, designed to stimulate an immune response against prostate cancer. In a recent clinical trial (NCT00715104), we found that neoadjuvant sipuleucel-T increased the number of activated T cells within the tumor microenvironment. The current analysis examined whether sipuleucel-T altered adaptive T cell responses by expanding pre-existing T cells or by recruiting new T cells to prostate tissue. Next-generation sequencing of the T cell receptor (TCR) genes from blood or prostate tissue was used to quantitate and track T cell clonotypes in these treated subjects with prostate cancer. At baseline, there was a significantly greater diversity of circulating TCR sequences in subjects with prostate cancer compared with healthy donors. Among healthy donors, circulating TCR sequence diversity remained unchanged over the same time interval. In contrast, sipuleucel-T treatment reduced circulating TCR sequence diversity versus baseline as measured by the Shannon index. Interestingly, sipuleucel-T treatment resulted in greater TCR sequence diversity in resected prostate tissue in sipuleucel-T-treated subjects versus tissue of non-sipuleucel-T-treated subjects with prostate cancer. Furthermore, sipuleucel-T increased TCR sequence commonality between blood and resected prostate tissue in treated versus untreated subjects with prostate cancer. The broadening of the TCR repertoire within the prostate tissue supports the hypothesis that sipuleucel-T treatment facilitates the recruitment of T cells into the prostate. Our results highlight the importance of assessing T cell response to immunotherapy both in the periphery and in tumor tissue.
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