Salvage Treatment of Adrenocortical Carcinoma with Trofosfamide

Abstract

Adrenocortical carcinoma (ACC) has a dismal prognosis in advanced stages. Despite treatment with the adrenal toxicant mitotane and/or aggressive chemotherapy, tumor control is often short-lived. Here, we examine trofosfamide as a salvage treatment of ACC in an observational cohort study within the German ACC registry. Response defined as progression-free survival (PFS) at first tumor evaluation was assessed by RECIST 1.1 or clinically, and PFS and overall survival (OS) were estimated by the Kaplan-Meier method. Twenty-seven patients (11 males; median age 46.9 years) progressing after mitotane and three (median, range 0–5) other systemic treatments were evaluated for safety. Trofosfamide (150 mg/day) was administered as monotherapy (n = 13) or in combination with mitotane (n = 14). Overall tolerability was good with only mild adverse events. Six patients did not meet criteria for response assessment. Of the 21 patients, 8 patients had clinically progressive disease (3 deaths from ACC); among the 13 patients evaluable by RECIST 1.1, best response to treatment was stable disease (SD, n = 3) or progressive disease (n = 10). Hence, predefined response criteria were met in 3/21 patients (14 %). Median PFS was 84 days (95 % confidence interval 74–95) and median OS survival 198 days (95 % CI 89–307). One prolonged disease stabilization (best response by RECIST 1.1 −26 %) was observed for 479 days. In conclusion, trofosfamide is overall well tolerated but disease stabilization is rather rare. Accordingly, it may be used in selected cases of ACC not amenable to other treatment options such as clinical trials.

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CUDC-101, a Novel Inhibitor of Full-Length Androgen Receptor (flAR) and Androgen Receptor Variant 7 (AR-V7) Activity: Mechanism of Action and In Vivo Efficacy

Abstract

Castration-resistant prostate cancer (CRPC) is an androgen receptor (AR)-dependent disease expected to cause the death of more than 27,000 Americans in 2015. There are only a few available treatments for CRPC, making the discovery of new drugs an urgent need. We report that CUDC-101 (an inhibitor od HER2/NEU, EGFR and HDAC) inhibits both the full length AR (flAR) and the AR variant AR-V7. This observation prompted experiments to discover which of the known activities of CUDC-101 is responsible for the inhibition of flAR/AR-V7 signaling. We used pharmacologic and genetic approaches, and found that the effect of CUDC-101 on flAR and AR-V7 was duplicated only by other HDAC inhibitors, or by silencing the HDAC isoforms HDAC5 and HDAC10. We observed that CUDC-101 treatment or AR-V7 silencing by RNAi equally reduced transcription of the AR-V7 target gene, PSA, without affecting viability of 22Rv1 cells. However, when cellular proliferation was used as an end point, CUDC-101 was more effective than AR-V7 silencing, raising the prospect that CUDC-101 has additional targets beside AR-V7. In support of this, we found that CUDC-101 increased the expression of the cyclin-dependent kinase inhibitor p21, and decreased that of the oncogene HER2/NEU. To determine if CUDC-101 reduces growth in a xenograft model of prostate cancer, this drug was given for 14 days to castrated male SCID mice inoculated with 22Rv1 cells. Compared to vehicle, CUDC-101 reduced xenograft growth in a statistically significant way, and without macroscopic side effects. These studies demonstrate that CUDC-101 inhibits wtAR and AR-V7 activity and growth of 22Rv1 cells in vitro and in vivo. These effects result from the ability of CUDC-101 to target not only HDAC signaling, which was associated with decreased flAR and AR-V7 activity, but multiple additional oncogenic pathways. These observations raise the possibility that treatment of CRPC may be achieved by using similarly multi-targeted approaches.

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Identification of Key Gaps in Cancer Survivorship Research: Findings From the American Society of Clinical Oncology Survey [Editorials]

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ReCAP: Cost Differential of Chemotherapy for Solid Tumors [BUSINESS OF ONCOLOGY]

QUESTION ASKED:

The objective of the present study is to determine the cost differentials between chemotherapeutic regimens (of similar or acceptable effectiveness) for common solid tumors in the metastatic and adjuvant settings.

SUMMARY ANSWER:

Of the 62 regimens included, the 6-month mean cost of chemotherapy was $26,989, and the median cost was $9,611. Mean cost of metastatic cancer therapy regimens was $35,315 compared with $18,107 for curative therapy. Regimens using biologics had higher mean costs than regimens not using biologics ($77,278 v $13,646). Cost differential between extremes of costs for regimens with presumed similar efficacy was $90,843; $79,165 in the curative therapy arms and $90,210 in the metastatic cancer therapy arms. The highest cost differential was noted in breast cancer regimens ($71,041 for metastatic v $63,926 for curative).

METHODS:

Chemotherapy regimens—curative (adjuvant/neoadjuvant) and metastatic—and dosages outlined in National Comprehensive Cancer Network guidelines (2013) were acquired for four common cancers: bladder, breast, colon, and lung. Baseline drug and treatment costs were calculated for the average US adult male using the payment allowance for Medicare part B drugs database (2013). Costs were extrapolated for a treatment period of 6 months.

BIAS, CONFOUNDING FACTOR(S), DRAWBACKS:

The calculations used payer perspective for the drug and the reimbursement, which may not truly reflect the actual costs incurred by the individual or society. However, the simplicity provides the strength of inferences which are fairly robust across the sensitivity analysis.

REAL-LIFE IMPLICATIONS:

A significant cost differential exists between chemotherapeutic regimens for the commonest solid tumors. In the absence of existing cost-effectiveness guidelines, cost differentials can help practicing oncologists in financially sound decision making regarding choosing therapy. Incorporation of costs and incremental effectiveness in currently established guidelines may encourage socially responsible practice patterns.

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The Promise and Burden of Peer Review in Radiation Oncology [Editorials]

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Using Quality Improvement Methods and Time-Driven Activity-Based Costing to Improve Value-Based Cancer Care Delivery at a Cancer Genetics Clinic [Quality in Action]

Purpose:

To meet increasing demand for cancer genetic testing and improve value-based cancer care delivery, National Cancer Centre Singapore restructured the Cancer Genetics Service in 2014. Care delivery processes were redesigned. We sought to improve access by increasing the clinic capacity of the Cancer Genetics Service by 100% within 1 year without increasing direct personnel costs.

Methods:

Process mapping and plan-do-study-act (PDSA) cycles were used in a quality improvement project for the Cancer Genetics Service clinic. The impact of interventions was evaluated by tracking the weekly number of patient consultations and access times for appointments between April 2014 and May 2015. The cost impact of implemented process changes was calculated using the time-driven activity-based costing method.

Results:

Our study completed two PDSA cycles. An important outcome was achieved after the first cycle: The inclusion of a genetic counselor increased clinic capacity by 350%. The number of patients seen per week increased from two in April 2014 (range, zero to four patients) to seven in November 2014 (range, four to 10 patients). Our second PDSA cycle showed that manual preappointment reminder calls reduced the variation in the nonattendance rate and contributed to a further increase in patients seen per week to 10 in May 2015 (range, seven to 13 patients). There was a concomitant decrease in costs of the patient care cycle by 18% after both PDSA cycles.

Conclusion:

This study shows how quality improvement methods can be combined with time-driven activity-based costing to increase value. In this paper, we demonstrate how we improved access while reducing costs of care delivery.

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Pharmaceutical Industry Influence on Duplicate Abstracts at National Oncology and Hematology Meetings [Editorials]

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ReCAP: Physician Experience and Attitudes Toward Addressing the Cost of Cancer Care [CARE DELIVERY]

QUESTION ASKED:

Because the cost of oncologic care is perpetually rising, we wanted to know how often physicians who treat cancer discuss the cost of care (both out-of-pocket and societal) with their patients, what the nature of those discussions is, and whether such discussions affect treatment decisions.

SUMMARY ANSWER:

Sixty percent of responding physicians reported addressing costs frequently or always in clinic, 40% addressed costs rarely or never, and 36% did not believe it is the doctor's responsibility to explain costs of care to patients. Additional responses are listed in Table 3. The majority of physicians feel their patients are not well informed about costs. "I don't know enough/lack of resources" is the largest reported barrier to cost discussions, and those who reported frequent discussions were significantly more likely to explain costs and to prioritize treatments in terms of cost.

Table 3.

Physician Attitudes Toward Out-of-Pocket Costs Versus Societal Costs

Question or Statement% Response by Attitude Strongly AgreeAgreeNeither Agree nor DisagreeDisagreeStrongly DisagreeDoctors should explain to patients the costs the patient will have to pay for his or her cancer treatment.123221288Doctors should explain to patients the costs society will have to pay for the patient's treatment.517333411When choosing a new treatment, doctors should consider the costs to the patient.15601572When choosing a new treatment, doctors should consider the costs to the insurance company or government.94419216I feel prepared to discuss cost effectiveness of treatments I recommend.113521268I have easy access to quality resources which assist me in cost discussions with my patients.818203916Society should only pay for treatments that improve survival, not those that only improve response or disease control.410154130If two treatments are the same, the doctor should prescribe the cheaper medicine.29501470Every US patient should have access to effective cancer treatments regardless of their cost.244415125The FDA should consider cost effectiveness of the treatment before issuing an approval.203621177METHODS:

A 15-question, study-specific, self-administered anonymous survey was sent electronically to a randomly selected sample of 2,290 ASCO physician members.

BIAS, CONFOUNDING FACTOR(S), DRAWBACKS:

Our overall response rate was somewhat low at 15%, with an adjusted response rate of 25% after adjusting for nonpracticing physician ASCO members. This increased the potential for selection bias, by which the respondents to this survey may not represent the true beliefs and practices of medical, radiation, and surgical oncologists.

REAL-LIFE IMPLICATIONS:

Our study offers a current snapshot of the frequency, nature, and attitudes toward cost discussions among medical, radiation, and surgical oncologists and their patients. Although the majority of responding physicians seem to agree that such discussions are legitimate—and arguably necessary—components of quality cancer care, there remains a substantial proportion who do not discuss costs nor feel it is their duty. Few believe they have adequate resources to discuss costs, suggesting that greater cost transparency, education concerning costs of care, tools to facilitate discussions, and validated interventions are needed.

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Data Sharing to Support the Cancer Journey in the Digital Era [Editorials]

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ReCAP: Oncologists Selection of Genetic and Molecular Testing in the Evolving Landscape of Stage II Colorectal Cancer [FOCUS ON QUALITY]

CONTEXT AND QUESTION ASKED:

Genetic testing can be used in the diagnosis of Lynch syndrome, formerly known as hereditary nonpolyposis colorectal cancer (CRC), the most common inherited disorder that increases the risk for CRC; however, test results related to Lynch syndrome screening may also be used for predictive and prognostic purposes in patients with stage II CRC. Although national guidelines recommend the use of several genetic and molecular tests for patients with CRC, little is known about how guidelines, particularly the complex testing recommendations for Lynch syndrome, are translated into clinical practice. In this study, we asked: how does the family history of patients with stage II CRC influence medical oncologists' selection of genetic and molecular testing, both related and unrelated to Lynch syndrome?

SUMMARY ANSWER:

We found that oncologists' self-reported ordering of Lynch syndrome–related tests was strongly associated with the strength of CRC family history, but even so, not all oncologists would order germline testing for mismatch repair (MMR) genes, much less screen for Lynch syndrome by ordering microsatellite instability and/or immunohistochemistry for MMR proteins, in a patient scenario with the strongest family history of CRC (Table 2). We also found overtesting of KRAS and Oncotype DX for stage II CRC associated with certain practice and provider characteristics, with graduates of non-US or non-Canadian medical schools and physicians compensated under fee-for-service or by productivity-based salaries being more likely to choose KRAS testing. Fee-for-service and productivity-based salaries were also associated with increased Oncotype DX testing.

Table 2.

Percentages of Oncologists Who Reported They Would Order Genetic and Molecular Testing for a Patient Newly Diagnosed With Stage II CRC, Unadjusted

TestOverall, No. (%)Clinical Scenario*No Family History, % (n = 109)Weak Family History,% (n = 103)Strong Family History, % (n = 109)PIndividual Germline143 (45)163287< .001 MSI and/or IHC for MMR proteins205 (64)535882< .001 BRAF44 (14)81024.001 Oncotype DX120 (38)373839.97 KRAS75 (24)202427.51Combinations BRAF and MSI and/or IHC for MMR proteins32 (10)4720< .001 Germline and MSI and/or IHC for MMR proteins124 (39)152677< .001 Germline and BRAF30 (10)1524< .001 Oncotype DX and MSI and/or IHC for MMR proteins87 (28)222635.11 KRAS and BRAF35 (11)7918.04

Abbreviations: IHC, immunohistochemistry; MMR, mismatch repair; MSI, microsatellite instability.

*

Maximum number of respondents for each scenario.

METHODS:

In 2012 and 2013, we surveyed medical oncologists in the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS) and evaluated their selection of microsatellite instability and/or immunohistorchemistry for MMR proteins, germline testing for MMR genes, BRAF and KRAS mutation analysis, and Oncotype DX in stage II CRC. Physicians were randomly assigned to receive one of three vignettes, varying by strength of CRC family history. We compared differences in testing by family history and provider and practice characteristics, and we used multivariate logistic regression to identify provider and practice characteristics associated with testing.

BIAS, CONFOUNDING FACTOR(S), DRAWBACKS:

Although we surveyed a large cohort of oncologists from diverse geographic and practice settings, there were several limitations to this study. Whereas CanCORS patients are representative of the national patient population, participants were mostly oncologists who care for patients enrolled in CanCORS and who may be slightly older than US oncologists as a whole. Furthermore, our measures of testing relied on physician self-reporting rather than direct measures of use. In addition, we did not ask oncologists to report on the sequence in which they would order the various tests, and we were unable to determine whether such respondents would have ordered simultaneous or sequential testing. Finally, our study focused on patients with stage II CRC and may not be further generalizable.

REAL-LIFE IMPLICATIONS:

The high lifetime risk of CRC and other cancers among affected individuals and family members and low detection rates led the Centers for Disease Control and Prevention to recommend universal Lynch syndrome screening of all patients newly diagnosed with CRC. Previous efforts to increase the identification of patients and family members with Lynch syndrome have unfortunately achieved limited success. It remains to be seen whether the recapitulation by the National Comprehensive Cancer Network of the Centers for Disease Control and Prevention recommendation to screen all incident CRC specimens for Lynch syndrome can increase diagnoses. Undertesting related to Lynch syndrome screening and overtesting involving molecular tests among surveyed oncologists highlight the need for improved implementation, targeted education, and evaluation of organizational and financial arrangements to promote the appropriate use of genetic and molecular tests.

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Chemotherapy for Bone Sarcoma in Adults [Clinical Reviews]

The largest studies of chemotherapy for bone sarcomas are in the pediatric population. Although increasing age is often found to be an adverse prognostic factor in these clinical trials, few studies are aimed at assessing regimens specifically in the adult population. Osteosarcoma and Ewing sarcoma have peak incidences in the pediatric and young adult population but also occur in adults. Chondrosarcoma and giant cell tumor of bone are generally found in adults. In this review, we describe the current status of our knowledge about treating adults with cancers of bone origin. We also describe our experience treating patients in the adult Sarcoma Medical Oncology group at The University of Texas MD Anderson Cancer Center.

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In Response to "Serum Tumor Marker Use in Patients With Advanced Solid Tumors" [Letters to the Editor]

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Contemporary Concerns in Managing Bone Sarcoma [COMMENTARIES]

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Implementation of a Breast/Reconstruction Surgery Coordinator to Reduce Preoperative Delays for Patients Undergoing Mastectomy With Immediate Reconstruction [Quality in Action]

Purpose:

Mastectomy with immediate reconstruction (MIR) requires coordination between breast and reconstructive surgical teams, leading to increased preoperative delays that may adversely impact patient outcomes and satisfaction. Our cancer center established a target of 28 days from initial consultation with the breast surgeon to MIR. We sought to determine if a centralized breast/reconstructive surgical coordinator (BRC) could reduce care delays.

Methods:

A 60-day pilot to evaluate the impact of a BRC on timeliness of care was initiated at our cancer center. All reconstructive surgery candidates were referred to the BRC, who had access to surgical clinic and operating room schedules. The BRC worked with both surgical services to identify the earliest surgery dates and facilitated operative bookings. The median time to MIR and the proportion of MIR cases that met the time-to-treatment goal was determined. These results were compared with a baseline cohort of patients undergoing MIR during the same time period (January to March) in 2013 and 2014.

Results:

A total of 99 patients were referred to the BRC (62% cancer, 21% neoadjuvant, 17% prophylactic) during the pilot period. Focusing exclusively on patients with a cancer diagnosis, an 18.5% increase in the percentage of cases meeting the target (P = .04) and a 7-day reduction to MIR (P = .02) were observed.

Conclusion:

A significant reduction in time to MIR was achieved through the implementation of the BRC. Further research is warranted to validate these findings and assess the impact the BRC has on operational efficiency and workflows.

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Bones: The Adult Sarcoma Drama [COMMENTARIES]

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ReCAP: Identifying Severe Adverse Event Clusters Using the National Cancer Institutes Common Terminology Criteria for Adverse Events [CARE DELIVERY]

CONTEXT & QUESTION ASKED:

Exploring the relationship among adverse events is important because those that arise from a common mechanism are amenable to a common intervention, which can improve symptom management, quality of life, and treatment adherence. To date, symptom cluster studies have used patient-reported data, which are not always available in clinical trials. In this study, we proposed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) to identify adverse event clusters because the CTCAE are collected as standard practice and can therefore be used when patient-reported outcomes are unavailable. Hence, is it feasible to identify severe adverse events clusters from data captured using the CTCAE in clinical trials?

SUMMARY ANSWER:

Six severe adverse events clusters were identified in patients with advanced prostate cancer. Identifying adverse events clusters using CTCAE data from clinical trials is feasible.

METHODS:

A variable-based hierarchical cluster analysis was conducted using the CTCAE data captured from 323 patients who experienced at least one grade 3 or higher adverse event in an advanced prostate cancer randomized clinical trial conducted by SWOG (S9916).

BIAS, CONFOUNDING FACTOR(S), DRAWBACKS:

The difficulty of using adverse event data from clinical trials is that often not all adverse events are recorded. In our study, only the highest severity grade for each adverse event type was recorded, and only grade 3 or higher adverse events were captured reliably. Moreover, in contrast to previous publications on symptom cluster that used patient-reported outcomes, the CTCAE is clinician reported and may not accurately reflect the presence of patient symptoms and the severity of these symptoms.

REAL-LIFE IMPLICATIONS:

Capturing adverse events using the CTCAE, which is standard practice in all clinical trials, can be used to understand the relationships among adverse events and to identify adverse events clusters when patient-reported outcomes are unavailable.

FIG 2.

Dendrogram for the cluster analysis. PRBC, packed RBC; w/o, without. Numbers in the figure are Spearman rank correlation, and Ps are from the Mantel-Haenszel ² test.

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Managing Liposarcomas: Cutting Through the Fat [Clinical Reviews]

Liposarcomas are one of the most common of more than 50 histologic subtypes of soft tissue sarcomas that, themselves, are heterogeneous. Liposarcomas fall into four distinct histologic subtypes: atypical lipomatous tumor/well-differentiated liposarcoma, dedifferentiated liposarcoma, myxoid (round cell) liposarcoma, and pleomorphic liposarcoma. Definitive treatment remains surgical resection with negative margins for resectable disease. However, well-differentiated liposarcomas that are large or difficult to operate upon should be followed with close surveillance as long as there is no radiologic concern for a dedifferentiated component. In contrast, first-line chemotherapy with anthracycline with or without ifosfamide, or gemcitabine and docetaxel should be used for inoperable myxoid (round cell) or pleomorphic liposarcomas, which are relatively responsive to chemotherapy. In the second- and third-line setting, myxoid liposarcomas, in particular, seem to be sensitive to trabectedin, which was recently approved by the US Food and Drug Administration (FDA). Eribulin offered a survival benefit when compared with dacarbazine in the third-line setting in liposarcomas (other than the well-differentiated subtype) and is now FDA approved. Recent studies have identified distinct genetic aberrations that not only aid in the diagnosis of liposarcoma subtypes but represent actionable targets. Cyclin-dependent kinase 4 and murine double minute 2 are overexpressed in well-differentiated and dedifferentiated liposarcomas and offer opportunities that are being pursued in clinical trials. It is critical that liposarcomas are not approached by oncologists as one disease entity but rather subclassified into distinct subtypes using histologic and molecular tools before formalizing a treatment plan.

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Improving gastric cancer preclinical studies using diverse in vitro and in vivo model systems

Abstract

Background

"Biomarker-driven targeted therapy," the practice of tailoring patients' treatment to the expression/activity levels of disease-specific genes/proteins, remains challenging. For example, while the anti-ERBB2 monoclonal antibody, trastuzumab, was first developed using well-characterized, diverse in vitro breast cancer models (and is now a standard adjuvant therapy for ERBB2-positive breast cancer patients), trastuzumab approval for ERBB2-positive gastric cancer was largely based on preclinical studies of a single cell line, NCI-N87. Ensuing clinical trials revealed only modest patient efficacy, and many ERBB2-positive gastric cancer (GC) patients failed to respond at all (i.e., were inherently recalcitrant), or succumbed to acquired resistance.

Method

To assess mechanisms underlying GC insensitivity to ERBB2 therapies, we established a diverse panel of GC cells, differing in ERBB2 expression levels, for comprehensive in vitro and in vivo characterization. For higher throughput assays of ERBB2 DNA and protein levels, we compared the concordance of various laboratory quantification methods, including those of in vitro and in vivo genetic anomalies (FISH and SISH) and xenograft protein expression (Western blot vs. IHC), of both cell and xenograft (tissue-sectioned) microarrays.

Results

The biomarker assessment methods strongly agreed, as did correlation between RNA and protein expression. However, although ERBB2 genomic anomalies showed good in vitro vs. in vivo correlation, we observed striking differences in protein expression between cultured cells and mouse xenografts (even within the same GC cell type). Via our unique pathway analysis, we delineated a signaling network, in addition to specific pathways/biological processes, emanating from the ERBB2 signaling cascade, as a potential useful target of clinical treatment. Integrated analysis of public data from gastric tumors revealed frequent (10 – 20 %) amplification of the genes NFKBIE, PTK2, and PIK3CA, each of which resides in an ERBB2-derived subpathway network.

Conclusion

Our comprehensive bioinformatics analyses of highly heterogeneous cancer cells, combined with tumor "omics" profiles, can optimally characterize the expression patterns and activity of specific tumor biomarkers. Subsequent in vitro and in vivo validation, of specific disease biomarkers (using multiple methodologies), can improve prediction of patient stratification according to drug response or nonresponse.

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Systemic delivery of chTNT-3/CpG immunoconjugates for immunotherapy in murine solid tumor models

Abstract

CpG oligodeoxynucleotides (CpG) potently activate the immune system by mimicking microbial DNA. Conjugation of CpG to chTNT-3, an antibody targeting the necrotic centers of tumors, enabled CpG to accumulate in tumors after systemic delivery, where it can activate the immune system in the presence of tumor antigens. CpG chemically conjugated to chTNT-3 (chTNT-3/CpG) were compared to free CpG in their ability to stimulate the immune system in vitro and reduce tumor burden in vivo. In subcutaneous Colon 26 adenocarcinoma and B16-F10 melanoma models in BALB/c and C57BL/6 mice, respectively, chTNT-3/CpG, free CpG, or several different control constructs were administered systemically. Intraperitoneal injections of chTNT-3/CpG delayed tumor growth and improved survival and were comparable to intratumorally administered CpG. Compared to saline-treated mice, chTNT-3/CpG-treated mice had smaller average tumor volumes by as much as 72 % in Colon 26-bearing mice and 79 % in B16-bearing mice. Systemically delivered free CpG and CpG conjugated to an isotype control antibody did not reduce tumor burden or improve survival. In this study, chTNT-3/CpG retained immunostimulatory activity of the CpG moiety and enabled delivery to tumors. Because systemically administered CpG rapidly clear the body and do not accumulate into tumors, chTNT-3/CpG provide a solution to the limitations observed in preclinical and clinical trials.

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From the image towards a new concept

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Testing the effects of narrative and play on physical activity among breast cancer survivors using mobile apps: study protocol for a randomized controlled trial

Abstract

Background

Physical activity reduces risk for numerous negative health outcomes, but postmenopausal breast cancer survivors do not reach recommended levels. Many interventions encourage self-monitoring of steps, which can increase physical activity in the short term. However, these interventions appear insufficient to increase motivation for sustained change. There is a need for innovative strategies to increase physical activity motivation in this population. Narratives are uniquely persuasive, and video games show promise for increasing motivation. This study will determine the effectiveness of an intervention that combines narrative and gaming to encourage sustained physical activity.

Methods/Design

SMARTGOAL (Self-Monitoring Activity: a Randomized Trial of Game-Oriented AppLications) is a randomized controlled intervention trial. The intervention period is six months, followed by a six month maintenance period. Participants (overweight, sedentary postmenopausal breast cancer survivors aged 45–75) will be randomized to a self-monitoring group or an enhanced narrative game group. The self-monitoring group will be encouraged to use a mobile application for self-monitoring and feedback and will receive 15 counseling phone calls emphasizing self-regulation. The narrative game group will be encouraged to use a mobile application that includes self-monitoring and feedback as well as a narrative-based active video game. The 15 calls for this group will emphasize concepts related to the game storyline. Counseling calls in both groups will occur weekly in months 1 – 3 and monthly in months 4 – 6. No counseling calls will occur after month 6, but both groups will be encouraged to continue using their apps. The primary outcome of the study is minutes of moderate to vigorous physical activity at six months. Other objectively measured outcomes include fitness and physical function. Self-reported outcomes include quality of life, depression, and motivation.

Discussion

This protocol will result in implementation and evaluation of two technology-based physical activity interventions among breast cancer survivors. Both interventions hold promise for broad dissemination. Understanding the potential benefit of adding narrative and game elements to interventions will provide critical information to interventionists, researchers, clinicians, and policymakers. This study is uniquely suited to investigate not just whether but how and why game elements may improve breast cancer survivors' health.

Trial registration

clinicaltrials.gov NCT02341235 (January 9, 2015)

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miRNA profiling, detection of BRAF V600E mutation and RET-PTC1 translocation in patients from Novosibirsk oblast (Russia) with different types of thyroid tumors

Abstract

Background

The postoperative typing of thyroid lesions, which is instrumental in adequate patient treatment, is currently based on histologic examination. However, it depends on pathologist's qualification and can be difficult in some cases. Numerous studies have shown that molecular markers such as microRNAs and somatic mutations may be useful to assist in these cases, but no consensus exists on the set of markers that is optimal for that purpose. The aim of the study was to discriminate between different thyroid neoplasms by RT-PCR, using a limited set of microRNAs selected from literature.

Methods

By RT-PCR we evaluated the relative levels of 15 microRNAs (miR-221, −222, −146b, −181b, −21, −187, −199b, −144, −192, −200a, −200b, −205, −141, −31, −375) and the presence of BRAF(V600E) mutation and RET-PTC1 translocation in surgically resected lesions from 208 patients from Novosibirsk oblast (Russia) with different types of thyroid neoplasms. Expression of each microRNA was normalized to adjacent non-tumor tissue. Three pieces of lesion tissue from each patient (39 goiters, 41 follicular adenomas, 16 follicular thyroid cancers, 108 papillary thyroid cancers, 4 medullary thyroid cancers) were analyzed independently to take into account method variation.

Results

The diagnostic classifier based on profiling of 13 microRNAs was proposed, with total estimated accuracy varying from 82.7 to 99 % for different nodule types. Relative expression of six microRNAs (miR-146b, −21, −221, −222, 375, −199b) appeared significantly different in BRAF(V600E)-positive samples (all classified as papillary thyroid carcinomas) compared to BRAF(V600E)-negative papillary carcinoma samples.

Conclusions

The results confirm practical feasibility of using molecular markers for typing of thyroid neoplasms and clarification of controversial cases.

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Adenocarcinoma of Gall Bladder Metastasis to Cervix: a Case Report with Review of Literature

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Aging of perennial cells and organ parts according to the programmed aging paradigm

Abstract

If aging is a physiological phenomenon—as maintained by the programmed aging paradigm—it must be caused by specific genetically determined and regulated mechanisms, which must be confirmed by evidence. Within the programmed aging paradigm, a complete proposal starts from the observation that cells, tissues, and organs show continuous turnover: As telomere shortening determines both limits to cell replication and a progressive impairment of cellular functions, a progressive decline in age-related fitness decline (i.e., aging) is a clear consequence. Against this hypothesis, a critic might argue that there are cells (most types of neurons) and organ parts (crystalline core and tooth enamel) that have no turnover and are subject to wear or manifest alterations similar to those of cells with turnover. In this review, it is shown how cell types without turnover appear to be strictly dependent on cells subjected to turnover. The loss or weakening of the functions fulfilled by these cells with turnover, due to telomere shortening and turnover slowing, compromises the vitality of the served cells without turnover. This determines well-known clinical manifestations, which in their early forms are described as distinct diseases (e.g., Alzheimer's disease, Parkinson's disease, age-related macular degeneration, etc.). Moreover, for the two organ parts (crystalline core and tooth enamel) without viable cells or any cell turnover, it is discussed how this is entirely compatible with the programmed aging paradigm.

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Erratum to: A comparison of heterosexual and LGBTQ cancer survivors’ outlooks on relationships, family building, possible infertility, and patient-doctor fertility risk communication

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Gastrostomy Complications in Pediatric Cancer Patients: A Retrospective Single-Institution Review

Background

Complications in pediatric cancer patients after a gastrostomy (GT) placement have not been widely investigated. We aimed to evaluate the complication rate and nature of complications in this specific population.

Procedure

Medical records of pediatric cancer patients having a GT placed at our institution from 1998 to 2013 were retrospectively reviewed. Variables analyzed included gender, age, diagnosis, surgical procedure, GT device, duration of GT usage, absolute neutrophil count (ANC) level at surgery, and complications.

Results

One hundred seventy-one patients (92 males, 79 females), median age of 6 years (range, 0.2–21), who underwent 181 procedures (110 open, 59 endoscopic, and 12 laparoscopic) were identified. Diagnosis included central nervous system tumor (n = 101), solid tumor (n = 45), and leukemia/lymphoma (n = 25). A GT tube was used in 139 procedures and a GT button in 42. Median ANC level at procedure was 3,300/mm³ (range, 0–38,988). Median duration of GT usage was 8 months (range, 0.2–142). One hundred seventy-seven complications occurred in 106 patients (61.9%) and were categorized as perioperative (<1 month after surgery, 20.3%) and late (>1 month after surgery, 79.7%). Major complications included 42 (23.7%) GT site infections and four (2.2%) intrabdominal complications. The most common minor complication was granulation tissue (28.8%). Younger age at procedure was associated with complications (P = 0.048) and an open technique was associated with GT site infection (P = 0.003). No statistical significance was observed between complications and gender, diagnosis, GT device, duration of GT usage, and ANC at procedure.

Conclusions

Younger patients were more likely to have complications, and GT site infections were more common after open GT procedures.

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Guideline for the Treatment of Breakthrough and the Prevention of Refractory Chemotherapy-Induced Nausea and Vomiting in Children With Cancer

This clinical practice guideline provides an approach to the treatment of breakthrough chemotherapy-induced nausea and vomiting (CINV) and the prevention of refractory CINV in children. It was developed by an international, interprofessional panel and is based on systematic literature reviews. Evidence-based interventions for the treatment of breakthrough and prophylaxis of refractory CINV are recommended. Gaps in the evidence used to support the recommendations made in this clinical practice guideline were identified. The contribution of these recommendations to breakthrough and refractory CINV control in children requires prospective evaluation.

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Systemic delivery of chTNT-3/CpG immunoconjugates for immunotherapy in murine solid tumor models

Abstract

CpG oligodeoxynucleotides (CpG) potently activate the immune system by mimicking microbial DNA. Conjugation of CpG to chTNT-3, an antibody targeting the necrotic centers of tumors, enabled CpG to accumulate in tumors after systemic delivery, where it can activate the immune system in the presence of tumor antigens. CpG chemically conjugated to chTNT-3 (chTNT-3/CpG) were compared to free CpG in their ability to stimulate the immune system in vitro and reduce tumor burden in vivo. In subcutaneous Colon 26 adenocarcinoma and B16-F10 melanoma models in BALB/c and C57BL/6 mice, respectively, chTNT-3/CpG, free CpG, or several different control constructs were administered systemically. Intraperitoneal injections of chTNT-3/CpG delayed tumor growth and improved survival and were comparable to intratumorally administered CpG. Compared to saline-treated mice, chTNT-3/CpG-treated mice had smaller average tumor volumes by as much as 72 % in Colon 26-bearing mice and 79 % in B16-bearing mice. Systemically delivered free CpG and CpG conjugated to an isotype control antibody did not reduce tumor burden or improve survival. In this study, chTNT-3/CpG retained immunostimulatory activity of the CpG moiety and enabled delivery to tumors. Because systemically administered CpG rapidly clear the body and do not accumulate into tumors, chTNT-3/CpG provide a solution to the limitations observed in preclinical and clinical trials.

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Annual Report to the Nation on the Status of Cancer, 1975-2012, featuring the increasing incidence of liver cancer

BACKGROUND

Annual updates on cancer occurrence and trends in the United States are provided through an ongoing collaboration among the American Cancer Society (ACS), the Centers for Disease Control and Prevention (CDC), the National Cancer Institute (NCI), and the North American Association of Central Cancer Registries (NAACCR). This annual report highlights the increasing burden of liver and intrahepatic bile duct (liver) cancers.

METHODS

Cancer incidence data were obtained from the CDC, NCI, and NAACCR; data about cancer deaths were obtained from the CDC's National Center for Health Statistics (NCHS). Annual percent changes in incidence and death rates (age-adjusted to the 2000 US Standard Population) for all cancers combined and for the leading cancers among men and women were estimated by joinpoint analysis of long-term trends (incidence for 1992-2012 and mortality for 1975-2012) and short-term trends (2008-2012). In-depth analysis of liver cancer incidence included an age-period-cohort analysis and an incidence-based estimation of person-years of life lost because of the disease. By using NCHS multiple causes of death data, hepatitis C virus (HCV) and liver cancer-associated death rates were examined from 1999 through 2013.

RESULTS

Among men and women of all major racial and ethnic groups, death rates continued to decline for all cancers combined and for most cancer sites; the overall cancer death rate (for both sexes combined) decreased by 1.5% per year from 2003 to 2012. Overall, incidence rates decreased among men and remained stable among women from 2003 to 2012. Among both men and women, deaths from liver cancer increased at the highest rate of all cancer sites, and liver cancer incidence rates increased sharply, second only to thyroid cancer. Men had more than twice the incidence rate of liver cancer than women, and rates increased with age for both sexes. Among non-Hispanic (NH) white, NH black, and Hispanic men and women, liver cancer incidence rates were higher for persons born after the 1938 to 1947 birth cohort. In contrast, there was a minimal birth cohort effect for NH Asian and Pacific Islanders (APIs). NH black men and Hispanic men had the lowest median age at death (60 and 62 years, respectively) and the highest average person-years of life lost per death (21 and 20 years, respectively) from liver cancer. HCV and liver cancer-associated death rates were highest among decedents who were born during 1945 through 1965.

CONCLUSIONS

Overall, cancer incidence and mortality declined among men; and, although cancer incidence was stable among women, mortality declined. The burden of liver cancer is growing and is not equally distributed throughout the population. Efforts to vaccinate populations that are vulnerable to hepatitis B virus (HBV) infection and to identify and treat those living with HCV or HBV infection, metabolic conditions, alcoholic liver disease, or other causes of cirrhosis can be effective in reducing the incidence and mortality of liver cancer. Cancer 2016. © 2016 American Cancer Society.

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The cancer registry as a cancer-control tool

Today's cancer registry is a powerful public health and cancer control tool. Assessment can provide insight into practice pattern and the effectiveness of interventions. The future of the cancer registry involves acquisition of big data from the electronic medical record. The challenge will be to use the technology wisely, because privacy concerns already are threatening some registries.

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The importance of margins in head and neck cancer

An estimated 200,000 deaths each year worldwide are due to cancer of the head and neck, mostly mucosal squamous cell carcinoma and nonmelanoma skin cancer. The status of surgical margins is important for prognosis and need for adjuvant therapy. We will discuss how margin status impacts outcomes and therapy, and the conundrum of determining margin status. J. Surg. Oncol. © 2015 Wiley Periodicals, Inc.

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miR-522 contributes to cell proliferation of hepatocellular carcinoma by targeting DKK1 and SFRP2

Abstract

The morbidity and mortality of hepatocellular carcinoma (HCC) is very high, finding new therapeutic targets are critical for HCC treatment. miR-522 has been demonstrated to be upregulated in HCC tissues, but its role in HCC progression remains to be elucidated. In this report, we found miR-522 was upregulated in HCC cells and tissues, miR-522 overexpression promoted cell proliferation, colony formation, and cell cycle progression, whereas knockdown of miR-522 reduced these effects. We also analyzed the expression of several key cell cycle regulatory proteins and found overexpression of miR-522-inhibited cell cycle inhibitors p21 and p27 expression and enhanced cyclin D1 expression and the level of Rb phosphorylation, vice versa. These suggested miR-522-accelerated G1/S transition. DKK1 (dickkopf-1) and SFRP2 (secreted frizzled-related protein 2) were the targets of miR-522, their expression was inversely with miR-522 in HCC tissues. DKK1 and SFRP2 the antagonists of Wnt signaling, suggesting miR-522-promoted HCC progression through activating Wnt signaling. miR-522 might be a valuable target for HCC therapy.

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Low level of FOXL1 indicates a worse prognosis for gastric cancer patients

Abstract

The aim of this study was to detect forkhead box L1 (FOXL1) expression in gastric cancer (GC) and to analyze its association with the prognosis of GC patients. Immunohistochemical staining, Western blotting, and quantitative reverse transcriptase polymerase chain reaction were performed to detect FOXL1 tissue expression in 109 GC patients. Clinicopathological characteristics and survival data were retrospectively analyzed to discover the clinical importance of FOXL1 expression. The chi-square test was used to analyze the relationship between FOXL1 expression and the clinicopathological characteristics. Survival curves were plotted by using the Kaplan–Meier method and compared using the log-rank test. Survival data were evaluated using univariate and multivariate Cox regression analyses. The expression of FOXL1 messenger RNA (mRNA) was significantly higher in adjacent normal samples than in the tumor tissues (P = 0.043). Clinicopathological analysis showed that FOXL1 expression was significantly correlated with depth of invasion (P = 0.017), lymph node metastasis (P = 0.019), and distant metastasis (P = 0.047). FOXL1-negative as opposed to the FOXL1-positive patients had lower 5-year overall survival (14.06 vs. 37.78 %, P < 0.001). Multivariate analysis suggested that FOXL1 expression might be an independent prognostic indicator (hazard ratio = 0.307, 95 % confidence interval, 0.187–0.505; P < 0.001) for GC patients. In conclusion, our findings provide evidence that FOXL1 might serve as a candidate tumor suppressor and a potential prognostic biomarker for GC.

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