Molecular Pathogenesis of Osteosarcoma

To develop a scoring system to identify the subset of patients who may benefit the most from adjuvant chemotherapy following curative-intent resection for incidental gallbladder cancer (IGBC). A novel scoring system was utilized to stratify patients relative to overall survival (OS), as well as potential benefit from adjuvant chemotherapy following curative resection for IGBC. Among 266 patients with IGBC, a total of 99 (37.2%) patients received adjuvant chemotherapy. Five risk factors were used to develop an integer-based score to predict OS. Risk of death at 5-years incrementally increased among patients in the low (n = 42, 69.0%), medium (n = 64, 56.3%) and high-risk groups (n = 40, 30.0%) (median OS, 99.4 vs. 33.5 vs. 15.6 months, all p < .001). Use of adjuvant chemotherapy did not provide a survival benefit among patients in the low-risk group (median survival, 99.4 vs. 60.7 months, p = .56). In contrast, utilization of adjuvant chemotherapy was associated with an improvement in survival among medium- (median survival, 21.7 vs. 59.5 months, p = .04) and high-risk patients (median survival, 11.6 vs. 20.1 months, p = .01). While low-risk patients did not benefit from adjuvant chemotherapy, individuals with medium or high-risk scores had an improved survival with the utilization of adjuvant chemotherapy.

: The Comprehensive Postdoctoral Training Program in Breast Cancer Biology has successfully completed its third year. The goal of the program is to significantly extend our existing, highly successful Doctoral Training Program in Tumor Biology and several Cancer Center mechanisms that provide traditional postdoctoral training and junior faculty career development. The education and training of new investigators is essential to our progress in the prevention, detection, diagnosis, and treatment of breast cancer. The Postdoctoral Training Program in Breast Cancer provides comprehensive career development and integrates interactive research in the basic biology of breast cancer, formal and informal course work in key areas, and individualized guidance in career development. The program is enriched with both new and existing courses of interest to postdoctoral fellows covering scientific writing, teaching methodologies, scientific resources and technologies for cancer research, ethics in science, career development seminar series, and provides a firm foundation in the skills needed to succeed in a career science, as well as a focused research experience in basic breast cancer biology in a strong laboratory environment.

Cells govern biological functions through complex biological networks. Perturbations to networks may drive cells to new phenotypic states, for example, tumorigenesis. Identifying how genetic lesions perturb molecular networks is a fundamental challenge. This study used large-scale human interactome data to systematically explore the relationship among network topology, somatic mutation, evolutionary rate, and evolutionary origin of cancer genes. We found the unique network centrality of cancer proteins, which is largely independent of gene essentiality. Cancer genes likely have experienced a lower evolutionary rate and stronger purifying selection than those of noncancer, Mendelian disease, and orphan disease genes. Cancer proteins tend to have ancient histories, likely originated in early metazoan, although they are younger than proteins encoded by Mendelian disease genes, orphan disease genes, and essential genes. We found that the protein evolutionary origin (age) positively correlates with protein connectivity in the human interactome. Furthermore, we investigated the network-attacking perturbations due to somatic mutations identified from 3,268 tumors across 12 cancer types in The Cancer Genome Atlas. We observed a positive correlation between protein connectivity and the number of nonsynonymous somatic mutations, whereas a weaker or insignificant correlation between protein connectivity and the number of synonymous somatic mutations. These observations suggest that somatic mutational network-attacking perturbations to hub genes play an important role in tumor emergence and evolution. Collectively, this work has broad biomedical implications for both basic cancer biology and the development of personalized cancer therapy.

This is a 1,576 page textbook.It may be a little bit more medical oncology than most people want to read.For medical oncologists, much of the field is fast moving enough that any text is somewhat outdated when it is published.A very broad spectrum of collaborators of very high quality, however, have made most of the material in this book worth reading.For nononcologists, nonspecialists, there is in-depth consideration of most of the aspects of medical oncology and most of the basic concepts that underlie our current

156P The impact of Ki-67 on prognosis and chemotherapy benefit in breast cancer patients with ER-positive/HER2-negative micrometastatic disease in sentinel lymph nodes: A register-based cohort study

Background. Recent meta-analysis of 21 randomised controlled trials (RCTs) supports the use of adjuvant chemotherapy for nonmetastatic rectal carcinoma. In order to define a subgroup of patients who can potentially benefit from postoperative adjuvant chemotherapy, this study aims to review trials investigating adjuvant chemotherapy with respect to stage of disease in patients with locally advanced rectal cancer who had undergone surgery for cure (stage II and stage III). Methods. We searched electronic information sources to identify randomised trials evaluating adjuvant chemotherapy in patients with stages II and III rectal cancer with overall survival or disease-free survival as outcomes. Scottish Intercollegiate Guidelines Network notes on methodology were used to assess the methodological quality of the selected studies. Random-effects models were applied to calculate pooled outcome data. Results. Eight studies reporting total of 5527 patients were selected for analysis. Adjuvant chemotherapy was associated with statistically significant improvement in disease-free survival and overall survival compared to surgery alone in both stage II and stage III cancer. Conclusions. This study indicates that both stage II and stage III rectal cancer patients may benefit from postoperative adjuvant chemotherapy. However, the benefits of adjuvant chemotherapy for patients who already had neoadjuvant chemoradiation still remain unknown.

Breast cancer in men is rare, and clinical trials are thus not feasible. This study aimed to describe the epidemiological characteristics, treatment and prognostic factors of breast cancer in men. A population-based study was performed using data from the Cote d'Or breast and gynaecological cancer registry. Data on male breast cancer diagnosed from 1982 to 2008 were provided. Relative survival rates were estimated at 5 years according to the characteristics of the patient and tumour, and treatment. Prognostic factors of survival in men with breast cancer were identified using a generalised linear model. Seventy-five men with invasive breast cancer were registered. Mean age at diagnosis was 66 years. The use of adjuvant chemotherapy (P= 0.013) and hormone therapy (P < 0.0001) increased over time. Relative survival rate at 5 years was 69% for the whole population. Analysis of relative survival according to the treatment showed that survival was longer for patients treated with surgery + radiotherapy + hormone therapy: 89% at 5 years. Scarff, Bloom and Richardson grade was independent prognostic factor of survival. Male breast cancer is a rare disease with a poor prognosis, and diagnosis is often made at an advanced stage. Early diagnosis and better knowledge of the disease would certainly lead to improvements in the prognosis.

The knowledge of GRPs as molecular chaperones is rapidly evolving. It is anticipated that the GRPs will make special contributions in the areas of basic cell biology, biotechnology, and cancer biology. In particular, they may play a role as the prototype of a class of genes that are regulated by signal transduction pathways originating in the ER and traveling to the nucleus. GRP78 and GRP94 function as molecular chaperones and can bind to malfolded proteins and unassembled complexes. They are induced in response to stress, but once the stress is removed the GRPs are posttranscriptionally modified into biologically inactive forms. The promoters of the grp genes are highly conserved, with several CCAAT-like motifs and GC-rich regions. The high level of redundancy that exists in the mammalian grp promoters may act to ensure that the expression of the genes, both of which are single copy, is unlikely to be significantly lowered in the event of mutation. These genes are thought to be controlled by several transcription factors whose complex interactions with the grp promoters allow variable patterns of grp induction. The promoters of the grp genes constitutively express their gene products, and their promoter activities can be further enhanced in cellular environments of low glucose or oxygen. The grp78 promoter is known to retain its strong activity in differentiated and undifferentiated tissues. These features make it an attractive alternative to viral promoters for use in gene therapy. Gene therapy may also be useful in treating cancer in some cases, especially solid tumors. In these instances, GRP levels are already likely to be quite high. These high levels of GRPs may inhibit the efficacy of several anti-cancer treatments. Suppression of GRP induction, perhaps by anti-sense or ribozyme technology, may prove to be useful in conjunction with anti-cancer drugs to treat tumors.

5-hydroxymethylcytosine (5hmC), an epigenetic modification derived from the oxidation of 5-methylcytosine (5mC) by the ten-eleven translocation (TET) family of dioxygenases, plays a pivotal role in the regulation of gene expression, cellular differentiation, and developmental plasticity. Once considered an intermediate in DNA demethylation, 5hmC is now recognized as a stable and functionally significant epigenetic mark with distinct genomic distributions and significant regulatory implications. This review provides a comprehensive analysis of the biological functions of 5hmC in normal cellular processes, including its role in maintaining tissue-specific gene expression, lineage commitment, and genomic integrity. We also describe its role in cancer, the mechanistic underpinnings of its loss or redistribution in tumor cells, and how these changes contribute to oncogenic signaling pathways, epithelial-mesenchymal transition, and tumor heterogeneity. Furthermore, we explore the utility of 5hmC as a biomarker in cancer diagnostics and prognostics, supported by recent advances in sequencing technologies and cell-free DNA profiling. We also examine the intersection of 5hmC and chemotherapy, highlighting how aberrant 5hmC levels can influence drug resistance and sensitivity, and assess the therapeutic potential of targeting TET enzymes and associated pathways. By integrating insights from basic epigenetics, cancer biology, and therapeutic research, this review underscores the multifaceted role of 5hmC in human malignancies and outlines the translational opportunities for exploiting 5hmC-related mechanisms in precision oncology.

To examine the population-level impacts of the introduction of novel cancer therapies with high cost in the United States, using immunotherapies in advanced nonsmall cell lung cancer (NSCLC) as an example. Surveillance, Epidemiology, and End Results data in 2012-2015 linked to Medicare fee-for-service claims until 2016. We examined population-level trends in treatment patterns, survival, and Medicare spending in patients diagnosed with advanced NSCLC, the leading cause of cancer death in the United States, between 2012 and 2015. We estimated the percentage of patients who received any antineoplastic therapy within two years of diagnosis, including novel immunotherapies. We compared the trends in overall survival and mean two-year Medicare spending per each patient before and after the introduction of immunotherapies in 2015. Not Applicable. The percentage of patients treated with any antineoplastic therapy remained the same at 46.7% in 2012 and 2015, whereas the use of immunotherapies increased from 0% to 15.2%. The two-year survival rate and median survival increased by 3.3 percentage points (95% CI: 2.0, 4.5) and 0.4months (CI: 0.0, 0.9), respectively, during the same period. The mean two-year total Medicare spending and outpatient spending per patient increased by $5735 (CI: 3479, 8040) and $7661 (CI: 5902, 9311), respectively, which were largely attributable to the increases in immunotherapy spending by $5806 (CI: 5165, 6459). The introduction of lung cancer immunotherapies was accompanied by improvements in survival and increases in spending between 2012 and 2015 in the Medicare population. As novel immunotherapies and other target therapies continue to change the clinical management of various cancers, further efforts are needed to ensure their effective and efficient use, and to understand their population-level impacts in the United States.

It is now 1 year and 8 months since Molecular Oncology became fully Open Access in 2017 under the FEBS Press platform and Wiley. Interestingly, the number of submissions remained comparable during 2016 and 2017, and we are delighted to report that so far in 2018, submissions have almost doubled as compared to the same period last year. To tackle the increase in submissions, we recently appointed Section Editors in basic/preclinical research (Michael Boutros, Heidelberg, Germany; George Calin, Houston, USA; Gerry Melino, Cambridge, UK) and in clinical research (Mef Nilbert, Copenhagen, Denmark; Klaus Pantel, Hamburg, Germany). Their expertise and commitment will be essential to the future development of the Journal, and together with the Editor-in-Chief, they will apply the same rigorous standards of peer review to ensure that the journal keeps its high standing among cancer journals worldwide. In addition, we have strengthened the Editorial office by appointing Duncan Wright as Editorial Associate to coordinate editorial matters. Moreover, we have put into operation significant changes to the Web site to facilitate access to critical information. I want to take this opportunity to thank José Moreira, with whom I started the Journal in 2007, for his instrumental and countless contributions to the development of the Journal, in particular during the more difficult early years. José will remain at the Journal as Review Editor. I would also like to thank Dorte Holst Pedersen, our Editorial Assistant, for her valuable support, and Mary Purton, Coordinator of FEBS Press, for her continuous advice during the transition process. Finally, I would like to convey my sincere thanks to the readers for their continuing support and take this opportunity to invite you to submit your research articles to Molecular Oncology. She has led a regional cancer center in Sweden with responsibilities for cancer registration, clinical guidelines, and political initiatives to improve modern cancer care. As part of this work, she has more recently contributed to research related to disease patterns, multidisciplinary treatment, and patients’ perspectives of cancer care. Since 2017, she is the head of the Danish Cancer Society Research Center in Copenhagen, which is an international research environment with particular strengths in basic cancer biology and cancer epidemiology. The institute's scientific projects range from basic genomic repair to environmental risk factors and survivorship perspectives. As director of research, it is Prof. Nilbert's aim to further develop the institute's research agenda, grant high-quality studies, support training of cancer researchers of tomorrow, and stimulate cross-disciplinary scientific interaction and collaboration. Professor Nilbert is also co-editor of Acta Oncologica that has a more epidemiological–clinical focus in cancer research. She is now looking forward to contributing to Molecular Oncology, in particular with regard to molecularly targeted therapies.

To evaluate nursery survival of very low birth weight infants (VLBW) over time, born in the same large inner-city hospital with a predominantly Hispanic population. All liveborn VLBW infants weighing 500-1500 g at birth were included in four time periods of 2 years' duration during 1982 to 1995. Demographics were collected for the obstetric population. Clinical data were collected including maternal and infant perinatal factors. All infants were assigned a cause of death and infants dying with lethal anomalies were then excluded from further evaluations. Overall survival improved progressively (p = 0.0001) with dramatic improvement in survival of infants 500-750 g birth weight (BW) in period 4 (1994-1995). The number of lethal anomalies did not increase but accounted for a larger portion of deaths in period 4. Decreases in other causes of death over time reflected changes in perinatal care. Although the mothers were high-risk, none of the maternal factors evaluated showed any consistent effect on infant survival. Improved labor and delivery care was associated with improvement in Apgar scores, a decrease in intracranial hemorrhage/intraventricular hemorrhage as a cause of death and an improvement in survival between the first two periods. In spite of the increase in Cesarean sections for infants of 500-750 g BW and their improved survival in period 4, no clear advantage for Cesarean section could be demonstrated. The marked improvement seen in period 4 was associated with three changes in care: increased use of maternal steroids, administration of surfactant, and the use of newer ventilatory methods including high-frequency oscillatory ventilation. Although female gender has been reported to confer a protective influence for survival, this was not found in the final period. Black mothers comprised only about 2.5% of the total obstetric population but delivered approximately 10% of the VLBW infants. Despite the increased incidence of small for gestational age (SGA) among black infants, there were no differences in survival between blacks and Hispanics. Mean birth weight and gestational age in both survivors and nonsurvivors decreased significantly over the four time periods. In period 4, 50% survival occurred at a birth weight of 600-700 g and a gestational age of 23 weeks. Nursery survival improved throughout the period of the study from 1982 to 1995 but especially during period 4 (1994-1995). Improved survival was associated with changes in both maternal and infant care. In infants of BW 500-750 g, gestational age rather than birth weight was more closely associated with survival.

Overall mortality rates in the general US population have declined substantially over the last 4-5 decades, but it is unclear whether patients with rheumatoid arthritis (RA) have experienced the same improvements in survival. The purpose of this study was to determine the mortality trends among RA patients compared with those in the general population. A population-based incidence cohort of RA patients was assembled, comprising all residents of Rochester, Minnesota ages > or = 18 years in whom RA was first diagnosed (according to the American College of Rheumatology [formerly, the American Rheumatism Association] 1987 criteria) between 1955 and 1995 and all residents of Olmsted County, Minnesota in whom RA was first diagnosed between 1995 and 2000. The patients were followed up longitudinally through their complete (inpatient and outpatient) medical records until death or January 1, 2007. Expected mortality was estimated from the National Center for Health Statistics life tables on the white population in Minnesota, using person-year methods. Poisson regression was used to model the observed mortality rates, adjusting for age, sex, and disease duration. A cohort of 822 RA patients (72% women, mean age at RA incidence 58 years) was followed up for a median of 11.7 years, during which 445 of the RA patients died. Between 1965 and 2005, the mortality rates across the calendar years for female and male RA patients were relatively constant at 2.4 and 2.5 per 100 person-years, respectively. In contrast, the expected mortality rate in the Minnesota white population decreased substantially over the same time period in both sexes. Mortality in the female general population declined from 1.0 per 100 person-years in 1965 to 0.2 per 100 person-years in 2000. Mortality in the male general population decreased from 1.2 per 100 person-years in 1965 to 0.3 per 100 person-years in 2000. Therefore, the difference between the observed and expected mortality rates increased in more recent years, resulting in a widening of the mortality gap. Our findings show that RA patients have not experienced improvements in survival over the past 4 decades, despite dramatic improvements in the overall rates of mortality in the general US population. Further research into the causes of the widening gap in mortality between RA patients and the general population, and the influence of current therapeutic strategies on mortality, is needed in order to develop strategies to reduce the excess mortality observed in RA patients.

journal's founding editor-in-chief, Dr. Opitz, who was one of the first physicians to recognize and characterize human congenital anomaly syndromes.

Stereotactic Ablative Radiotherapy for Oligometastatic Disease: a Treatment in Search of Evidence – a Response