In this issue.

This issue starts with a couple of review papers on colorectal cancer. De Smedt et al. (DOI 10.1007/s00428-015-1886-5) address morphological evidence of invasive growth, a process histopathologists tend to call budding. The morphological definition is detachment of individual or small clusters of up to five tumour cells from the main tumour mass and invasion into the surrounding stroma. About one third of colorectal cancers show this feature, which has been associated with lymphovascular invasion, lymph node and distant metastasis and poor prognosis. Two important issues are addressed. Firstly, for a morphological parameter to be used as a biomarker it needs to be quantified. Generally accepted and reproducible approaches for semi-quantitative assessment of budding are lacking, however, which hampers the use of this parameter in clinical practice. Secondly, mechanisms involved need to be unravelled in detail. Budding in all likelihood is associated with epithelial-mesenchymal transition and the stromal response to invasive cells. Understanding the details might provide better parameters to assess budding. The paper presents an overview of tumour budding including its definition, scoring systems, prognostic relevance and biological mechanisms involved. The paper by Polonia et al. (DOI 10.1007/s00428-016-19033) presents an interesting example of how changing guidelines might lead to shifts in selection criteria of patients for treatment. They compared results ofHER2 testing of breast cancer using the 2007 ASCO/CAP criteria with those using the 2013 guideline. They applied the standard immunohistochemical staining and for HER2 amplification assessment by in situ hybridization with silver chromogenic development. The good news is that the proportion of HER2-equivocal cases was significantly reduced. This, however, went along with an increase in the proportion of HER2-positive cases which reached beyond 50 %. Important follow-up information needs to be collected in such a situation: do the ‘new’ HER2 positive cases respond equally well to antiHER2 targeted therapy than the ‘conventional’ HER2 positive cases? The paper does not explicitly address this issue but hopefully studies are under way to provide an answer to this question. In the paper of Pelosi et al. (DOI 10.1007/s00428-016-19060) the question is raised whether or not DNA retrieved from tissue sections that has been H&E or immunohistochemically stained and stored can be used for molecular testing. They used as methods fluorescence in situ hybridization (FISH) with a variety of probes as well as Sanger or targeted next generation sequencing for detection of BRAF, EGFR, KRAS, C-KIT and TP53. It turns out that for FISH almost perfect concordance is reached between test results obtained on pre-stained sections. For immunohistochemically stained sections there was no difference between alkaline phosphatase or peroxidase as label. When sequencing was performed on sections with negative immunohistochemical results the concordance with fresh unstained sections was perfect. For immunohistochemical stains with nuclear reactivity concordance dropped to about 50%. The conclusion is that stained sections are a valuable resource for FISH or sequencing analysis when no other tissue sample is available, but on cases expressing nuclear markers cautious interpretation is called for. The image on the cover shows a FISH result from this paper. Finally Cerni et al. (DOI 10.1007/s00428-016-1909-x) address the question how reliable micro-invasion in in situ breast cancer can be assessed. The distinction between in situ carcinoma and micro-invasive carcinoma is of clinical significance as it impacts on clinical staging with therapy implications. The authors requested a sizeable group of dedicated breast pathologists to make this call on H&E stained digitized images using predefined criteria. After a ‘wash-out’ period the same group was requested to make the call using additional slides immunohistochemically stained for myoepithelial cells. It is not surprising that consistency in the recognition of microinvasion significantly improved with the use of myoepithelial markers, which corroborates previous recommendations to use myoepithelial markers in case of uncertainty exists about the presence of micro-invasion. When doubt remains, a second-opinion by an independent pathologist is advocated. * Fred Bosman fred.bosman@citycable.ch

Y oung adulthood is a time of impor tant transitions. During this period, people are forming adult identities, building mature relationships, and preparing for their careers. Increased alcohol use during this time of emerg ing adulthood may be attributed to a variety of factors, but drinking can undermine the ability of some people to make the developmental transitions typ ical of this age. Drs. Helene Raskin White and Kristina Jackson examine the developmental changes and related drinking patterns and problems that occur during emerging adulthood as well as the sociodemographic and psycho social factors that influence drinking in this population. These factors include gender, race/ethnicity, marital status, college, employment, peer and family influences, individual temperament, and attitudes toward drinking. The authors also discuss the need for prevention pro grams targeted to college students and to young adults not in college, who may be at particularly high risk for alcoholrelated problems. (pp. 182-190) ALCOHOL USE AND VIOLENCE AMONG YOUNG ADULTS Y oung adults experience more vio lence than other age groups, with bars and clubs being the setting of the most severe violence for young men, and young women tending to encounter the most severe violence in the home. Drs. Brian M. Quigley and Kenneth E. Leonard report that in both environ ments, intoxicated aggression appears to be provoked by personality differences among people and by characteristics of the triggering situations. Permissive atmospheres in bars increase the proba bility of intoxicated aggression, and the more alcohol consumed, the greater the likelihood of injury. In domestic vio lence situations, alcohol use by the hus band is predictive of severe violence only in marriages already high in conflict. Many important questions about the relationship between alcohol and vio lence await further study. Does alcohol reduce a person's attention to informa tion that would inhibit aggression, as some have hypothesized? Does alcohol have pharmacological effects on deci sionmaking in conflict situations that could contribute to violent outcomes? How does alcohol affect people with specific personality traits such as anger and impulsiveness? More information on these questions is needed so that effective prevention and treatment efforts can be developed. (pp. 191-194)

TRAJECTORIES OF ALCOHOL USE DURING THE TRANSITION TO ADULTHOOD
A s young people make the transition from their late teens to adulthood, their drinking practices may follow a variety of tracks, or trajectories. Some young adults will establish lifelong pat terns of alcohol use. Others may engage in a particular pattern of alcohol use in their late teen or young adult years that later changes course. Still others may never engage in drinking or heavy drinking. Generally, people increase the amounts they drink as they progress through their early twenties, and decrease their drinking when they take on adult roles. In this article, Drs. Jennifer L. Maggs and John E. Schulenberg describe both the average (or normative) pattern of alcohol use among young adults and the various subgroups of people whose drinking patterns follow different trajectories. They maintain that by identifying com mon trajectories of alcohol use during the transition to adulthood, researchers can gain a better understanding of how alcohol use disorders originate and evolve, how different trajectories lead to different outcomes, and how to plan prevention, diagnosis, and intervention. (pp. 195-201)

MATURING OUT OF PROBLEMATIC ALCOHOL USE
A fter peaking when young people are about 22 years old, heavy drinking rates among both college students and their nonstudent age-mates decline steadily, probably in response to the new roles and responsibilities that come with adulthood. Dr. Patrick M. O'Malley describes key transitions to adulthood and how they are associated either with increased drinking or with "maturing out" of alcohol use. The first major change, moving out of the parental home, often coincides with increasing rates of heavy drinking among many young people, whether they attend college or not. College students then may be exposed to campus social environments that sometimes encourage excessive drinking. As adult responsibilities-such as employment, marriage, and parent hood-mount, problematic drinking declines, partly because of the limita tions these responsibilities place on social activities in general and because of changes in young adults' attitudes toward drinking. Young alcohol users who would be diagnosed as alcohol dependent may be less affected by the more stabilizing, socializing effects of marriage and parenthood because of personality characteristics that make them less attracted to these choices, or because their drinking behavior is less susceptible to such influences. (pp. 202-204)

ALCOHOL AND THE ADOLESCENT BRAIN: HUMAN STUDIES
A dolescents and young adults who drink heavily could place them selves at risk for alcohol-related impair ment of brain development and brain function. As Dr. Susan F. Tapert, Ms. Lisa Caldwell, and Ms. Christina Burke explain, heavy alcohol use in young people has been found to affect neuro psychological functioning, such as memory, attention, planning, and abstract reasoning, although the observed impairment in most cases was not severe. Young people with alcohol use disorders may have subtle abnormalities in the structure of various brain areas, such as the hippocampus, a region that is involved in learning and memory for mation. These abnormalities, in turn, may be associated with some loss in brain functioning. A person's risk for impaired brain development and function is influenced by a number of factors, including genetics and other influences such as drinking patterns and use of other drugs. (pp. 205-212)

ALCOHOL'S EFFECTS ON THE ADOLESCENT BRAIN: WHAT CAN BE LEARNED FROM ANIMAL MODELS
R esearch into the effects of alcohol on the developing human brain typi cally has depended on a variety of ani mal models-including rats, mice, and other laboratory animals-because both ethical and practical considerations make it impossible to carry out these investigations in humans. Analyses of animal models have demonstrated that adolescents may be more susceptible than adults to some of alcohol's effects on the brain, especially to alcohol's memory-impairing effects. As Drs. Susanne Hiller-Sturmhöfel and H. Scott Swartzwelder explain, this enhanced sus ceptibility may be linked in particular with the hippocampus, an area of the brain that appears to be especially sen sitive to alcohol-induced damage. Alcohol interferes with hippocampal function to a greater extent in adolescents than in adults. Conversely, adolescents appear to be less sensitive than adults to some of alcohol's other effects, such as alcohol-related impairment of motor coordination, alcohol-induced sedation, and susceptibility to withdrawal seizures. Dick. The authors posit that a person's drinking behavior is a manifestation of an unfolding developmental process involving both genetic and environmental factors, a process that is continuously modulated by gene-environment corre lations and interactions. For example, initiation of drinking is determined pri marily by environmental factors (e.g., familial environment and peers). Conversely, the establishment of drink ing patterns once drinking has been ini tiated is increasingly influenced by genetic predisposition, and researchers are working to identify specific genes involved. Environmental factors such as place of residence or marital status con tinue to modify the effects of these genetic factors. (pp. 222-229)

ENVIRONMENTAL INFLUENCES ON YOUNG ADULT DRINKING
E nvironmental alcohol control policies may be effective in reducing alcohol use and related problems among young adults, although the population of 18 to 25-year-olds is seldom specifically tar geted by these policies or by research evaluating them. According to Drs. Alexander C. Wagenaar and Traci Toomey and Ms. Kathleen M. Lenk, many studies have shown that estab lishing a minimum legal drinking age (MLDA) of 21 is effective in reducing alcohol consumption and traffic crashes among 18-to 20-year-olds. Underage youth appear to be especially suscepti ble to prevention measures that limit alcohol availability, specifically price increases. And because young adults fre quent retail alcohol establishments more often than members of other age groups, they also may be disproportionately affected by policies that target these out lets, such as limiting the number of retail alcohol establishments in a geographic area, training staff and management in responsible beverage service, and restrict ing the marketing of alcoholic beverages through special promotions and adver tising. The authors describe three com prehensive programs that have used combinations of these measures and list policy recommendations that are sup ported by current evidence. (pp. 230-235) DRINKING AMONG YOUNG ADULTS: SCREENING, BRIEF INTERVENTION, AND OUTCOME T wenty-five percent of young adult males and 14 percent of females have at some time met the diagnostic criteria for alcohol dependence. Although many young people mature out of problem drinking during early adulthood, excessive drinking during adolescence and young adulthood can have serious and long-lasting negative consequences. Because young people do not tend to identify themselves as having alcohol problems, Drs. Peter M. Monti, Tracy O'Leary Tevyaw, and Brian Borsari suggest that people in this group may be better identified using proactive screening in locations where they are likely to seek treatment related to alcohol problems, such as hospital emergency rooms, college campuses, or workplaces. Young adults engaging in risky levels of alcohol use may respond better to brief, intensive interventions, known as brief motivational interventions, than to tra ditional, long-term treatments, which originally were designed for adults with more extensive histories of alcohol use. Other Drugs (ESPAD) has revealed a wide range of behaviors among European ado lescents and young adults in terms of age at onset of drinking, prevalence of absti nence, drinking to intoxication, and fre quency and amount of drinking. As Dr. Salme K. Ahlström and Ms. Esa L. Öster berg report, differences in social norms, the context of drinking occasions, and alcohol pricing policies contribute to the observed variations in drinking patterns. Particularly for the age group of young adults, how ever, substantial gaps remain in the understanding of drinking behavior. (pp. 258-268) COMMUNITY PREVENTION OF YOUNG ADULT DRINKING AND ASSOCIATED PROBLEMS W hether they are working, attending college, or in the military, young adults are typically part of a community. In this article, Dr. Harold D. Holder examines three research-based commu nity prevention programs that use a com bination of environmental strategies to reduce heavy drinking and related prob lems. Trials of programs provide strong evidence that comprehensive strategies can effect substantial changes in alcohol-related behavior. Research indi cates that local policies to reduce young adult drinking or alcohol-related prob lems are most likely to be effective when they are adequately enforced and when the intended targets of the intervention are aware of both the policies and their enforcement. By restructuring the total alcohol environment in a way that can be self-sustaining, these approaches are likely to be more effective than one-time interventions. (pp. 245-249)

PREVENTING ALCOHOL RELATED PROBLEMS ON COLLEGE CAMPUSES
N ews headlines of alcohol-related injuries and deaths among college students highlight the need for effective prevention measures on college cam puses. The National Institute on Alcohol Abuse and Alcoholism Task Force on College Drinking addressed this problem. The Task Force reviewed existing interventions, most of which target individual drinkers rather than the college population as a whole, and issued recommendations on which interventions might be effective in a col lege setting. Dr. Robert Saltz summa rizes these recommendations, which classify potential interventions into four tiers. Of these, only Tier 1 strategies (e.g., cognitive-behavioral skills train ing, motivational enhancement inter ventions, or interventions to challenge alcohol expectancies) have been demon strated effective among college students. Tier 2 strategies, which include enforce ment of laws to prevent alcoholimpaired driving, restrictions on alco hol retail outlet density, and responsible beverage service policies, have been suc cessful with other populations and show promise for the college environment. (pp. 249-251)