Anal squamous cell carcinoma is rare in the general population but certain populations, such as persons with HIV, are at increased risk. High-risk populations can be screened for anal cancer using strategies similar to those used for cervical cancer. However, little is known about the use of such screening practices across jurisdictions. Data were collected using an online survey. Health care professionals currently providing anal cancer screening services were invited to complete the survey via email and/or fax. Information was collected on populations screened, services and treatments offered, and personnel. Over 300 invitations were sent; 82 providers from 80 clinics around the world completed the survey. Fourteen clinics have each examined more than 1000 patients. Over a third of clinics do not restrict access to screening; in the rest, eligibility is most commonly based on HIV status and abnormal anal cytology results. Fifty-three percent of clinics require abnormal anal cytology prior to performing high-resolution anoscopy (HRA) in asymptomatic patients. Almost all clinics offer both anal cytology and HRA. Internal high-grade anal intraepithelial neoplasia (AIN) is most often treated with infrared coagulation (61%), whereas external high-grade AIN is most commonly treated with imiquimod (49%). Most procedures are performed by physicians, followed by nurse practitioners. Our study is the first description of global anal cancer screening practices. Our findings may be used to inform practice and health policy in jurisdictions considering anal cancer screening. Anal squamous cell carcinoma is rare in the general population, but its incidence is rising Anal cancer and cervical cancer are biologically very similar; both are caused by persistent infection with high-risk types of human papillomavirus (HPV) leading to cellular oncogenic transformation at squamo-columnar junctions The objective of this study was to characterize anal cancer screening practices in jurisdictions around the world with the aims of providing clinical and operational guidance for clinicians, describing the current practice and providing information from other jurisdictions for health care policy makers.Clinicians and scientists currently providing anal cancer screening were invited to complete an Internet-based survey. We used a variety of strategies to contact participants from around the world. Potential respondents were identified from a review of the published literature, conference abstract books, and list of physicians who had been trained in HRA provided by the American Society for Colposcopy and Cervical Pathology (ASCCP). To our knowledge, the ASCCP is the only organization that provides formal training in HRA in the world. As such, our recruitment strategy should have identified a high percentage of clinicians who are practicing in this field.Participants were invited to complete the survey via email and/or fax in April 2011. Survey questions were deployed using a web-based survey tool . Participants were asked to answer up to 40 questions about their practice and their clinic or program. Information was collected on populations screened, services and treatments offered, and personnel. Respondent data were exported from Survey Monkey and descriptive analyses  were performed.Over 300 email/fax invitations were sent; 82 providers from 80 clinics in Canada, USA, Europe, Asia, and Australia completed the survey.Most clinics are relatively new and consequently, have only provided care to a small volume of patients. While 34 (43%) clinics have examined fewer than 100 patients, 14 (18%) clinics have examined more than 1000 patients since their inception Table. ApproxiFifty-three percent of clinics will perform HRA in asymptomatic patients only if the anal cytology result is abnormal. Of these clinics, 74% use a cytology result of abnormal squamous cells of uncertain significance (ASC-US) or worse to trigger HRA, whereas 24% use low-grade squamous intraepithelial lesion (LSIL) or higher and 2% use a threshold of high-grade squamous intraepithelial lesion (HSIL). When performing HRA, 68% of respondents routinely do anal cytology concurrently while 32% of physicians routinely do HPV testing concurrently. Seventy-six percent routinely assess persons with external high-grade AIN, including Bowen's disease, for the presence of internal AIN with HRA and guided biopsies, whereas only 28% of clinics routinely perform mapping or systematic four-quadrant biopsies to assess the extent of their external disease.Different therapeutic approaches were used for the treatment of internal and external AIN. The most commonly used treatment for internal disease is infrared coagulation (IRC) (61%) followed by imiquimod (54%) and bi/trichloroacetic acid (51%). External high-grade disease is most commonly treated with imiquimod (49%) followed by local fulguration strategies, including but not limited to IRC Fig.A and B.Respondents were asked to estimate the risk of recurrence of high-grade AIN after treatment in their clinics in various clinical scenarios. HIV-infected patients with a high burden of AIN were estimated to have the highest risk of recurrence of their high-grade disease Fig.. PractitThe majority of clinics have dedicated supporting services such as colorectal surgeons (69%), cytologists (66%), and histopathologists (66%). Most providers learned HRA by attending a formal course (82%) and/or by apprenticing with an experienced colleague (79%). Forty-four percent of providers train other personnel to do HRA.Private insurance, closely followed by public funds, are the two most common methods of payment for anal cancer screening tests in the United States, whereas in Canada and other countries public funds are almost exclusively used for payment Fig.. In the Our study is the first to describe current anal cancer screening practices globally. Just over half of the clinics that responded require that patients have an abnormal anal cytology result in order to proceed to HRA; the rest are performing HRA directly. Most clinics restrict their services to selected high-risk populations. Treatment of both high-grade and low-grade AIN is also offered in most clinics, however, less than two third of clinics offer HPV testing. Our respondents used ablative therapy most commonly for internal AIN and patient applied topical treatment for external AIN. However, there was considerable variation in the types of treatment offered for both internal and external AIN, suggesting either a lack of consensus about the best treatment strategy among our respondents or differences in respondent expertise and access to the necessary equipment. Severity of AIN appears to be the principal factor in determining the interval respondents recommend between surveillance visits.We found that almost half of clinics do not require an abnormal cytology result in order to proceed to HRA. To date, no long-term controlled trials have been performed to evaluate anal cancer screening; hence, practitioners often rely on the approaches used for cervical cancer screening We found relatively low rates of HPV testing in our sample. MSM and HIV-infected individuals have high rates of anal cancer High-grade AIN is difficult to treat—recurrence is common, especially in immunocompromised populations where there is a higher likelihood of HPV persistence. According to our survey, IRC is most frequently used in clinical practice, particularly for the treatment of internal AIN. Goldstone et al. External high-grade AIN, including perianal Bowen's disease, poses its own challenges. It is prone to local recurrence and treatment remains controversial The optimal surveillance protocol for persons with AIN is unknown. When recommending an interval to repeat surveillance, the majority of respondents in our study relied on the severity of the AIN and to a lesser extent, on immune status. Recommendations reported by our respondents appear to be consistent with an algorithm proposed by Abbasakoor and Boulos Despite the relatively large number of clinicians who responded, our sample may still not be entirely representative. Efforts were made to be as inclusive as possible when identifying potential respondents by capitalizing on all existing resources available to us, including a literature review to identify persons who had published in the field. As a result, our response rate appears low, but this likely reflects the fact that our recruitment strategy included a high proportion of persons who do not perform HRA. To our knowledge, the ASCCP is the only organization that provides formal training in HRA in the world. Abbreviated introductory courses in HRA have also been sponsored by the American Society of Colon and Rectal Surgeons (ASCRS) and the American College of Surgeons (ACS) via the ASCCP, but these organizations were not surveyed. Even so, our recruitment strategy should have identified most clinicians practicing in this field. However, we may have missed some clinicians, such as those who are trained by colleagues, for example, and not through a formal course. Nonetheless, we have responses from a large number of anal cancer screening clinics from around the world thus providing an arguably global perspective on the practice of anal cancer screening.We have demonstrated considerable variation in anal cancer screening practice; there appears to be no universal consensus on optimal strategies for anal cancer screening, treatment, and follow-up. In large part, this is due to the lack of prospective controlled studies or well-designed observational studies. The incidence of anal cancer worldwide continues to increase likely in part because progression to invasive anal cancer from AIN is slow and HIV-infected individuals are now living longer. Hence, there is a need for rigorous studies to identify the most effective screening and treatment strategies in populations at high risk for anal cancer such as HIV-infected MSM. In the interim, the variation in practice that we have demonstrated is concerning and suggests the need for a formal consensus process whereby screening for, diagnosis and treatment of AIN is standardized using best available evidence and expert opinion.None declared.


The concept of immunological memory stipulates that past exposures shape present immune function. These exposures include not only specific antigens impacting adaptive immune memory but also conserved pathogen or danger associated molecular patterns that mold innate immune responses for prolonged periods of time. It should thus not come as a surprise that there is a vast range of external or environmental factors that impact immunity. The importance of environmental factors modulating immunity is most readily recognized in early life, a period of rapidly changing environments. We here summarize available data on the role of environment shaping immune development and from it derive an overarching hypothesis relating the underlying molecular mechanisms and evolutionary principles involved. The immune system is an organ that specializes in responding to environmental exposures. Its tasks are to determine friend from foe, innocuous from dangerous, inert from toxic. This highly complex task is most readily recognized during rapid changes of environmental exposures such as those occurring in early life. The purpose of this review is to amalgamate existing data into a cohesive vision on how early life environmental exposures leave a lasting impression on the human immune system, and how this impression can either have beneficial or potentially deleterious effects. This vision incorporates the key principles of the developmental origin of health and diseases (DOHaD) hypothesis, the hygiene hypothesis as well insights from the field of developmental immunotoxicology (DIT) and posits that the sum of these mold immune memory. Immune education includes not only the classical acquired adaptive immune system with the cardinal feature of long-term immune memory but also the more recently described trained memory of the innate immune system. Understanding the environmental engines that drive development of the immune system is not only necessary to address specific pediatric diseases but also to identify the strategies to change trajectories toward long-term, life-long protection from disease.Ontogeny refers to the study of development. As multicellular life evolved so too did cell types with discrete functions. The immune system has evolved to meet a fundamental challenge of multicellular life determining whether exposures are benign or harmful. The seeding and growth of mammalian organs are a highly regulated sequence of events. Periods of rapid development represent windows of vulnerability for dysregulation with subsequent downstream effects that may manifest much later in adult life. Our interest in the immune system is focused upon how it comes to be fully functional, and to try to elucidate how and when aberration can result in disease, and how to best prevent undesirable outcomes. Thus, it is necessary to first understand the earliest origins of immune cells.Cells making up adaptive and innate arms of the immune system are derived from lymphoid or myeloid progenitors. Hematopoietic stem cells (HSCs) are the canonical precursors of all immune cell lineages and are defined by their capability to replace all blood lineages in lacking recipients . HSCs miAge dependent differences in human immunity are implied by the clinical observation of altered disease susceptibility and substantiated by differences in immune cell activities. Newborns are more susceptible to several diseases when compared to adults; this appears to be at least partially due to a lack of acquired immune memory and differential regulation of innate immune responses , 8. ThisThe abridged Th1 response is manifest in reduced defense against intracellular pathogens and is influenced in part by different innate cell cytokine responses to pathogen associated molecular patterns (PRRs) that direct subsequent adaptive immune functions . These ain utero exposures. Observations that nutritional status during gestation can influence organogenesis and metabolism in later adulthood lead Dr. David Barker to pursue and expand the ideas of DOHaD  hypothesis have been gradually increasing in popularity since the 1980s. Conceptually, DOHaD posits that presentation of adulthood disease can be traced back to childhood, perinatal, or of DOHaD . The curof DOHaD , 15. AltEpigenetic modifications are defined as mitotically or meiotically heritable changes in accessibility of genes for expression that do not involve a change in DNA sequence . There aNumerous environmental factors can influence immune activity, and the field of developmental immunotoxicology (DIT) has arisen to assess how chemical, biological, physical, or physiological factors alter the development of the immune system. Immunotoxic substances have traditionally been identified based on observation of pathology in adults, and may miss potential harm during development. Only now are we beginning to investigate how some exposures may affect pediatric populations and human development . FollowiIn utero exposure to methylmercury can decrease T-cell functionality, alter circulating immunoglobulin levels and has been implicated with low birth weight and preterm birth  can be either immunopotentiating or immunosuppressive . Heavy mrm birth –29. Neonrm birth . Arsenicrm birth –36.o-dioxins (TCDDs), perfluorinate compounds (PFCs), and polychlorinated biphenyls (PCBs); all of which are capable of crossing the placenta and the latter two have been detected in breast milk , extensively reviewed elsewhere . BrieflyThe field of DIT is demanding increased immune-surveillance in developing subjects and shows promise for explaining some underlying risk of infectious and non-communicable global disease burden. There is limited and incomplete knowledge about the developmental immunotoxicology of many compounds  but there is compelling evidence that these substances can subtly and dramatically alter human immune systems. It has been suggested that even relatively mild or seemingly benign alteration of immune response may set the stage for disease . FactorsPregnancy impacts both neonatal and maternal immune status. Half of neonatal genetic material is paternally derived and can be targeted by maternal immune responses as non-self, resulting in targeted rejection of the developing neonate. Extensive research has revealed that interaction between maternal and fetal tissues is mitigated by local immune evasion as well as maternal immune modulation, though exactly how is not yet fully understood . For insThere is clinical evidence for maternal immune modulation given that pregnant women have different susceptibility and severity to certain infectious diseases when compared to the general population . While pin utero exposure to inflammation, soluble factors, and antigen can alter neonatal immune status  children have increased morbidity and morality compared to unexposed children , 94. HEUin utero exposure to HIV are not currently known but will gradually unfold as this population increases in size and maturity.Altered neonatal immune status may be due to transplacental transmission of soluble immune factors, exposure to viral antigen, or reduction of breastfeeding by HIV+ mothers. Maternal burden of infection may have significant implications for neonatal immune ontogeny; high maternal viremia has been associated with significantly lower CD4+ T-cell count in uninfected progeny . TransmiBreast feeding provides not only necessary caloric and nutritional provisions for the growing neonate but also important factors for immune development. Human milk contains proteins that aid digestion, have antimicrobial activities, and act as sources of amino acids for the developing neonate. Bile salt-stimulated lipase aid lipid digestion, alpha amylase may promote complex carbohydrate metabolism, beta casein increases the bioavailability of divalent cations such as calcium and zinc, and lactoferrin facilitates uptake of iron, stimulates gut cytokine production and release, and may have antimicrobial effects . These aSystematic review and meta-analysis of breastfeeding research in developed countries has shown that a history of breastfeeding is associated with a reduced risk of acute otitis media, non-specific gastroenteritis, sever lower respiratory tract infections, atopic dermatitis, asthma, obesity, type 1 diabetes, childhood leukemia, sudden infant death syndrome, and necrotizing enterocolitis . Beneficin utero given that food and environment antigen specific T-cell responses are detectable in virtually all neonatal cord blood samples , congenital neural defects, obstructive airway disease, coronary heart disease, altered renal function, fivefold increases in breast cancer risk among women and reduced glucose and insulin tolerance  and lasting nutritional deficit have a lower probability of responding to typhoid vaccines than their peers . In contin utero exposure, acquisition during childbirth, and transmission through breast milk.The hygiene hypothesis has expanded from initial observations of allergy and social position to include assessment of observed increases in inflammatory diseases, atopy, and allergy inversely correlated with risk of infectious disease and parasite burden . During in utero microbial exposures, the vast majority and continued interaction with microbes takes place post-partum.There is ample evidence suggesting that the womb and developing fetus are not sterile, thus, it may be the case that neonatal tolerance to certain microbes may begin before birth. Clinical evidence from perinatal infections implies that the womb is not perfectly sterile, and bacteria may invade the uterus from the abdominal cavity, blood, or the cervix . Aside fAs the neonate transitions from the intrauterine environment into the external environment rapid colonization takes place, influenced by mode of birth. Cesarean and vaginal birth result in different microbes initially colonizing the neonate, either reflecting maternal skin and local surface or vaginal microbes, respectively , 135. ClContinued interaction with microbes that live upon and within us represents a most intimate environmental exposure and challenge for the immune system. The microbiota colonizing human gut, skin, and mucosal membranes are integral for energy harvest from food sources , metabolThe human microbiota appears to have some implications in human health and disease, likely through participation in immunological education. Early life microbial exposure may be exceedingly important within the context of trained innate immunity. In this process, independent of adaptive immune mechanisms primary exposure to pathogen can alter innate immune cell programed responses to subsequent re-exposure. Depending on the stimuli, exposure can result in innate cell training with resulting heightened or attenuated cytokine responses, lasting programing occurs through epigenetic histone modification . Both muHumans have incredibly plastic immune responses to the myriad of toxic, infectious, nutritional, and microbial exposures encountered throughout life. With added genetic variability, it is no wonder that promoting global health has been an ongoing struggle. Age-related patterns in innate immunity development vary depending on the area assessed , 156. InEven when cold chain and distribution requirements are adequately met vaccines are not ubiquitously successful. One of the best studied and most globally relevant examples of geographic variation in immune system function are the response to vaccination with bacille Calmette-Guerin (BCG) against tuberculosis (TB). Widely used with variable outcomes, a comprehensive meta-analysis of BCG has shown that it reduces tuberculosis risk by 50% , but proMycobacterium, host genetics, and geographic differences in clinical isolates , derailed development due to altered metabolism (nutrition and toxicology), and inappropriate immune system decision-making (for both adaptive and innate arms).A living world is defined by change, in terms of both environment and human populations. It is fitting that the immune system is in a constant state of flux to adapt to local constraints and conditions. Though selective pressures of environments have shaped the evolution of our immune systems, in recent years we have rapidly altered our lifestyle and environments. As a result, today we live in a world foreign to our ancestors. Given the inherent plasticity of the immune system, it follows that with exposure to entirely different organisms and chemicals than those we coexisted with for the last millenia can result in undesirable outcomes. Through medical interventions we are also living much longer lives, beyond the threshold of selective pressure. In order to promote immune-mediated health for life, we must consider the importance of environmental exposures for immune programing, and learn how to direct the developing immune system to optimize health outcomes. For example, the result of perinatal toxic exposures highlight the need to include assessment of the developing immune system for modulation in animal models beyond short-term adult toxicity, and include multi-generational monitoring. This also suggests surveillance of human populations need to be conducted for longer periods of time, to determine whether chemical exposures are hazardous for immune health in different physiologically relevant combinations and over time. And while we only recently have begun to understand that the microbiome is likely centrally involved in a number of chronic diseases, such profound and wide-spread impact highlights the power of microbial exposure in early life to modulate developmental trajectories. For example, it appears possible to reduce global morbidity and mortality with targeted early life probiotic interventions, as has been recently suggested in preliminary results from an active yogurt culture study in India .Bass Becking and Beijerinck once stated that “everything is everywhere; but the environment selects” . We woulThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Liver metastases of colorectal cancer are frequent and potentially fatal event inthe evolution of patients.  In the second module of this consensus, management of resectable liver metastaseswas discussed.  Concept of synchronous and metachronous metastases was determined, and bothscenarius were discussed separately according its prognostic and therapeuticpeculiarities.  Special attention was given to the missing metastases due to systemicpreoperative treatment response, with emphasis in strategies to avoid itsreccurrence and how to manage disappeared lesions.  Were presented validated ressectional strategies, to be taken into account inclinical practice. Liver metastases of colorectal cancer (CRC) are common and life-threatening events inthe evolution of patients with these malignancies. In this module is contextualized thepossibilities of resection and results of various treatment modalities.It was held discussion on the strategy on how and when to resect liver metastaticcolorectal cancer, as well as the results of its application.,,Synchronous colorectal liver metastases (CLM) are those diagnosed before, at the sametimeThis temporal definition led to two clinical scenarios in synchronous resectabledisease, namely patients with primary in loco and those who received surgical treatmentof the primary tumor but had metastatic disease detected within six months, likely theresult of sub-optimal initial staging or rapid progression after the colorectal tumortreatment. The latter clinical scenario is particularly worrying when real diseaseprogression is detected, especially during adjuvant treatment of the primary tumor, asit constitutes a poor prognostic factor with recommendation of upfront systemic therapy(or a change of regimen in adjuvant treatment) before liver resectionFor patients with the primary tumor in loco, two distinctions are fundamental: if thereare symptoms/risk of complications related to it during systemic treatment and whetherthe primary is a locally advanced mid/low rectal tumor and therefore demands neoadjuvanttreatment.The definition of symptomatic primary varies in the literature. The consensus adopted isthe presence of obstructive syndrome  and active bleeding(enterorrhagia requiring blood transfusion) as parameters indicating surgical treatmentof the primary tumor as the initial treatmentAnother critical point in the initial assessment is the identification of patients whohave higher risks of progressing with symptoms of the primary tumor during systemictreatment. For this reason, the incidence of emergency surgery seems low: between 3-15%in different series. The consensus adopted is that if an adult colonoscope device doesnot advance through the lesion, there would be a higher risk of obstructive symptonsduring systemic treatment. This does not necessarily mean that these patients, even ifthey do not exhibit clinical manifestations that fall within the definition ofsymptomatic primary mentioned above, must obligatorily receive surgical treatment of theprimary before the start of systemic treatment, but it serves as a warning to maintainrigorous clinical follow-up in these cases,As for the initial approach of asymptomatic cases, in spite of the absence ofprospective randomized data in the literature, the consensus points out that initialsystemic treatment prioritizes occult micrometastatic disease, chemosensitivity testingof the disease to the proposed regimen, an increased rate of R0 resections and appearsto improve recurrence-free survival (data extrapolated from a metachronous scenario),thus recommending this as standard conductConversely, in patients with low-volume disease, complete preoperative staging and asimultaneous resection of the primary tumor and metastases with little risk ofcomplication, the consensus is performing upfront surgery with postoperativechemotherapy for six months,,,,,,In relation to the sequence of surgical treatment of primary tumors and metastases,there is great heterogeneity in the terms used in the literature and the consensusadopted uses the following definitions: classical or staged approach, where theresection of colorectal tumor and metastases is done in separate procedures and in thesequence: primary first and then metastases; Simultaneous approach in cases where theremoval of the primary tumor and metastases is made in a single surgical procedure;and the reverse approach, when liver metastases are resected first and in an isolatedsurgical procedureA distinction was made for patients with primary tumors of the mid and low rectumbecause in cases of T3/T4 and/or N(+) lesions, neoadjuvant treatment must have radiationand chemotherapy included at some point of the its plan• Synchronous liver metastases are those detected before, concurrently or within sixmonths of primary tumor diagnosis.Agreement: 92%Symptomatic primary tumors or at high risk of complications during systemic treatmentshould be resected and/or palliated prior.Agreement: 94%• For synchronous tumors with asymptomatic primary, consensus recommendation is toprioritize systemic treatment. Simultaneous upfront surgery and adjuvant chemotherapy isa valid option in cases of low risk of postoperative complications.Agreement: 92%• Primary rectal tumors with resectable liver metastases should receive as muchtreatment of both clinical conditions, including effective chemotherapy and neoadjuvantradio/chemotherapy of the primary when indicated. Case-by-case multidisciplinarydiscussion is strongly recommended for the definition of the treatment sequence.Agreement: 87%• The simultaneous approach is safe in capable patients and when at least one ofresections (primary or metastases) is not complex. In all other cases the classical orreverse approaches should be preferred.Agreement: 90%Treatment of CRC liver metastases can vary according to the time of diagnosis inrelation to the primary tumor. In relation to this, the lesions can be described assynchronous or metachronous. Since the aim of this discussion is the treatment ofmetachronous lesions, the definition of metachronicity must first be established. Although some studies propose different time intervals, most of the series definemetachronous liver metastases as those characterized in an adequate imaging test morethan six months after diagnosis of the primary tumor. The main justification for theadoption of this interval is the rationale that lesions that recur until six monthshave similar biology to those diagnosed simultaneously. Some authors have questionedwhether within the current scenario where the systemic treatment modalities areincreasingly effective, the time interval should not be counted from the end ofadjuvant treatment for the primary tumorIt should be mentioned that the presence of a prior imaging test is crucial toproperly determine the time of metastasis diagnosisMetachronous lesions can be treated with upfront surgery followed by chemotherapy orin a multimodal treatment regimen with perioperative chemotherapy and surgerydescribed in the EORTC 40983 study, in which 364 patients were randomized to receivesix cycles of preoperative FOLFOX followed by surgery and another six adjuvantcycles, versus a control group treated with surgery alone. In this study there was a7.3% gain of progression-free survival (35.4% vs 28.1%), but no significant gain inoverall survivalSome patients are better candidates for initial surgery, but there is no conclusiveevidence to determine who these individuals are. The consensus from the EuropeanRegistration of Cancer Care (EURECCA) recommends initial surgery for patients whohave only metachronous lesions up to 2.0 cm because of the risk of completeradiological response if treatment starts with chemotherapyIn selected cases, individuals treated with upfront surgery may not be candidates toreceive chemotherapy, thus being treated with surgery alone. These patients are thosewhose systemic treatment was associated with a higher risk of morbidity, such as theelderly or others who have compromised performance status at that time. Anotherscenario in which this treatment may be considered is when an excellent regimen ofchemotherapy has recently been adopted and there is the onset of metachronousdisease. This is known to be a worse prognosis scenarioThe best evidence of multimodal treatment for CRC liver metastases is found in thepreviously mentioned EORTC 40983 study. From this data, both in patients undergoingperioperative chemotherapy and those who first receive surgery and subsequentchemotherapy, the chemotherapy of initial choice is oxaliplatin-based. Only inpatients with metachronous lesions up to one year after adjuvant treatment withoxaliplatin is it considered not to repeat the drug. The use of biological agents associated with perioperative chemotherapy wasinvestigated in the "New EPOC" study, in which the addition of cetuximab tochemotherapy was shown to lead to a reduction of overall and progression-freesurvival The use of other systemic treatment regimens associated with resection of livermetastases has also been investigated. Similar to anti-EGFR antibodies (cetuximab),the use of irinotecan did not improve survival compared to standard treatment• Definition of metachronicity: hepatic recurrence six months after onset of the primarytumo.Agreement: 93%• Initial surgery indication: Patients with favorable prognostic factors; there is noevidence that allows the individualization of this group of patients. These individualsshould receive chemotherapy for six months after resection.Agreement: 63%• Consider surgery alone in individual candidates to initial surgery with compromisedperformance status or recurrence up to one year after adjuvant treatment withoxaliplatin.Agreement: 71%• When the decision is for perioperative treatment, the preferred chemotherapy regimento be adopted is based on oxaliplatin and fluorouracil. After resection, the bestevidence in the literature is to use isolated fluorouracil, although the consensusrecommends adding oxaliplatin depending on the adjuvant treatment of the primary.Agreement: 76%• In the scenario of resectable disease, there is no evidence in the literature for theuse of targeted therapy as well as irinotecan-based chemotherapy after R0 resection.Agreement: 82%In recent years, with more effective chemotherapy regimens and increased use ofpreoperative chemotherapy in patients with liver metastases from colorectal cancer, camethe concept of "missing metastases." This term defines CRC liver metastases that are notidentified in the imaging methods after preoperative chemotherapy, not detectedintraoperatively and that end up not being resected Obviously, the identification of metastases depends on the quality and extent ofpreoperative radiologic assessment. In general, "missing metastasis" occur is 5% ofpatients, but it may reach 36% in some series depending on the chemotherapy regimenused True response is defined as the absence of viable tumor cells in the surgical specimen(pathologic complete response - pCR) or in the absence of local recurrence in anon-resected lesion after follow-up for at least 1 year Importantly, complete radiological response has limited predictive value for completepathologic response. Likewise, the permanence of nodes in imaging tests does notnecessarily mean that there are viable tumor cells in that lesion. Often fibroticlesions with no viable cells appear in preoperative imaging tests as residual lesionsafter chemotherapy Literature data are very heterogeneous regarding correlation between radiologicalresponse and pCR. Imaging response is associated with pCR in 15-70% of cases. Therecurrence rate for lesions that disappeared and were not resected can reach 74% There are no criteria to predict pCR. Some factors may help, such as normalization ofCEA levels, absence of lesions on MRI and the use of intrahepatic arterialchemotherapy The main imaging tests used to assess liver metastases after preoperative chemotherapyare CT, MRI, PET-CT and intraoperative ultrasound (IOUS).  CT is the most widely available test but has difficulty detecting nodules smaller than1 cm and suffers interference from changes in the hepatic parenchyma after chemotherapy.MRI is the method that has better sensitivity to small nodules (<1 cm) and suffersless interference with post-chemotherapy changes, but it can be associated with highercosts and less availability at some centers. PET-CT is a costly method, has limitedaccess and low sensitivity in this scenario due to decreased tumor metabolic activityafter chemotherapy IOUS is the best test to assess hepatic lesions after preoperative chemotherapy. Itprovides extensive mobilization of the liver associated with visual inspection andpalpation, aiding in locating deep and non-palpable lesions. Thus, it allows locating onaverage 30% (up to 67%) of the lesions that were not identified preoperatively In summary, it is recommended that preoperative chemotherapy for CRC liver metastasesbe used cautiously for lesions <2 cm and in cases of unresectable disease, its use becontinued until the disease becomes resectable and not until maximum response. MRI isthe modality of choice for the identification of small lesions after chemotherapy. IOUS,when available, is strongly recommended for "missing" lesions, as they are often foundduring surgical exploration with its use. Liver resection should be based on imaging tests immediately preceding chemotherapytreatment (neoadjuvant/conversion) and include the resection of segments containing the"missing" lesions when possible. When the "missing" lesion is present in a hepatic segment that cannot be resected (riskof impaired liver function), surgical treatment continues to be a good option, providedthat all other identified lesions are resected or ablated.Preoperative chemotherapy for CRC liver metastases should be indicated with cautionin the presence of lesions <2 cm due to the risk of disappearance and earlyre-assessment with image is recommended.Agreement: 91%In cases of unresectable disease, chemotherapy should be continued until the diseasebecomes resectable and not until maximal response.Agreement: 91%MRI - test of choice to identify small lesions after chemotherapy;Agreement: 84%Intraoperative ultrasound (IOUS) - strongly recommended .Agreement: 85%Liver resection should be based on imaging tests immediately preceding chemotherapytreatment (neoadjuvant/conversion) and include the resection of the segmentscontaining the "missing" lesions when possible.Agreement: 89%When the missing lesion is present in a hepatic segment that can not be resected(risk of impaired liver function), surgical treatment continues to be a good option,provided that all other identified lesions are resected or ablated. When notresected, missing metastases deserve close follow-up (CT/MRI every four months).Agreement: 84%Resection strategies were presented and validated in several circumstances to be appliedin clinical practice.


Since then, a wealth of studies has further debated this issue, and two additional accounts have been proposed, offering intriguing alternative explanations. Contingency learning accounts put forward that predictive relationships between stimuli and responses drive the CSE, whereas the repetition expectancy hypothesis suggests that top-down, expectancy-driven control adjustments affect the CSE. In the present paper, we build further on the previous review (Congruency sequence effects (CSEs) refer to the observation that congruency effects in conflict tasks are typically smaller following incongruent compared to following congruent trials. This measure has long been thought to provide a unique window into top-down attentional adjustments and their underlying brain mechanisms. According to the renowned conflict monitoring theory, CSEs reflect enhanced selective attention following conflict detection. Still, alternative accounts suggested that bottom-up associative learning suffices to explain the pattern of reaction times and error rates. A couple of years ago, a review by s review  by summa The seminal  control , 2009. H control  or subje control . Given tcongruency effect – the difference between incongruent (I) and congruent (C) trials. This difference is typically strongly reduced when the previous trial was incongruent compared to when it was congruent – the CSE. In this review, we first elaborate on the standard interpretation of this CSE in terms of conflict adaptation and its underlying neural signature. Building further on a previous review by The studies reviewed in the present paper investigated the CSE in typical conflict tasks such as the Stroop , EriksenThe CSE has been a major inspiration to the conflict-monitoring theory of The CSE has proven to be a very robust and generalizable effect. Following its initial report in the context of an Eriksen flanker task , it was The conflict-monitoring theory’s broad appeal can partly be attributed to the clear predictions it makes concerning the underlying brain mechanism involved in different cognitive control operations. According to Other neurophysiological studies generally confirm the predictions of the conflict-monitoring theory. A series of EEG studies has uncovered deflections in event-related potentials that readily map onto the behavioral pattern of the CSE  has become common practice in experiments on the CSE, this design choice actually comes at a price. Since most researchers decide to expand the stimulus set of their conflict tasks while at the same time maintaining a 50% congruent/incongruent ratio, they artificially increase the amount of congruent trials that would result from a random feature selection. Congruent trials would indeed occur less often, if stimulus features are selected randomly . As Even though controlling for feature integration effects  constructed versions of three common conflict tasks that controlled for both feature integration and contingency confounds ker task . In ordeker task .∧” or “v”). To rule out contingency confounds, four unique incongruent stimulus-distractor pairings were selected . Even though the task comprised of different stimulus sets  and response sets (left vs. right hand), Corroborating evidence comes from other recent studies showing significant sequential modulation in the absence of both stimulus/response repetitions and contingency learning. Finally, repetition expectancy account assumed that participants were biased to expect repeating stimulus conditions over successive trials, regardless of the objective probability of these conditions to occur  and inter-stimulus-interval , Finally, a series of studies have manipulated expectancies more directly, by investigating the impact of explicit cues on the CSE. In their original paper reporting on the CSE, Since its first report by post hoc or controlled for in the statistical analyses. Third, a 50% congruent/incongruent ratio should be installed while keeping all contingencies equal. One way of accomplishing this is to (a) create a unique set of incongruent stimuli , so that irrelevant stimulus information is equally predictive of a congruent and incongruent response, and (b) constrain random selection of stimuli to avoid feature overlap  value congruency task. Second, all transitions involving feature repetitions should preferably be excluded by design, rather than excluded Second, given that the evidence to date is indicative of a contribution of both attentional adjustments and episodic memory effects, the key theoretical question no longer pertains to which mechanism accounts for the CSE, but rather how these mechanisms interact and work together in producing adaptive behavior. Even if a CSE is still found in the absence of memory confounds, this does not at all imply that feature integration and/or contingency learning have no share in bringing about the CSE in designs that do not (fully) control for these. One promising avenue for further research therefore lies in parametrically manipulating these influences within the same experiment to systematically explore their contribution to the CSE. It could, for example, well be that inserting contingencies in the design precludes the need to engage in attentional control adjustments, as picking up and adapting to these regularities would be advantageous and less metabolically costly. In this light, Third, in almost all of the studies reviewed above, conflict-induced cognitive control has been the default explanation in situations where the CSE was found and confounding memory effects were controlled for. Rather than confirming the predictions of the conflict-monitoring theory, such findings mainly show that memory confounds cannot be the whole story. Therefore, the field is in need of observations that positively confirm specific predictions of the conflict-monitoring theory, and may at the same time benefit from a systematic exploration of other cognitive control processes that could  drive the CSE. In the present paper, we have evaluated one such additional source: repetition expectancy . The sturecent conflict  relies on a similar mechanism as adaptation to frequent conflict, or not. The latter is often studied in proportion congruency tasks, where specific proportions of (in)congruent trials modulate the congruency effect – and thus presumably the amount of cognitive control. Interestingly, the literature on this proportion congruency effect sparked similar debates as for the CSE reviewed here. For example, it has been discussed if the proportion congruency effect reflects conflict adaptation or merely S-R contingency learning processes activate some crucial challenges for further research. For example, it should be explored which precise mechanism(s) underlie such adaptation. These strategic adjustments could entail the altering of perceptual attention to target and/or distractor information e.g., , the facrocesses , 2009 orrocesses . These tFinally, the neurophysiological data on the CSE to date do seem to nicely confirm predictions of the conflict monitoring account: Both imaging results , EEG datThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The inadequacy of existing therapeutic tools together with the paucity of organ donors have always led medical researchers to innovate the current treatment methods or to discover new ways to cure disease. Emergence of cell-based therapies has provided a new framework through which it has given the human world a new hope. Though relatively a new concept, the pace of advancement clearly reveals the significant role that stem cells will ultimately play in the near future. However, there are numerous uncertainties that are prevailing against the present setting of clinical trials related to stem cells: like the best route of cell administration, appropriate dosage, duration and several other applications. A better knowledge of these factors can substantially improve the effectiveness of disease cure or organ repair using this latest therapeutic tool. From a certain perspective, it could be argued that by considering certain proven clinical concepts and experience from synthetic drug system, we could improve the overall efficacy of cell-based therapies. In the past, studies on synthetic drug therapies and their clinical trials have shown that all the aforementioned factors have critical ascendancy over its therapeutic outcomes. Therefore, based on the knowledge gained from synthetic drug delivery systems, we hypothesize that by employing many of the clinical approaches from synthetic drug therapies to this new regenerative therapeutic tool, the efficacy of stem cell-based therapies can also be improved. Stem cell technology has generated a great deal of interest in this new era of medical research due to its potential application in regenerative medicine. The two main types of stem cells basically categorized are, embryonic and non-embryonic cells. Embryonic stem cells (ESCs) are derived from the inner cell mass of the blastocyst whereas, non-embryonic stem cells, mostly adult stem cells ; multipotent stem cells (MPCs); progenitor cells (PC) and somatic stem cells (SSC) are specialized cells types found in various tissues within the body . RecentlIt is generally hypothesized that cell therapy using adult stem cells hold greatest prospect of changing the face of human diseases and alleviating suffering in the near future. Consequently, the therapeutic potential of adult stem cells is the main focus of scientific research; however, in parallel, the ESCs and iPSCs have also been proposed as promising candidates for future therapies due to their pluripotency and personalized therapeutic possibilities . In factThe use of stem cell therapy for many human clinical trials is a relatively new concept in the biomedical field . Since tIn the near future, it is anticipated that stem cell therapy would surpass the conventional synthetic drug therapy, which is the only treatment modality currently available for many illness. A question still remains however: can stem cells themselves can be considered as a biological drug? If we consider them as a drug, in fact, both synthetic drugs and stem cells have similar purpose in their role to cure diseases. Indeed, both therapies aim to achieve the same goal, but they are unparallel in their administration and clinical handlings due to their biochemical properties and mechanism of action in delivering their curative effects. However, it provides better opportunities to yield a more fruitful outcome if certain translational clinical concepts are merged from both therapies to formulate effective treatment strategies. Thereby, we hypothesize that the approach in curing disease through biological means can be more beneficial if we could adopt certain concepts of synthetic drug therapies, which in turn would become decisive factors. In fact, the current stem cell-based therapy in clinical trials has not yet attempted many of the concepts practiced in synthetic drug delivering systems. Nonetheless, it is anticipated that by adopting some effective strategies or procedures from synthetic drug therapy into stem cell-based therapies, an increased efficacy of the treatment could be expected.At present, the therapeutic use of stem cells poses some challenges because the underlying mechanism of action of the transplanted cells are largely unknown. Indeed, a better understanding of the properties and behaviour of these stem cells and their mechanism of action may open up an avenue for development of targeted therapies for various diseases. In fact, some critical factors have to be thoroughly considered before aligning and integrating the stem cells with the host tissues for long term beneficial outcomes.Stem cells for therapeutic applications can be of autologous or allogeneic sources. Within our bodies they normally reside in complex environments and constitute heterogeneous populations . NeglectAnother critical area that requires intense attention and is essential to the ultimate success of cell therapies is to explore the disease progression rate for developing tailor-made therapy with long-lasting results. This requires detailed information about the disease especially degenerative disorders to offer more personalized treatment . With thStem cells offer exquisite cell therapy due to their environment sensing cytokine receptors enabling these cells to migrate towards gradients of chemokine secreted by damaged tissues or tumors –28. The The key challenge in considering novel therapies is to analyze the complex biochemical and physiological events that occur during therapeutic implications, by using animal models before translating such therapies to humans . Cell thDespite the success of several clinical trials using stem cell-based therapy, there are findings reporting the failure in treating diseases –45. InfaConsidering the most pressing cell therapy challenges, development of innovative pathways is highly recommended because conventional approaches have some limitations as far as efficacy is concerned. To address these challenges, concepts from pharmaceutical drug research is highly recommended to harness the power of stem cells for improved, long-lasting outcomes. The success in pharmaceutical research is highly dependent on the evaluation of the drug-disease relationship. The process of following such relationship is attained by a series of therapeutic interventions, which requires the identification of a broad range of biomedical data sources. Such accumulating evidence has led to the adoption of certain key approaches in cell therapies from lessons learned in pharmaceutical drug setting.via different pathways to activate the same pro-survival targets.In clinical practices, doses or levels of therapy need to be tuned based on the severity of the illness or other metabolic characteristics of the patient’s underlying condition. Employing a range of therapies could provide physicians with the flexibility to formulate an effective therapy which is tailor-made for the patient because it takes into consideration the nature and stage of the disease progression. In this regard, there is now an increasing interest in the co-administration of drugs or biomolecules which are often reformulated into fixed-dose combinations . The benSimilarly, we are theorizing here that by co-administrating with different types of stem cells either concurrently or in the course of events can greatly augment the efficacy of stem cell treatment. Our notion is supported by a previous study where co-administration of endothelial and smooth muscle progenitor cells of umbilical cord blood has boosted the efficiency of vessel development in a nude mouse model of critical hind limb ischemia . AdditioIn light of these findings, the use of multiple cell types, or genetically engineered cells, or combinations of progenitor cells with cytokines, growth factors, or even clinically proven drugs can greatly increase the therapeutic potential. Further studies to interrogate the molecular mechanism of these approaches would, therefore, give better insight for the formulation of effective treatment.in vitro as well as post-transplantation [Pharmacological preconditioning is potentially a strong therapeutic tool. Preconditioning has shown to be involved in the protective effect from some membrano-tropic drugs on activation of metabolic processes, thereby improving the resistance of cell structures to various stress factors, in particular ischemia  and hypoxia –62. Therantation ,65. Geneantation  and use antation .One of the major challenges of stem cell transplantation from bench to bedside is to maintain the cell survival hindering the manipulation of stem cells before transplantation. This is due to the pro-apototic signals presence in the culture environment, which acts on the cells upon their dissociation. Preconditioned stem cells and progenitors generally showed improved characteristics such as better cell survival, increased differentiation potential, enhanced paracrine effect, efficient homing and integration at site of injury or diseased tissue/organ upon transplantation . ContinuATP) channels by preconditioning agents, which attenuates the mitochondrial Ca2+ overload thus preventing mitochondrial permeability transition pore induction. Additionally, preconditioning can induce the upregulation of heat shock proteins, which facilitates translocation of gap junction proteins like connexins Cx43, an important mediator between adjacent cells in the form of hemichannels. Opening of Cx43 hemichannels helps in early communication between the transplanted and host cells [Recent studies on cardiovascular diseases have also shown that preconditioning of stem cells  could play a vital role in cardio-protection and it has also enhanced the therapeutic efficacy invariably. These studies have successfully used a variety of pre-conditioners including: transforming growth factor-alpha ; hypoxicst cells ,80. Thisex vivo expansion before transplantation could greatly increase the efficacy of stem cell therapy.Another significant element of endogenous preconditioning mechanisms involves the up-regulation of stromal-derived factor −1 (SDF-1) and CXCR4 factors which play critical roles in mobilization, homing and engraftment of stem cells ,81,82. TWhenever new methods or routes are introduced for synthetic drug administration, it becomes vitally important to gain better insight into their pharmacokinetics and pharmacodynamic implications . For anySimilarly, a better understanding on the route of administration for efficient viable cell delivery becomes a necessity for stem cell therapies ,85. Howe6 MSCs per kilogram body weight for transplantation [7 cell/kg ex-vivo expanded autologous bone marrow derived mesenchymal stem cells (BM-MSCs) were administrated into each patient with multiple sclerosis [6 cells/kg were transplanted [6 cells/kg allogeneic bone marrow MSCs were transplanted via intravenous infusion through a single administration for treating refractory systemic lupus erythematosus. Clinical trials for graft-versus-host disease (GVHD) using allogeneic MSCs  demonstrated beneficial responses in both pediatric and adult patients when infused (single to multiple times) with different doses based on severity of the disease [Every patient has a unique therapeutic threshold for each prescribed drug due to individual drug sensitivities ,103. Ageantation . Howeverclerosis  whereas splanted . Liang esplanted  reported disease . An over disease . Current disease ,116. In  disease . Further disease .While study results provide assurance for the safety of allogeneic human mesenchymal stem cells (hMSCs), further work is in demand to delineate the mechanism of action of this MSC therapy in dose responsiveness manner. In addition, other factors such as source of stem cells, their functionality level, disease stage and route of administration, niche microenvironment can also influence the dosage and duration of stem cell therapy for a particular disease. For example, studies have reported poor engraftment of transplanted stem cells which could be due to impaired target niche microenvironment after intensive chemoradiotherapy or lower doses of cell infusion . Hence, Although, promising results have been highlighted using MSCs in clinical trials, the underlying dose and follow up dose associated mechanisms still remains unclear. Nevertheless, studies involving MSC therapy demonstrates a clear involvement of intricate mechanism of migration, homing efficiency, immunological properties, differentiation and secretions of bioactive molecules in an integrative manner. Taking all these notes together, it is possible that dose associated potential efficacy of allogeneic/autologous stem cells with single or repeated infusions can translate significant changes in clinical aspects. Further, it is plausible to propose that treating a disease with terminally differentiated cells would require higher cell number than by progenitors because the latter option provides the opportunity for this cell to proliferate and produce a larger mass and may differ in its secretions of bioactive molecules to substitute or repair the lost functional tissue. However, the unique tropism of cell therapy has to be taken into account for the optimization of cell infusion doses and duration to prevent cell losses for an effective transplantation setting. Taking all these issues together, stem cell therapy has a great potential to evolve further answers to the challenges associated with cell therapy transplantations as to ensure reproducible personalized therapy Figure .Figure 2Globally there are between 300 to 700 companies, ranging from small university spinouts to multinational corporations involved in developing cell-based therapy such as GlaxoSmithKline, Johnson & Johnson, Pfizer, and Sanofi (Genzyme) . PersistAlthough the differentiation potential of embryonic stem (ES) cells is greater than of somatic stem cells, studies have proven that MSCs can be conferred into more pluripotent state by epigenetic modification which facilitates an efficient differentiation into cells of different lineages . Hence, in vitro manipulated cells as an attractive and promising curative bio-reagents for many regenerative, anti-inflammatory and autoimmune related diseases. Indeed, studies have revealed the suitability of both autologous and allogeneic culture-expanded MSCs in cardiovascular studies [In some instances, there are studies addressing the safety concerns associated with the preparation of allogeneic cells, which showed a detectable level of HLA once they are integrated and differentiated in the host. This leads to the graft rejection and chronic immune responses . Therefo studies , in whic studies . While t studies –145. HavA great new venture in which the cell therapy based industry moving towards is the generation of patient specific induced-pluripotent stem cells (iPSCs), bringing a whole new dimension in developing cell based therapy to the next level moving this endeavour from bench to bedside application. Various aspect of biological properties and therapeutic models are under investigation in order to develop such patient specific stem cells. Although, a recent study has reported limited immunogenicity of transplanted cells differentiated from iPSCs and embryonic stem cells , the immAnother approach would be the development of HLA-matched cell banks, which are the focus of stem cell biobank services provided by some of the healthcare industrial players . Considein vivo microenvironment factors. Mostly, pharmaceutical treatments deliver a single agent at a specific dose to either catalyse or inhibit the biochemical reactions. On the other hand, stem cells are site-regulated and they are capable to secrete bioactive factors and give signals at variable concentrations in response to local microenvironmental cues [Both synthetic and natural drugs are generally well-characterized of their formulation, biochemical reactions, pharmacokinetics, pharmacodynamics and predictable end and by-products. On the other hand, the significant limitations to the development of stem cell therapy for patients includes; a) the lack of knowledge on the active cellular constituent of stem cells that are responsible for the reparative action b) the possibility that therapeutically active cells may represent only a very small fraction of the total stem cell population and, c) their potential to differentiate into variety of cell lineages govern by the tal cues . Thus, wAlbeit therapies based on drugs and stem cells have to be paved in a different way. Certain critical curative concepts of drugs therapies like the pharmacogenomics will be of high importance in developing cell therapies. In pharmacogenomics, it has been hypothesized that human genetic variations could dictate the efficacy and toxicity of drugs . Thus thTo better understand these factors and to optimize the beneficial effect of these therapies, it is important to monitor the clinical trials and the outcomes. While the best treatment strategy either by employing conventional drugs or stem cell transplant adds to the socioeconomic considerations, in other situations research investigating the psychosocial experience and quality of life of patients undergoing such treatments should also be considered. Clearly, the beneficial effect of these therapies must be weighed against the risks, but experimental studies must be encouraged to design combinational procedures by exploring newly developed concepts and protocols.Regenerative medicine and cell therapy are poised to have a tremendous impact on the future of medicine by delivering more effective, long-lasting, safe and cost-effective therapies for life- threatening and life-altering conditions than are currently available today. The extent to which we are able to achieve effective cell therapies will depend on assimilating a rapidly developing base of scientific knowledge with the practical considerations of design, delivery, and host response. Hence, a continuous effort is required to achieve a refined application of stem cell therapy to expand the role of stem cells for their vanguard uses. Table This hypothesis is aimed to propose the possible mimicking or recapitulation of certain clinical approaches from conventional drug therapy to stem cell-based therapy to improve their efficacy. Adopting such approaches will give immense value in translating stem cell therapy from bench to bedside. In addition to satisfying the scientific basis of stem cell treatments, this approach will bring about viable options to overcome current limitations in stem cell therapy. Implication of this approach in stem cell therapy is expected to not only modulate the outcome of intended therapy, but also will be a feasible option for the cost effectiveness of stem cell-based regenerative therapies in the near future. Therefore we suggest that the stem cells therapy should be also be seen from the point of view drug.


Panallergens  are responsible for polysensitization to various allergens including pollen and food allergens in a number of individuals which might account for a problem in distinguishing between true allergy from cross reactivity in allergy testing.A broad range of pollen- and plant-derived allergens contain profilins and it has been shown in selected populations that 10% to 20% of patients with pollen allergy are sensitized to them. Patients with profilin-specific IgE antibodies in serum show higher risk of developing of the sensitization to multiple allergens.Sensitization to common pollen allergens using commercial extracts  and profilin (provided by ALK) was assessed in 77 patients suffering from seasonal allergic rhinitis during the pollen season  by skin prick tests (SPT). The wheal mean diameter of > 3 mm was considered positive.18,18% of patients showed positive test results to profilin. 62,33% of patients had positive SPT to grass pollen and 57,14% were sensitized to mugwort pollen. Profilin positive subjects were sensitized to various pollen allergens and in some cases also to fungal allergens, but those patients were most frequently sensitized to mugwort, birch and plantain pollen . In both, birch or mugwort pollen positive patients sensitization to profilin was more prevalent than in the birch or mugwort negative subjects .Sensitization to profilin is prevalent among pollen allergic population in South-West Poland. Prevalence of sensitization to profilin can differ in patients allergic to mugwort, birch or plantain. Profilin sensitization is a risk factor for allergic reactions to multiple pollen and food allergen sources. Patients sensitized to panallergens should be tested by an adequate panel of allergenic molecules in order to identify the allergens that are responsible for the allergic disease.


This book includes contributions from renowned experts in the field of cognitive–behavioural therapy (CBT) for anxiety disorders such as panic disorder, agoraphobia, generalised anxiety disorder, social anxiety disorder, obsessive–compulsive disorder, post-traumatic stress disorder, specific phobias and health anxiety. It is well laid out into easy-to-read chapters, taking each of the anxiety disorders in turn and providing a clear account of the latest cognitive–behavioural models and CBT treatment methods for those conditions. In addition, there are subsections with descriptions of the diagnostic issues, epidemiology, comorbidities and pharmacological treatments. Each chapter concludes with a paragraph summarising the key points discussed.The CBT treatment methods are covered in a great deal of detail and readers will appreciate the helpful case histories and therapist–patient dialogues in addition to the tables and figures interspersed throughout. The evidence base behind the treatment modalities is also included.The last two chapters were particularly interesting. Chapter 8 focuses on adapting CBT techniques and making them culturally appropriate. It describes how anxiety disorders develop in people from different cultures and the authors give an illuminating insight into ‘matching the cultural characteristics of the treatment with those of the patient’ (p. 191), focusing particularly on their own experiences with using culturally adapted CBT for post-traumatic stress disorder. The final chapter gives an overview of newest entrants to the field of CBT such as acceptance and commitment therapy and mindfulness-based therapies, emphasising that newer treatments are ‘not meant to replace traditional methods of CBT but merely [refocus] attention on certain psychological processes and treatment goals’ (p. 227). The stress on improving functioning and not just symptom control is one underlying theme in the newer therapies.Theoretical approaches in CBT have changed over the years and this book provides a comprehensive update on current theories and treatment models in this field. It will prove useful for trainees and seasoned therapists alike.


Intimate partner violence (IPV) is most broadly defined as behavior that is abusive and perpetrated by someone who is in a current or previous relationship with the victim ; see Table 1. Intimate partner violence may occur on a continuum ranging from isolated incidents described as situational couple violence to intimate terrorism encompassing multiple aspects of psychological and physical abuse . Although few studies have focused solely on the oncology population, a 2006 study by Modesitt and colleagues states that a staggering 75% of women under treatment for breast, ovarian, endometrial, or ovarian cancer report having experienced some form of intimate partner abuse during adulthood . Results from a 2002 National Violence Against Women Survey confirmed this high rate of incidence .In January 2013, the US Preventive Services Task Force (USPSTF) issued a recommendation for health-care providers to begin routine screening of women patients for IPV . The USPSTF’s recommendation aligns with the 2011 recommendation by the Institute of Medicine that all women of childbearing age should be routinely screened by their health-care provider for IPV . These recommendations are based on current evidence that screening and intervention in the health-care setting reduce both the incidence of IPV and the related health outcomes. Intimate partner violence and oncology intersect because IPV occurrence is a public health concern; the reported incidence of IPV ranges from 22% to 39% over a woman’s lifetime. This high rate of incidence greatly increases the likelihood that oncology patients may experience IPV in addition to their cancer diagnosis .Although current recommendations are for screening women of childbearing age, older women also have the potential to be vulnerable to IPV . In addition to the likelihood that older women may remain in an abusive relationship because of financial dependence, older women are also at increased risk to sustain injury if physical abuse and neglect occur .No single IPV screening tool is routinely used in practice or has, to date, well-established psychometric properties . However, the most frequently used screening tools in this review included the Women’s Experience with Battering (WEB) Scale and the Psychological Maltreatment of Women Inventory (Short-Form); see Appendices A and B on pages 459 and 460. Both tools provide basic screening questions for patients in the clinical setting . These screening tools provide the additional benefit of sensitivity in screening for emotional IPV .Owen-Smith and colleagues (2008) identified advanced practitioners as the health-care providers most able to integrate IPV screening into their practice. Advanced practitioners routinely assess oncology patients in the outpatient setting and facilitate referrals, which may include psychosocial support. Advanced practitioners also routinely spend significant time with the patient assessment, allowing for an opportunity to develop rapport and encourage domestic violence disclosure . Survivors of IPV recommend repeated screenings, as this routine may facilitate future disclosure of abuse . In fact, a literature review with case examples by Schmidt, Woods, and Stewart (2006) noted that in each of the case studies presented, neither the oncologist nor the nurses identified the abuse based on injury or suspicious behavior; patients had been referred to psychiatry for "evaluation of mood."Screening for IPV may be uncomfortable for health-care providers, so using a routine approach for all female patients may be most efficacious; providing a statement disclosing that the policy of the health-care provider is to screen all female patients diminishes the burden of trying to implement a targeted screening. When health-care providers routinely assess for IPV as part of the standard psychosocial assessment, they should (a) be aware of their state laws for reporting a positive screening, (b) remain nonjudgmental and supportive when IPV screening is positive and provide resource information, and (c) facilitate referral to the appropriate social services when indicated . Resources for the advanced practitioner and the patient can be found in Table 2.


Aggregatibacter actinomycetemcomitans to inhibit biofilm formation by the fungal opportunistic pathogen Candida albicans. C. albicans is considered to be the most common fungal pathogen of humans, manifesting itself in the oral cavity , female reproductive tract (commonly referred to as a yeast infection), and less commonly in the digestive tract. It is also a notable blood-borne nosocomial pathogen  of this fungal opportunistic pathogen.Autoinducer 2 (AI-2), encoded by d Kolter , it woulC. albicans virulence might be an undesired consequence of this quorum-inhibiting strategy, as is the case with antibiotic-induced normal flora reduction (Gow and Hube, In summary, while there is considerable interest in exploiting quorum signal disruption as an antimicrobial therapy (Christensen et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


There are currently largescale efforts to understand the brain as a connection machine. However, there has been little emphasis on understanding connection patterns between functionally specific cortical columns. Here, we review development and application of focal electrical and optical stimulation methods combined with optical imaging and fMRI mapping in the non-human primate. These new approaches, when applied systematically on a large scale, will elucidate functionally specific intra-areal and inter-areal network connection patterns. Such functionally specific network data can provide accurate views of brain network topology. However, one aspect of these connectome studies that has largely been neglected is the fact that in humans and in primates, cerebral cortex is composed of basic functional columnar units. These units are on the order of a few hundred microns in size and have specific functions  and are connected in networks with other cortical columns of similar or related functionality . Such columnar networks form a basic feature of primate brain architecture. Thus, inherent in understanding the connection machine in primates is developing the ability to systematically map connection patterns between sets of cortical columns.In primates (both human and non-human), much of brain volume (up to 80%) is occupied by connections between different parts of the cerebral cortex. Specificity of these connections forms information processing networks that are critical to normal sensory, motor, and cognitive function. Interruption of these connections  leads to loss or alteration of function. In this sense, the brain can be viewed as a connection machine. There are now largescale projects (termed connectome projects) underway worldwide to study this connection machine ; networks of voxels  therefore represent connections between averages of multiple functional networks. Due to the differential connectivity patterns of individual columns  lack the spatial resolution for examining connection patterns at the columnar scale and therefore lack functional specificity inherent in columnar organization. Individual voxels in these studies represent averages of multiple functional columns  as well as other sensory, parietal, and prefrontal areas and have been termed columns, puffs, blobs, clusters, modules, and domains. Although each term is based on slightly different functional and/or anatomical criteria, they all capture the concept of modularity. For purposes of this review, we will use the term ‘column,’ as it is a generally familiar term and portrays the concepts of: ‘small’ (200–300 μm in size), ‘repeated’ , and ‘functional’ (composed of cluster of neurons which share similar function). This review proposes ways to examine the ‘columnar connectome.’Note that the concept of a column has of late been controversial, partly because there is not a single accepted definition and because by some criteria cortex is not clearly columnar . Furthermore, monkeys can undergo experimental manipulations to answer questions in ways that are not possible in humans. Note that while mouse connectomes have decided advantages , mouse cerebral cortex (except for barrel cortex) is not columnar in the same way as primate cortex. For example, visual orientation selective neurons are not organized in columnar fashion (Table 1). A columnar based understanding, we predict, would provide a fundamental component for developing a connectional theory of brain function, one that is not diluted by inaccurate averaged information.We propose to pursue a  horizon , the abi horizon , and in  horizon . Moreove fashion . These dAnatomical connections can be conducted at columnar scale and have provided some breathtaking views of cortical connection patterns. Perhaps some of the best examples come from monkey V1 where intra-areal patterns of connections have been well documented e.g., . There aIn vivo diffusion imaging is limited in spatial resolution and therefore accuracy. While it has been useful for some tracts  electrical microstimulation, Figure 3C); both revealed a focal 1 mm activation site consistent with a single digit representation. Increasing intensity of stimulation  led to increasing magnitudes of imaged reflectance change. Importantly, stimulation  elicited not only a focal activation at the site of stimulation but other focal activations within 1–2 mm of the stimulated site . This activation pattern is very similar in appearance to typical intra-areal columnar networks revealed by anatomical tracer studies . Direct confirmation of this anatomical correspondence is currently in progress.This finding by inter-areal columnar connections. Such an approach has been used to examine connections between motor and parietal areas in the prosimian primate the Galago  and revealed site-dependent differential topography . In another study, There is also potential for this approach to be used for mapping e Galago . Previoue Galago . To unde2015 has been designated by the United Nations as the International Year of Light. We owe this to pioneers such as Nobel Laureates in Physics 2009 Charles Kao, Willard Boyle, and George Smith who were innovators in the development of fiber optics and CCD chips. These technologies enabled many advances in optical engineering and in medicine, including technologies for brain stimulation. There are several advantages to replacing wires with light. The most important advantage of this method over electrical stimulation is that it is not encumbered by current spread, making its effect focal. The volume of affected neural tissue is determined by the light wavelength and size of the delivery fiber optic. By selecting optical fibers with illumination spot sizes of 100 μm to 1 mm in diameter, activation of single to several cortical columns can be achieved , 2013. FOptical stimulation techniques can now be introduced via optical windows on the brain. In monkeys, both in anesthetized and awake behaving states, such windows offer the opportunity to probe the brain with multiple techniques. These windows permit multiscale study in individual animals, using methods such as behavioral study, fMRI, optical imaging, electrophysiology, focal stimulation , and the study of anatomical connectivity via targeted tracer injections through the window.The use of infrared wavelength light to evoke neural response was developed by Duco Jansen and colleagues at Vanderbilt University ,b. FirstFigures 5A–C). This focal stimulation can elicit functionally specific effects related to columnar organization. In visual cortex, application of focal stimulation to single ocular dominance columns in V1 can, in combination with visual stimulation, enhance response of shared eye ocular dominance columns , suggesting a selective modulation of functionally specific intra-areal networks in V1. Similar modulatory results, by electrical stimulation, have been obtained by Focal INS stimulation induces neural response as assessed with electrophysiology, optical imaging, and BOLD fMRI imaging. Magnitude of this response is related to the intensity of stimulation . We interpret this as the larger fibers recruiting additional inhibitory circuits in the surround which change the balance of ongoing intra-areal networks and result in relative suppression.Note that, similar to inhibitory effects of electrical stimulation, optical stimulation can also lead to relative suppression of cortical response. We have observed this using fiber optics of different diameters aimed at cortical columns. We find a U-shaped response where small fibers (100 μm) evoke a response weaker than 200 μm fibers and 400 μm or 1 mm diameter fibers lead to relatively suppressed effects . Preliminary studies in squirrel monkeys implanted with optical chambers over somatosensory cortex (imaged with surface coil in a 9.4T Varian magnet) have shown that targeted stimulation of single digit locations  via apposition of the stimulating fiber optic to the cortical surface at one somatosensory cortical location  leads to significant BOLD response in topographically appropriate locations in nearby areas . When imaged in coronal slices, activations appear localized to superficial or middle layers of cortical laminae, suggesting that this resolution is sufficient for superficial, middle, or deep laminar localization . INS combined with fMRI thus provides the opportunity to examine intra- and inter-areal connection patterns of a stimulated site, as well as identify resulting laminar profiles, that will be useful for interpretation of feedforward or feedback connection patterns.Having characterized the effects of INS stimulation, we next examined whether it could be used as a tool for functional tract tracing. To further motivate the use of this approach, we examined the compatibility of INS with fMRI . With fMThere is a long history of focal electrical stimulation producing highly specific behavioral effects  during performance of target selected eye saccades, Vanduffel and colleagues demonstrated that saccades in trials with stimulation occurred with significantly shorter latency than in those without . The shoFigures 5D–F), and stimulation of single orientation domains led to relative enhancement of other orientation domains of similar selectivity. The differences between these studies may relate to intensity or effective depth of stimulation. Further studies are needed to evaluate these effects.At a local scale, optogenetic stimulation has also been used to probe the effect of stimulating single or multiple orientation domains in V1 of the tree shrew . Rather in vivo functional tract tracing will make studying column-specific brain connections on a large scale more feasible.We have explored three different functional tract tracing methods that can be presented at the columnar scale in a targeted, functionally specific fashion. These methods do not require animal sacrifice and lengthy anatomical reconstruction, and potentially permit the study of connections from a greater number of sites within an individual animal. The similarities and differences between these methods and traditional anatomical tract tracing methods  need to be further characterized and understood. While these methods cannot replace the gold standard of anatomical tract tracing, the advantages of The three methods presented each have their strengths and weaknesses. Electrical microstimulation is complicated by current spread but, at least within certain parameters and at a population level, appears to bias the activated circuits in a way that permits visualization of connections via functional imaging methods. Given that there is a wealth of studies demonstrating behavioral modulation using electrical stimulation, the use of electrical stimulation to map connections in the brain provides a direct link to these studies and could be conducted via methods that are already readily accessible. INS stimulation is a new method that is being developed for superficial and deep tissue stimulation. Applied via fiber optics, INS permits focal stimulation. INS does not require the use of viruses, giving it greater potential for human use. However, at this point in time, INS requires the delivery of specific infrared light wavelengths that are not yet commercially available. Optogenetics is a cell specific stimulation method that has revolutionized neuroscience. It requires the introduction of viruses that express light-sensitive rhodopsin molecules. Optogenetics has been enormously useful in studies in mice; its use in monkeys now also looks promising. Given the need for viral transfection, it is less amenable to use in humans.in vivo functional tract tracing studies calls for new future studies. We propose: (1) targeted, systematic, and large scale evaluation of columnar networks in different functional brain systems in monkeys , (2) cell type specific columnar mapping, (3) direct correlation of behavioral effects and mapped columnar networks, and (4) designing brain-machine interfaces based on targeting of columnar networks.The promise of conducting The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Categorization enables listeners to efficiently encode and respond to auditory stimuli. Behavioral evidence for auditory categorization has been well documented across a broad range of human and non-human animal species. Moreover, neural correlates of auditory categorization have been documented in a variety of different brain regions in the ventral auditory pathway, which is thought to underlie auditory-object processing and auditory perception. Here, we review and discuss how neural representations of auditory categories are transformed across different scales of neural organization in the ventral auditory pathway: from across different brain areas to within local microcircuits. We propose different neural transformations across different scales of neural organization in auditory categorization. Along the ascending auditory system in the ventral pathway, there is a progression in the encoding of categories from simple acoustic categories to categories for abstract information. On the other hand, in local microcircuits, different classes of neurons differentially compute categorical information. Auditory categorization is a computational process in which sounds are classified and grouped based on their acoustic features and other types of information . For example, when we hear the word “Hello” from different speakers, we can categorize the gender of each speaker based on the pitch of the speaker's voice. On the other hand, in order to analyze the linguistic content transmitted by speech sounds, we can ignore the unique pitch, timbre etc. of each speaker and categorize the sound into the distinct word category “Hello.” Thus, auditory categorization enables humans and non-human animals to extract, manipulate, and efficiently respond to sounds , but birds into a separate category. However, if we use different criteria to form a category of “pets,” dogs, cats, and birds would be members of this “pet” category but not killer whales.Behavioral responses to auditory communication signals  also provide evidence for abstract categorization. One example is the categorization of food-related species-specific vocalizations by rhesus monkeys  contribute to these categorical computations.The ventral pathway is targeted because neural computations in this pathway are thought to underlie sound perception, which is critically related to auditory categorization and auditory scene analysis  and the latter stages . For example, neurons in the core auditory cortex are more sharply tuned for tone bursts than neurons in the lateral belt , studies using more complex sounds, such as human-speech sounds, have shown that core neurons primarily encode the acoustic features that compose these complex sounds but do not encode their category membership  process categories for even more complex sounds? A re-examination of previous findings from our lab   and discuss how different classes of neurons process categorical information.A cortical microcircuit can be defined as a functional unit that processes inputs and generates outputs by dynamic and local interactions of excitatory pyramidal neurons and inhibitory interneurons  play in auditory categorization should be also tested. Recent advances in experimental and analysis techniques should enable us to clarify the functional role of different classes of neurons in auditory categorization (Letzkus et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.