This economic evaluation compares the cost-effectiveness of finger replantation vs revision amputation after traumatic finger amputation. Is replantation after traumatic finger amputation cost-effective compared with revision amputation?In this economic evaluation of data on 257 adults from the Finger Replantation and Amputation Challenges in Assessing Impairment, Satisfaction, and Effectiveness study, the incremental cost-effectiveness ratio for replantation compared with revision amputation was $99 157 in single-finger (not thumb), $66 278 in thumb, $18 388 in multifinger excluding thumb, and $21 528 in multifinger including thumb injury patterns per quality-adjusted life years.With proper patient selection, replantation of all finger amputation patterns, whether single-finger or multifinger injuries, may be cost-effective compared with revision amputation. Traumatic digit amputation is the most common type of amputation injury, but the cost-effectiveness of its treatments is unknown.To assess the cost-effectiveness of finger replantation compared with revision amputation.This economic evaluation was conducted using data from the Finger Replantation and Amputation Challenges in Assessing Impairment, Satisfaction, and Effectiveness (FRANCHISE), a retrospective, multicenter cohort study at 19 centers in the United States and Asia that enrolled participants from August 1, 2016, to April 12, 2018. Model variables were based on the FRANCHISE database, Centers for Medicare & Medicaid Services, and published literature. A total of 257 participants with unilateral traumatic finger amputations treated with revision amputation or replantation distal to the metacarpophalangeal joint and at least 1 year of follow-up after treatment were included in the analysis.Revision amputation or replantation of traumatic finger amputations.Main outcome measures were quality-adjusted life-years (QALYs), total costs (in US dollars), and incremental cost-effectiveness ratios (ICERs). A willingness-to-pay threshold of $100 000 per QALY was used to assess cost-effectiveness.Of the 257 study participants , 178 underwent finger replantation and 79 underwent revision amputation. In a base case of a 46.7-year-old patient, replantation was associated with QALY gains of 0.30  for single-finger (not thumb), 0.39  for thumb, 1.69  for multifinger excluding thumb, and 1.27  for multifinger including thumb injury patterns. Corresponding ICERs for replantation compared with revision amputation were $99 157 per QALY for single-finger (not thumb), $66 278 per QALY for thumb, $18 388 per QALY for multifinger excluding thumb, and $21 528 per QALY for multifinger including thumb injury patterns. Sensitivity analysis revealed that age at time of injury, life expectancy, postinjury utility, wages, and time off work for recovery had the strongest associations with cost-effectiveness. Probabilistic sensitivity analysis revealed the following chances of replantation being cost-effective: 47% in single-finger (not thumb), 52% in thumb, 78% in multifinger excluding thumb, and 64% in multifinger including thumb injury patterns.With proper patient selection, replantation of all finger amputation patterns, whether single-finger or multifinger injuries, may be cost-effective compared with revision amputation. Multifinger replantations had a higher probability of being cost-effective than single-finger replantations. Cost-effectiveness may depend on injury pattern and patient factors and thus appears to be important for consideration when patients and surgeons are deciding whether to replant or amputate. Replantation applies microsurgical techniques to reattach digital nerves, arteries, and veins, as well as bone fixation and tendon repairs to restore finger length, sensation, and function. Revision amputation shortens the finger while achieving wound closure; this mode of treatment is less costly, is less complex, and requires less postoperative therapy than replantation.Traumatic finger amputation represents more than 90% of all amputations in the United States and has a yearly incidence of 45 000.9 have evaluated the clinical outcomes associated with replantation and revision amputation. However, there is a dearth of evidence on their cost-effectiveness. To our knowledge, the only economic analysis comparing the 2 treatments is reported in the study by Sears et al,10 in which a decision tree model based on a time trade-off survey of healthy individuals was used. That study10 concluded that the number of fingers amputated is substantially associated with the cost-effectiveness of replantation. However, a limitation of that study was that the time trade-off survey was based on a healthy population, which may have biased and inaccurately assessed disease burden. Given the increasing scrutiny of health care expenditures and pressure to attain maximal clinical efficacy with minimal expense, cost-effectiveness is essential to consider in clinical practice.Previous studiesWe aimed to perform a cost-utility analysis of finger replantation and revision amputation with use of data from an international collaborative group. To our knowledge, this is the only cost-effectiveness study to compare finger replantation and revision amputation using data from a patient cohort who sustained traumatic finger amputations. We evaluated the most pertinent factors associated with cost-effectiveness of finger replantation to assist in the decision-making process of traumatic finger amputation management.11 This study followed the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) reporting guideline.This economic evaluation used data from the Finger Replantation and Amputation Challenges in Assessing Impairment, Satisfaction, and Effectiveness (FRANCHISE) study, which recruited adult participants from 19 US and Asian international centers between August 1, 2016, and April 12, 2018. The research protocol was approved by the participating sites’ local institutional review boards. Separate institutional review board exemption for the present study was obtained from the University of Michigan before analysis commenced. All human participants gave written informed consent in their native languages before the start of the FRANCHISE study. The consent obtained included consent to the use of the FRANCHISE data in future planned studies, and all data were deidentified. All unilateral traumatic finger amputations treated with revision amputation or replantation distal to the metacarpophalangeal joint were eligible. Patients who could not provide consent, underwent nontraumatic amputations, sustained bilateral amputations, or had amputations proximal to the metacarpophalangeal joint were excluded. Patients were asked to evaluate their outcomes with 4 patient-reported outcomes instruments at least 1 year postoperatively: Michigan Hand Outcomes Questionnaire; Disabilities of the Arm, Shoulder and Hand; Patient-Reported Outcomes Measurement Information System Upper Extremity Module; and Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), version 2. Data were collected in a database established by the Plastic Surgery Foundation using research electronic data capture.We performed a model-based economic analysis from a societal perspective. A decision tree was constructed based on finger injury pattern, procedure type, stages of recovery, and potential complications with a lifetime horizon. The SF-36 patient-reported outcomes for each procedure and injury type from the FRANCHISE database were used to determine the long-term health outcomes associated with each decision tree end point.36 The postoperative time off work for recovery and mean complication rates were based on literature review. Only complications that require operative intervention were included because they differed the most between the 2 treatments. Five potential complications were identified that can affect cost utility: neuroma, vascular reexploration, bone revision procedure, tendon revision procedure, and other minor revision procedures. Probabilities of these complications are given in 33The base case scenario was a 46.7-year-old adult (based on the mean age in FRANCHISE) who sustained a single finger (not thumb) traumatic finger amputation and underwent an uncomplicated replantation. Other scenarios considered were thumb-only revision amputation vs replantation, multifinger excluding thumb revision amputation vs replantation, and multifinger including thumb revision amputation vs replantation. Patients first incur the costs of the initial procedure, recovery, and rehabilitation, which vary by procedure type . Life ex12 , which are a function of level of health  over time (years). Health utility of each injury scenario and procedure type was derived from SF-36 surveys in FRANCHISE based on the methods developed by Brazier and Roberts12 . Because12  codes. For single-finger and thumb-only revision amputation procedures, a mean of CPT codes 26951 and 26952 were used. For 2-, 3-, and 4-finger revision amputation procedures, we doubled, tripled, and quadrupled the costs by multiplying the 1-finger cost by the total number of fingers involved to approximate the variation in reimbursement. For replantation, we used CPT code 20816 for 1-, 2-, 3-, and 4-finger replantation and 20827 for thumb replantation. Anesthesia costs were drawn from Medicare reimbursements and were accounted for the initial procedures and complications. Hand therapy costs were provided by hand therapists at Michigan Medicine based on CPT codes  were varied based on sources listed in 40 Two-way sensitivity analysis was performed by varying the difference in the most important key clinical variables between the 2 procedure types, determined by 1-way sensitivity analyses of all model variables. A probabilistic sensitivity analysis was conducted to simulate uncertainty in all parameters simultaneously. To accomplish this, we used a Monte Carlo simulation with 10 000 iterations of randomly varied inputs in the model. We used those simulation results to calculate 95% credible intervals (CrIs). An a priori significance level was set at P = .05. Statistical package R, version 3.6.0  and Excel (Microsoft Inc) were used for modeling and analysis.The primary outcome measure of this study was the incremental cost-effectiveness ratio (ICER) between replantation and revision amputation. This ratio was calculated by dividing the difference in total cost between the 2 procedures by the difference in QALY gained. We initially performed the base case calculation using mean values of the clinical variables in FRANCHISE. We then performed sensitivity analyses by varying key clinical, utility, and cost factors to determine which factors would have the strongest association with the ICER. Health utility scores were varied by the 95% CI of our data set. Remaining clinical variables , and patients undergoing replantation were younger than those undergoing revision amputation . The overall utility score difference between white and nonwhite patients was not significantly different . The revision amputation cohort had significantly more single-finger injury patterns than the replantation cohort . Health utility scores were higher for those with single-finger injuries  vs multifinger injuries  (P = .001). The mean health utility score was 0.01 to 0.08 points higher for patients undergoing replantation compared with patients undergoing revision amputation depending on injury pattern  participated in the study. Of these patients, 178 underwent finger replantation and 79 underwent revision amputation. Baseline clinical factors between the 2 cohorts, including injured hand laterality, insurance status, sex, and educational level, were not significantly different. More nonwhite patients than white patients underwent replantation , and patients undergoing replantation tended to be younger than their counterparts . In the 36 patients in the thumb-only injury cohort, the patients undergoing replantation had lower education levels  and were more likely to be nonwhite individuals  compared with the patients undergoing revision amputation  for patients younger than 48 years for single-finger (not thumb) injury, younger than 63 years for thumb-only injury, and 78 years for multifinger injuries A. BecausThe relative differences of model variables between replantation and revision amputation were associated with altered cost-effectiveness; thus, 2-way sensitivity analyses of the differences in time off work and utility were conducted. As time off work after replantation increased, replantation became less cost-effective. If the utility difference of replantation vs revision amputation was higher, replantation was more cost-effective. For younger patients between 20 and 40 years of age, even if patients took 6 to 7 months more time off work after replantation compared with revision amputation, when there is a utility difference of at least 0.02, replantation would still be cost-effective A. Two-waProbabilistic sensitivity analysis with 10 000 iterations revealed that the chance of being cost-effective at a willingness-to-pay threshold of $100 000 per QALY would be 47% for single-finger (not thumb) replantation, 52% for thumb-only replantation, 78% for multifinger excluding thumb replantation, and 64% for multifinger including thumb replantation .This study suggests that replantation in single-finger and multifinger injury patterns including or excluding thumb involvement can be cost-effective in certain settings. Furthermore, replantation was more likely to be cost-effective in younger patients (<48 years of age) and those with preinjury wages less than $42 000 per year. For certain older patients with anticipated shorter lifespans and higher costs of recovery, revision amputation may be a more cost-effective choice. Single-finger amputations had a lower probability of being cost-effective after replantation compared with multifinger amputations. However, the results were sensitive to the variability in postsurgical utility scores and wages. Our findings highlight the importance of careful patient selection based on finger amputation pattern, expected postsurgery utility, anticipated recovery time until return to work, and comorbidities to assess the potential cost-effectiveness after replantation.In addition to age at time of injury, life expectancy, and preinjury wages, 2-way sensitivity analyses revealed that minimizing time off work, maximizing postinjury wages, and higher utility gain after replantation vs revision amputation were associated with cost-effectiveness. Because a large proportion of the total cost was attributable to postsurgery wages, the perioperative direct cost associated with complications did not substantially affect the overall cost-effectiveness of replantation. Motivated patients who want to return to work sooner and actively participate in hand therapy may have increased probability of more cost-effective replantation by optimizing time off work and increasing postsurgical salaries.40 Depending on the age at time of injury and life expectancy, presurgery and postsurgery salary, and time off work for recovery, the optimal intervention for traumatic finger amputation may vary. This finding highlights the importance of patient selection in traumatic amputation management before performing replantation or revision amputation.On the basis of the willingness-to-pay threshold of $100 000 per QALY, our study suggests that all traumatic finger amputation patterns, including single-finger injuries, may be cost-effective.One of the strengths of the current study is that the economic analysis was based on a sample of real-world patients who underwent traumatic finger amputations. Another strength of our study is that patients were assessed with the SF-36 at least 1 year after their latest hand surgery, which should ensure incorporation of long-term utility after the acute perioperative changes of quality of life have resolved.41 Future studies should use data from the National Hand Trauma Center Network42 to determine utilities that better reflect the psychological sequelae of traumatic finger amputations by using other methods, such as the discrete choice experiment.43 Despite differences in eliciting utilities, we found similar results as the prior study10 that replantation cost-effectiveness may be associated with injury patterns.This study has limitations. An inherent limitation of the SF-36–derived utilities is that the SF-36 does not directly assess body image or psychological trauma that results from a traumatic finger amputation. However, traditional methods of eliciting utilities, such as the standard gamble and time trade-off for non–life-threatening disease processes, may yield inflated utility values.In addition, we assumed that long-term SF-36 values after replantation or revision amputation are stable 1 year after surgery. More nonwhite patients underwent replantation than white patients, although we found that the utility scores between the 2 racial groups were not significantly different. Ideally, utilities and model parameters should be based on randomized clinical trials, but to our knowledge, there are no randomized clinical trials comparing finger replantation with revision amputation because of ethical reasons. Consequently, the best evidence for this condition is a multicenter study, such as FRANCHISE. Because of the lack of randomization, there is a potential for confounding bias, but our model attempted to overcome such uncertainty through sensitivity analyses. Because of the relative rarity of certain traumatic finger amputation patterns, some injury pattern subgroups had small sample sizes. Our model excluded ambulance costs to the hospital and emergency department fees because we assumed that almost all patients, regardless of their eventual surgical management, initially had similar ambulance costs and were triaged in the emergency department. In addition, transportation costs to clinic visits were excluded because we assumed that the wages lost secondary to time off work would render transportation costs negligible. Also, emergency department fees were excluded in our analysis because patients in both cohorts likely were billed similar amounts for emergency services.Replantation of all finger amputation patterns, whether single-finger or multifinger injuries, may be cost-effective with proper patient selection. Because cost-effectiveness was associated with injury pattern and patient characteristics, if replantation is technically feasible, a thorough patient assessment and interview appear to be advisable before the surgeon chooses a treatment modality. Cost-effectiveness should not be the sole basis of clinical decision-making; however, cost-effectiveness information combined with patient-reported outcomes and clinical outcomes should be the foundation for a national traumatic finger amputation management guideline.


Disease, trauma, and aging account for a significant number of clinical disorders. Regenerative medicine is emerging as a very promising therapeutic option. The design and development of new cell-customised biomaterials able to mimic extracellular matrix (ECM) functionalities represents one of the major strategies to control the cell fate and stimulate tissue regeneration. Recently, hydrogels have received a considerable interest for their use in the modulation and control of cell fate during the regeneration processes. Several synthetic bioresponsive hydrogels are being developed in order to facilitate cell-matrix and cell-cell interactions. In this review, new strategies and future perspectives of such synthetic cell microenvironments will be highlighted. Bioresponsive hydrogels are dynamic systems that are capable of responding to or stimulating specific signals through the natural biological processes . The posOn the basis of their composition, it is possible to distinguish natural, synthetic, and composite or hybrid hydrogels .d-glucuronic acid and N-acetyl-β-d-glucosamine units, overproduced during the wound healing process.Natural hydrogels are made up of natural biomacromolecules including proteins and polysaccharides. These biomacromolecules have different natural origins . Several polysaccharide-based or protein-based hydrogels have been synthesized. A number of examples of polysaccharide-based hydrogels with tuneable properties are available for cartilage and bone tissue engineering applications. Most cited hydrogels for these applications have been prepared using hyaluronic acid , chitosad-glucosamine and N-acetyl-d-glucosamine units derived from chitin, a constituent of arthropod exoskeletons, but its structure is similar to naturally occurring GAGs. One of the main chitosan properties is its solubility in diluted acids by protonation of the amino groups so that it can be gelled, for example, by pH increase. Chitosan hydrogels were also obtained via UV-assisted photopolymerization, via cross-linking agents , or thermal variations . Ep. Ep41]. In other examples, transforming growth factor-β1 (TGF-β1) was linked to photopolymerizable methacrylated chitosan (MeGC) hydrogels  and to aToward cardiac tissue regeneration, several hydrogels functionalised with different or multiple growth factors have been proposed. For example, stromal derived factor-1α (SDF-1α) conjugated to a PEG hydrogel  in vivo 121) and the recombinant fibronectin type III repeat 9-10 fragment (FN9-10) , w, w57], we groups b.Alginate functionalised with the knuckle epitope was shown to increase alkaline phosphatase activity in clonally derived murine osteoblasts, while with clonally derived murine mesenchymal stem cells it initiated Smad signalling, up-regulated osteopontin production, and increased mineral deposition.Alginate-based hydrogels were also bioconjugated to the YIGSR peptide through amide bonds to the carboxylic acid groups of the alginate. The peptide-modified alginate hydrogels allowed adhesion of NB2a neuroblastoma cells and promoted neurite outgrowth . The adh2O2) and horseradish peroxidase (HRP) allowed the formation of the gel by oxidative cross-linking [Thanks to their unique properties in signalling and cell development, glycans represent an interesting class of molecules to incorporate in hydrogels to make them bioresponsive. There are several examples of glycan epitopes used to bio-activate natural and synthetic materials . In hydr-linking . In vivoLong-term in vitro maintenance of primary hepatocytes is a burden for hepatic tissue engineering, since these cells lose their phenotype in standard culture conditions. Foster et al. studied the use of heparin-containing hydrogels as scaffolds for the culture and for the maintenance of functional primary hepatocytes . ThiolatPromising approaches in tissue regeneration rely on both suitable scaffold design and on the application of stem cells and the development of efficient approaches to control their fate. Recently, several small molecules have been identified as able to induce stem cell differentiation both in vitro and in vivo . Within 2O2.For example, tyramine ,64 and dThe resulting hydrogels are cytocompatible when assayed with NIH 3T3 cells. In addition, compared with unfunctionalised alginate hydrogels, the dopamine-conjugated hydrogel showed higher cell adhesion and elasticity properties.4 [Catechol moieties were also grafted onto chitosan by reductive amination, and the resulting macromers were gelled through coordinative interaction with transition metal ions, such as iron, or in oxidative conditions by NaIO4 .Chitosan–catechol conjugates were also used as precursors for the synthesis of hybrid hydrogels in the presence of thiolated Pluronic F-127 triblock copolymer; the resulting hybrid material showed temperature-sensitive and adhesive properties to mucous layers and to soft tissues, together with good hemostatic properties useful for wound healing .Other small molecule motifs have been proposed for the formation of biofunctional supramolecular hydrogels, such as bisphosphonates or glucosamine, that showed wound-healing properties .Small molecules can be grafted onto hydrogel macromers in order to induce a specific cellular response or to promote cell differentiation. Bisphosphonate moieties have been grafted onto hyaluronic acid hydrogels in order to promote BMP-2 sequestration and bone regeneration . In moreBiological studies showed that BMP-2 entrapped in hyaluronic acid-bisphosphonates hydrogel maintains its bioactivity, as shown by the induction of osteogenic differentiation of mesenchymal stem cells.A similar approach toward bone tissue regeneration was proposed by Furukawa and co-workers , who devDexamethasone, a synthetic corticosteroid, was also used as a small-molecule for the stimulation of osteogenic differentiation ,72. ThusThe field of hydrogels started with the pioneering Wichterle and Lim in the 1960s ,74. Sinc


Do patients with early-stage bladder cancer undergo cancer surveillance that is aligned with their risk of cancer recurrence?In this US national cohort study of patients with early-stage bladder cancer treated in 85 Department of Veterans Affairs facilities, surveillance was performed at a comparable frequency for low- and high-risk patients within 70 of 85 facilities, differing by less than 1 cystoscopy over 2 years. Across facilities, these findings were reflected in a moderately strong and significant correlation of cystoscopy frequencies for high- and low-risk patients.Risk-aligned surveillance for early-stage bladder cancer is not widely practiced, which should alert those who care for patients with bladder cancer as well as those who care for patients with other neoplasms for which risk-aligned surveillance is recommended. This cohort study assesses cystoscopy frequency for patients with low-risk vs high-risk bladder cancer treated at US Veterans Affairs facilities. Cancer care guidelines recommend aligning surveillance frequency with underlying cancer risk, ie, more frequent surveillance for patients at high vs low risk of cancer recurrence.To assess the extent to which such risk-aligned surveillance is practiced within US Department of Veterans Affairs facilities by classifying surveillance patterns for low- vs high-risk patients with early-stage bladder cancer.US national retrospective cohort study of a population-based sample of patients diagnosed with low-risk or high-risk early-stage bladder between January 1, 2005, and December 31, 2011, with follow-up through December 31, 2014. Analyses were performed March 2017 to April 2018. The study included all Veterans Affairs facilities (n = 85) where both low- and high-risk patients were treated.Low-risk vs high-risk cancer status, based on definitions from the European Association of Urology risk stratification guidelines and on data extracted from diagnostic pathology reports via validated natural language processing algorithms.Adjusted cystoscopy frequency for low-risk and high-risk patients for each facility, estimated using multilevel modeling.r = 0.52; P < .001).The study included 1278 low-risk and 2115 high-risk patients . Across facilities, the adjusted frequency of surveillance cystoscopy ranged from 3.7 to 6.2  procedures over 2 years per patient for low-risk patients and from 4.6 to 6.0  procedures over 2 years per patient for high-risk patients. In 70 of 85 facilities, surveillance was performed at a comparable frequency for low- and high-risk patients, differing by less than 1 cystoscopy over 2 years. Surveillance frequency among high-risk patients statistically significantly exceeded surveillance among low-risk patients at only 4 facilities. Across all facilities, surveillance frequencies for low- vs high-risk patients were moderately strongly correlated (Patients with early-stage bladder cancer undergo cystoscopic surveillance at comparable frequencies regardless of risk. This finding highlights the need to understand barriers to risk-aligned surveillance with the goal of making it easier for clinicians to deliver it in routine practice. Such risk-aligned surveillance entails more frequent surveillance for patients at high vs low risk of recurrence. For example, recommendations for computed tomography surveillance after treatment for kidney cancer range from every 3 to 6 months for stage II or III disease to every year for stage I disease.7 When cancer is identified, patients typically undergo transurethral resection.8 Based on pathologic findings, three-quarters of patients are diagnosed with early-stage disease and then undergo periodic cystoscopic surveillance with close inspection of the bladder mucosa.10 Broad consensus holds that the frequency of cystoscopic surveillance should align with each patient’s cancer risk,11 with risk-aligned surveillance recommended by 8 national and international panels.18 Specifically, low-risk patients are recommended to receive no more than 3 cystoscopy procedures during the first 2 years after diagnosis; high-risk patients should receive 6 to 8.11 Previous studies, including those using Surveillance Epidemiology and End Results Medicare data,19 have demonstrated that bladder cancer surveillance is often not aligned with underlying cancer risk. However, studies were limited to assessing care delivered in a fee-for-service environment and by lack of the longitudinal pathology data needed to accurately assign risk.Surveillance after treatment of early-stage bladder cancer is a prime example of risk-aligned surveillance. Bladder cancer is the fourth most prevalent noncutaneous cancer in the United States.20 we sought to study national patterns of care and simultaneously identify local models of best-practice risk-aligned surveillance.We assessed the extent to which risk-aligned surveillance is practiced across and within Department of Veterans Affairs (VA) facilities by classifying surveillance patterns for low- vs high-risk patients with early-stage bladder cancer. Taking advantage of national data—including longitudinal pathology data—from the largest integrated health care system in the United States,STROBE) reporting guideline. Patient informed consent was waived because use of the data involved no more than minimum risk to the privacy of patients and the research could not be practically conducted without waiving informed consent.Our overall goal was to compare the frequency of cystoscopic surveillance among patients with low-risk vs high-risk bladder cancer across and within all facilities that perform bladder cancer surveillance in the VA. We proceeded along the following 4 steps: (1) identification of a cohort of patients with newly diagnosed bladder cancer who underwent surveillance in the VA, (2) assessment of low- or high-risk cancer status, (3) measurement of cystoscopic surveillance, and (4) analyses focused on comparing surveillance frequency among low- and high-risk patients across and within facilities. The study was approved by the Veteran’s Institutional Review Board of Northern New England and the University of Utah Institutional Review Board and follows the Strengthening the Reporting of Observational Studies in Epidemiology , and those without pathology data around the diagnosis date  of missing pathology reports (256 patients from 39 facilities). After excluding patients with incomplete covariate data (n = 16), 6708 patients with complete clinical information remained. Of these, 2417 had ineligible pathology  and thus were not eligible for cystoscopic surveillance. Eight hundred sixty patients had uncertain pathology , leaving 3431 patients with early-stage bladder cancer from 91 facilities .22 we defined low-risk cancer status as a primary low-grade noninvasive urothelial carcinoma and high-risk cancer status as a urothelial carcinoma that was either high-grade noninvasive, invasive into the lamina propria (T1), or associated with carcinoma in situ. We operationalized these definitions using data extracted from full-text pathology reports via validated natural language processing algorithms.23 We used pathology reports dated 90 days before to 90 days after the diagnosis date. Because of our focus on comparing cystoscopic surveillance for low- vs high-risk patients across and within facilities, we excluded 38 patients from 6 facilities where either only low- or high-risk patients were treated. Thus, 1278 low-risk and 2115 high-risk patients from 85 facilities remained for analyses , whichever occurred first. We followed patients only until they had a cancer recurrence, because a recurrence increases risk for further recurrences and thus changes a patient’s cancer risk status.22 We ascertained cancer recurrences using data extracted from full-text pathology reports via the validated natural language processing algorithms.23 Next, we enumerated the number of cystoscopy procedures each patient underwent during the follow-up period. We only counted those cystoscopy procedures that occurred at least 30 days following a previous procedure,25 because procedure codes occurring in close proximity to each other are unlikely to indicate routine surveillance  and may sometimes even refer to the same procedure. The majority of patients (86.6% [2937 of 3393]) received cystoscopy procedures at only 1 facility; the remaining patients were assigned to the facility where they received the plurality of their cystoscopy procedures.We used 26 Facility characteristics were obtained from the Veterans Health Administration’s Support Service Center and included number of hospital beds, unique patients per year, urology outpatient visits per year, urologist full-time equivalents, rural location, and academic affiliation.27Data management was performed from December 2015 to February 2017. Data analyses were performed from March 2017 to April 2018. Descriptive statistics were used to describe both patient and facility characteristics. Patient characteristics included age at the time of bladder cancer diagnosis, sex, race, year of diagnosis, and comorbidity using the enhanced Elixhauser index.28 The logarithm of length of follow-up was included as an offset.Negative binomial multilevel models were used to calculate the adjusted cystoscopy frequency for each facility. The outcome was the patient-level number of cystoscopy procedures during the follow-up period. Models contained a random intercept for facility. They were adjusted for age (≥80 years) and comorbidity (>3 comorbidities) to account for differences across facilities in age and comorbidity, which might independently inform surveillance frequency. To account for time trends, we adjusted for year of diagnosis. We also included an indicator variable to denote whether patients were followed for longer than 2 years, because guideline recommendations specify that frequency of follow-up can be decreased at that point.29 This approach accounted for differences in the reliability of estimated facility-level cystoscopy frequencies due to differences in sample size by shrinking the estimates of facilities with a small number of patients closer to the overall mean.29Separate models were fit for low- and high-risk patients. From these models, we then calculated the frequency of cystoscopic surveillance for each facility with corresponding 95% confidence intervals for an average low- or high-risk patient diagnosed in 2011 using empirical Bayes estimation.To assess the strength of correlation between cystoscopy frequencies for low- and high-risk patients across facilities, we calculated the Pearson correlation coefficient. We determined which facilities, on average, performed at least 1 cystoscopy more over 2 years for high-risk than for low-risk patients. We also assessed whether surveillance frequency was statistically significantly different within each facility for high- vs low-risk patients. For this, a separate negative binomial model for each facility was fit, with the main exposure being high- vs low-risk cancer status while adjusting for the same covariates.29 In this analysis, we calculated the number of cystoscopies performed per 2 years for each patient. We only included patients who had at least 1 year of follow-up and followed them for up to 2 years after diagnosis. This was done to limit the effect of very short or very long follow-up on the calculated number of cystoscopies per 2 years. Next, we limited this sensitivity analysis to facilities that had at least 10 low-risk and 10 high-risk patients in the data set (618 low-risk and 709 high-risk patients across 33 facilities). For each facility, we calculated the unadjusted mean frequency of cystoscopy for low- and high-risk patients. Strength of correlation was assessed between these frequencies using the Pearson correlation coefficient.We performed 2 sensitivity analyses. First, we performed a simpler analysis to address the potential concern that the multivariable multilevel modeling, adjustment, and shrinkage may have affected our findings.Second, to determine whether reliance on pathology data extracted via natural language processing affected our results, the main analyses were repeated using data abstracted by tumor registrars to characterize cancer risk rather than the natural language processing results. This sensitivity analysis included 1290 low-risk and 3987 high-risk patients. All analyses were performed using SAS statistical software version 9.4 (SAS Institute Inc) and Stata MP statistical software version 15 (StataCorp LLC). Statistical significance was set at 2-sided α < .05 for all analyses.We included 1278 low-risk and 2115 high-risk patients with a median (interquartile range [IQR]) age of 77 (71-82) years; 99% (3368 of 3393) were male. Patients received care across 85 VA facilities from 45 states, the District of Columbia, and Puerto Rico. Each facility contributed a mean (range) of 40 (3-150) patients. 1237 of 3393 patients (36.5%) were aged 80 years or older, and 670 of 3393 (19.8%) had more than 3 comorbidities . FacilitPatients with low-risk cancer underwent a mean (SD) of 5.3 (3.4) cystoscopy procedures during a median (IQR) follow-up of 2.6 (0.9-4.7) years. As expected, patients with high-risk cancer had shorter follow-up periods due to a higher recurrence rate  during which they underwent a mean (SD) of 4.7 (3.7) cystoscopy procedures.Across all facilities, the adjusted frequency of surveillance cystoscopy ranged from 3.7 to 6.2  procedures over 2 years for low-risk patients A and fror = 0.52; P < .001)  . At most < .001) .r = 0.45; P = .008) and cystoscopy was performed at a similar frequency for high- and low-risk patients at most facilities (28 of the 33 included)  could not be assessed. Thus, among low-risk patients, there are likely subgroups of patients who are at lower and somewhat higher risk of cancer recurrence. However, as all low-risk patients had low-grade disease, they are all still at substantially lower risk than the high-risk patients. Finally, the analysis examining differences in surveillance frequency between low- and high-risk patients is predicated on recommendations for risk-aligned surveillance that are based on lower level evidence.11 Nevertheless, 8 panels reviewing current evidence have recommended risk-aligned surveillance,18 which allows for timely detection of progression to muscle-invasive cancer among high-risk patients while sparing low-risk patients unnecessary procedures. Timely detection is important because delays in diagnosis of muscle-invasive cancer are associated with increased mortality.34 Avoiding unnecessary procedures is relevant for patients as they lead to more anxiety, discomfort, and costs.36Although the present study is informed by national data and our findings reflect care received across a large number of distinct facilities, it is not without limitations. First, our data are from the VA and thus generalizability to other settings may be limited. However, previous studies of surveillance of early-stage bladder cancer using Surveillance Epidemiology and End Results Medicare data have also found that risk of cancer recurrence had little impact on the care patients receive.These limitations notwithstanding, our study has important strengths. Because we had access to full-text pathology reports, this is the first population-based study, to our knowledge, on early-stage bladder cancer surveillance in which cancer recurrence could be ascertained. Because recurrence elevates patients’ future risk of further recurrence and thus influences further surveillance, we censored follow-up at the time of cancer recurrence, which has not been possible using other population-based data sets. Second, we used multilevel modeling to account for differences in reliability of facility-level estimates due to differences in the number of patients per facility. Third, to address potential concerns that the use of complex modeling or data obtained via natural language processing affected the validity of our findings, we performed sensitivity analyses using unadjusted data and data abstracted by tumor registrars, which supported our main findings.37 Thus, other factors are likely important contributors to the lack of risk-aligned surveillance and may include limited clinician knowledge of the guidelines, clinicians’ habit to continue what they have always done, and complexity and variability of risk stratification across different guidelines.11 Future work should focus on understanding the barriers to risk-aligned surveillance and on developing strategies to improve surveillance. These strategies should facilitate providers’ ability to deliver risk-aligned surveillance, thus reducing adverse consequences of overuse of surveillance among low-risk patients and of underuse of surveillance among high-risk patients.Our study is the first to assess risk-aligned bladder cancer surveillance in the VA, which has important implications for health policy and future research. Some may argue that financial incentives in a fee-for-service environment are an important factor contributing to more cystoscopy procedures than recommended. However, the VA is a capitated health care system in which such financial incentives do not exist, and we still find substantial overuse of cystoscopy among low-risk patients. In fact, we recently performed patient-level analyses to examine the extent of overuse and found that the number of cystoscopy procedures among low-risk patients is about double what it should be.11 Our findings should alert those who care for patients with bladder cancer and those who care for patients with other neoplasms for which risk-aligned surveillance is recommended. While risk factors, natural history, and tumor-specific characteristics differ across neoplasms, the challenges clinicians face to align surveillance with underlying cancer risk are likely similar.In conclusion, our study highlights that risk-aligned surveillance for early-stage bladder cancer is not widely practiced. On the contrary, patients with high- and low-risk cancer undergo surveillance at comparable frequency, despite recommendations that high-risk patients warrant surveillance at least twice as often.


We are facing a significant challenge in combatting the current opioid and drug epidemic worldwide. In the USA, although there has been notable progress, in 2017 alone 72,000 people died from a narcotic overdose. The NIAAA & NIDA continue to struggle with innovation to curb or eliminate this unwanted epidemic. The current FDA list of approved Medication Assistance Treatments (MATS) work by primarily blocking dopamine function and release at the pre-neuron in the nucleus accumbens. We oppose this option in the long term tertiary treatment but agree for short term harm reduction potential.®) and the development of “Precision Addiction Management (PAM)” to potentially combat the opioid/psychostimulant epidemic.As an alternative motif, the utilization of a well-researched neuro-nutrient called KB220 has been intensely investigated in at least 38 studies showing evident effects related to everything from AMA rate, attenuation of craving behavior, reward system activation including BOLD dopamine signaling, relapse prevention, as well as reduction in stress, anger, and aggressive behaviors. We are continuing research especially as it relates to genetic risk, including the now patented Genetic Addiction Risk Score .With that said, we are encouraged about these results as published over the last 50 years and look forward to continued advancements related to appropriate nutrigenomic solutions to the millions of victims of all addictions  called Reward Surfeit Syndrome (RSS) in adolescents and Reward Deficiency Syndrome (RDS) in adulthood. Such phenotypes are precisely characterized using the Genetic Addiction Risk Score (GARS). Dopamine homeostasis may thus be achieved via PAM, the customization of neuro-nutrient supplementation (KB220 variants based on previous research with KB220) tied to the GARS test result, along with a behavioral/ spiritual intervention ,42. The opioid crisis/epidemic including over-prescription and overuse of opioid drugs in North America since over the last three decades is of major concern. Opioids fit within a diverse class of moderately strong painkillers, including oxycodone, hydrocodone, and a powerful painkiller, fentanyl, which is synthesized to resemble other opiates such as opium-derived morphine and heroin. The CDC estimate of $78.5 billion as the annual cost of prescription opioid abuse is only a fraction of the total cost of chronic pain on society. Using data from 2008, researchers from Johns Hopkins University estimated that the economic cost of pain in the United States ranged from $560 to $635 billion annually. Others have estimated that it is now north of one trillion. The origins of the opioid crisis, which killed approximately 72k last year based on federal figures, were also shown in 1986 when the World Health Organization identified the inadequate treatment for pain as a serious public health concern and encouraged physicians to prescribe opioid analgesics for cancer patients. Drug overdose deaths are continuing to increase in the US:Within the years of 1999 to 2016, greater than 630k people passed away from an overdose.Approximately 66% of the more than 63.6k overdose fatalities in 2016 involved an opioid.In 2016, the number of overdose deaths involving opioids  was five times higher than in 1999.On average, 115 Americans die every day from an opioid overdose see .While the current use of MATS may have the ability to reduce societal harm in the short term, they are only the tip of the iceberg and do not address the cause of the epidemic. We contend that instead of blocking brain dopamine, balancing dopamine, is more reasonable.In this regard, we present here in an annotated body of work representing approximately five decades of research related to a neuro-nutrient called KB220, providing a scientific basis for its adoption in the addiction and even pain space.In genetically prone alcohol-liking mice, the increase of brain opioid peptides, such as enkephalin, by administering D-phenylalanine (now in KB220/restoregen), significantly reduced their intake of alcohol to the same level of alcohol-hating mice . This reIn two independent studies in mice, it has been shown that both the serotonin precursor amino-acid L-Tryptophan, and the dopamine precursor L-Dopa, significantly increase sleep-time in mice following alcohol administration compared to saline placebo ,3. This Administering the KB220 variant in 22 sever alcoholics attending a residential program undergoing withdrawal resulted in an attenuated drink score, required no PRN benzodiazepines, and patients ceased having tremors 24 hours earlier and had less depression . Results demonstrate the AMA rates to be:- [C] 37.5%; [S] 26.6%; [T] 4.2%. Moreover, Tropamine decreased the AMA rate by significant reduction of drug hunger. This represents the beginning of precision medication therapy  (a narcotic antagonist) and amino-acids was used to detoxify either methadone or heroin addicts. Results were dramatic regarding significantly enhancing compliance in taking Trexan. When taking Trexan alone for rapid detoxification, the average number of days of compliance calculated on 1000 patients is 37 days.In this study, 12 subjects received the combined Trexan and amino-acid therapy, taking the combination for an average of 262 days of compliance. This study suggests the importance of coupling amino-acid therapy and enkephalinase inhibition, thereby leading to dopamine balance while blocking the delta-receptors with a pure narcotic antagonist and demonstrating a rapid and novel technique to induce detox in chronic methadone patients and prevent relapse  to combat obesity with particular emphasis on body composition . A group of 21 participants was evaluated in a preliminary investigational study of LG839. Pre- and post-ad hoc analysis revealed a significant difference between the starting BMI and the BMI following an average of 41 days (range of 2870 days) of LG839 intake in the 21 individuals. The pre-BMI was 31.2 . Polymorphic correlates were obtained for many genes  with various clinical parameters. We observed significant results for the appetite suppression; decreases in sugar cravings, snacks and late night eating and even weight. There was also an increase in energy. It is of interest that only the DRD2 gene polymorphism  had a significant Pearson correlation with days on treatment, indicating that carriers of the A1 allele of DRD2 were the most compliant to treatment . The impIt was hypothesized that genotyping specific known candidate genes would provide DNA-individualized customized nutraceuticals that may have a significant influence on body composition by countering various genetic traits. Twenty-one subjects were genotyped for the dopamine D2 receptor (DRD2), as well as methylenetetrahydrofolate reductase (MTHFR), the serotonin receptor (5-HT2a), Peroxisome Proliferator Activated Receptor gamma (PPAR-γ), and the Leptin (OB) genes. These genes were systematically evaluated of these five candidate genes as potentially critical biological targets used in the development of the nutraceutical LG839  to combat obesity with particular emphasis on body composition . In a trail of 41-day, we observed a trend in weight loss whereby 71.4% of subjects lost weight . This exBrain dopamine has been referred to as the so-called “anti-stress molecule”. In one study, the anti-anxiety effects of Synaptamine Complex (previous version of KB220), a pro-dopamine regulator, was investigated in a randomized, double-blind placebo-controlled study in alcoholics and polydrug abusers attending an inpatient chemical dependency program. 62 patients receiving Synaptamine Complex had significantly reduced stress compared to patients receiving the placebo. Two-factor measures analyses of variance (ANOVA) divulged significant differences as a function of time and treatment, as well as a significant interaction between them [A case study evaluated sustained weight loss associated with treatment with the Synaptamine complex was used in conjunction with Diethypropion (Tenuate®), a hormonal repletion therapy, the use of the Rainbow Diet®, and the addition of light exercise. After one year, the 58-year-old male patient’s BMI decreased from 32 to 25.4. Additionally, his body fat composition showed a proportional decrease from 36.91% to 17.8%on the Hologic DEXA scanner. This study represents synergism with known anti-weight loss products . This reIn two open-label case studies, intravenous Synaptamine complex KB220 variant) was administered during protracted abstinence from alcohol and opiates. Results indicate that the qEEG of an alcoholic (with widespread theta activity) and a heroin abuser  during protracted abstinence are significantly normalized by the administration of one intravenous dose of Synaptamine Complex Variant KB220 [0 variantIt is well-known that both food and drug addicts have a “dopamine resistance” due to the Taq A1 allele of the DRD2 receptor gene. Based on earlier studies, the evidence is emerging wherein the potential of utilizing a natural, non-addicting, dopamine precursors may play a significant role in the recovery of individuals with RDS, including those addicted to psychoactive chemicals.In a randomized, triple-blind, placebo-controlled crossover study with Synaptose Complex KB220Z™, positive outcomes were observed using qEEG. Within the parietal lobes, an increase in both alpha and low beta waves was found. Also, a significant difference between placebo and the compound across the frontal lobes after both weeks one and two was found. The results are divulged a phase change from a low amplitude to a more regulated state by increasing amplitude across the prefrontal cortex. In the first experiment, while 50% of the subjects carried the DRD2 A1 allele, 100% carried at least one risk allele. Specifically, based on our proposed addiction risk score for these 14 participants, 72% of them had a moderate-to-severe addiction risk. Similar findings by repeating the experiment in three additional currently abstinent polydrug abusers carrying the DRD2 A1 allele was also observed . This exIn this study, the effects of combined administration of tyrosine, lecithin, L-glutamine, and L-5-hydroxytryptophan (5-HTP) [ingredients in KB220) on heroin withdrawal symptoms within detoxified heroin addicts was evaluated. In the cluster-randomized placebo-controlled trial, the authors utilized 83 detoxified heroin addicts from a detoxification treatment center in Wuhan, China. The patients in the intervention group (n=41) were given the combined treatment with lecithin, L-glutamine, L-tyrosine, and 5-HTP. Those within the control group (n=42) were administered a placebo. The results showed that scored for withdrawal and insomnia was significantly improved in the intervention group. A more significant reduction in tension-anxiety, depression-dejection, anger-hostility, fatigue-inertia, and total mood disturbance, and a more significant increase in their vigor-activity symptoms were found at day 6 in the intervention group than in the control placebo group . This reIn this study, the authors evaluated a known natural dopaminergic agonist KB220IV (KB220 variant) along with oral variants directed toward overcoming hypodopaminergic function in 129 subjects. In their first pilot experiment, they found a significant reduction of chronic symptoms as measured by the Chronic Abstinence Symptom Severity (CASS) Scale for both intravenous (IV) and oral compared to only oral administration. Specifically, the IV and the oral group did significantly better than the oral only group over the first week and additionally over the following 30 days. In a two year follow-up of 23 subjects who underwent KB220IV therapy (with a minimum of five IV treatments over a one week period) plus orals for at least 30 days: 21 (91%) were sober after six months. Additionally, 19 (82%) had no relapse. Furthermore, 19 (82%) were sober at one year, with 18 (78%) having no relapse. Finally, 21 (91%) were sober at two-years post-treatment with 16 (70%) having no relapse. Overall KB220 variants induced a high degree of abstinence even after a two-year period . While tNumerous studies have supported the efficacy of methadone and buprenorphine treatments for the stabilization and maintenance of opioid dependence. As expected, there are often clinically significant withdrawal symptoms that occur upon tapering and cessation of dosage of the opioid.We present a case study of a 35-year-old Caucasian female. She was prescribed increasing dosages of prescription opioids after carpel tunnel surgery secondary to chronic pain from reflex sympathetic dystrophy and fibromyalgia. Over the next five years, her daily dosage requirements continued to increase to over 80mg of Methadone combined with 300ug/hr Fentanyl transdermal patches, along with combinations of 12–14 1600mcg Actiq lollipop and oral 100mg Morphine and 30mg oxycodone 1–2 tabs q 4–6hr. PRN for any breakthrough pain. Her total monthly prescription costs, including those of supplemental benzodiazepines, hypnotics, and stimulants, exceeded $50k. The patient was genotyped using a reward gene panel including : DRD 2,3,4; MOA-A; COMT; DAT1; 5-HTTLPR; OPRM1; and GABRA3. We documented with great care her withdrawal symptoms when she hastily discontinued her buprenorphine/ naloxone combination. At 432 days post-Suboxone® withdrawal, the patient is being maintained on KB220Z, has been urine tested, and is opioid-free. Genotyping data divulged a moderate genetic risk for addiction showing a hypodopaminergic trait . The utiLucid dreams might be associated with various psychiatric conditions. This may include Post-Traumatic Stress Disorder (PTSD) and as well as Reward Deficiency Syndrome-associated diagnoses. In a publication, we presented two cases of the dramatic alleviation of terrifying lucid dreams in patients with PTSD. The medication-visit notes revealed changes in the frequency, intensity, and nature of these dreams after the complex putative dopamine agonist KB220Z (a KB220 variant) was added as an adjunct to the first patient’s regimen. When the second PTSD patient, one with a history of lucid nightmares, was administered KB220Z to attenuate his methadone withdrawal symptoms, he incidentally reported dreams full of happiness and laughter . It is c™ (KB220 variant), was correlated with the elimination of unpleasant and terrifying, lucid nightmares in 87.5% of our cases. Additionally, one very heavy cocaine abuser had minimal response. Each of the patients was diagnosed with a type of RDS, i.e., ADHD, or Tourette’s syndrome. Furthermore, they also suffered from comorbidities such as Post-Traumatic-Stress-Disorder (PTSD) and various other psychiatric diagnoses as well [In another publication, we reported eight cases of SUD, with a history of PTSD/RDS and childhood abuse. KB200Z as well . While tet al. reported that cocaine users and even non-substance-related addictive behavior increases as the dopaminergic function is decreased. Chronic cocaine use has been shown to cause decreases in D2/ D3 receptors. This also correlated with decreased activation to cues in the cerebellum and occipital lobe in a recent PET study by Volkow’s et al. KB220Z (a KB220 variant) induced an increase in BOLD fMRI activation in caudate-accumbens-dopaminergic pathways compared to placebo following 1-hour acute administration in ten abstinent heroin addicts. The authors observed an increase in functional connectivity in a brain network that included medial frontal gyrus, dorsal anterior cingulate, posterior cingulate, nucleus accumbens, cerebellum, and occipital cortex. Results suggested an apparent anti-craving/anti-relapse role of KB220Z in addiction by direct or indirect dopaminergic interaction [Willuhn eraction .This work extends the positive findings using QEEG with heroin dependence as reported earlier. The BOLD rsfMRI findings showing actuiavtion of dopamine at the caudate-accumbens and the attenuation of the BOLD signal at the cerebellum, provides a clear representation of Pro-dopamine regulation and subsequent induction of “doamine homeostasis”. Importantly, these data supports the role of hypodopaminergia linked to escalation of cocaine seeking behavior.In order to explore the initiation of detoxification of addictive patients to opiates/opioids , the authors developed a protocol to be utilized in treatment centers particularly with heavily dependent opiate/opioid subjects. Out of 17 subjects, only three received Buprenorphine/ Naloxone (Bup/nx) along with KB220Z. In this pilot, we first used a dose of KB220Z of 2 oz twice daily before meals along with clonidine and benzodiazepines and other anti-nausea and sleep aids including Gabapentin. The dose of KB220Z was maintained for six days in five individuals. In a second scenario, we utilized a higher dose of 4 oz every 6 hours, over a 6-day period. The higher dose was employed in another 12 patients. It is noteworthy that only three people have relapsed utilizing these two protocols during the first two weeks of the study, allowing for the remaining 82% to be maintained on KB220Z. The patients have been maintained without any additional Bup/nx for a minimum of 120 days and in one subject, 214 days . While tA reward dysfunction in dopaminergic/addictive behaviors is supported by a plethora of studies. There is ample evidence that changes in synchronous neural activity between brain regions involved in reward-related behaviors and various cognitive functions, which may significantly contribute to SUDs. One study presented the first evidence showing that a pro-dopaminergic nutraceutical (KB220Z a KB220 variant) significantly enhanced, greater than placebo, the functional connectivity between reward and the cognitive areas of the rat brain. These brain areas included the nucleus accumbens, neighboring hippocampus, anterior cingulate gyrus, anterior thalamic nuclei, prelimbic and infralimbic loci. Results revealed significant functional connectivity with increased brain connectivity and volume recruitment , and dopaminergic functionality was found across the brain’s reward circuitry. These increases in functional connectivity tended to be specific to these regions. They were not broadly distributed across the entire brain. While these initial findings have been found within drug naïve rodents, this robust, yet selective response implies clinical relevance for addicted individuals at risk for relapse, who show reductions in functional connectivity after protracted withdrawal. Future studies will evaluate KB220Z in animal models of addiction . While tIn another publication, the authors presented four cases in which there was a noticeable and persistent alleviation of terrifying, lucid nightmares in patients diagnosed with comorbid ADHD and PTSD with a specific SUD (opiate/opioid addictions).The cessation of these nightmares may be permanent, as the patients had stopped taking the nutraceutical for between 10 −12 months, without recurrence. In case one, the authors evaluated a 47-year-old married man that required the chronic use of Buprenorphine/ Naloxone (Suboxone) treatments. In case two, we had a 32-year-old female with ADHD. In case three, we had a 38-year-old man with ADHD and comorbid SUD. In case four, the authors presented a 50-year-old female with comorbid diagnoses of ADHD, PTSD and alcohol abuse. Perhaps pertinently, to attempt to understand neuroplasticity, they employed KB220Z (a KB220 variant) in non-opioid-addicted rats utilizing fMRI methods. While the authors cannot make any definitive claims because the functional connectivity of the rat brain may not correspond precisely to that of humans, it does provide some interesting clues. The authors did find the following seeding of the dorsal hippocampus, enhanced connectivity volume across several Regions of Interest (ROIs), except for the prefrontal cortex (PFC). Most notably, the PFC is infrequently activated during lucid dreaming .th percentile (pretest) to the 76th percentile, after the first administration of KB220z and, later, to the 98th percentile, after the second administration of KB220z, six months later [With aging, there is a well-known decline in both long and short-term memory. This effect is intensified by epigenetic insults on specific, dopamine-related genes . Additionally, long-term memory ability and dopamine function are positively correlated. There is ample evidence that aging is associated with a decrease in brain dopamine D2 receptors, with an acceleration seen in aging-induced dementia. In one study, the authors examined the acute effect of a KB220Z (liquid Nano variant) on a specific aspect of long-term memory performance in a 77-year-old, highly functional male, using the Animal Naming Test (ANT). The improvement of long-term memory retrieval had initially been noted during the patient’s follow-up neurology exam, after he had been, for other reasons, taking KB220z. The patient had been given many ANTs by his primary and, later, another neurologist, from 2013 to 2016. Because the number of ANT observations was small (N=7 with two groups) and the data uncorrelated, a non-parametric Wilcoxon-Mann-Whitney test was performed to test mean differences. After KB220z, the patient had much higher scores (p=0.04762) on the ANT vs. when not taking it. His scores increased from the 30hs later . Since tAttention Deficit-Hyperactivity Disorder (ADHD) often fails to abate beyond adolescence, lasting into adulthood. Recent neuroimaging studies of such individual’s divulged lower baseline of dopamine tone within the brains of these affected individuals might place them at risk for comorbid Substance Use Disorder (SUD) as well. This is an observational case study about the potential for innovative management of Adult ADHD with a non-addictive glutamatergic-dopaminergic optimization complex KB200z (a KB220 variant). Low-resolution electromagnetic tomography (LORETA) was employed to evaluate the effects of KB220z on a 72-year-old male with ADHD, at a baseline condition and subsequently one hour following administration of the compound. Analysis of z-scores that were averaged across various conditions , were increased within each frequency band, within the dorsal, anterior, and posterior regions of the cingulate, as well as the right dorsolateral prefrontal cortex during the working memory task with the KB220z compound.These results are consistent with various human and animal neuroimaging studies that have demonstrated an increased connectivity volume in reward circuitry. This may offer a new approach to ADHD treatment . While aThe authors report a self-assessment of a highly functional professional under work-related stress following KB220Z (a KB220 variant) use, a liquid (aqua) Nano-glutamatergic-dopaminergic optimization complex (GDOC). The subject took GDOC for one month. During the first three days in the compound, unique brain activation occurred. This resembled that of white noise after 30 minutes, and the sensation was intense for 45 minutes and then dissipated. He described the effect as if his eyesight improved slightly and pointed out that his sense of smell and sleep significantly improved. His subjectively experienced a calming effect that was similar to meditation which could be linked to increased dopamine release. Additionally, he claimed to be able to control going over the edge after a stressful day’s work. This was paired with a slight, yet noticeable increase in energy, increased motivation to work, increased focus and multi-tasking, with a more definite purpose of the tasks at hand. Subjectively, he felt less inhibited in a social setting and suggested that the GDOC increased his Behavioral Activation System (reward) while having a decrease in his Behavioral Inhibition System (caution) . This caBased on previous scientific evidence showing KB220Z nutrigenomic amino-acid therapy (a KB220 variant) to rapidly (post-one-hour) activate dopaminergic pathways in both the pre-frontal cortex cingulate gyrus (relapse loci) and ventral tegmental area-caudate-accumbens-putamen (craving and emotion loci), the patient was prescribed KB220Z. Within one week of utilization, the repetitive paraphilia was eliminated. There were also many other positive effects such as enhanced focus that persisted even after the patient stopped using KB220Z suggesting neuroplasticity  . This caBinge drinking (BD) is a serious but preventable public health problem in the United States and worldwide. BD and substance use disorders may be co-morbid with more generalized Reward Deficiency Syndrome (RDS), characterized by a reduction in dopamine (DA) signaling within the reward pathway, and classically associated with increased drug-seeking behavior. It is postulated here that increasing dopamine availability and thus restoring DA homeostasis in the mesocorticolimbic system could reduce the cravings and motivation to seek and consume ethanol. In this study, the authors used neuro-nutrient KB220, a nutraceutical product designed to supply the brain with molecular precursors and neurotransmitter catabolic inhibitors that augment DA signaling to elucidate its effects specifically on ethanol drinking. Using alcohol-preferring (P) adult male and female rats in an operant binge drinking paradigm genetically, the authors evaluated whether KB220 was sufficient to reduce drinking and the most efficacious route for its administration.They also evaluated its effects on open field activity and risk-taking behavior. KB220 markedly and immediately reduced binge drinking in both male and female rats via IP and SC administration (p<0.05) whereas P.O. took at least three days to decrease lever pressing in both male and female rats (p<0.05), suggesting a slower metabolism and delayed effect on the brain by P.O. Elevated activity in the open field was significantly decreased (p<0.05), and risk-taking behavior was moderately reduced. Overall, this data suggests that KB220 attenuates drinking behavior and other RDS behaviors in P rats possibly by acting on the dopaminergic system . Work isOver a two-year period, the authors carried out a prospective analysis of 247 outpatients in a very-low-calorie fasting program. Subjects having difficulty attaining their desired weight or maintaining their desired weight constituted the experimental group. At two years, the experimental group that took the amino acid regimen of PhenCal™ (KB220 variant) compared with the non-PhenCal/Centrum™ vitamin control group showed a twofold decrease in the percent overweight . There was a 70% decrease in food cravings for females . Additionally, there was a 66% decrease in binge-eating for females . Most importantly, the experimental group  regained only 14.7% of the weight lost during fasting while the control group  regained 41.7% of the lost weight with PhenCal treatment. Furthermore, morbid obesity and binge eating scores were significant predictors of weight gain after two years. In contrast, family history of chemical dependence was most closely associated, although not statistically significant, with improved results with PhenCal. These data suggest that PhenCal may be an anti-obesity adjunct . This reThis published case series demonstrates the epigenetic repair of the Brain Reward Cascade (BRC) by incorporating pro-dopamine regulation with (KB220ZBR) into treatment. Three case studies of patients with various conditions including mitochondrial metabolic disorder, dysautonomia, hyperacusis, unspecified mood and anxiety disorders, chronic fatigue syndrome, and restless leg syndrome are presented. Patients’ responses to treatment of these conditions with the adjunctive chronic administration of a nutraceutical, prodopamine dietary supplement (KB220ZBR), were assessed before supplementation and following chronic treatment. Significant improvements in psychiatric/neurological symptoms were documented. Following confirmatory results, we encourage other neurologists to consider this safe alternative treatment  While thThis unpublished case study used a double-blind, placebo controlled, cross-over design, to evaluate the effect of KB220Z, a pro-dopamine regulator, on working memory, neuropsychological and behavioral measures of attention in an adult female with Attention Deficit-Hyperactivity Disorder. The participant was tested with eyes closed and with a phonological working memory task. The working memory task required her to remember a random sequence of letters and numbers, and recall them in alphabetical and numerical order.Response measures included the Conner Continuous Performance Test, the Delis-Kaplan Executive Function Inventory, quantitative electroencephalography (QEEG), as well as Low-resolution Electromagnetic Tomography (LORETA). KB220Z, compared to placebo, improved vigilance, response inhibition and verbal fluency functions. Working memory performance substantially improved in response to KB220Z. Quantitative EEG (QEEG) analysis revealed that absolute power in the alpha and theta EEG bands increased during the working memory task, under KB220Z. In addition, Low-resolution Electromagnetic Tomography analysis revealed increases in current source density at 10Hz in the bilateral dorsal cingulate cortices, bilateral hippocampi and bilateral dorsolateral prefrontal cortices, and at 11Hz in the right hippocampus and right dorsolateral prefrontal cortex, during the working memory task in response to KB220Z. Collectively, these results indicate that pro-dopamine regulation with KB220Z improved working memory and prefrontal, neuropsychological function in conjunction with increased activation of brain regions known to manage executive function, working memory and retrieval of declarative information. These findings replicate and extend our prior case study research with KB220Z and support the value of continued research with this Pro-dopamine regulator . The issAs mentioned earlier worldwide daily, millions of people are unable to end their often fatal romance with getting high. For many, the ‘high’ may be just experiencing feelings of normalcy or well-being. The neuroscience community conducts and funds outstanding research using sophisticated neuroimaging and molecular-genetic applied technology to improve understanding of the complex functions of brain reward circuitry, having a key role in addiction symptomatology. While it is an agreed consensus dopamine is a major neurotransmitter implicated in behavioral and substance addictions, there remains controversy about how to modulate dopamine clinically, to treat and prevent various types of addictive disorders see ..As described in this report, a prudent approach may be biphasic, to include a short-term blockade followed by long-term dopaminergic upregulation. The goal of treatment would be to enhance brain reward functional connectivity volume, and target reward deficiency and the stress-like anti reward symptomatology of addiction including attendance of self-help groups . In our


Personalized treatment for cancer patients is a hot topic of debate, particularly the decision to initiate chemotherapy in patients with Estrogen receptor (ER)-positive, HER2-negative tumors in the early stages of breast cancer (BC). Owing to significant advancements in information technology (IT) and genomics, clinicians are increasingly attaining therapeutic goals rapidly and safely by effectively differentiating patient subsets that require chemotherapy. IBM Watson for Oncology (WFO) is a cognitive computing system employed by clinicians to provide evidence-based treatment options for cancer. WFO aids in clinical diagnosis, with claims that it may be superior in performance to human clinicians. The current study was based on the hypothesis that WFO alone cannot effectively determine whether or not chemotherapy is essential for the subset of ER-positive, HER2-negative BC patients.From December 2015 to July 2017, 95 patients with ER-positive, HER2- negative BC subjected to treatment were retrospectively examined using WFO, and outputs compared to real clinical practice. Treatment options were suggested by WFO, and WFO recommendations calculated both with and without data from the gene expression assay (GEA).WFO without GEA was unable to determine the groups of patients that did not require chemotherapy. Concordant therapeutic recommendations between real clinical practice and WFO without GEA were obtained for 23.2% of the patient group. On the other hand, the results of WFO with GEA showed good clinical applicability. Sensitivity, specificity, positive predictive and negative predictive values of WFO with GEA were 100%, 80%, 61% and 100%, respectively.Our collective findings indicate that WFO without the gene expression assay has limited clinical utility. Biomarkers in breast cancer (BC) are essential contributors to therapeutic assessment. In addition to conventional prognostic factors, such as tumor size, grade and nodal status, three established predictive biomarkers, estrogen (ER) and progesterone (PR) receptors and human epidermal growth factor receptor 2 (HER2) status, are utilized for making treatment decisions. Substantial evidence suggests that patients with the ER-positive, HER2-negative subtype in early-stage BC carry a much better prognosis –4. ER-poThe EndoPredict (EP) assay is an RT-qPCR-based 12-gene test based on RNA from FFPE tissue in hormone receptor-positive, HER2-negative, nodal-negative and -positive BC managed with adjuvant hormonal treatment alone  that hasRecent advances in information technology (IT) have included the development of IBM Watson for Oncology (WFO), a Memorial Sloan Kettering Cancer Center-trained cognitive computing system, to provide clinicians with evidence-based treatment options for cancer –22. WhenThis retrospective study was based on the hypothesis that the current WFO guidelines do not provide sufficient information for clinicians to make informed decisions on personalized therapy. Clinicopathologic data with or without genomic data were entered into the WFO formula for each patient in a retrospective manner. Therapeutic options generated by WFO were compared with those recommended in real clinical practice for each patient of the study group.Our study included 95 patients treated for early BC in Gachon University Gil Medical Center between Dec 2015 and July 2017. The study group was limited to estrogen receptor (ER)-positive and HER2-negative breast cancer (BC) for which EP assays were conducted successfully. All patients underwent breast conserving surgery or total mastectomy as well as sentinel lymph node biopsy in cases of clinically and radiologically negative axillary lymph nodes. Level I and II axillary dissection were performed for macrometastases or micrometastases of the sentinel lymph node. Formalin-fixed paraffin-embedded (FFPE) tissue samples were derived from patients with primary ER-positive, HER2-negative BC. All FFPE tumor blocks were collected at the time of surgery prior to adjuvant therapy.Clinicopathologic data  were extracted from the pathologic reports. The Ki-67 cutoff point was applied based on the St. Gallen guidelines .The protocol for this retrospective study was reviewed and approved by the Institutional Review Board  of the Gachon University Gil Medical Center. As the study was conducted on a total of 95 consecutive patients from our database and involved no more than minimal risk for the subjects, the Institutional Review Board approved our request for waiver of informed consent. Recommendations of the Declaration of Helsinki for biomedical research engaging human subjects were also followed.EP, a new RNA-based multigene scoring system predicting the likelihood of distant recurrence in patients with early stage, ER-positive and HER2-negative BC treated with adjuvant endocrine therapy, has been described in the literature . EP scorWe retrospectively investigated 95 patients treated with or without chemotherapy in a blinded manner using WFO. Following entry of clinicopathologic data into WFO, EPclin results for each patient were additionally entered into ‘Genetic risk assessment’ within WFO. Treatment options recommended by WFO were calculated either in conjunction with or without EPclin results. Currently, the IBM formula uses Oncotype Dx data that facilitate categorization into three groups: low, intermediate and high risk. In contrast, EP score leads to low and high dichotomous classifications. We further examined the concordance in prognostic ability between Oncotype Dx and EP and substituted the EP score for Oncotype Dx. Based on the assessments, possible therapies were assigned into green, yellow, and red “buckets”, specifically, green for recommended, yellow for under-consideration, and red for not-recommended. Therapeutic option in the green bucket were regarded as a single therapeutic approach by WFO. Within this study group, all patients were categorized as suitable for either endocrine therapy alone or with added chemotherapy. Therapeutic option assigned to the yellow “bucket” were not considered in this study.Statistical analysis was conducted using SPSS Statistics Version 19.0 . The correlations between EP score and tumor grade and trends between EP score and Ki-67 data were analyzed using the Jonckheere-Terpstra test. Associations between WFO options and real clinical practice were calculated using the chi-square test. We used the logistic regression model to compute the odds ratio for chemotherapy. Graphics were generated with GraphPad Prism 6 .Patients and tumor characteristics are detailed in Regarding the molecular EP score, samples from 41 patients (43.2%) showed a low-risk and 54 patients (56.8%) showed a high-risk gene profile. After integration of clinicopathologic factors , the combined clinical and molecular score (EPclin) indicated low risk in 60 (63.2%) and high risk in 35 (36.8%) patients .EPclin-based estimated median 10-year risk for metastases with endocrine therapy alone was 7% for the whole cohort. The estimated median risk was 6% for the EPclin-low group and 16% for the EPclin- high group.The median EP score increased from 4.2 to 5.3 and 8.5 for tumors assigned G1, G2 and G3 grades. In addition, the EP score had a higher median value of 6.9 in tumors with a high Ki-67 index, compared to 4.5 in lingering proliferative tumors. p<0.001). On the other hand, data obtained using WFO combined with EPclin showed good clinical applicability. The sensitivity, specificity, positive predictive and negative predictive values of WFO with EPclin were 100%, 80%, 61% and 100%, respectively. In real clinical practice, nodal positivity was the only significant factor for inclusion of chemotherapy in all cases .WFO results were assessed both with and without EPclin. In the WFO alone assessments, chemotherapy was recommended rather than endocrine therapy only . PatientOwing to better understanding of the utility of biologic markers, such as ER, PR, and HER2, in treatment guidance, tumor biology has become a surrogate of prognosis in BC. Different therapeutic strategies based on biologic subtype have gained prominence in the clinic in recent years. Besides the predictive power of intrinsic breast cancer phenotypes , anatomic staging systems are associated with outcomes, offering predictive synergy. This creates a dilemma that has a particular impact on prognosis in cases of discordance between staging and biological data. In an earlier study, Park and co-workers suggested that patients with node-positive luminal A breast cancer may not benefit from systemic chemotherapy . Accordith edition prognostic stage groups also take into consideration multigene panel testing [Following efforts to incorporate biologic factors in the American Joint Committee for Cancer (AJCC) staging, the 8 testing , 27. AltIn our study, Watson recommended the addition of chemotherapy in most cases when genomic data were not incorporated into the calculation. Chemotherapy was not recommended for 17 out of 95 patients. Differences in chemotherapy indications were related to tumor size and staging. Interestingly, upon integration of EPclin results with WFO and re-assessment of the group for which chemotherapy was not suggested, 5 out of 17 patients were recommended chemotherapy. These 5 patients included 4 with high-risk and 1 with low-risk EPclin scores. The patient classified as low-risk had node-positive BC. In contrast, chemotherapy was not recommended for 44 of 78 patients, among which 31 were grouped as high-risk and 47 as low-risk according to EPclin data. Despite being categorized as low risk, chemotherapy was recommended for 3 patients, since they all had node-positive BC. A higher proportion of patients did not receive chemotherapy in real practice. However, high-risk tumor was detected in 10 of these cases. Clinicians' discretion, clinical decisions, low levels of Ki-67 and patient opinion were associated with these findings. In the clinic, the Ki-67 level is regarded as an important prognostic factor. However, Ki-67 index as a single marker of proliferation was not considered for addition to staging due to its known lack of reproducibility as well as discrepancies in the optimal cutoff point between different laboratories. Our data clearly indicate that Watson combined with EPclin has clinical utility for consideration of chemotherapy, with sensitivity, specificity, positive predictive and negative predictive values of 100%, 80%, 61% and 100%, respectively. Relatively low clinical utility of WFO without genomic data is expected. However, the combination of WFO and genomic risk assay is of considerable utility, and yields similar therapeutic choices to those recommended by clinicians. Therefore, the IBM formula should consider inclusion of genomic assessment as essential rather than optional.Our study had several limitations. First, several unknown confounding factors may affect the results due to its retrospective design. Secondly, a relatively small number of patients were enrolled in our study group. Lastly, the use of different genomic assessment tools could lead to calculation errors in the IBM formula. The IBM formula originally uses Oncotype Dx data with three risk types . However, EPclin generates low and high dichotomous classifications. The predefined cut-off values for diagnostic decisions corresponding to 10% distant recurrence rate at 10 years are applied to stratify patients into EPclin low-risk (<3.3) and EPclin high-risk (≥3.3) groups . Based oIn terms of making informed therapeutic decisions and selecting chemotherapy for treatment of ER-positive, HER2-negative early BC, WFO may deliver significant benefits for clinicians.In ER-positive, HER2-negative early BC cases with low clinicopathologic or genomic risk, chemotherapy is not recommended. Risk stratification by WFO may be not be sufficient for indication of the appropriate therapy.Artificial Intelligence (AI) should be intensively developed and improved to maintain consistency with real diagnostic reasoning performed by human clinicians. Genomic risk assessment may play a positive role in elevating the concordance rate between clinical practice and WFO therapeutic options.We believe that the differences between real practice and Watson do not indicate the superiority of one form of diagnosis (computed versus human) over the other. However, clinicians are ultimately responsible for treatment. AI delivers emerging genomic information but requires further development for effective implementation in the unfolding genomic revolution.


The progress in molecular biology has revolutionized systemic treatment of advanced non-small-cell lung cancer (NSCLC) from conventional chemotherapy to a treatment stratified by histology and genetic aberrations. Tumors harboring a translocation of the anaplastic-lymphoma-kinase (ALK) gene constitute a distinct genetic and clinico-pathologic NSCLC subtype with patients with ALK-positive disease being at a higher risk for developing brain metastases. Due to the introduction of effective targeted therapy with ALK-inhibitors, today, patients with advanced ALK-positive NSCLC achieve high overall response rates and remain progression-free for long time intervals. Moreover, ALK-inhibitors seem to exhibit efficacy in the treatment of brain metastases. In the light of this, it needs to be discussed how treatment algorithms for managing patients with brain metastases should be modified. By integrating systemic ALK-inhibitor therapy, radiotherapy, in particular whole brain radiotherapy might be postponed deferring potential long-term impairment by neurocognitive deficits to a later time point in the course of the disease. An early treatment of asymptomatic brain metastases might offer patients a longer time without impairment of cerebral symptoms or radiotherapeutic interventions. Based on an updated extensive review of the literature this article provides an overview on the epidemiology and the treatment of patients’ brain metastases. It describes the specifics of ALK-positive disease and proposes an algorithm for the treatment of patients with advanced ALK-positive NSCLC and brain metastases. Lung cancer remains one of the major challenges in oncology. It is the most frequent cause of cancer death worldwide , 2, 3. ITreatment of patients with non-small-cell lung cancer (NSCLC) is guided by disease stage. Early stages and some of the locally advanced stages are treated with a curative intent. Surgery, radiation, primary (neoadjuvant) and adjuvant chemotherapy are the respective treatment options, mostly as one component of combined multimodality therapy , 6. TreaOver the last 15 years medical research and, in particular, the progress in molecular biology has fundamentally changed our understanding of lung cancer. Meanwhile we know that the genotype of the tumor is an important prognostic and in some cases predictive factor besides the classical clinico-pathologic factors such as disease stage, histology, gender, performance status or comorbidity. Moreover, the progress in molecular biology revolutionized systemic treatment of advanced NSCLC from chemotherapy to a treatment stratified by histology and genetic aberrations consisting of monoclonal antibodies, a panel of targeted kinase-inhibitors and chemotherapy . All NSCTumors harboring a translocation of the anaplastic-lymphoma-kinase (ALK) gene constitute a distinct genetic and clinico-pathologic NSCLC subtype. An inversion on the short arm of chromosome 2 results in a fusion of the ALK-gene with the „echinoderma microtubule-associated protein-like 4“ (EML4)-gene. Transcription of this newly formed oncogene results in the production of the fusion protein EML4-ALK. By activation of subsequent signal transduction cascades, the fusion protein leads to cell proliferation, inhibition of apoptosis and ultimately to the stimulation of tumor growth. This particular genetic NSCLC subtype was initially described by Soda and colleagues . Since tALK-positive NSCLC is not only a genetic subtype but also a clinical entity, ie patients having this tumors do carry specific clinical characteristics. ALK-positive tumors are mainly, but not exclusively associated with adenocarcinoma histology. Patients with ALK-positive NSCLC more commonly are never- or light smokers, and they have a median age of between 50 and 55 years, which is about 10 to 15 years lower than for the general NSCLC population and also the EGFR mutated patients , 23, 84.While mutations of the EGFR gene represent a prognostic and a predictive marker, an ALK translocation is mainly a predictive marker, as the prognosis of patients not treated with ALK-specific tyrosine kinase inhibitors (TKI) is as unfavorable as the prognosis of NSCLC patients with no detectable EGFR or ALK gene mutation (wild-type (WT) NSCLC). Inhibition of the ALK tyrosine kinase and its subsequent signal transduction pathway with specific TKI's results in tumor growth arrest, improved clinical response and a survival benefit in ALK-positive NSCLC as compared to WT NSCLC , 27, 28.Brain metastases are a relevant problem in NSCLC. Up to 64% of all patients with lung cancer develop brain metastases during the course of the disease , 29. NumAge < 60 years and adenocarcinoma histology are risk factors for developing brain metastases , 37, 38.Patients with ALK-positive NSCLC seem to be at higher risk for developing brain metastases , 43. HowA number of factors contribute to the detection of brain metastases among them disease stage, subtype, tumor biology and prior therapies but also the diagnostic methods and intervals , 52. A rCurrently, screening for brain metastases is not recommended as a routine follow-up measure for asymptomatic patients , 54. ThePatients with brain metastases are compromised by headaches, signs of increased intracranial pressure, focal neurological signs , epileptic seizures or neurocognitive deficits , 57, 58.Studies documenting the follow-up of curatively resected NSCLC patients show that those with asymptomatic recurrences have a survival benefit compared to patients with symptomatic recurrences , 60. It Overall prognosis of NSCLC patients with central nervous system (CNS) metastases is poor. A study with 1,833 patients reported a median OS of 7 months . PatientTreatment of brain metastases depends on the number of lesions, location and on the patient's performance status and mostly involves radiotherapy. In case of a solitary lesion, local treatment by surgical resection or stereotactic radiotherapy may suffice and whole brain radiotherapy (WBRT) may be postponed until recurrence or progression. A similar strategy can be followed for patients in a good performance status with 2- 4 brain metastases. In that situation postponement of WBRT may only be an option for individual patients in order to prevent radiotherapy associated side effects. However, one should keep in mind that while adjuvant WBRT has an effect on local tumor control, it has no proven impact on overall survival , 65, 66.Systemic treatment with drugs crossing the blood-brain barrier is recommended for patients with asymptomatic or only minor symptomatic brain metastases. For those patients, radiotherapy is not generally indicated upfront but represents a therapeutic option in case of further progress .Radiotherapy is associated with short- and long-term side effects. It may lead to acute exacerbation of peritumoral edema resulting in a transient, yet further deterioration of neurologic symptoms. Radiation-induced necrosis, encephalopathy, vascular damages or demyelination may occur 6 months after WBRT, in many cases irreversible and progressive. They may constitute solely radiographic findings or can result in neurocognitive impairment . There iThe situation of patients with ALK-positive NSCLC has changed dramatically since the introduction of effective targeted therapy with ALK-inhibitors. Today, patients with advanced ALK-positive NSCLC achieve high overall response rates and remain progression-free for long time intervals. After prior platinum therapy, crizotinib resulted in ORR of 65%, median PFS of 7.7 months and median OS of 21.7 months . First-lA randomized phase-II study comparing two doses of brigatinib (90 mg qd and 180 mg qd) in 222 crizotinib-resistant patients reported ORR of 45% and 54% and median PFS of 9.2 months and 12.9 months, respectively .A recent Japanese phase-III study in ALK-inihibitor naïve patients showed an ORR of 78.9% for crizotinib and 91.6% for alectinib. First-line treatment with alectinib resulted in a significant PFS benefit . Median PFS with crizotinib was 10.2 months (95% CI 8.2-12.0) while it had not been reached after 24 months with alectinib (95% CI 20.3-NR) . In the Moreover, ALK-inhibitors exhibit efficacy in the treatment of brain metastases. The ALK-inhibitor alectinib seems to cross the blood-brain barrier to a relevant extent and, unlike crizotinib and ceritinib, is not a substrate for P-gp (p-glycoprotein). Therefore, alectinib is not actively eliminated from CNS tissue by efflux-mechanisms either. That is supported by preclinical data in mouse models with EML4-ALK-positive NSCLC showing a high brain-to-plasma ratio of alectinib  and by aThe first-line crizotinib study PROFILE 1014 allowed inclusion of patients with brain metastases if they had been treated and were neurologically stable without corticosteroid medication. Rate of intracranial disease control  in 39 patients with brain metastases was 85% after 12 weeks, 56% after 24 weeks and median time to intracranial disease progression was 15.7 months . After pA retrospective analysis of 94 patients with brain metastases treated with ceritinib in the multicenter phase-1 study ASCEND-1 found a median time to intracranial response of 6.1 weeks. The rate of intracranial disease control was 79% in ALK-inhibitor naïve patients and 61% in those pretreated with ALK-inhibitors. There was no difference in intracranial response in patients with or without prior radiotherapy . In the The randomized phase-II study comparing two doses of brigatinib (90 mg qd and 180 mg qd) reported rates for intracranial response of 36% and 67% and for intracranial disease control of 88% and 83%, respectively, in crizotinib-resistant patients with active brain metastases-. Indepennd line chemotherapy  after failure of one platinum doublet chemotherapy and crizotinib. The primary study endpoint of PFS was reached with a HR of 0.15 by investigator assessment. The CNS response rate of patients with measurable brain metastases treated with alectinib was 54.2% and with chemotherapy it was 0% [Treatment of 84 crizotinib-resistant patients with brain metastases with alectinib resulted in a rate of intracranial disease control of 84.5% with 31% of all patients actually achieving a complete response. Median duration of CNS-response was 11.2 months . Anothert was 0% . Within t was 0% . Furthert was 0% . This ist was 0% . This, fst line treatment of ALK-positive NSCLC patients [Treating brain metastases represents an important challenge in the management of patients with ALK-positive NSCLC. ALK-inhibitor therapy results in high overall response rates and in long progression-free intervals. Yet, eventually, patients will progress, often due to secondary mutations or induction of other oncogenic drivers  and devepatients , 87, 27 Indications for surgical interventions and stereotactic radiotherapy while postponing WBRT have become wider. WBRT can be planned sparing cerebral regions critical for neurocognitive functioning e.g. hippocampal-sparing whole-brain radiotherapy . Given tFigure