Implementing a Program of Talimogene laherparepvec.

BACKGROUND: Oncolytic viruses are genetically engineered or naturally occurring viruses that selectively replicate in cancer cells without harming normal cells. Talimogene laherparepvec (Imlygic®), the first oncolytic viral therapy approved for treatment of cancer, was approved for treatment of locally advanced melanoma in October 2015. PURPOSE: As a biologic product, use of T. laherparepvec in the clinical setting requires pretreatment planning and a unique systematic approach to deliver the therapy. The processes we describe herein could be adopted by other centers that choose to prescribe T. laherparepvec. METHODS: We studied our clinical trial experience with T. laherparepvec before we embarked on using commercially available T. laherparepvec. We created a standard operating procedure (SOP) with multidisciplinary buy-in and oversight from leadership in Infection Control at our institution. We reflected on clinical cases and the actual procedures of administering T. laherparepvec to create the SOP. RESULTS: The preimplementation planning, patient selection, identification of lesions to treat, the actual procedure, and ongoing assessment of patients are described. Tumoral-related factors that lead to unique challenges are described. CONCLUSIONS: A process to ensure safe and responsible implementation of a program to administer T. laherparepvec for treatment of melanoma may improve the quality of treatment for patients who suffer from advanced melanoma.

Pathway to Independence Awards (K99/R00): Funding Dynamics and Prediction of Future National Institutes of Health Research Project Funding.

PURPOSE: The authors used the National Institutes of Health (NIH) RePORTER (Research Portfolio Online Reporting Tools) to evaluate funding trends and historic NIH investment increase in the K99 award pathway and examine whether R00 to R01 or R21 achievement time correlated with the future success of an early-stage NIH-funded investigator. METHOD: All K99 awards and funding data in this study were limited to all clinical departments. The authors identified all researchers and awards through a K99 search from fiscal years (FYs) 2007 to 2022 across all clinical departments and investigated trends in K99 awards and funding from NIH FYs 2007 to 2022. They generated an R00 data set and analyzed the K99 to R00 achievement statistics from FYs 2007 to 2022. The authors aggregated NIH annual data files for FYs 2007 to 2021 to generate a master data file of all R01 and R21 awards. They linked R01 and R21 award data to the researcher previously identified through the K99 search and focused on the connection between K99/R00 awardees and subsequent R01 or R21 awards. RESULTS: From FY 2008 to FY 2022, the NIH K99 budget increased 127.0%, whereas the NIH program-level budget increased 17.3%. A principal investigator's mean funding per year significantly decreased as time from R00 to R01 or R21 increased ( P < .001); 7 of 15 comparisons differed significantly (2 at P < .01 and 5 at P < .001). CONCLUSIONS: NIH investment in the K99 award pathway has substantially outpaced the NIH program-level budget increase, and there is a strong association between mean funding per year since the start of the R00 phase and time from R00 to R01 or R21. This analysis may be useful to clinical departments as they evaluate selecting new and retaining current biomedical scientists for independent research positions.

Clinical and Histological Response to Talimogene Laherparepvec Therapy in Advanced Melanoma: Impact on Overall Survival.

BACKGROUND: Talimogene laherparepvec (T-VEC) is an FDA-approved oncolytic herpesvirus therapy used for unresectable stage IIIB through IV metastatic melanoma. However, the correlation between clinical complete response (cCR) and pathologic complete response (pCR) in patients treated with T-VEC is understudied. STUDY DESIGN: We conducted a retrospective study from a prospectively maintained IRB-approved melanoma single-center database in patients treated with T-VEC from October 2015 to April 2022. Patients were categorized into 3 groups: cCR with pCR, cCR without pCR, and less than cCR. The primary endpoint was overall survival. We used descriptive statistics, chi-square tests, and Wilcoxon rank-sum tests to compare key covariates among exposure groups. We used survival analysis to compare survival curves and reported hazard ratio of death (95% CI) across exposure groups. RESULTS: We included 116 patients with a median overall survival (interquartile range) of 22.7 (14.8-39.3) months. The majority were men (69%) and White (97.4%), with a median age of 74.5 years. More than half of patients (n = 60, 51.6%) achieved cCR. Distribution among the groups was as follows: cCR with pCR (35.3%), cCR without pCR (16.3%), and less than cCR (48.4%). Median overall survival time (interquartile range) was 26.5 (18.6-36.0) months for cCR with pCR, 22.7 (14.4-35.5) months for cCR without pCR, and 17.8 (9.2-47.0) months for less than cCR (log-rank p value = 0.0033). CONCLUSIONS: Patients achieving cCR with pCR after T-VEC therapy have the most favorable overall survival outcomes, whereas those achieving cCR without pCR have inferior survival and those achieving less than cCR have the poorest overall survival outcomes. These findings emphasize the importance of histological confirmation and provide insights for optimizing T-VEC therapy in patients with advanced melanoma.

National Institutes of Health Funding Gaps for Principal Investigators.

Importance: Early-stage and established investigators compete for a limited supply of funds from the National Institutes of Health (NIH). Regardless of their previous funding success, many principal investigators (PIs) encounter a funding gap in which they no longer receive ongoing funding from the NIH. Objective: To determine incidence rates of PI-level funding gaps, the mean funding gap length, and whether these 2 metrics are associated with previous funding success. Design, Setting, and Participants: This study was conducted using data from NIH RePORTER. Historical datafiles for fiscal year (FY) 2011 to FY 2021 were aggregated to generate 2 master datafiles for this period: all NIH awards and only R01 awards. PIs with no funding in FY 2011 or FY 2021 were removed. PIs were sorted by FY 2011 total funding amounts and grouped by quarter of amount. Results: A total of 39 944 unique researchers were awarded 220 131 NIH awards, of which 103 753 were R01 awards. For all NIH awards, there was an overall linear increase from top quarter to bottom quarter in the percentage of PIs who had at least 1 year without funding (from 27% to 75%), percentage of these gap PIs who had at least 2 consecutive years without funding (from 56% to 68%), and mean maximum consecutive years without funding for gap PIs (2.2 years to 3.1 years). For only R01 awards, there was an overall linear increase from top quarter to bottom quarter in the percentage of PIs who had at least 1 year without funding (50% to 74%), percentage of gap PIs who had at least 2 consecutive years without funding (59% to 71%), and mean maximum consecutive years without funding for gap PIs (2.4 years to 3.1 years). Conclusions and Relevance: In this cohort study of NIH-funded investigators, PIs with higher NIH funding were less likely to experience a funding gap. Additionally, when these PIs encountered a funding gap, this period without funding was shorter; however, among all PIs, funding gaps typically lasted 2 to 3 years. These associations were found inclusive of all NIH awards and when analysis was limited to only R01 awards. These findings may be useful to PIs and academic institutions as they prepare, structure, and project research resource allocations.

Increased tryptophan, but not increased glucose metabolism, predict resistance of pembrolizumab in stage III/IV melanoma.

Clinical trials of combined IDO/PD1 blockade in metastatic melanoma (MM) failed to show additional clinical benefit compared to PD1-alone inhibition. We reasoned that a tryptophan-metabolizing pathway other than the kynurenine one is essential. We immunohistochemically stained tissues along the nevus-to-MM progression pathway for tryptophan-metabolizing enzymes (TMEs; TPH1, TPH2, TDO2, IDO1) and the tryptophan transporter, LAT1. We assessed tryptophan and glucose metabolism by performing baseline C11-labeled α-methyl tryptophan (C11-AMT) and fluorodeoxyglucose (FDG) PET imaging of tumor lesions in a prospective clinical trial of pembrolizumab in MM (clinicaltrials.gov, NCT03089606). We found higher protein expression of all TMEs and LAT1 in melanoma cells than tumor-infiltrating lymphocytes (TILs) within MM tumors (n = 68). Melanoma cell-specific TPH1 and LAT1 expressions were significantly anti-correlated with TIL presence in MM. High melanoma cell-specific LAT1 and low IDO1 expression were associated with worse overall survival (OS) in MM. Exploratory optimal cutpoint survival analysis of pretreatment 'high' vs. 'low' C11-AMT SUVmax of the hottest tumor lesion per patient revealed that the 'low' C11-AMT SUVmax was associated with longer progression-free survival in our clinical trial (n = 26). We saw no such trends with pretreatment FDG PET SUVmax. Treatment of melanoma cell lines with telotristat, a TPH1 inhibitor, increased IDO expression and kynurenine production in addition to suppression of serotonin production. High melanoma tryptophan metabolism is a poor predictor of pembrolizumab response and an adverse prognostic factor. Serotoninergic but not kynurenine pathway activation may be significant. Melanoma cells outcompete adjacent TILs, eventually depriving the latter of an essential amino acid.

Method of detection of initial recurrence of stage II/III cutaneous melanoma: analysis of the utility of follow-up staging.

BACKGROUND: The follow-up of patients with cutaneous melanoma is controversial. Current recommendations suggest routine history and physical examination every 3 to 6 months for the first 3 years and correlate studies including laboratory tests and radiographic imaging. However, the utility of these recommendations are unclear. The purpose of this study was to determine the impact of routine imaging on the method of detection of first recurrence in patients with stage II and sentinel lymph node-positive stage III melanoma. METHODS: We analyzed a prospective database of all cutaneous melanoma patients treated at our institution from 1997 to 2005 who had at least 2 years of follow-up. The method of detection of initial recurrence was analyzed. RESULTS: One hundred eighteen patients with stage II (n = 83) or III (n = 35) melanoma who were followed for at least 2 years were identified. Forty-three of these patients developed recurrence (median time to recurrence, 14 months). Site of first recurrence was as follows: 4 local, 17 in transit, 7 regional lymph node, and 15 distant. Twenty-nine recurrences (67%) were either patient detected or symptomatic. Eleven (26%) were detected by the physician at routine follow-up. Only three (7%) were identified by imaging (two chest X-ray and one brain magnetic resonance imaging) in an otherwise asymptomatic patient. CONCLUSIONS: Two-thirds of all initial recurrences of cutaneous melanoma were either detected by a patient or were symptomatic, with most of the remainder detected during routine physical examination. Routine imaging added little value in the detection of initial recurrence.

Attraction to sexual violence towards women, sexual abuse of children, and non-sexual criminal behavior: testing the specialist vs. generalist models in male college students.

A sample of 492 college men anonymously completed an expanded version of the Sexual Experiences Survey, the revised Attraction to Sexual Aggression Scale, and the Marlowe-Crowne Social Desirability Scale Short Form to investigate the relations among perpetration of sexual violence (including rape and sexual assault), attraction to sexual violence, attraction to childhood sexual abuse, and attraction towards other crimes while controlling for the impact of social desirability. Analyses indicated that attractions towards sexual violence, general criminality, and childhood sexual abuse were all significantly interrelated. In addition, sexual assault perpetrators reported higher levels of all three types of attraction as compared to nonperpetrators whereas rape perpetrators reported higher levels of attraction to sexual aggression and criminality. Clinical and research implications are discussed.

Reliability and validity of the SCL-90-R PTSD subscale.

Two studies examined the psychometric properties of the Posttraumatic Stress Disorder (PTSD) subscale of the SCL-90-R. Study 1 examined SCL-90-R responses from 2,361 college women to determine whether this subscale can appropriately assess the three dimensions of PTSD. Factor analysis and Cronbach's alpha suggest that this subscale is best conceptualized as a unidimensional index of PTSD symptomatology. Study 2 confirmed these results in a sample of 1,044 college men and women. Findings in the second sample also supported the subscale's validity, as it correlates well with the Posttraumatic Diagnostic Scale and with trauma frequency and can discriminate between individuals with and without PTSD diagnoses. Results suggest that the SCL-90-R PTSD subscale is a reliable, but unidimensional, measure for screening for distress associated with PTSD. Although there is some support for the usefulness of this scale, especially with women, it should only be considered a general indicator of distress with limited use for men.

Constitutional duplication of a region of chromosome Yp encoding AMELY, PRKY, and TBL1Y: implications for sex chromosome analysis and bone marrow engraftment analysis.

Amelogenin has chromosome X (AMELX) and Y (AMELY) homologs that can be differentiated based on the length of polymerase chain reaction (PCR) amplification products. In addition to being useful for gender identification, analysis of amelogenin has utility for monitoring bone marrow engraftment in patients after a sex-mismatched bone marrow transplant, characterizing sex chromosome abnormalities, and for forensic purposes for analyzing mixtures of male and female DNA. Here, we describe two brothers in which PCR analysis demonstrated twofold greater AMELY products compared with AMELX products. Karyotype and X/Y fluorescence in situ hybridization analysis demonstrated a single copy of the X and Y chromosomes without any identifiable abnormalities. Oligonucleotide comparative genomic hybridization array analysis demonstrated a duplication of a portion of chromosome Yp that encompassed a region of at least 2.6 Mb but not greater than 4.0 Mb. The amplified region contains the genes AMELY, transducin (beta)-like 1 protein Y (TBL1Y), and protein kinase Y (PRKY). To our knowledge, duplication of this region has not previously been reported. The family history is unremarkable, and the brothers are without ap-parent dysmorphic features. Although this and other genetic variants involving AMELY are uncommon, one should use caution when using amelogenin for sex chromosome analysis and bone marrow engraftment analysis.

Late presentation of Cryptococcus gattii meningitis in a traveller to Vancouver Island: A case report.

Since 1999, Cryptococcus gattii has been identified as a primary pathogen on Vancouver Island in British Columbia, and it has resulted in infection of both people and animals living in that area. A previously healthy 45-year-old female resident of Alberta developed C gattii infection 11 months after travelling to an endemic region of Vancouver Island. A case of an immunocompetent patient, with an atypically long incubation time, who presented with subacute meningitis secondary to disseminated pulmonary cryptococcosis is presented. The present report highlights the need for clinical vigilance in treating patients presenting with atypical pulmonary infections or meningitis who have been holiday travellers to endemic areas of Vancouver Island.

College women's experiences of psychological maltreatment and sexual assault.

A sample of 648 college women recruited from undergraduate psychology classes was examined to explore the relationship between past psychological maltreatment and sexual assault. Based on responses to the Sexual Experiences Survey and the Psychological Maltreatment Inventory, women were classified by level of unwanted sexual contact (i.e., vaginal or anal intercourse; oral genital contact and/or object penetration; or kissing and/or fondling), by method used to obtain the sexual assault (i.e., women were classified as experiencing coerced assaults, forced assaults, or both), and by identity of perpetrator (i.e., acquaintances or strangers). Results pointed to significant differences in the amount of past psychological maltreatment reported by women experiencing any type of assault as compared to women without assault experiences, regardless of perpetrator identity. Moreover, higher levels of psychological maltreatment were associated with having experienced any type of coerced sexual activities. There were no differences by type of assault. Finally, a series of ANOVAs was conducted to examine the interaction between coercion and force in the psychological maltreatment reported by women experiencing different forms of assault. With few exceptions, greater maltreatment was associated both with the occurrence of coerced assaults and with the occurrence of forced assaults. A significant interaction was seen with one form of assault, unwanted kissing and/or fondling perpetrated by an acquaintance. This interaction may suggest that, at least for this one form of contact perpetrated by acquaintances, the presence of past psychological maltreatment is uniquely associated with experiencing adult sexual assaults involving both force and coercion.

Web-based networking in CNS education.

PURPOSE: An important component of the clinical nurse specialist (CNS) educational program involves anticipatory guidance for students assimilating the CNS role. This article describes a strategy for facilitating this transition through online discussion about CNS practice among students and experienced CNSs. DESCRIPTION OF THE PROCESS: Six students in the final semester of their CNS program and 5 CNSs from across the country used the WebCT platform to participate in an online learning experience. This article outlines the process of structuring an online discussion, soliciting an expert panel, and preparing the participants. Students' concerns and panelists' responses are presented. CONCLUSIONS: Themes that emerged from students' questions to the panelists were certification and title protection; developing a career trajectory, including tips for interviewing and negotiation; and current and future trends in CNS practice. Benefits to participants are described, as well as suggestions for using Web-based discussion in other applications.

Cytogenetic study of malignant triton tumor: a case report.

Malignant triton tumor (MTT) is a highly malignant neoplasm, classified as a variant of malignant peripheral nerve sheath tumor (MPNST) with rhabdomyoblastic differentiation. Few cytogenetic studies of MTT have been reported using conventional cytogenetic analysis. Here, we report a comprehensive cytogenetic study of a case of MTT using G-banding, Spectral Karyotyping(), and fluorescence in situ hybridization (FISH) for specific regions. A complex hyperdiploid karyotype with multiple unbalanced translocations was observed: 48 approximately 55,XY,der(7)add(7)(p?)dup(7)[2],der(7) t(7;20)(p22;?)ins(20;19)[5],der(7)ins(8;7)(?;p22q36)t(3;8)t(8;20)[15],-8[5],-8[19],r(8)dup(8), +der(8)r(8;22)[4],-9[9],der(11)t(11;20)(p15;?)ins(20;19)[22],der(12)t(8;12)(q21;p13)[21],der(13) t(3;13)(q25;p11),-17,-19,der(19)t(17;19)(q11.2;q13.1),-20,-22,+4 approximately 7r[cp24]/46,XY[13]. The 1995 International System for Human Cytogenetic Nomenclature was followed where possible. Note that breakpoints were frequently omitted where only SKY information was known for a small part of an involved chromosome. Our analysis revealed some breakpoints in common with those previously reported in MTT, MPNST, and rhabdomyosarcoma, namely 7p22, 7q36, 11p15, 12p13, 13p11.2, 17q11.2, and 19q13.1. FISH showed high increase of copy number for MYC and loss of a single copy for TP53.

The role of childhood sexual abuse sequelae in the sexual revictimization of women: an empirical review and theoretical reformulation.

There is now widespread empirical evidence that child sexual abuse (CSA) survivors are at greater risk for sexual revictimization in adulthood, but less is known of the mechanisms underlying this relationship. Despite the lack of a conceptual framework to guide research, there has been a recent influx of studies examining explanatory variables, with most focusing on the psychological sequelae of CSA: alcohol and drug use, sexual behavior, dissociation, posttraumatic symptomatology, poor risk recognition, and interpersonal difficulties. With the exception of sexual behavior, the studies reviewed here provide limited or mixed support for the role of intrapersonal factors in revictimization. Future research may benefit from a focus on the function of psychological distress that is expressed as psychological vulnerability, as opposed to individual forms of psychopathology or maladaptive behavior. An ecological framework may be useful as a guide to future investigations, as this model focuses on factors outside of the victim, including childhood factors such as family environment, contextual factors including the behavior of the perpetrator, and societal and cultural factors that impact revictimization. Future investigations should focus on the interaction between victim vulnerability and perpetrator behavior. Implications for prevention programming, clinical intervention, and future research are discussed.

The influence of childhood sexual abuse, physical abuse, family environment, and gender on the psychological adjustment of adolescents.

OBJECTIVE: The primary aim of the current study was to examine the contributions of sexual abuse, physical abuse, family cohesion, and conflict in predicting the psychological functioning of adolescents. Additional analyses were conducted to determine whether adolescent victims of child sexual abuse and physical abuse perceive their family environments as more conflictual and less cohesive than nonabused adolescents. METHOD: Participants were 131 male and female adolescents, ages 16 years to 18 years, receiving services at a residential vocational training program. Participants completed well established psychological assessment tools to assess abuse history, family environment characteristics, and current adjustment. RESULTS: Physically abused adolescent females perceived their family environments as more conflictual and less cohesive than females without physical abuse, and sexually abused females perceived their family environments as more conflictual and less cohesive than females without sexual abuse. Physically abused adolescent males reported more conflict than males without physical abuse, but did not differ with regard to cohesion. Adolescent males with and without a sexual abuse history did not differ on the family dimensions. Multiple regression analyses revealed that both conflict and cohesion, in addition to a history of sexual and physical abuse, predicted depression and distress. Separate analyses by gender revealed these variables differentially impact adjustment in male and female adolescents. Results of a power analysis indicated sufficient power to detect these differences. CONCLUSIONS: Findings indicate that in addition to child sexual abuse and physical abuse, family conflict and cohesion are risk factors for the development of psychological distress and depression in adolescence. Implications for treatment and directions for future research are discussed.

Alcohol and substance use disorders as predictors of child to adult sexual revictimization in a sample of community women.

Alcohol- and substance-related diagnoses were examined as factors in child to adult sexual revictimization. Three hundred community women completed interviews and self-report instruments to obtain information regarding victimization and to diagnose substance use disorders (alcohol and substance abuse/dependence). Childhood sexual abuse (CSA) survivors were more likely than nonvictims to meet criteria for both substance use disorders and to report rape (e.g., unwanted intercourse due to threat or use of force, or due to the inability to consent due to the respondent's alcohol or drug use) and coerced intercourse (e.g., unwanted intercourse due to verbal coercion or misuse of authority by the perpetrator) by acquaintances, strangers, and husbands. In general, both CSA and substance use disorders were predictive of adult sexual victimization, but there were no significant interactions between these factors. Overall, substance use disorders were related to rape for all women; this relationship was not unique to CSA survivors. Alcohol- and substance-related diagnoses predicted rape by all three types of perpetrators, but CSA was predictive of rape only by acquaintances and strangers and not husbands. In contrast, CSA predicted coerced intercourse by all three perpetrators, while alcohol- and substance-related diagnoses predicted coerced intercourse by acquaintances and strangers, but not husbands. Results highlight the need to continue the study of revictimization of CSA survivors, including examination of both rape and sexually coercive experiences by different types of perpetrators. Findings support continued research of substance use disorders as risk factors for sexual victimization among all women.

Sexual assault and alcohol use: exploring the self-medication hypothesis.

Though a link between sexual victimization and alcohol use has been well documented, the mechanisms underlying this relationship remain unclear. The current study used path analysis to examine the role of self-reported levels of psychological distress and the function of alcohol use as indirect pathways between adult sexual assault and alcohol use. Participants were 318 undergraduate female victims and nonvictims of adult sexual assault. Results showed that a history of sexual assault was associated with increased psychological distress, which in turn contributed to alcohol use via negative reinforcement. Taken together, these findings provided support for the hypothesis that women who have been sexually assaulted consume alcohol, in part, to self-medicate. The implications for future research are discussed.

Relative value unit impact of complex skin closures to academic surgical melanoma practices.

BACKGROUND: Melanoma excisions frequently are associated with significant soft-tissue defects, creating the need for complex closures. These closures could be performed by either surgical oncologists or plastic surgeons. We sought to quantify the relative value units (RVUs) and describe the practice patterns of 2 academic surgical subspecialties after a melanoma excision. METHODS: After institutional review board approval, a retrospective data analysis of a billing database was conducted on all melanoma patients undergoing an excision and closure by surgical oncology and plastic surgery departments in 2007. Data were obtained using billing records for Current Procedural Terminology diagnosis codes. RVUs were used to quantify the value added to each practice from these closures. The surgical oncologist and patient decided if a plastic surgeon was needed. RESULTS: A total of 270 closures were performed, 53 (19.9%) primary and 217 (80.1%) complex. The surgical oncologists performed most complex closures (188; 86.6%), and the plastic surgeons performed the remainder (29; 13.4%), generating a total of 1,921 RVUs (1,630 by the surgical oncologists and 291 by the plastic surgeons). For analysis, complex closures were divided among 4 anatomic sites: trunk, upper extremity, lower extremity, and head and neck. Most closures by the surgical oncologists were adjacent tissue rearrangements (155; 82%) and the remainder were skin grafts (33; 18%). Closures by the plastic surgeons were more likely to be a full-thickness skin graft (P < .0027) in the head and neck region (P < .0001), with a higher associated median RVU/case (10.15 compared with 8.44 for the surgical oncologists; P < .0002). CONCLUSIONS: At our institution, the majority of melanoma closures were performed by surgical oncologists. However, plastic surgery often was involved in more complex closures in the head and neck. This data set quantifies the RVUs added and describes the types of closures performed in an academic melanoma practice.

Sexual assault and rape perpetration by college men: the role of the big five personality traits.

A sample of 521 college men completed the Revised NEO Personality Inventory and an expanded version of the Sexual Experiences Survey to examine whether variation in the Big Five personality traits in a normal, college population provides any insight into the nature of sexual assault and rape perpetrators. Rape perpetrators reported lower levels of Agreeableness and Conscientiousness when compared to both sexual assault perpetrators and nonperpetrators, and lower levels of Extraversion when compared to nonperpetrators. Rape perpetrators also endorsed lower levels of tendermindedness, excitement-seeking, warmth, positive emotions, feelings, altruism, competence, and dutifulness, and higher levels of vulnerability. Contrary to expectation, overall personality profiles followed remarkably comparable patterns for sexual assault and nonperpetrators, suggesting that sexual assault perpetrators were more similar to nonperpetrators than to rape perpetrators. Findings suggest that individuals who perpetrate sexual offenses, particularly rape, differ from nonperpetrators on dimensions of normal personality. Clinical and research implications are discussed.