Expanding the landscape of oncogenic drivers and treatment options in acral and mucosal melanomas by targeted genomic profiling.

Despite advancements in treating cutaneous melanoma, patients with acral and mucosal (A/M) melanomas still have limited therapeutic options and poor prognoses. We analyzed 156 melanomas (101 cutaneous, 28 acral, and 27 mucosal) using the Foundation One cancer-gene specific clinical testing platform and identified new, potentially targetable genomic alterations (GAs) in specific anatomic sites of A/M melanomas. Using novel pre-clinical models of A/M melanoma, we demonstrate that several GAs and corresponding oncogenic pathways associated with cutaneous melanomas are similarly targetable in A/M melanomas. Other alterations, including MYC and CRKL amplifications, were unique to A/M melanomas and susceptible to indirect targeting using the BRD4 inhibitor JQ1 or Src/ABL inhibitor dasatinib, respectively. We further identified new, actionable A/M-specific alterations, including an inactivating NF2 fusion in a mucosal melanoma responsive to dasatinib in vivo. Our study highlights new molecular differences between cutaneous and A/M melanomas, and across different anatomic sites within A/M, which may change clinical testing and treatment paradigms for these rare melanomas.

Minorities Face Delays to Pancreatic Cancer Treatment Regardless of Diagnosis Setting.

INTRODUCTION: Our analysis was designed to characterize the demographics and disparities between the diagnosis of pancreas cancer during emergency presentation (EP) and the outpatient setting (OP) and to see the impact of our institutions pancreatic multidisciplinary clinic (PMDC) on these disparities. METHODS: Institutional review board-approved retrospective review of our institutional cancer registry and PMDC databases identified patients diagnosed/treated for pancreatic ductal adenocarcinoma between 2014 and 2022. Chi-square tests were used for categorical variables, and one-way ANOVA with a Bonferroni correction was used for continuous variables. Statistical significance was set at p < 0.05. RESULTS: A total of 286 patients met inclusion criteria. Eighty-nine patients (31.1%) were underrepresented minorities (URM). Fifty-seven (64.0%) URMs presented during an EP versus 100 (50.8%) non-URMs (p = 0.037). Forty-one (46.1%) URMs were reviewed at PMDC versus 71 (36.0%) non-URMs (p = 0.10). No differences in clinical and pathologic stage between the cohorts (p = 0.28) were present. URMs took 22 days longer on average to receive treatment (66.5 days vs. 44.8 days, p = 0.003) in the EP cohort and 18 days longer in OP cohort (58.0 days vs. 40.5 days, p < 0.001) compared with non-URMs. Pancreatic Multidisciplinary Clinic enrollment in EP cohort eliminated the difference in time to treatment between cohorts (48.3 days vs. 37.0 days; p = 0.151). RESULTS: Underrepresented minorities were more likely to be diagnosed via EP and showed delayed times to treatment compared with non-URM counterparts. Our PMDC alleviated some of these observed disparities. Future studies are required to elucidate the specific factors that resulted in these findings and to identify solutions.

Machine learning to predict completion of treatment for pancreatic cancer.

BACKGROUND: Chemotherapy enhances survival rates for pancreatic cancer (PC) patients postsurgery, yet less than 60% complete adjuvant therapy, with a smaller fraction undergoing neoadjuvant treatment. Our study aimed to predict which patients would complete pre- or postoperative chemotherapy through machine learning (ML). METHODS: Patients with resectable PC identified in our institutional pancreas database were grouped into two categories: those who completed all intended treatments (i.e., surgery plus either neoadjuvant or adjuvant chemotherapy), and those who did not. We applied logistic regression with lasso penalization and an extreme gradient boosting model for prediction, and further examined it through bootstrapping for sensitivity. RESULTS: Among 208 patients, the median age was 69, with 49.5% female and 62% white participants. Most had an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2. The PC predominantly affected the pancreatic head. Neoadjuvant and adjuvant chemotherapies were received by 26% and 47.1%, respectively, but only 49% completed all treatments. Incomplete therapy was correlated with older age and lower ECOG status. Negative prognostic factors included worsening diabetes, age, congestive heart failure, high body mass index, family history of PC, initial bilirubin levels, and tumor location in the pancreatic head. The models also flagged other factors, such as jaundice and specific cancer markers, impacting treatment completion. The predictive accuracy (area under the receiver operating characteristic curve) was 0.67 for both models, with performance expected to improve with larger datasets. CONCLUSIONS: Our findings underscore the potential of ML to forecast PC treatment completion, highlighting the importance of specific preoperative factors. Increasing data volumes may enhance predictive accuracy, offering valuable insights for personalized patient strategies.

ATM kinase inhibitor AZD0156 in combination with irinotecan and 5-fluorouracil in preclinical models of colorectal cancer.

BACKGROUND: AZD0156 is an oral inhibitor of ATM, a serine threonine kinase that plays a key role in DNA damage response (DDR) associated with double-strand breaks. Topoisomerase-I inhibitor irinotecan is used clinically to treat colorectal cancer (CRC), often in combination with 5-fluorouracil (5FU). AZD0156 in combination with irinotecan and 5FU was evaluated in preclinical models of CRC to determine whether low doses of AZD0156 enhance the cytotoxicity of irinotecan in chemotherapy regimens used in the clinic. METHODS: Anti-proliferative effects of single-agent AZD0156, the active metabolite of irinotecan (SN38), and combination therapy were evaluated in 12 CRC cell lines. Additional assessment with clonogenic assay, cell cycle analysis, and immunoblotting were performed in 4 selected cell lines. Four colorectal cancer patient derived xenograft (PDX) models were treated with AZD0156, irinotecan, or 5FU alone and in combination for assessment of tumor growth inhibition (TGI). Immunofluorescence was performed on tumor tissues. The DDR mutation profile was compared across in vitro and in vivo models. RESULTS: Enhanced effects on cellular proliferation and regrowth were observed with the combination of AZD0156 and SN38 in select models. In cell cycle analysis of these models, increased G2/M arrest was observed with combination treatment over either single agent. Immunoblotting results suggest an increase in DDR associated with irinotecan therapy, with a reduced effect noted when combined with AZD0156, which is more pronounced in some models. Increased TGI was observed with the combination of AZD0156 and irinotecan as compared to single-agent therapy in some PDX models. The DDR mutation profile was variable across models. CONCLUSIONS: AZD0156 and irinotecan provide a rational and active combination in preclinical colorectal cancer models. Variability across in vivo and in vitro results may be related to the variable DDR mutation profiles of the models evaluated. Further understanding of the implications of individual DDR mutation profiles may help better identify patients more likely to benefit from treatment with the combination of AZD0156 and irinotecan in the clinical setting.

A Learning Healthcare System for pregnant and breastfeeding women: what do women during preconception, pregnancy, and nursing think? - A qualitative study : A contribution from the ConcePTION project.

BACKGROUND: Most medications lack evidence-based information about its safety and efficacy during pregnancy and breastfeeding, because pregnant women are often not included in clinical research. Another way to generate evidence is by using a Learning Healthcare System (LHS) approach. In an LHS, care and research are aligned in such a way that it can accelerate evidence generation and outcomes for patients, based on real-life medication use. For the development of an ethically responsible and sustainable LHS, it is of crucial importance to understand what women think of such an alternative approach to knowledge generation. Therefore, this paper explores their views on an LHS for pregnant and breastfeeding women. METHOD: For this qualitative study, we interviewed 20 women during preconception, pregnancy, or nursing to explore their views on an ethically responsible LHS for pregnant and breastfeeding women. The pseudonymized transcripts were analyzed thematically. RESULTS: We identified four main themes describing women's views on LHSs. The first theme describes that respondents were positive about learning healthcare systems, and considered them to function as a central point for information about their medication, which they felt is currently lacking. The second theme shows that respondents want to contribute to and engage in generating new information because they want to help others and contribute to scientific research. Respondents also mentioned that, currently, not every woman is aware of the risks of the lack of evidence for medication used in pregnancy. The third theme shows that respondents regard their healthcare professional as essential for the translation and interpretation of information, regardless of a learning healthcare system. The last theme describes that respondents will trust a learning healthcare system more if the medical community supports it, and when data collection and processing is transparent. CONCLUSION: Women during preconception, pregnancy and nursing agree that an LHS could be a viable alternative to help close the knowledge gap on the safety of medication used during pregnancy and breastfeeding. The obtained insights from our interviews provide valuable stepping-stones for the development of an ethically responsible and sustainable LHS, as well as for the engagement of women in an LHS.

Infant temperament, early-childhood parenting, and early-adolescent development: Testing alternative models of Parenting × Temperament interaction.

Here we evaluate whether infant difficult temperament (6 months) functions as a vulnerability or more general plasticity factor when investigating effects of early-childhood parenting (8-42 months) on both positive and negative early-adolescent socioemotional development (age 8-11 years). Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC, N = 14,541) and a re-parameterized model-testing approach to distinguish alternative person × environment conceptual models, results indicated that temperament × parenting interacted in predicting externalizing (i.e., hyperactivity, conduct problems), but not other behavior (i.e., emotional symptoms, peer problems), in a (weak) differential susceptibility manner. While more and less supportive parenting predicted, respectively, fewer and more behavior problems, it did so more strongly for children who were more difficult as infants.

RX-5902, a novel ß-catenin modulator, potentiates the efficacy of immune checkpoint inhibitors in preclinical models of triple-negative breast Cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited systemic treatment options. RX-5902 is a novel anti-cancer agent that inhibits phosphorylated-p68 and thus attenuates nuclear ß-catenin signaling. The purpose of this study was to evaluate the ability of ß-catenin signaling blockade to enhance the efficacy of anti-CTLA-4 and anti-PD-1 immune checkpoint blockade in immunocompetent, preclinical models of TNBC. METHODS: Treatment with RX-5902, anti-PD-1, anti-CTLA-4 or the combination was investigated in BALB/c mice injected with the 4 T1 TNBC cell line. Humanized BALB/c-Rag2nullIl2rγnullSIRPαNOD (hu-CB-BRGS) mice transplanted with a human immune system were implanted with MDA-MB-231 cells. Mice were randomized into treatment groups according to human hematopoietic chimerism and treated with RX-5902, anti-PD-1 or the combination. At sacrifice, bone marrow, lymph nodes, spleen and tumors were harvested for flow cytometry analysis of human immune cells. RESULTS: The addition of RX-5902 to CTLA-4 or PD-1 inhibitors resulted in decreased tumor growth in the 4 T1 and human immune system and MDA-MB-231 xenograft models. Immunologic analyses demonstrated a significant increase in the number of activated T cells in tumor infiltrating lymphocytes (TILs) with RX-5902 treatment compared to vehicle (p < 0.05). In the RX-5902/nivolumab combination group, there was a significant increase in the percentage of CD4+ T cells in TILs and increased systemic granzyme B production (p < 0.01). CONCLUSIONS: Conclusions: RX-5902 enhanced the efficacy of nivolumab in a humanized, preclinical model of TNBC. Several changes in immunologic profiles were noted in mice treated with RX-5902 and the combination, including an increase in activated TILs and a decrease in human myeloid populations, that are often associated with immunosuppression in a tumor microenvironment. RX-5902 also was shown to potentiate the effects of checkpoint inhibitors of CTLA4 and the PD-1 inhibitor in the 4 T-1 murine TNBC model. These findings indicate that RX-5902 may have important immunomodulatory, as well as anti-tumor activity, in TNBC when combined with a checkpoint inhibitor.

Prenatal stress enhances postnatal plasticity: The role of microbiota.

Separate fields of inquiry indicate (a) that prenatal stress is associated with heightened behavioral and physiological reactivity and (b) that these postnatal phenotypes are themselves associated with increased susceptibility to both positive and negative environmental influences. Collectively, this work supports Pluess and Belsky's (Psychopathology, 2011, 23, 29) claim that prenatal stress fosters, promotes or "programs" postnatal developmental plasticity. Herein, we review animal and human evidence consistent with this hypothesis before advancing the novel idea that infant intestinal microbiota may be one candidate mechanism for instantiating developmental plasticity as a result of prenatal stress. We then review research indicating that prenatal stress predicts differences in infant intestinal microbiota; that infant intestinal microbiota is associated with behavioral and physiological reactivity phenotypes; and, thus, that prenatal stress may influence infant intestinal microbiota in a way that results in heightened physiological and behavioral reactivity and, thereby, postnatal developmental plasticity. Finally, we offer ideas for testing this claim and consider implications for intervention and use of probiotics during early infancy.

Prenatal Stress as a Risk-and an Opportunity-Factor.

Two separate lines of research indicate (a) that prenatal stress is associated with heightened behavioral and physiological reactivity and (b) that these postnatal phenotypes are associated with increased susceptibility to both positive and negative developmental experiences. Therefore, prenatal stress may increase sensitivity to the rearing environment. We tested this hypothesis by manipulating prenatal stress and rearing-environment quality, using a cross-fostering paradigm, in prairie voles. Results showed that prenatally stressed voles, as adults, displayed the highest behavioral and physiological reactivity when cross-fostered to low-contact (i.e., low-quality) rearing but the lowest behavioral and physiological reactivity when cross-fostered to high-contact (i.e., high-quality) rearing; non-prenatally stressed voles showed no effect of rearing condition. Additionally, while neither prenatal stress nor rearing condition affected oxytocin receptor binding, prenatally stressed voles cross-fostered to high-contact rearing showed the highest vasopressin-1a receptor binding in the amygdala. Results indicate that prenatal stress induces greater environmental sensitivity, making it both a risk and an opportunity factor.

Prenatal stress and enhanced developmental plasticity.

Two separate lines of inquiry indicate (a) that prenatal stress is associated with heightened behavioral and physiological reactivity, and (b) that these postnatal phenotypes are associated with increased susceptibility to both positive and negative developmental experiences and environmental exposures. This research considered together raises the intriguing hypothesis first advanced by Pluess and Belsky (Dev Psychopathol 23:29-38, 2011) that prenatal-stress fosters, promotes or "programs" postnatal developmental plasticity. In this paper, we review further evidence consistent with this proposition, including a novel animal study which experimentally manipulated both prenatal stress and postnatal rearing. Directions for future work focused on mechanisms mediating the plasticity-inducing effects of prenatal stress and the moderators of such effects are outlined.

Prenatal programming of postnatal plasticity revisited-And extended.

Two sets of evidence reviewed herein, one indicating that prenatal stress is associated with elevated behavioral and physiological dysregulation and the other that such phenotypic functioning is itself associated with heightened susceptibility to positive and negative environmental influences postnatally, raises the intriguing hypothesis first advanced by Pluess and Belsky (2011) that prenatal stress fosters, promotes, or "programs" postnatal developmental plasticity. Here we review further evidence consistent with this proposition, including new experimental research systematically manipulating both prenatal stress and postnatal rearing. Collectively this work would seem to explain why prenatal stress has so consistently been linked to problematic development: stresses encountered prenatally are likely to continue postnatally, thereby adversely affecting the development of children programmed (by prenatal stress) to be especially susceptible to environmental effects. Less investigated are the potential benefits prenatal stress may promote, due to increased plasticity, when the postnatal environment proves to be favorable. Future directions of research pertaining to potential mechanisms instantiating postnatal plasticity and moderators of such prenatal-programming effects are outlined.

Decomposing environmental unpredictability in forecasting adolescent and young adult development: A two-sample study.

To illuminate which features of an unpredictable environment early in life best forecast adolescent and adult functioning, data from two longitudinal studies were examined. After decomposing a composite unpredictability construct found to predict later development, results of both studies revealed that paternal transitions predicted outcomes more consistently and strongly than did residential or occupational changes across the first 5 years of a child's life. These results derive from analyses of the NICHD Study of Early Child Care and Youth Development, which included diverse families from 10 different sites in the United States, and from the Minnesota Longitudinal Study of Risk and Adaptation, whose participants came from one site, were disproportionately economically disadvantaged, and were enrolled 15 years earlier than the NICHD Study sample. The finding that results from both studies are consistent with evolutionary, life history thinking regarding the importance of males in children's lives makes this general, cross-study replication noteworthy.

External-environmental and internal-health early life predictors of adolescent development.

A wealth of evidence documents associations between various aspects of the rearing environment and later development. Two evolutionary-inspired models advance explanations for why and how such early experiences shape later functioning: (a) the external-prediction model, which highlights the role of the early environment (e.g., parenting) in regulating children's development, and (b) the internal-prediction model, which emphasizes internal state (i.e., health) as the critical regulator. Thus, by using data from the NICHD Study of Early Child Care and Youth Development, the current project draws from both models by investigating whether the effect of the early environment on later adolescent functioning is subject to an indirect effect by internal-health variables. Results showed a significant indirect effect of internal health on the relation between the early environment and adolescent behavior. Specifically, early environmental adversity during the first 5 years of life predicted lower quality health during childhood, which then led to problematic adolescent functioning and earlier age of menarche for girls. In addition, for girls, early adversity predicted lower quality health that forecasted earlier age of menarche leading to increased adolescent risk taking. The discussion highlights the importance of integrating both internal and external models to further understand the developmental processes that effect adolescent behavior.

Titi Monkeys as a Novel Non-Human Primate Model for the Neurobiology of Pair Bonding
.

It is now widely recognized that social bonds are critical to human health and well-being. One of the most important social bonds is the attachment relationship between two adults, known as the pair bond. The pair bond involves many characteristics that are inextricably linked to quality of health, including providing a secure psychological base and acting as a social buffer against stress. The majority of our knowledge about the neurobiology of pair bonding comes from studies of a socially monogamous rodent, the prairie vole (Microtus ochrogaster), and from human imaging studies, which inherently lack control. Here, we first review what is known of the neurobiology of pair bonding from humans and prairie voles. We then present a summary of the studies we have conducted in titi monkeys (Callicebus cupreus)-a species of socially monogamous New World primates. Finally, we construct a neural model based on the location of neuropeptide receptors in the titi monkey brain, as well as the location of neural changes in our imaging studies, with some basic assumptions based on the prairie vole model. In this model, we emphasize the role of visual mating stimuli as well as contributions of the dopaminergic reward system and a strong role for the lateral septum. This model represents an important step in understanding the neurobiology of social bonds in non-human primates, which will in turn facilitate a better understanding of these mechanisms in humans.

An Evolutionary Perspective on Family Studies: Differential Susceptibility to Environmental Influences.

An evolutionary perspective of human development provides the basis for the differential-susceptibility hypothesis which stipulates that individuals should differ in their susceptibility to environmental influences, with some being more affected than others by both positive and negative developmental experiences and environmental exposures. This paper reviews evidence consistent with this claim while revealing that temperamental and genetic characteristics play a role in distinguishing more and less susceptible individuals. The differential-susceptibility framework under consideration is contrasted to the traditional diathesis-stress view that "vulnerability" traits predispose some to being disproportionately affected by (only) adverse experiences. We raise several issues stimulated by the literature that need to be clarified in further research. Lastly, we suggest that therapy may differ in its effects depending on an individual's susceptibility.

Genetic moderation of effects of maternal sensitivity on girl's age of menarche: Replication of the Manuck et al. study.

Manuck, Craig, Flory, Halder, and Ferrell (2011) reported that a theoretically anticipated effect of family rearing on girls' menarcheal age was genetically moderated by two single nucleotide polymorphisms (SNPs) of the estrogen receptor-α gene. We sought to replicate and extend these findings, studying 210 White females followed from birth. The replication was general because a different measure of the rearing environment was used in this inquiry (i.e., maternal sensitivity) than in the prior one (i.e., family cohesion). Extensions of the work included prospective rather than retrospective measurements of the rearing environment, reports of first menstruation within a year of its occurrence rather than decades later, accounting for some heritability of menarcheal age by controlling for maternal age of menarche, and using a new model-fitting approach to competitively compare diathesis-stress versus differential-susceptibility models of Gene × Environment interaction. The replication/extension effort proved successful in the case of both estrogen receptor-α SNPs, with the Gene × Environment interactions principally reflecting diathesis-stress: lower levels of maternal sensitivity predicted earlier age of menarche for girls homozygous for the minor alleles of either SNP but not for girls carrying other genotypes. Results are discussed in light of the new analytic methods adopted.

Examination of Wnt signaling as a therapeutic target for pancreatic ductal adenocarcinoma (PDAC) using a pancreatic tumor organoid library (PTOL).

Pancreatic ductal adenocarcinoma (PDAC) presents at advanced stages and is refractory to most treatment modalities. Wnt signaling activation plays a critical role in proliferation and chemotherapeutic resistance. Minimal media conditions, growth factor dependency, and Wnt dependency were determined via Wnt inhibition for seven patient derived organoids (PDOs) derived from pancreatic tumor organoid libraries (PTOL). Organoids demonstrating response in vitro were assessed in vivo using patient-derived xenografts. Wnt (in)dependent gene signatures were identified for each organoid. Panc269 demonstrated a trend of reduced organoid growth when treated with ETC-159 in combination with paclitaxel or gemcitabine as compared with chemotherapy or ETC-159 alone. Panc320 demonstrated a more pronounced anti-proliferative effect in the combination of ETC-159 and paclitaxel but not with gemcitabine. Panc269 and Panc320 were implanted into nude mice and treated with ETC-159, paclitaxel, and gemcitabine as single agents and in combination. The combination of ETC-159 and paclitaxel demonstrated an anti-tumor effect greater than ETC-159 alone. Extent of combinatory treatment effect were observed to a lesser extent in the Panc320 xenograft. Wnt (in)dependent gene signatures of Panc269 and 320 were consistent with the phenotypes displayed. Gene expression of several key Wnt genes assessed via RT-PCR demonstrated notable fold change following treatment in vivo. Each pancreatic organoid demonstrated varied niche factor dependencies, providing an avenue for targeted therapy, supported through growth analysis following combinatory treatment of Wnt inhibitor and standard chemotherapy in vitro. The clinical utilization of this combinatory treatment modality in pancreatic cancer PDOs has thus far been supported in our patient-derived xenograft models treated with Wnt inhibitor plus paclitaxel or gemcitabine. Gene expression analysis suggests there are key Wnt genes that contribute to the Wnt (in)dependent phenotypes of pancreatic tumors, providing plausible mechanistic explanation for Wnt (in)dependency and susceptibility or resistance to treatment on the genotypic level.

A phase II study of potentiation of pembrolizumab with binimetinib and bevacizumab in refractory microsatellite stable colorectal cancer.

PURPOSE: In this single-institution phase II investigator-initiated study we assessed the ability of MAPK and VEGF pathway blockade to overcome resistance to immunotherapy in microsatellite stable metastatic colorectal cancer (MSS mCRC). PATIENTS AND METHODS: Patients with MSS, BRAF wild-type mCRC who progressed on ≥2 prior lines of therapy received pembrolizumab, binimetinib, and bevacizumab until disease progression or unacceptable toxicity. After a safety run-in, patients were randomized to a 7-day run-in of binimetinib or simultaneous initiation of all study drugs, to explore whether MEK inhibition may increase tumor immunogenicity. The primary endpoint was objective response rate in all patients combined (ORR, by RECIST v1.1). RESULTS: Fifty patients received study drug treatment; 54% were male with median age 55 years (range 31-79). The primary endpoint, ORR, was 12.0% (95% confidence interval [CI] 4.5-24.3%), which was not statistically different than the historical control data of 5% (p=0.038, exceeding pre-specified threshold of 0.025). The disease control rate was 70.0% (95% CI 55.4-82.1%), median progression-free survival 5.9 months (95% CI 4.2-8.7 months), and median overall survival 9.3 months (95% CI 6.7-12.2 months). No difference in efficacy was observed between the randomized cohorts. Grade 3 and 4 adverse events were observed in 56% and 8% of patients, respectively; the most common were rash (12%) and increased aspartate aminotransferase (12%). CONCLUSION: Pembrolizumab, binimetinib, and bevacizumab failed to meet its primary endpoint of higher ORR compared to historical control data, demonstrated a high disease control rate, and demonstrated acceptable tolerability in refractory MSS mCRC.