To Revise or Not Revise? Isolated Margin Positivity in Localized Pancreatic Ductal Adenocarcinoma.

BACKGROUND: The study determined the proportion of patients with pancreatic adenocarcinoma (PDAC) who had margin-positive disease and no other adverse pathologic findings (APF) using institutional and administrative datasets. METHODS: Patients with clinical stage I or II PDAC in the National Cancer Database (NCDB 2010-2020) and those who underwent pancreatectomy at the authors' institution (2010-2021) were identified. Isolated margin positivity (IMP) was defined as a positive surgical margin with no APF (negative nodes, no lymphovascular/perineural invasion). RESULTS: The study included 225 patients from the authors' institution and 23,598 patients from the NCDB. The margin-positive rates were 21.8% and 20.3%, and the IMP rates were 0.4% and 0.5%, respectively. In the institutional cohort, 68.4% of the patients had recurrence, and most of the patients (65.6%) had distant recurrences. The median recurrence-free survival (RFS) was 63.3 months for no APF, not reached for IMP, 14.8 months for negative margins & 1 APF, 20.3 months for positive margins & 2 APFs, and 12.9 months with all APF positive. The patients in the NCDB with IMP had a lower median OS than the patients with no APF (20.5 vs 390 months), but a higher median OS than those with margin positivity plus 1 APF (20.5 vs 18.0 months) or all those with APF positivity (20.5 vs 15.4 months). Based on institutional rates of IMP, any margin positivity, neck margin positivity (NMP), and no APF, the fraction of patients who might benefit from neck margin revision was 1 in 100,000, and those likely to benefit from any margin revision was 1 in 18,500. In the NCDB, those estimated to derive potential benefit from margin revision was 1 in 25,000. CONCLUSIONS: Isolated margin positivity in resected PDAC is rare, and most patients experience distant recurrence. Revision of IMP appears unlikely to confer benefit to most patients.

Perfusion Strategies for Cytoreductive Surgery With Heated Intraperitoneal Chemotherapy for Malignant Peritoneal Mesothelioma.

Cytoreductive surgery (CRS) with heated intraoperative intraperitoneal chemotherapy (HIPEC) has been shown to improve survival for patients with malignant peritoneal mesothelioma (MPM). Presently, there is no standardized HIPEC protocol with respect to chemotherapeutic agent, dose, administration temperature, or duration and limited literature comparing outcomes in different regimens. In this study, we analyze common practices and outcomes of published HIPEC regimens to gain insight into current practice to inform future directions of study. We conducted a literature search for investigational studies of CRS and HIPEC for MPM treatment in adults and identified 35 such articles. These studies were analyzed for institution type and location, drug regimens, perfusion temperatures and time, and study outcomes including median survival, complication rates, and perioperative mortality rates. On review, there is significant heterogeneity in HIPEC regimens and outcome reporting metrics, suggesting a need for multi-institutional standardized study protocols to better determine the safest and most efficacious treatment regimen.

Reasons for Surgical Attrition Among Nonmetastatic Upper Gastrointestinal Cancer Patients: A Single Institutional Experience.

INTRODUCTION: Upper gastrointestinal (UGI) cancers require multidisciplinary treatment, but surgery provides the only potentially curative option. We sought to understand reasons for attrition before surgery within our regional hospital network. METHODS: We performed chart reviews of patients (age 18-80) with stage I-III UGI cancers (gastroesophageal junction, gastric, and hepatopancreatobiliary adenocarcinomas) in our multihospital cancer registry from 2015 to 2021. Our primary outcome was reasons for surgical attrition. Univariable analysis identified factors related to surgical attrition and the Kaplan-Meier method estimated overall survival based on surgery receipt. RESULTS: Seven hundred and ninety-two patients were included in our analysis, of whom 107 (13.5%) did not undergo curative surgery. Reasons for not undergoing surgery included medical comorbidities (30.8%), patient preference/nonmedical barriers (24.3%, which included: not interested without further explanation, worried about complications, nonadherence to appointments, insurance issues, did not wish for blood transfusion, lack of social support, preferring home care, and worried about recurrence), psychosocial (5.6%), progression while on neoadjuvant therapy or waiting for transplant (15.0% and 7.5%), poor performance status (3.7%), side effects of neoadjuvant therapy (3.7%), and death unrelated to treatment or unknown cause (9.4%). Nonsurgical management was not associated with race, socioeconomic status, or distance traveled for care. Survival was greatly improved for patients who underwent surgery (158 vs. 63 weeks, p < 0.05). CONCLUSION: Nearly one in seven patients (18-80 years old) with UGI cancers evaluated at our academic cancer center did not undergo surgical resection. Reasons for surgical attrition included potentially modifiable issues, and addressing these barriers could help overcome inequities in cancer treatment and survival.

Predictors of sentinel lymph node metastasis in very thin invasive melanomas.

BACKGROUND: Melanomas < 0.8 mm in Breslow depth have less than a 5% risk for nodal positivity. Nonetheless, nodal positivity is prognostic for this group. Early identification of nodal positivity may improve the outcomes for these patients. OBJECTIVES: To determine the degree to which ulceration and other high-risk features predict sentinel lymph node (SLN) positivity for very thin melanomas. METHODS: The National Cancer Database was reviewed from 2012 to 2018 for patients with melanoma with Breslow thickness < 0.8 mm. Data were analysed from 7 July 2022 through to 25 February 2023. Patients were excluded if data regarding their ulceration status or SLN biopsy (SLNB) performance were unknown. We analysed patient, tumour and health system factors for their effect on SLN positivity. Data were analysed using χ2 tests and logistic regressions. Overall survival (OS) was compared by Kaplan-Meier analyses. RESULTS: Positive nodal metastases were seen in 876 (5.0%) patients who underwent SLNB (17 692). Factors significantly associated with nodal positivity on multivariable analysis include lymphovascular invasion [odds ratio (OR) 4.5, P < 0.001], ulceration (OR 2.6, P < 0.001), mitoses (OR 2.1, P < 0.001) and nodular subtype (OR 2.1, P < 0.001). Five-year OS was 75% and 92% for patients with positive and negative SLN, respectively. CONCLUSIONS: Nodal positivity has prognostic significance for very thin melanomas. In our cohort, the rate of nodal positivity was 5% overall in these patients who underwent SLNB. Specific tumour factors (e.g. lymphovascular invasion, ulceration, mitoses, nodular subtype) were associated with higher rates of SLN metastases and should be used to guide clinicians in choosing which patients will benefit from SLNB.

Prodromal depression and anxiety are associated with worse treatment compliance and survival among patients with pancreatic cancer.

OBJECTIVE: To determine the frequency of depression or anxiety preceding a diagnosis of pancreatic cancer (PC). Further, to examine the association of PC-associated depression or anxiety with treatment compliance and survival. METHODS: 856 patients with PC from a single institution were identified using International Classification of Diseases (ICD) codes. For each case, two non-cancer age- and sex-matched controls were included. Dates of depression or anxiety diagnosis identified using ICD codes were compared to the date of PC diagnosis. The medical record was queried to further explore psychiatric symptoms. Multivariable analyses were performed to examine if prediagnosis depression or anxiety was associated with receipt of treatment or survival. RESULTS: A greater proportion of patients with PC experienced depression or anxiety in the year preceding diagnosis than the overall frequency in controls (4.6% vs. 2.6%, p = 0.005) based on ICD codes. Patients with PC exhibited signs of prodromal depression or anxiety based on ICD codes, clinical documentation of psychiatric symptoms, or initiation of new psychiatric medications more often than controls (20.7% vs. 6.7%, p < 0.001). Prediagnosis depression or anxiety was associated with a reduced likelihood of receiving chemotherapy (OR = 0.58, p = 0.04). There was an associated decrease in overall survival among patients with metastatic disease who experienced depression or anxiety before PC diagnosis (HR = 1.32, p = 0.04). CONCLUSIONS: The frequency of depression or anxiety among patients with PC was higher than the general population. Prediagnosis psychiatric symptoms were associated with reduced chemotherapy utilization and worse overall survival. Thus, timely identification and treatment of these symptoms may improve outcomes.

The autophagy protein Ambra1 regulates gene expression by supporting novel transcriptional complexes.

Ambra1 is considered an autophagy and trafficking protein with roles in neurogenesis and cancer cell invasion. Here, we report that Ambra1 also localizes to the nucleus of cancer cells, where it has a novel nuclear scaffolding function that controls gene expression. Using biochemical fractionation and proteomics, we found that Ambra1 binds to multiple classes of proteins in the nucleus, including nuclear pore proteins, adaptor proteins such as FAK and Akap8, chromatin-modifying proteins, and transcriptional regulators like Brg1 and Atf2. We identified biologically important genes, such as Angpt1, Tgfb2, Tgfb3, Itga8, and Itgb7, whose transcription is regulated by Ambra1-scaffolded complexes, likely by altering histone modifications and Atf2 activity. Therefore, in addition to its recognized roles in autophagy and trafficking, Ambra1 scaffolds protein complexes at chromatin, regulating transcriptional signaling in the nucleus. This novel function for Ambra1, and the specific genes impacted, may help to explain the wider role of Ambra1 in cancer cell biology.

Immunomodulatory Role of Complement Proteins in the Neuropathology Associated with Opiate Abuse and HIV-1 Co-Morbidity.

The complement system which is a critical mediator of innate immunity plays diverse roles in the neuropathogenesis of HIV-1 infection such as clearing HIV-1 and promoting productive HIV-1 replication. In the development of HIV-1 associated neurological disorders (HAND), there may be an imbalance between complement activation and regulation, which may contribute to the neuronal damage as a consequence of HIV-1 infection. It is well recognized that opiate abuse exacerbates HIV-1 neuropathology, however, little is known about the role of complement proteins in opiate induced neuromodulation, specifically in the presence of co-morbidity such as HIV-1 infection. Complement levels are significantly increased in the HIV-1-infected brain, thus HIV-induced complement synthesis may represent an important mechanism for the pathogenesis of AIDS in the brain, but remains underexplored. Anti-HIV-1 antibodies are able to initiate complement activation in HIV-1 infected CNS cells such as microglia and astrocytes during the course of disease progression; however, this complement activation fails to clear and eradicate HIV-1 from infected cells. In addition, the antiretroviral agents used for HIV therapy cause dysregulation of lipid metabolism, endothelial, and adipocyte cell function, and activation of pro-inflammatory cytokines. We speculate that both HIV-1 and opiates trigger a cytokine-mediated pro-inflammatory stimulus that modulates the complement cascade to exacerbate the virus-induced neurological damage. We examined the expression levels of C1q, SC5b-9, C5L2, C5aR, C3aR, and C9 key members of the complement cascade both in vivo in post mortem brain frontal cortex tissue from patients with HAND who used/did not use heroin, and in vitro using human microglial cultures treated with HIV tat and/or heroin. We observed significant expression of C1q and SC5b-9 by immunofluorescence staining in both the brain cortical and hippocampal region in HAND patients who abused heroin. Additionally, we observed increased gene expression of C5aR, C3aR, and C9 in the brain tissue of both HIV-1 infected patients with HAND who abused and did not abuse heroin, as compared to HIV negative controls. Our results show a significant increase in the expression of complement proteins C9, C5L2, C5aR, and C3aR in HIV transfected microglia and an additional increase in the levels of these complement proteins in heroin-treated HIV transfected microglia. This study highlights the a) potential roles of complement proteins in the pathogenesis of HIV-1-related neurodegenerative disorders; b) the combined effect of an opiate, like heroin, and HIV viral protein like HIV tat on complement proteins in normal human microglial cells and HIV transfected microglial cells. In the context of HAND, targeting selective steps in the complement cascade could help ameliorating the HIV burden in the CNS, thus investigations of complement-related therapeutic approaches for the treatment of HAND are warranted.

Preoperative therapy in melanoma: Evolving perspectives in clinical trials.

We reviewed phase II and III trials beginning after 2010 studying preoperative therapy in melanoma (61 trials). Compared to standard adjuvant treatment, neoadjuvant immune checkpoint inhibitors (ICIs) show improved outcomes with approximately 70-80% recurrence free survival at 2 years. Several biomarkers demonstrate predictive value for pathological response (higher PD-L1 expression) and survival (IFN-γ signatures, CD8 + cell density). A number of 'non-standard' treatment mechanisms are being studied in combination with ICI therapies such as TLR-9 agonists, and anti-LAG3 checkpoint inhibitors, which show promise for alternative therapy options in the neoadjuvant setting. Finally, trials for advanced unresectable melanomas show improved survival compared to definitive systemic treatment when upfront systemic therapies lead to resectability. To conclude, in the preoperative setting for melanoma, ICIs have potential to improve outcomes for patients, and will likely change the standard treatment approach for advanced resectable disease.

Extended antibiotic therapy is associated with a lower rate of clinically relevant postoperative pancreatic fistula after pancreatoduodenectomy in intermediate- and high-risk patients: A single-institution analysis.

BACKGROUND: Clinically relevant postoperative pancreatic fistula remains a common complication after pancreatoduodenectomy. The fistula risk score is a validated tool to predict the risk of clinically relevant postoperative pancreatic fistula. To mitigate complications, we have implemented an extended antibiotic pathway for patients at increased risk of clinically relevant postoperative pancreatic fistula (fistula risk score ≥3). We report outcomes after pancreatoduodenectomy in patients at increased risk for clinically relevant postoperative pancreatic fistula who received extended antibiotic therapy compared to those who received standard perioperative antibiotics (single dose before incision). METHODS: Single-institution analysis of 87 patients who underwent elective pancreatoduodenectomy (2018-2022) with soft gland texture and fistula risk score ≥3 and were treated with (n = 34) or without (n = 53) 10 days of broad-spectrum antibiotics (piperacillin/tazobactam converted to amoxicillin/clavulanic acid at discharge) after surgery. Associations between extended antibiotics and postoperative outcomes were analyzed. RESULTS: Baseline clinicodemographic factors were similar between cohorts. Patients who received extended antibiotics had shorter index days (6 vs 8 days, P = .004) and 90-day composite length of stay (8.5 vs 12 days, P = .018). Patients who received extended antibiotics had lower rates of clinically relevant postoperative pancreatic fistula (11.8% vs 37.7%; odds ratio = 0.17, 95% confidence interval: 0.04-0.68), wound infections (8.8% vs 30.2%; odds ratio = 0.08, 95% confidence interval: 0.01-0.50), organ space infections (14.7% vs 43.4%; odds ratio = 0.15, 95% confidence interval: 0.04-0.52), and image-guided drain placement (8.8% vs 34.0%; odds ratio = 0.15, 95% confidence interval: 0.04-0.62). There were no Clostridium difficile infections in the extended antibiotic group. CONCLUSION: Extended antibiotic therapy is associated with a lower rate of clinically relevant postoperative pancreatic fistula and associated complications after pancreatoduodenectomy in patients with a fistula risk score ≥3. These results form the basis of a randomized controlled trial (NCT05753735).

An Age-Stratified Analysis of Early Postoperative Mortality Among Medicare-Eligible Patients With Common Gastrointestinal and Hepato-pancreato-biliary Malignancies.

Background: The frequency of major cancer surgery in the elderly (≥80 years) has increased concomitantly with the rise in average age of the population. We assessed early postoperative mortality following hepato-pancreato-biliary (HPB) and gastrointestinal (GI) procedures for common malignancies stratified by age. Methods: The National Cancer Database (2004-2017) was queried for patients who underwent resection for GI (gastroesophageal and colorectal) or HPB (pancreatic adenocarcinoma, biliary tract, and primary liver) cancers. We compared early postoperative mortality (30 d and 90 d) stratified by age (65-79 vs ≥80 years) and procedure, and compared survival outcomes by age and operative vs nonoperative management. Results: A total of 709,358 patients were included. The 30-day mortality ranged from 1.8% to 5.8% among patients 65-79 years and from 3.2% to 12.4% among patients ≥80 years depending on procedure. The 90-day mortality ranged from 3.6% to 10.6% in patients 65-79 years compared to 8.4%-21.0% among patients ≥80 years. The overall 90-day mortality was 5.2% for patients 65-79 years and 12.0% for patients ≥80 years (P < .001). Age ≥80 was associated with worse survival among operatively managed patients with each upper GI, HPB, and lower GI malignancy relative to younger patients on multivariable analysis. However, operative management of patients ≥80 years was associated with improved survival relative to nonoperative management. Discussion: Elderly patients suffer higher postoperative mortality after major GI and HPB cancer surgery, but operative management is associated with improved survival among patients ≥80 years as compared to nonoperative management. These data are important to contextualize when counseling elderly patients on their treatment options for localized GI and HPB cancers.

Therapeutic implications of the metabolic changes associated with BRAF inhibition in melanoma.

Melanoma metabolism can be reprogrammed by activating BRAF mutations. These mutations are present in up to 50% of cutaneous melanomas, with the most common being V600E. BRAF mutations augment glycolysis to promote macromolecular synthesis and proliferation. Prior to the development of targeted anti-BRAF therapies, these mutations were associated with accelerated clinical disease in the metastatic setting. Combination BRAF and MEK inhibition is a first line treatment option for locally advanced or metastatic melanoma harboring targetable BRAF mutations. This therapy shows excellent response rates but these responses are not durable, with almost all patients developing resistance. When BRAF mutated melanoma cells are inhibited with targeted therapies the metabolism of those cells also changes. These cells rely less on glycolysis for energy production, and instead shift to a mitochondrial phenotype with upregulated TCA cycle activity and oxidative phosphorylation. An increased dependence on glutamine utilization is exhibited to support TCA cycle substrates in this metabolic rewiring of BRAF mutated melanoma. Herein we describe the relevant core metabolic pathways modulated by BRAF inhibition. These adaptive pathways represent vulnerabilities that could be targeted to overcome resistance to BRAF inhibitors. This review evaluates current and future therapeutic strategies that target metabolic reprogramming in melanoma cells, particularly in response to BRAF inhibition.

A Comprehensive Analysis of Metastatic Disease following Surgery for Clinically Localized Cutaneous Melanoma.

INTRODUCTION: The NCCN considers "baseline staging" (whole body CT or PET scan +/- brain MRI) for all asymptomatic melanoma patients with a positive sentinel lymph node biopsy. The true yield of these workups is unknown. METHODS: We created cohorts of adult malignant melanoma patients, using the National Cancer Database (2012-2020) to mimic three common scenarios: (1) clinically node negative, with positive sentinel lymph node(s) (SLNB[+]); (2) clinically node negative, with negative sentinel lymph node(s) (SLNB[-]); (3) clinically node positive with confirmed lymph node metastases (cN[+] and pN[+]). Multivariable regression, supervised decision trees, and nomograms were constructed to assess the risk of metastases based on key features. RESULTS: 10,371 patients were SLNB[+], 55,172 were SLNB[-], and 4,012 were cN[+] and pN[+]. The proportion of patients with any metastatic disease (brain metastases) were as follows: SLNB[+]: 1.4% (0.3%); SLNB[-] 0.3% (<0.1%); cN[+] and pN[+] 11.6% (1.6%). On multivariable regression, Breslow depth > 4, ulceration, and lymphovascular invasion were associated with greater risk of metastatic disease. A supervised decision tree for SLNB[+] and SLNB[-] patients found the only groups with >2% risk of metastases were T4 tumors or T2/T3 tumors with ulceration and LVI. Most groups had a negligible risk (<0.1%) of brain metastases. CONCLUSION: This is the first large analysis to guide the use of imaging for cutaneous melanoma. Among clinically node negative patients, metastatic disease is uncommon and brain metastases are exceedingly rare. Further investigation could promote a tailored approach to metastatic workups guided by individual risk factors.

IDH1 Inhibition Potentiates Chemotherapy Efficacy in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is associated with a 5-year overall survival rate of just 13%, and development of chemotherapy resistance is nearly universal. PDAC cells overexpress wild-type isocitrate dehydrogenase 1 (IDH1) that can enable them to overcome metabolic stress, suggesting it could represent a therapeutic target in PDAC. Here, we found that anti-IDH1 therapy enhanced the efficacy of conventional chemotherapeutics. Chemotherapy treatment induced reactive oxygen species (ROS) and increased tricarboxylic acid cycle activity in PDAC cells, along with the induction of wild-type IDH1 expression as a key resistance factor. IDH1 facilitated PDAC survival following chemotherapy treatment by supporting mitochondrial function and antioxidant defense to neutralize ROS through the generation of α-ketoglutarate and NADPH, respectively. Pharmacologic inhibition of wild-type IDH1 with ivosidenib synergized with conventional chemotherapeutics in vitro and potentiated the efficacy of subtherapeutic doses of these drugs in vivo in murine PDAC models. This promising treatment approach is translatable through available and safe oral inhibitors and provides the basis of an open and accruing clinical trial testing this combination (NCT05209074). Significance: Targeting IDH1 improves sensitivity to chemotherapy by suppressing mitochondrial function and inducing oxidative stress, supporting the potential of the combination as an effective strategy for treating pancreatic cancer.

A Ketogenic Diet Sensitizes Pancreatic Cancer to Inhibition of Glutamine Metabolism.

Pancreatic cancer is the third leading cause of cancer death in the United States, and while conventional chemotherapy remains the standard treatment, responses are poor. Safe and alternative therapeutic strategies are urgently needed 1 . A ketogenic diet has been shown to have anti-tumor effects across diverse cancer types but will unlikely have a significant effect alone. However, the diet shifts metabolism in tumors to create new vulnerabilities that can be targeted (1). Modulators of glutamine metabolism have shown promise in pre-clinical models but have failed to have a marked impact against cancer in the clinic. We show that a ketogenic diet increases TCA and glutamine-associated metabolites in murine pancreatic cancer models and under metabolic conditions that simulate a ketogenic diet in vitro. The metabolic shift leads to increased reliance on glutamine-mediated anaplerosis to compensate for low glucose abundance associated with a ketogenic diet. As a result, glutamine metabolism inhibitors, such as DON and CB839 in combination with a ketogenic diet had robust anti-cancer effects. These findings provide rationale to study the use of a ketogenic diet with glutamine targeted therapies in a clinical context.

Patient and provider factors predict non-surgical management for complex upper gastrointestinal cancers.

BACKGROUND: Surgery is the only potentially curative treatment for non-metastatic upper gastrointestinal cancers. We analyzed patient and provider characteristics associated with non-surgical management. METHODS: We queried the National Cancer Database for patients with upper gastrointestinal cancers from 2004 to 2018 who underwent surgery, refused surgery, or for whom surgery was contraindicated. Multivariate logistic regression identified factors associated with surgery being refused or contraindicated, and Kaplan-Meier curves assessed survival. RESULTS: We identified 249,813 patients based on our selection criteria-86.3% had surgery, 2.4% refused, and for 11.3%, surgery was contraindicated. Median overall survival was 48.2 months for patients who underwent surgery versus 16.3 and 9.4 months for the refusal and contraindicated groups. Medical and non-medical factors predicted both surgery refusals and contraindications, such as increasing age (odds ratio = 1.07 and 1.03, respectively, P < .001), Black race (odds ratio = 1.72 and 1.45, P < .001), comorbidities (Charlson-Deyo score 2+, odds ratio = 1.18 and 1.66, P < .001), low socioeconomic status (odds ratio = 1.70 and 1.40, P < .001), no health insurance (odds ratio = 3.26 and 2.34, P < .001), community cancer programs (odds ratio = 1.43 and 1.40, P < .001), low volume facilities (odds ratio = 1.82 and 1.52, P < .001), and stage 3 disease (odds ratio = 1.51 and 6.50, P < .001). On subset analysis (excluding patients age >70, Charlson-Deyo score 2+, and stage 3 cancer), non-medical predictors of both outcomes were similar. CONCLUSION: Refusal of and medical contraindications for surgery profoundly impact overall survival. The same factors (ie, race, socioeconomic status, hospital volume, and hospital type) predict these outcomes. These findings suggest variation and potential bias that may exist between physicians and patients discussing cancer surgery.

Mena regulates nesprin-2 to control actin-nuclear lamina associations, trans-nuclear membrane signalling and gene expression.

Interactions between cells and the extracellular matrix, mediated by integrin adhesion complexes, play key roles in fundamental cellular processes, including the sensing and transduction of mechanical cues. Here, we investigate systems-level changes in the integrin adhesome in patient-derived cutaneous squamous cell carcinoma cells and identify the actin regulatory protein Mena as a key node in the adhesion complex network. Mena is connected within a subnetwork of actin-binding proteins to the LINC complex component nesprin-2, with which it interacts and co-localises at the nuclear envelope. Moreover, Mena potentiates the interactions of nesprin-2 with the actin cytoskeleton and the nuclear lamina. CRISPR-mediated Mena depletion causes altered nuclear morphology, reduces tyrosine phosphorylation of the nuclear membrane protein emerin and downregulates expression of the immunomodulatory gene PTX3 via the recruitment of its enhancer to the nuclear periphery. We uncover an unexpected role for Mena at the nuclear membrane, where it controls nuclear architecture, chromatin repositioning and gene expression. Our findings identify an adhesion protein that regulates gene transcription via direct signalling across the nuclear envelope.

Increased glucose availability sensitizes pancreatic cancer to chemotherapy.

Pancreatic Ductal Adenocarcinoma (PDAC) is highly resistant to chemotherapy. Effective alternative therapies have yet to emerge, as chemotherapy remains the best available systemic treatment. However, the discovery of safe and available adjuncts to enhance chemotherapeutic efficacy can still improve survival outcomes. We show that a hyperglycemic state substantially enhances the efficacy of conventional single- and multi-agent chemotherapy regimens against PDAC. Molecular analyses of tumors exposed to high glucose levels reveal that the expression of GCLC (glutamate-cysteine ligase catalytic subunit), a key component of glutathione biosynthesis, is diminished, which in turn augments oxidative anti-tumor damage by chemotherapy. Inhibition of GCLC phenocopies the suppressive effect of forced hyperglycemia in mouse models of PDAC, while rescuing this pathway mitigates anti-tumor effects observed with chemotherapy and high glucose.

Trends in Melanoma Phase 3 Clinical Trials since 2010: Is there Hope for Advanced Melanoma Therapies beyond Approved Treatment Mechanisms?

BACKGROUND: Several drugs and treatment modalities are under investigation to improve current melanoma therapy options. This review profiles the trends in clinical trial investment in late-stage melanoma, and anticipates what changes are expected in melanoma treatment, with a focus on exploratory drug mechanisms. METHODS: We reviewed nine international clinical trial databases for registered, interventional, and phase 3 cutaneous melanoma clinical trials since 2010. RESULTS: 73 trials studied drug therapies in late-stage (stage III and IV) melanoma. Exploratory mechanisms were investigated in 32% (23/73) of the late-stage melanoma drug therapy trials. Most exploratory drug trials include immunotherapy drug mechanisms (15/23 trials). Two exploratory mechanisms showed promise: the anti-LAG3 antibody, relatlimab, and the hapten modified vaccine, MVax. Many (52%) trials of exploratory mechanisms are ongoing including the use of adoptive cell transfer immunotherapies, dendritic cell vaccine therapy, and histone deacetylase (HDAC) inhibitors, among others. CONCLUSIONS: Since most clinical trials focus on previously approved drug mechanisms, it is likely that paradigm-changing treatments will involve these therapies being used in new treatment contexts or combinations. Only 2 exploratory drug mechanisms studied since 2010 have achieved promising results in the phase 3 setting, though many other trials are ongoing at this time.

IDO1 Is a Therapeutic Target for Pancreatic Cancer-Associated Depression.

Metabolites of tryptophan degradation are known to alter mood. Their effects have only been superficially examined in the context of pancreatic cancer. Herein, we study the role of indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme important in the conversion of tryptophan to kynurenine, in a murine model of pancreatic cancer-associated depression. Behavioral tests (open field, forced swim, tail suspension, and elevated plus maze) and biochemical assays (LC-MS metabolomics) were used to characterize a depressive-phenotype in tumor-bearing mice (relative to non-tumor-bearing mice). In addition, we determine whether pharmacologic blockade of IDO1 affects mood in tumor-bearing mice. Immunocompetent mice bearing orthotopic pancreatic tumors exhibit depressive-like behavior relative to non-tumor-bearing mice. Pancreatic tumors strongly express IDO1. Consequently, serum kynurenine levels in tumor-bearing mice are elevated relative to non-tumor-bearing mice. Tumor-bearing mice treated with epacadostat, an IDO1 inhibitor, exhibited improved mood relative to mice receiving vehicle. There was a 95% reduction in serum kynurenine levels in mice receiving epacadostat relative to mice treated with vehicle. As confirmatory evidence of on-target activity, tumors of mice treated with epacadostat exhibited a compensatory increase in IDO1 protein levels. Escitalopram, an approved antidepressant, was ineffective at improving mood in tumor-bearing mice as measured by behavioral assays and did not affect kynurenine levels. Neither epacadostat, nor escitalopram, affected overall survival relative to vehicle. Mice with pancreatic cancer exhibit depressive-like behavior. Epacadostat was effective as an antidepressant for pancreatic cancer-associated depression in mice. These data offer a rationale to consider IDO1 inhibition as a therapeutic strategy to mitigate depressive symptoms in patients with pancreatic cancer.