Calcium channel blockers potentiate gemcitabine chemotherapy in pancreatic cancer.

There is currently no effective treatment for pancreatic ductal adenocarcinoma (PDAC). While palliative chemotherapy offers a survival benefit to most patients, nearly all will eventually progress on treatment and long-term survivability remains poor. Given the lack of subsequent line treatment options, in this study, we sought to identify novel strategies to prevent, delay, or overcome resistance to gemcitabine, one of the most widely used medications in PDAC. Using a combination of single-cell RNA sequencing and high-throughput proteomic analysis, we identified a subset of gemcitabine-resistant tumor cells enriched for calcium/calmodulin signaling. Pharmacologic inhibition of calcium-dependent calmodulin activation led to the rapid loss of drug-resistant phenotypes in vitro, which additional single-cell RNA sequencing identified was due to impaired activation of the RAS/ERK signaling pathway. Consistent with these observations, calcium chelation or depletion of calcium in the culture media also impaired ERK activation in gemcitabine-resistant cells, and restored therapeutic responses to gemcitabine in vitro. We observed similar results using calcium channel blockers (CCBs) such as amlodipine, which inhibited prosurvival ERK signaling in vitro and markedly enhanced therapeutic responses to gemcitabine in both orthotopic xenografts and transgenic models of PDAC. Combined, these results offer insight into a potential means of gemcitabine resistance and suggest that select CCBs may provide a clinical benefit to PDAC patients receiving gemcitabine-based chemotherapy.

XP-524 is a dual-BET/EP300 inhibitor that represses oncogenic KRAS and potentiates immune checkpoint inhibition in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is associated with extensive dysregulation of the epigenome and epigenetic regulators, such as bromodomain and extraterminal motif (BET) proteins, have been suggested as potential targets for therapy. However, single-agent BET inhibition has shown poor efficacy in clinical trials, and no epigenetic approaches are currently used in PDAC. To circumvent the limitations of the current generation of BET inhibitors, we developed the compound XP-524 as an inhibitor of the BET protein BRD4 and the histone acetyltransferase EP300/CBP, both of which are ubiquitously expressed in PDAC tissues and cooperate to enhance tumorigenesis. XP-524 showed increased potency and superior tumoricidal activity than the benchmark BET inhibitor JQ-1 in vitro, with comparable efficacy to higher-dose JQ-1 combined with the EP300/CBP inhibitor SGC-CBP30. We determined that this is in part due to the epigenetic silencing of KRAS in vitro, with similar results observed using ex vivo slice cultures of human PDAC tumors. Accordingly, XP-524 prevented KRAS-induced, neoplastic transformation in vivo and extended survival in two transgenic mouse models of aggressive PDAC. In addition to the inhibition of KRAS/MAPK signaling, XP-524 also enhanced the presentation of self-peptide and tumor recruitment of cytotoxic T lymphocytes, though these lymphocytes remained refractory from full activation. We, therefore, combined XP-524 with an anti-PD-1 antibody in vivo, which reactivated the cytotoxic immune program and extended survival well beyond XP-524 in monotherapy. Pending a comprehensive safety evaluation, these results suggest that XP-524 may benefit PDAC patients and warrant further exploration, particularly in combination with immune checkpoint inhibition.

Hereditary Spherocytosis with Mitochondrial Retention, Increased Oxidative Stress, and Alterations to Bioactive Membrane Lipids.

The clinical course for Hereditary Spherocytosis (HS) patients is highly varied, even within families with identical driving mutations. Here, we describe four siblings with HS attributed to an unreported SPTB mutation. All patients displayed an increased fraction of mitochondria-positive erythrocytes. This was associated with increased reactive oxygen species (ROS) generation and alteration to alterations to bioactive membrane lipids associated with oxidant stress. Given the early promise for mitophagy-inducing agents in sickle cell disease and ready availability of antioxidants, this concept warrants continued exploration as a disease-modifying factor and a potential target for therapy.

Serum Depletion of Complement Component 5a Is Associated With Increased Inflammation and Poor Clinical Outcomes in Patients With Perianal Fistulas.

BACKGROUND: Persistent disease is a significant issue in the management of perianal fistulas, with up to 50% of patients requiring additional treatment after surgery. OBJECTIVE: This study aimed to identify a novel prognostic modality in hopes of risk-stratifying patients for persistent disease following corrective surgery. DESIGN: This was a retrospective study based on prospectively collected data using a combination of histopathology, high-throughput proteomic arrays, and ELISA-based methods. SETTINGS: This study used data obtained from patients who underwent corrective surgery for perianal fistulas at the University of Illinois Hospital between June 2019 and July 2020. PATIENTS: A cohort of 22 consecutive patients who had corrective surgery for perianal fistulas were included in this study. The patients were divided into 2 groups: those with resolving fistulas (N = 13) and those with persisting fistulas (N = 9). MAIN OUTCOME MEASURES: Nonresolving fistulas were determined by disease representation within 2 months of corrective surgery. RESULTS: Serum samples from patients with persistent perianal fistulas displayed a consistent decrease in the expression of complement pathway component C5a compared with either healthy controls or patients with resolving forms of disease. This was paralleled by an increase in the fistula expression of C5a and an associated increase in tissue infiltrating leukocytes and interleukin-1ß expression. LIMITATIONS: This study was limited by its retrospective design, relatively small sample size, and single-center data analysis. CONCLUSIONS: These results suggest that C5a is modestly depleted in patients with nonresolving forms of disease and traffics to the site of tissue damage and inflammation. Accordingly, serum C5a warrants continued investigation as a prognostic biomarker and predictor of recurrence in patients presenting with perianal fistulas. See Video Abstract at http://links.lww.com/DCR/B982 . LA DEPLECIN SRICA DEL COMPONENTE A DEL COMPLEMENTO SE ASOCIA CON UN AUMENTO DE LA INFLAMACIN Y MALOS RESULTADOS CLNICOS EN PACIENTES CON FSTULAS PERIANALES: ANTECEDENTES:La persistencia de la enfermedad es un problema significativo en el manejo de las fístulas perianales, presente hasta en el 50 % de los pacientes después de la cirugía y que requieren tratamiento adicional.OBJETIVO:DISEÑO:Se trata de un estudio retrospectivo basado en datos recolectados prospectivamente usando una combinación de histopatología, arreglos proteómicos de alto rendimiento y métodos basados en ELISA.ENTORNO CLÍNICO:Este estudio utilizó datos de pacientes que se sometieron a cirugía correctiva por fístulas perianales en el Hospital de la Universidad de Illinois entre junio de 2019 y julio de 2020.PACIENTES:Se incluyó en este estudio una cohorte de 22 pacientes consecutivos que se sometieron a cirugía correctiva de fístulas perianales. Los pacientes se dividieron en 2 grupos: aquellos con fístulas en resolución (N = 13) y aquellos con fístulas persistentes (N = 9).PRINCIPALES MEDIDAS DE VALORACIÓN:Las fístulas que no se resuelven fueron determinadas por la reaparición de la enfermedad dentro de los 2 meses posteriores a la cirugía correctiva.RESULTADOS:Las muestras de suero de pacientes con fístulas perianales persistentes mostraron una disminución constante en la expresión del componente C5a de la vía del complemento en comparación con controles sanos o pacientes con formas de resolución de la enfermedad. Esto fue paralelo a un aumento en la expresión de C5a en la fístula y un aumento asociado en los leucocitos que se infiltran en el tejido y la expresión de IL-1ß.LIMITACIONES:El estudio estuvo limitado por su diseño retrospectivo, tamaño de muestra relativamente pequeño y análisis de datos de un solo centro.CONCLUSIONES:Estos resultados sugieren que C5a se reduce moderadamente en pacientes con formas de enfermedad que no se resuelven y se desplaza al sitio del daño tisular e inflamación. En consecuencia, el C5a sérico justifica una investigación continua como biomarcador pronóstico y predictor de recurrencia en pacientes que presentan fístulas perianales. Consulte Video Resumen en http://links.lww.com/DCR/B982 . (Traducción- Dr. Ingrid Melo ).

Leukocyte subtyping predicts for treatment failure and poor survival in anal squamous cell carcinoma.

BACKGROUND: Anal squamous cell carcinoma (SCC) generally carries a favorable prognosis, as most tumors are highly sensitive to standard of care chemoradiation. However, outcomes are poor for the 20-30% of patients who are refractory to this approach, and many will require additional invasive procedures with no guarantee of disease resolution. METHODS: To identify the patients who are unlikely to respond to the current standard of care chemoradiation protocol, we explored a variety of objective clinical findings as a potential predictor of treatment failure and/or mortality in a single center retrospective study of 42 patients with anal SCC. RESULTS: Patients with an increase in total peripheral white blood cells (WBC) and/or neutrophils (ANC) had comparatively poor clinical outcomes, with increased rates of death and treatment failure, respectively. Using pre-treatment biopsies from 27 patients, tumors with an inflamed, neutrophil dominant stroma also had poor therapeutic responses, as well as reduced overall and disease-specific survival. Following chemoradiation, we observed uniform reductions in nearly all peripheral blood leukocyte subtypes, and no association between peripheral white blood cells and/or neutrophils and clinical outcomes. Additionally, post-treatment biopsies were available from 13 patients. In post-treatment specimens, patients with an inflamed tumor stroma now demonstrated improved overall and disease-specific survival, particularly those with robust T-cell infiltration. CONCLUSIONS: Combined, these results suggest that routinely performed leukocyte subtyping may have utility in risk stratifying patients for treatment failure in anal SCC. Specifically, pre-treatment patients with a high WBC, ANC, and/or a neutrophil-dense tumor stroma may be less likely to achieve complete response using the standard of care chemoradiation regimen, and may benefit from the addition of a subsequent line of therapy.

Metastatic Thymoma Harboring a Deleterious BRCA2 Mutation Derives Durable Clinical Benefit from Olaparib.

Thymomas comprise a group of rare epithelial neoplasms of the anterior mediastinum. Whereas localized disease carries a favorable prognosis, the majority of patients with metastatic thymomas experience progression or recurrence over a 10-year period. Although targeted therapies have become standard of care in many malignancies, no clinically actionable mutations have consistently been identified in metastatic thymomas. Here, we describe a patient with an aggressive thymoma complicated by extensive pleural metastases. Over a 16-year period, she progressed on multiple treatment regimens. To identify additional treatment options, tissue from a pleural metastasis was sent for next-generation sequencing, revealing mutations in BRCA2, tyrosine kinase 2, and SET domain containing 2. Based on supporting evidence for poly (ADP-ribose) polymerase (PARP) inhibition in other BRCA-mutated tumors, the patient was started on the PARP inhibitor olaparib. She derived significant clinical benefit from treatment, with imaging showing overall stabilization of her disease. Here, we review the genotyping results of her tumor and discuss the functional and clinical significance of the mutations in her cancer as well as implications for managing patients with advanced BRCA-mutant thymomas. KEY POINTS: Targeted therapy has yet to enter the standard clinical management of metastatic thymomas. Patients with BRCA2-mutant thymomas may benefit from poly (ADP-ribose) polymerase inhibition.

Activin and TGFß use diverging mitogenic signaling in advanced colon cancer.

BACKGROUND: Understanding cell signaling pathways that contribute to metastatic colon cancer is critical to risk stratification in the era of personalized therapeutics. Here, we dissect the unique involvement of mitogenic pathways in a TGFß or activin-induced metastatic phenotype of colon cancer. METHOD: Mitogenic signaling/growth factor receptor status and p21 localization were correlated in primary colon cancers and intestinal tumors from either AOM/DSS treated ACVR2A (activin receptor 2) -/- or wild type mice. Colon cancer cell lines (+/- SMAD4) were interrogated for ligand-induced PI3K and MEK/ERK pathway activation and downstream protein/phospho-isoform expression/association after knockdown and pharmacologic inhibition of pathway members. EMT was assessed using epithelial/mesenchymal markers and migration assays. RESULTS: In primary colon cancers, loss of nuclear p21 correlated with upstream activation of activin/PI3K while nuclear p21 expression was associated with TGFß/MEK/ERK pathway activation. Activin, but not TGFß, led to PI3K activation via interaction of ACVR1B and p85 independent of SMAD4, resulting in p21 downregulation. In contrast, TGFß increased p21 via MEK/ERK pathway through a SMAD4-dependent mechanism. While activin induced EMT via PI3K, TGFß induced EMT via MEK/ERK activation. In vivo, loss of ACVR2A resulted in loss of pAkt, consistent with activin-dependent PI3K signaling. CONCLUSION: Although activin and TGFß share growth suppressive SMAD signaling in colon cancer, they diverge in their SMAD4-independent pro-migratory signaling utilizing distinct mitogenic signaling pathways that affect EMT. p21 localization in colon cancer may determine a dominant activin versus TGFß ligand signaling phenotype warranting further validation as a therapeutic biomarker prior to targeting TGFß family receptors.

Ablation of 5-lipoxygenase mitigates pancreatic lesion development.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC), which continues to have a dismal prognosis, is associated with a pronounced fibroinflammatory response. Inflammation in vivo can be mediated by 5-lipoxygenase (5LO), an enzyme that converts omega-6 fatty acids (FA) to eicosanoids, including leukotriene B4 (LTB4). We have previously shown that diets rich in omega-6 FA increase pancreatic lesions and mast cell infiltration in EL-Kras mice. In this study, we evaluated the role of 5LO in generating higher levels of LTB4 from human cells and in mediating lesion development and mast cell infiltration in EL-Kras mice. MATERIALS AND METHODS: Human pancreatic ductal epithelial and cancer cells were treated with omega-6 FA in vitro. EL-Kras mice lacking 5LO (EL-Kras/5LO(-/-)) mice were generated and fed standard chow or omega-6 FA diets. Pancreatic lesion frequency and mast cell infiltration were compared with EL-Kras/5LO(+/+) mice. Human PDAC tumors were evaluated for 5LO expression and mast cells. RESULTS: Human pancreatic ductal epithelial and pancreatic cancer cells treated with omega-6 FA generated increased LTB4 levels in vitro. EL-Kras/5LO(-/-) mice developed fewer pancreatic lesions and had decreased mast cell infiltration when compared with EL-Kras/5LO(+/+) mice. Human PDAC tumors with increased 5LO expression demonstrate increased mast cell infiltration. Additionally, diets rich in omega-6 FA failed to increase pancreatic lesion development and mast cell infiltration in EL-Kras/5LO(-/-) mice. CONCLUSIONS: The expansion of mutant Kras-induced lesions via omega-6 FA is dependent on 5LO, and 5LO functions downstream of mutant Kras to mediate inflammation, suggesting that 5LO may be a potential chemopreventive and therapeutic target in pancreatic cancer.

Diabetic ketoacidosis masked by both Euglycemia and a primary metabolic alkalosis.

Diabetic ketoacidosis (DKA) is an acute, life-threatening metabolic complication of diabetes classically associated with hyperglycemia, metabolic acidosis, and ketosis. Though relatively uncommon, patients can also develop DKA with relative euglycemia, further complicating diagnosis. Here, we describe the case of a patient who presented with intractable vomiting secondary to diabetic gastroparesis. He was euglycemic, non-acidemic, and serum bicarbonate was within normal limits. However, labs were significant for ketonuria, an elevated anion gap, and an elevated beta-hydroxybutyrate. Given the high concern for euglycemic DKA in the setting of a competing primary metabolic alkalosis, he was transferred to the intensive care unit for intravenous insulin infusion and fluid resuscitation with significant clinical improvement and normalization of laboratory results. This serves as an important reminder that DKA can be masked by euglycemia as well as additional metabolic derangements, and should be suspected in any diabetic patient with an anion gap and/or ketosis.

Patients deriving long-term benefit from immune checkpoint inhibitors demonstrate conserved patterns of site-specific mutations.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy and are now the preferred treatment for several tumor types. Though ICIs have shown remarkable efficacy in several cancer histologies, in many cases providing long-term disease control, not all patients will derive clinical benefit from such approaches. Given the lack of a reliable predictive biomarker for therapeutic responses to ICIs, we conducted a retrospective analysis of publicly available genomic data from a large pan-cancer cohort of patients receiving ICI-based immunotherapy. Consistent with previous results, patients in the combined cohort deriving a long-term survival benefit from ICIs were more likely to have a higher tumor mutational burden (TMB). However, this was not uniform across tumor-types, failing to predict for long-term survivorship in most non-melanoma cancers. Interestingly, long-term survivors in most cancers had conserved patterns of mutations affecting several genes. In melanoma, this included mutations affecting TET1 or PTPRD. In patients with colorectal cancer, mutations affecting TET1, RNF43, NCOA3, LATS1, NOTCH3, or CREBBP were also associated with improved prognosis, as were mutations affecting PTPRD, EPHA7, NTRK3, or ZFHX3 in non-small cell lung cancer, RNF43, LATS1, or CREBBP mutations in bladder cancer, and VHL mutations in renal cell carcinoma patients. Thus, this study identified several genes that may have utility as predictive biomarkers for therapeutic responses in patients receiving ICIs. As many have no known relationship to immunotherapy or ICIs, these genes warrant continued exploration, particularly for cancers in which established biomarkers such as PD-L1 expression or TMB have little predictive value.

Precision Medicine for BRCA/PALB2-Mutated Pancreatic Cancer and Emerging Strategies to Improve Therapeutic Responses to PARP Inhibition.

Pancreatic cancer is projected to become the second leading cause of cancer-related death by 2030. As patients typically present with advanced disease and show poor responses to broad-spectrum chemotherapy, overall survival remains a dismal 10%. This underscores an urgent clinical need to identify new therapeutic approaches for PDAC patients. Precision medicine is now the standard of care for several difficult-to-treat cancer histologies. Such approaches involve the identification of a clinically actionable molecular feature, which is matched to an appropriate targeted therapy. Selective poly (ADP-ribose) polymerase (PARP) inhibitors such as Niraparib, Olaparib, Talazoparib, Rucaparib, and Veliparib are now approved for several cancers with loss of high-fidelity double-strand break homologous recombination (HR), namely those with deleterious mutations to BRCA1/2, PALB2, and other functionally related genes. Recent evidence suggests that the presence of such mutations in pancreatic ductal adenocarcinoma (PDAC), the most common and lethal pancreatic cancer histotype, significantly alters drug responses both with respect to first-line chemotherapy and maintenance therapy. In this review, we discuss the current treatment paradigm for PDAC tumors with confirmed deficits in double-strand break HR, as well as emerging strategies to both improve responses to PARP inhibition in HR-deficient PDAC and confer sensitivity to tumors proficient in HR repair.

Blunt cardiac injury presenting as a left-sided coronary artery dissection.

The presentation of blunt cardiac injuries (BCIs) following thoracic trauma is extremely varied, classically affecting the right-sided chambers of the heart. In extremely rare cases, BCIs can affect the coronary arteries. Diagnosing a traumatic coronary dissection can be challenging, as not only is presentation highly variable, but dissections are often masked by concomitant injuries. Here, we present the unusual case of a patient presenting to the emergency department following blunt thoracic trauma from an automobile accident. He demonstrated diffuse S and T wave segment elevations on electrocardiogram, and coronary angiography was significant for occlusion of the apical left anterior descending artery and stenosis of the second obtuse marginal artery. The patient was diagnosed with a BCI causing a left-sided coronary artery dissection. This serves as an important reminder that BCIs can manifest in any part of the cardiac anatomy, and should be considered in any patient with a history of thoracic trauma.

Chromium (VI) promotes lung cancer initiation by activating EGF/ALDH1A1 signalling.

Lung cancer is the leading cause of cancer-related death worldwide and is strongly associated with tobacco smoke exposure. Though smoking remains the most important and best studied risk factor, recent data suggests that several other carcinogens have a driving role in lung cancer development, particularly in select populations at risk of high or prolonged exposure. Hexavalent chromium [Cr(VI)] is a known carcinogen that is widely used in the manufacturing industry. While the link between Cr(VI) and lung cancer incidence is well-accepted, the mechanisms through which Cr(VI) promotes lung cancer development are poorly understood. In the present study by Ge and colleagues published in Clinical and Translational Medicine, the authors explored the effects of prolonged Cr(VI) on non-malignant lung epithelial cells. They determined that Cr(VI) initiates lung tumorigenesis by transforming a subpopulation of stem-like, tumor initiating cells with increased expression of Aldehyde dehydrogenase 1 family member A1 (ALDH1A1). The observed increase in ALDH1A1 was dependent on transcriptional upregulation via Krüppel-like factor 4 (KLF4), and associated with enhanced Epidermal Growth Factor (EGF) biosynthesis. Cr(VI)-transformed tumor initiating cells accelerated tumor formation in vivo, which was ameliorated by therapeutic inhibition of ALDH1A1. Importantly, ALDH1A1 inhibition also sensitized Cr(VI)-driven tumors to Gemcitabine chemotherapy and extended overall survival in mice. This study not only offers novel insight into the mechanisms through which Cr(VI) exposure initiates lung tumorigenesis, but identifies a potential therapeutic target for patients with lung cancer secondary to Cr(VI) exposure. Additionally, this study underscores the importance of limiting exposure to Cr(VI) in the workplace and finding safer alternatives for use in the manufacturing industry.

Case report: Rapid onset, ischemic-type gastritis after initiating oral iron supplementation.

Oral iron supplements are commonly administered to patients with chronic iron deficiency anemia. This approach is generally well-tolerated, causing only mild adverse effects. Rarely, oral iron supplementation can cause more severe symptoms, one of the most concerning being acute gastritis. This predominantly affects elderly patients and is extremely uncommon in young, otherwise healthy people. Here, we report the case of a 43-year-old woman who presented with upper gastrointestinal (GI) symptoms and iron deficiency anemia and was started on oral iron supplementation following the resolution of her acute symptoms. She soon re-presented with a severe, Helicobacter pylori-negative gastritis with iron deposition on histology. These new onset symptoms resolved rapidly with cessation of iron supplements, consistent with iron pill gastritis. In addition to the limited body of literature describing iron pill gastritis, this case serves as a reminder that any patient receiving oral iron supplementation is at a potential risk for gastritis, particularly in the setting of an ongoing GI pathology. Hence, it is important to provide continued follow-up for patients receiving iron supplementation regardless of age or comorbidity, particularly in the weeks following the start of the treatment.

The difficulty in translating the preclinical success of combined TGFß and immune checkpoint inhibition to clinical trial.

Immune checkpoint inhibitors (ICIs) have transformed the treatment paradigm for solid tumors. However, even in cancers generally considered ICI-sensitive, responses can vary significantly. Thus, there is an ever-increasing interest in identifying novel means of improving therapeutic responses, both for cancers in which ICIs are indicated and those for which they have yet to show significant anti-tumor activity. To this end, Transforming Growth Factor ß (TGFß) signaling is emerging as an important barrier to the efficacy of ICIs. Accordingly, several preclinical studies now support the use of combined TGFß and immune checkpoint blockade, with near-uniform positive results across a wide range of tumor types. However, as these approaches have started to emerge in clinical trials, the addition of TGFß inhibitors has often failed to show a meaningful benefit beyond the current generation of ICIs alone. Here, we summarize landmark clinical studies exploring combined TGFß and immune checkpoint blockade. These studies not only reinforce the difficulty in translating results from rodents to clinical trials in immune-oncology but also underscore the need to re-evaluate the design of trials exploring this approach, incorporating both mechanism-driven combination strategies and novel, predictive biomarkers to identify the patients most likely to derive clinical benefit.

The immune modifying effects of chemotherapy and advances in chemo-immunotherapy.

Immune checkpoint inhibitors (ICIs) have transformed the treatment paradigm for several malignancies. While the use of single-agent or combined ICIs has achieved acceptable disease control rates in a variety of solid tumors, such approaches have yet to show substantial therapeutic efficacy in select difficult-to-treat cancer types. Recently, select chemotherapy regimens are emerging as extensive modifiers of the tumor microenvironment, leading to the reprogramming of local immune responses. Accordingly, data is now emerging to suggest that certain anti-neoplastic agents modulate various immune cell processes, most notably the cross-presentation of tumor antigens, leukocyte trafficking, and cytokine biosynthesis. As such, the combination of ICIs and cytotoxic chemotherapy are beginning to show promise in many cancers that have long been considered poorly responsive to ICI-based immunotherapy. Here, we discuss past and present attempts to advance chemo-immunotherapy in these difficult-to-treat cancer histologies, mechanisms through which select chemotherapies modify tumor immunogenicity, as well as important considerations when designing such approaches to maximize efficacy and improve therapeutic response rates.

Intestinal adenocarcinoma originating from an undiagnosed Meckel's diverticulum.

Meckel's diverticulum is a congenital anomaly leading to the formation of a true diverticulum in the distal small intestine. Though most are asymptomatic and discovered incidentally, Meckel's diverticuli can give rise to a wide range of symptoms. Rarely, this can be a malignancy, most commonly a carcinoid tumor. Other cancers have also been reported, with adenocarcinomas being particularly rare. Here, we report the case of a 62-year-old man presenting to the emergency room with vague gastrointestinal symptoms. Subsequent workup revealed a 3 cm mass in the distal jejunum/proximal ileum, which was located within a previously undiagnosed Meckel's diverticulum. The mass was sent to pathology, who confirmed an adenocarcinoma arising from a small bowel diverticulum. This case serves as an important reminder of the malignant potential of a Meckel's diverticulum and adds to the ongoing discussion regarding whether prophylactic diverticulectomy should be recommended to patients with a known Meckel's diverticulum.

Ets1 mediates sorafenib resistance by regulating mitochondrial ROS pathway in hepatocellular carcinoma.

The incidence and mortality of hepatocellular carcinoma (HCC) are on a rise in the Western countries including US, attributed mostly to late detection. Sorafenib has been the first-line FDA-approved drug for advanced unresectable HCC for almost a decade, but with limited efficacy due to the development of resistance. More recently, several other multi-kinase inhibitors (lenvatinib, cabozantinib, regorafenib), human monoclonal antibody (ramucirumab), and immune checkpoint inhibitors (nivolumab, pembrolizumab) have been approved as systemic therapies. Despite this, the median survival of patients is not significantly increased. Understanding of the molecular mechanism(s) that govern HCC resistance is critically needed to increase efficacy of current drugs and to develop more efficacious ones in the future. Our studies with sorafenib-resistant (soraR) HCC cells using transcription factor RT2 Profiler PCR Arrays revealed an increase in E26 transformation-specific-1 (Ets-1) transcription factor in all soraR cells. HCC TMA studies showed an increase in Ets-1 expression in advanced HCC compared to the normal livers. Overexpression or knocking down Ets-1 modulated sorafenib resistance-related epithelial-mesenchymal transition (EMT), migration, and cell survival. In addition, the soraR cells showed a significant reduction of mitochondrial damage and mitochondrial reactive oxygen species (mROS) generation, which were antagonized by knocking down Ets-1 expression. More in-depth analysis identified GPX-2 as a downstream mediator of Ets-1-induced sorafenib resistance, which was down-regulated by Ets-1 knockdown while other antioxidant pathway genes were not affected. Interestingly, knocking down GPX2 expression significantly increased sorafenib sensitivity in the soraR cells. Our studies indicate the activation of a novel Ets-1-GPX2 signaling axis in soraR cells, targeting which might successfully antagonize resistance and increase efficacy.

Loss of SMAD4 Is Associated With Poor Tumor Immunogenicity and Reduced PD-L1 Expression in Pancreatic Cancer.

Transforming Growth Factor ß (TGFß) is a key mediator of immune evasion in pancreatic ductal adenocarcinoma (PDAC), and the addition of TGFß inhibitors in select immunotherapy regimens shows early promise. Though the TGFß target SMAD4 is deleted in approximately 55% of PDAC tumors, the effects of SMAD4 loss on tumor immunity have yet to be fully explored. Using a combination of genomic databases and PDAC specimens, we found that tumors with loss of SMAD4 have a comparatively poor T-cell infiltrate. SMAD4 loss was also associated with a reduction in several chemokines with known roles in T-cell recruitment, which was recapitulated using knockdown of SMAD4 in PDAC cell lines. Accordingly, JURKAT T-cells were poorly attracted to conditioned media from PDAC cells with knockdown of SMAD4 and lost their ability to produce IFNγ. However, while exogenous TGFß modestly reduced PD-L1 expression in SMAD4-intact cell lines, SMAD4 and PD-L1 positively correlated in human PDAC samples. PD-L1 status was closely related to tumor-infiltrating lymphocytes, particularly IFNγ-producing T-cells, which were more abundant in SMAD4-expressing tumors. Low concentrations of IFNγ upregulated PD-L1 in tumor cells in vitro, even when administered alongside high concentrations of TGFß. Hence, while SMAD4 may have a modest inhibitory effect on PD-L1 in tumor cells, SMAD4 indirectly promotes PD-L1 expression in the pancreatic tumor microenvironment by enhancing T-cell infiltration and IFNγ biosynthesis. These data suggest that pancreatic cancers with loss of SMAD4 represent a poorly immunogenic disease subtype, and SMAD4 status warrants further exploration as a predictive biomarker for cancer immunotherapy.

Inhibition of MNKs promotes macrophage immunosuppressive phenotype to limit CD8+ T cell antitumor immunity.

To elicit effective antitumor responses, CD8+ T cells need to infiltrate tumors and sustain their effector function within the immunosuppressive tumor microenvironment (TME). Here, we evaluate the role of MNK activity in regulating CD8+ T cell infiltration and antitumor activity in pancreatic and thyroid tumors. We first show that human pancreatic and thyroid tumors with increased MNK activity are associated with decreased infiltration by CD8+ T cells. We then show that, while MNK inhibitors increase CD8+ T cells in these tumors, they induce a T cell exhaustion phenotype in the tumor microenvironment. Mechanistically, we show that the exhaustion phenotype is not caused by upregulation of programmed cell death ligand 1 (PD-L1) but is caused by tumor-associated macrophages (TAMs) becoming more immunosuppressive following MNK inhibitor treatment. Reversal of CD8+ T cell exhaustion by an anti-PD-1 antibody or TAM depletion synergizes with MNK inhibitors to control tumor growth and prolong animal survival. Importantly, we show in ex vivo human pancreatic tumor slice cultures that MNK inhibitors increase the expression of markers associated with immunosuppressive TAMs. Together, these findings demonstrate a role of MNKs modulating a protumoral phenotype in macrophages and identify combination regimens involving MNK inhibitors to enhance antitumor immune responses.