Tumor FAK orchestrates immunosuppression in ovarian cancer via the CD155/TIGIT axis.

High-grade serous ovarian cancer (HGSOC) is a lethal malignancy characterized by an immunosuppressive tumor microenvironment containing few tumor infiltrating lymphocytes (TILs) and an insensitivity to checkpoint inhibitor immunotherapies. Gains in the PTK2 gene encoding focal adhesion kinase (FAK) at Chr8 q24.3 occur in ∼70% of HGSOC tumors, and elevated FAK messenger RNA (mRNA) levels are associated with poor patient survival. Herein, we show that active FAK, phosphorylated at tyrosine-576 within catalytic domain, is significantly increased in late-stage HGSOC tumors. Active FAK costained with CD155, a checkpoint receptor ligand for TIGIT (T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains), in HGSOC tumors and a selective association between FAK and TIGIT checkpoint ligands were supported by patient transcriptomic database analysis. HGSOC tumors with high FAK expression were associated with low CD3 mRNA levels. Accordingly, late-stage tumors showed elevated active FAK staining and significantly lower levels of CD3+ TILs. Using the KMF (Kras, Myc, FAK) syngeneic ovarian tumor model containing spontaneous PTK2 (FAK) gene gains, the effects of tumor intrinsic genetic or oral small molecule FAK inhibitior (FAKi; VS-4718) were evaluated in vivo. Blocking FAK activity decreased tumor burden, suppressed ascites KMF-associated CD155 levels, and increased peritoneal TILs. The combination of FAKi with blocking TIGIT antibody (1B4) maintained elevated TIL levels and reduced TIGIT+ T regulatory cell levels, prolonged host survival, increased CXCL13 levels, and led to the formation of omental tertiary lymphoid structures. Collectively, our studies support FAK and TIGIT targeting as a rationale immunotherapy combination for HGSOC.

The impact of the California state lockdown during the COVID-19 pandemic on management of patients with pancreatic ductal adenocarcinoma.

BACKGROUND AND OBJECTIVES: The SARS-COVID-19 pandemic significantly limited healthcare access. We sought to evaluate whether California's lockdown in March 2020 affected staging and time to treatment of pancreatic ductal adenocarcinoma (PDAC). We hypothesized that patients diagnosed after the lockdown would have longer time to treatment and higher stage at presentation. METHODS: We retrospectively identified and categorized 1294 patients presenting to five University of California healthcare systems with a new diagnosis of PDAC into "pre-lockdown" and "post-lockdown" groups based on timing of pathologic diagnosis. RESULTS: In the 12 months pre-lockdown, 835 patients were diagnosed with PDAC, and 459 patients in the 6 months post-lockdown. Demographics, staging, and treatment type were similar between eras. There was a decreased male:female ratio post- versus pre-lockdown (0.97 vs. 1.25; p = 0.03). Time from symptom onset to first treatment was significantly increased among females post-lockdown (p = 0.001). However, overall time from diagnosis to first treatment was shorter in the post-lockdown era (median 23 vs. 26 days, p < 0.001). CONCLUSIONS: The COVID-19 lockdown did not significantly delay initial presentation, diagnosis, or treatment of newly diagnosed PDAC patients. Time from diagnosis to first treatment was shorter post-lockdown. Reduced healthcare utilization for minor complaints and increased telehealth utilization may have contributed.

The Landmark Series: Locally Advanced Pancreatic Cancer and Ablative Therapy Options.

Locally advanced pancreatic cancer (LAPC) is a challenging disease to treat. There is consensus that systemic chemotherapy should be the first line of therapy for most patients. However, there is no consensus on how to manage those patients who do not have sufficient response to become candidates for resection but also do not have distant progression after weeks or months of systemic therapy. Radiation therapy is the most commonly used and best-studied local ablative therapy. One recent randomized controlled trial (LAP-07) failed to demonstrate an overall survival benefit for conventional chemoradiation therapy after induction chemotherapy versus chemotherapy alone. This study had several limitations, and ongoing studies are re-evaluating the role of chemoradiation after more effective chemotherapy regimens as well as more advanced radiation techniques. In parallel, there has been increasing interest in other thermal and non-thermal methods of ablation. In particular, irreversible electroporation has gained traction for treatment of LAPC, with at least one ongoing randomized controlled trial designed to address its role compared with systemic chemotherapy alone. Multiple preclinical and clinical studies are investigating combinations of local ablation and immunotherapy with the goal of generating immune responses that will meaningfully improve outcomes.

Reflecting on culturally responsive goal achievement with indigenous clients using the Australian Therapy Outcome Measure for Indigenous Clients (ATOMIC).

INTRODUCTION: Appropriate evaluation of health services for First Australians demands culturally responsive goal setting tools that can be used by inter-professional teams. The Australian Therapy Outcome Measure for Indigenous Clients (ATOMIC) is a purpose-designed tool for measuring therapy outcomes for First Australians. The aim of this study was to establish the clinical utility of the ATOMIC by investigating its alignment with the practice perspectives of an inter-professional First Australian health service. METHODS: Using action research cycles, 12 occupational therapists and 8 speech pathologists applied two successive versions of the ATOMIC in practice. Focus group feedback after use of the first version (ATOMICv1) prompted adaptations to the tool (ATOMICv2). Therapists participated in four focus groups, two after using ATOMICv1 and two after using ATOMICv2. Focus group transcripts were analysed inductively using a qualitative description approach. RESULTS: Challenges in setting SMART goals early in therapy and defining specific measurement increments in ATOMICv1 led to therapists favouring skill-based goals that were easier to measure rather than broader daily life goals, thereby impacting on occupation- and client-centred practice. ATOMICv2 allowed goal setting at any point in therapy, evaluated goals using visual analogue scales, and gathered evidence for rating goal achievement throughout the therapy process. Therapists found the ATOMICv2 to be a culturally responsive tool that aligned with practice perspectives by foregrounding relationship building, facilitating clinical reasoning, documenting daily life changes, and providing integrated inter-professional care. CONCLUSION: The ATOMIC demonstrated good clinical utility in an inter-professional service for First Australian children. It aligned with a culturally responsive practice perspective and captured goal achievement in daily life contexts. Further research is needed to gain client perspectives across the lifespan and to investigate its application by other health professions.

Aptamers as Therapeutics.

Aptamers are single-stranded nucleic acid molecules that bind to and inhibit proteins and are commonly produced by systematic evolution of ligands by exponential enrichment (SELEX). Aptamers undergo extensive pharmacological revision, which alters affinity, specificity, and therapeutic half-life, tailoring each drug for a specific clinical need. The first therapeutic aptamer was described 25 years ago. Thus far, one aptamer has been approved for clinical use, and numerous others are in preclinical or clinical development. This review presents a short history of aptamers and SELEX, describes their pharmacological development and optimization, and reviews potential treatment of diseases including visual disorders, thrombosis, and cancer.

Role of lymphadenectomy in resectable pancreatic cancer.

BACKGROUND: Pancreatic cancer (PC) remains one of the most devastating malignant diseases, predicted to become the second leading cause of cancer-related death by 2030. Despite advances in surgical techniques and in systemic therapy, the 5-year relative survival remains a grim 9% for all stages combined. The extent of lymphadenectomy has been discussed intensively for decades, given that even in early stages of PC, lymph node (LN) metastasis can be detected in approximately 80%. PURPOSE: The primary objective of this review was to provide an overview of the current literature evaluating the role of lymphadenectomy in resected PC. For this, we evaluated randomized controlled studies (RCTs) assessing the impact of extent of lymphadenectomy on OS and studies evaluating the prognostic impact of anatomical site of LN metastasis and the impact of the number of resected LNs on OS. CONCLUSIONS: Lymphadenectomy plays an essential part in the multimodal treatment algorithm of PC and is an additional therapeutic tool to increase the chance for surgical radicality and to ensure correct staging for optimal oncological therapy. Based on the literature from the last decades, standard lymphadenectomy with resection of at least ≥ 15 LNs is associated with an acceptable postoperative complication risk and should be recommended to obtain local radicality and accurate staging of the disease. Although radical surgery including appropriate lymphadenectomy of regional LNs remains the only chance for long-term tumor control, future studies specifically assessing the impact of neoadjuvant therapy on extraregional LNs are warranted.

Real gains: development of a tool to measure outcomes for urban First Australian children accessing culturally responsive interprofessional therapy.

Healthcare services are accountable to their clients, communities, governments and funding sources to clearly demonstrate the effectiveness of interventions. A First Australian children's therapy service delivering culturally responsive, interprofessional collaborative practice aimed to evaluate their service. However, this process was constrained by available outcome measures which lacked the flexibility necessary for meaningful use within the dynamic and relational nature of their service delivery. This paper outlines an action research process in three cycles which was used to develop the Australian Therapies Outcome Measure for Indigenous Clients (ATOMIC) with the aim of evaluating therapy outcomes for urban First Australian children engaged in culturally responsive interprofessional therapy. Interrater reliability values of 0.995 and 0.982 were established for ATOMIC pre- and post-therapy measures, respectively, during a pilot phase involving 16 participants. Participants in the main study were 80 First Australian children aged two to 16 years who attended between two and nine interprofessional therapy sessions with occupational therapists and speech pathologists. Pre- and post-therapy ATOMIC scores confirmed progress on pre-determined functional goals across a range of skill domains. Outcomes of this study demonstrated that real gains are being made in urban First Australian children's lives following interprofessional collaborative service provision.

Polymer-Mediated Inhibition of Pro-invasive Nucleic Acid DAMPs and Microvesicles Limits Pancreatic Cancer Metastasis.

Nucleic acid binding polymers (NABPs) have been extensively used as vehicles for DNA and RNA delivery. More recently, we discovered that a subset of these NABPs can also serve as anti-inflammatory agents by capturing pro-inflammatory extracellular nucleic acids and associated protein complexes that promote activation of toll-like receptors (TLRs) in diseases such as lupus erythematosus. Nucleic-acid-mediated TLR signaling also facilitates tumor progression and metastasis in several cancers, including pancreatic cancer (PC). In addition, extracellular DNA and RNA circulate on or within lipid microvesicles, such as microparticles or exosomes, which also promote metastasis by inducing pro-tumorigenic signaling in cancer cells and pre-conditioning secondary sites for metastatic establishment. Here, we explore the use of an NABP, the 3rd generation polyamidoamine dendrimer (PAMAM-G3), as an anti-metastatic agent. We show that PAMAM-G3 not only inhibits nucleic-acid-mediated activation of TLRs and invasion of PC tumor cells in vitro, but can also directly bind extracellular microvesicles to neutralize their pro-invasive effects as well. Moreover, we demonstrate that PAMAM-G3 dramatically reduces liver metastases in a syngeneic murine model of PC. Our findings identify a promising therapeutic application of NABPs for combating metastatic disease in PC and potentially other malignancies.

Hand-Foot Coupling: An Advantage for Crossed Legs.

It is difficult to perform distinct, simultaneous motor actions with the ipsilateral hand and foot; for example, clockwise circles with the right hand and counter-clockwise circles with the right foot. By chance, we discovered that this hand-foot coupling task is easier when seated with legs crossed. We consider various explanations. First, that there are reduced demands on the contralateral hemisphere when the motor programme of the right foot is executed on the left side of the body. Second, that the legs-crossed scenario is easier because movements are symmetrical with respect to body midline. By considering related motor actions, we conclude that neither of these explanations provides a full account. Thus, we suggest a third explanation, which is that coupling effects are reduced by virtue of increased postural stability and reduced anticipatory postural adjustments.

A prospective, multi-institution assessment of irreversible electroporation for treatment of locally advanced pancreatic adenocarcinoma: initial outcomes from the AHPBA pancreatic registry.

BACKGROUND: The optimal treatment and management of locally advanced pancreatic cancer (LAPC) remains unclear and controversial. This study aimed to report the initial outcomes of the AHPBA Registry and evaluate the reproducibility of existing evidence that the addition of Irreversible Electroporation (IRE), a nonthermal ablative treatment, confers survival benefits beyond standard therapeutic options for patients with LAPC. METHODS: From December 2015 to October 2017, patients with LAPC were treated with open-technique IRE following the AHPBA Registry Protocols. Patient demographics, long-term outcomes, and adverse events were recorded. Survival analyses were performed using Kaplan-Meier (KM) curves for overall survival (OS), progression free survival (PFS) and time to progression (TTP). RESULTS: A total of 152 patients underwent successful IRE. Morbidity and mortality were 18% and 2% respectively, with 19 (13%) patients experiencing severe adverse events. Nine (6%) patients presented with local recurrence. Median TTP, PFS, and OS from diagnosis were 27.3 months, 22.8 months, and 30.7 months respectively. CONCLUSION: The combination of IRE with established multiagent therapy is safe and demonstrates encouraging survival among patients with LAPC. IRE is associated with a low rate of serious adverse events and has been optimized for more widespread adoption through the standardized protocols available through the AHPBA registry.

Inattentional blindness on the full-attention trial: Are we throwing out the baby with the bathwater?

When attention is otherwise engaged, observers may experience inattentional blindness, failing to notice objects or events that are presented in plain sight. In an inattentional blindness experiment, an unexpectedstimulus ispresented alongside primary-task stimuli, and its detection is probed. We evaluate a criterion that is commonly used to exclude observers from the data analysis. On the final experimental trial, observers do not perform the primary task, but instead look for anything new. Observers who fail to report the unexpected stimulus on thisfull-attention trialare excluded. On the basis of 4 hypothetical experiments and a review of 128 actual experiments from the literature, we demonstrate some potentially problematic consequences of implementing the full-attention-trial exclusion criterion. Excluded observers may cluster in experimental conditions and the exclusion criterion may lead researchers to understate the pervasiveness of inattentional blindness. It may even render usblindto inattentional blindness on the full-attention trial.

Differential Induction of Immunogenic Cell Death and Interferon Expression in Cancer Cells by Structured ssRNAs.

Activation of the RNA-sensing pattern recognition receptor (PRR) in cancer cells leads to cell death and cytokine expression. This cancer cell death releases tumor antigens and damage-associated molecular patterns (DAMPs) that induce anti-tumor immunity. However, these cytokines and DAMPs also cause adverse inflammatory and thrombotic complications that can limit the overall therapeutic benefits of PRR-targeting anti-cancer therapies. To overcome this problem, we generated and evaluated two novel and distinct ssRNA molecules (immunogenic cell-killing RNA [ICR]2 and ICR4). ICR2 and ICR4 differentially stimulated cell death and PRR signaling pathways and induced different patterns of cytokine expression in cancer and innate immune cells. Interestingly, DAMPs released from ICR2- and ICR4-treated cancer cells had distinct patterns of stimulation of innate immune receptors and coagulation. Finally, ICR2 and ICR4 inhibited in vivo tumor growth as effectively as poly(I:C). ICR2 and ICR4 are potential therapeutic agents that differentially induce cell death, immune stimulation, and coagulation when introduced into tumors.

TGF-ß-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer in part due to inherent resistance to chemotherapy, including the first-line drug gemcitabine. Although low expression of the nucleoside transporters hENT1 and hCNT3 that mediate cellular uptake of gemcitabine has been linked to gemcitabine resistance, the mechanisms regulating their expression in the PDAC tumor microenvironment are largely unknown. Here, we report that the matricellular protein cysteine-rich angiogenic inducer 61 (CYR61) negatively regulates the nucleoside transporters hENT1 and hCNT3. CRISPR/Cas9-mediated knockout of CYR61 increased expression of hENT1 and hCNT3, increased cellular uptake of gemcitabine and sensitized PDAC cells to gemcitabine-induced apoptosis. In PDAC patient samples, expression of hENT1 and hCNT3 negatively correlates with expression of CYR61 . We demonstrate that stromal pancreatic stellate cells (PSCs) are a source of CYR61 within the PDAC tumor microenvironment. Transforming growth factor-ß (TGF-ß) induces the expression of CYR61 in PSCs through canonical TGF-ß-ALK5-Smad2/3 signaling. Activation of TGF-ß signaling or expression of CYR61 in PSCs promotes resistance to gemcitabine in PDAC cells in an in vitro co-culture assay. Our results identify CYR61 as a TGF-ß-induced stromal-derived factor that regulates gemcitabine sensitivity in PDAC and suggest that targeting CYR61 may improve chemotherapy response in PDAC patients.

A standardized care plan is associated with shorter hospital length of stay in patients undergoing pancreaticoduodenectomy.

BACKGROUND: In this retrospective review, we evaluate a standardized care plan (SCP) for patients undergoing pancreaticoduodenectomy, which included selective placement of feeding jejunostomy tubes (FJTs) and a perioperative fast-track recovery pathway (FTRP). METHODS: A review of 242 patients undergoing pancreaticoduodenectomy was completed. Patients treated pre- and post-SCP implementation were compared. Univariate comparison followed by multivariable linear regression were performed to identify predictors of hospital length of stay (HLOS). RESULTS: SCP patients (n = 100) were slightly older but otherwise similar to pre-SCP patients (n = 142). FJT placement occurred less frequently in SCP patients (38 versus 94%, P < 0.001). All SCP patients were initiated on the FTRP. Among SCP patients, an oral diet was introduced earlier (5 versus 8.5 d, P < 0.001) and HLOS was shorter (11 versus 13 d, P = 0.015). Readmission rates were similar. Following adjustment with linear regression, we confirmed SCP status as a predictor of HLOS. To assess SCP components, HLOS was evaluated separately based on FTRP status and FJT placement. Although both were highly associated with HLOS, neither was independently predictive in multivariable analysis. CONCLUSIONS: Implementation of an SCP resulted in shorter HLOS without an increase in readmissions. Future studies are necessary to identify specific components of SCPs that most influence outcomes.

Defining the learning curve for team-based laparoscopic pancreaticoduodenectomy.

BACKGROUND: The purpose of this study was to define the learning curves for laparoscopic pancreaticoduodenectomy (LPD) with and without laparoscopic reconstruction, using paired surgical teams consisting of advanced laparoscopic-trained surgeons and advanced oncologic-trained surgeons. METHODS: All patients undergoing PD without vein resection at a single institution were retrospectively analyzed. LPD was introduced by initially focusing on laparoscopic resection followed by open reconstruction (hybrid) for 18 months prior to attempting a totally LPD (TLPD) approach. Cases were compared with Chi square, Fisher's exact test, and Kruskal-Wallis analysis of variance (ANOVA). RESULTS: Between March 2010 and June 2013, 140 PDs were completed at our institution, of which 56 (40 %) were attempted laparoscopically. In 31/56 procedures we planned to perform only the resection laparoscopically (hybrid), of which 7 (23 %) required premature conversion before completion of resection. Following the first 23 of these hybrid cases, a total of 25 TLPDs have been performed, of which there were no conversions to open. For all LPD, a significant reduction in operative times was identified following the first 10 patients (median 478.5 vs. 430.5 min; p = 0.01), approaching open PD levels. After approximately 50 cases, operative times and estimated blood loss were consistently lower than those for open PD. CONCLUSIONS: In our experience of building an LPD program, the initial ten cases represent the biggest hurdle with respect to operative times. For an experienced teaching center using a staged and team-based approach, LPD appears to offer meaningful reductions in operative time and blood loss within the first 50 cases.

The role of clinical care pathways: an experience with distal pancreatectomy.

BACKGROUND: Previous studies have indicated that clinical pathways may shorten hospital length of stay (HLOS) among patients undergoing distal pancreatectomy (DP). Here, we evaluate an institutional standardized care pathway (SCP) for patients undergoing DP. MATERIALS AND METHODS: A retrospective review of patients undergoing DP from November 2006 to November 2012 was completed. Patients treated before and after implementation of the SCP were compared. Multivariable linear regression was then performed to identify independent predictors of HLOS. RESULTS: There were no differences in patient characteristics between SCP (n=50) and pre-SCP patients (n=100). Laparoscopic technique (62% versus 13%, P<0.001), splenectomy (52% versus 38%, P=0.117), and concomitant major organ resection (24% versus 13%, P=0.106) were more common among SCP patients. Overall, important complication rates were similar (24% versus 26%, P=0.842). SCP patients resumed a normal diet earlier (4 versus 5 d, P=0.025) and had shorter HLOS (6 versus 7 d, P=0.026). There was no increase in 30-d resurgery or readmission. In univariate comparison, SCP, cancer diagnoses, intraductal papillary mucinous neoplasm diagnoses, neoadjuvant therapy, operative technique, major organ resection, and feeding tube placement were associated with HLOS; however, after multivariable adjustment, only laparoscopic technique (-33%, P=0.001), concomitant major organ resection (+38%, P<0.001), and feeding tube placement (+68%, P<0.001) were independent predictors of HLOS. CONCLUSIONS: Implementation of a clinical pathway did not improve HLOS at our institution. The increasing use of laparoscopy likely accounts for shorter HLOS in the SCP cohort. In the future, it will be important to identify clinical scenarios most likely to benefit from implementation of a clinical pathway.

Wound classification reporting in HPB surgery: can a single word change public perception of institutional performance?

INTRODUCTION: The drive to improve outcomes and the inevitability of mandated public reporting necessitate uniform documentation and accurate databases. The reporting of wound classification in patients undergoing hepato-pancreatico-biliary (HPB) surgery and the impact of inconsistencies on quality metrics were investigated. METHODS: The 2005-2011 National Surgical Quality Improvement Program (NSQIP) participant use file was interrogated to identify patients undergoing HPB resections. The effect of wound classification on post-operative surgical site infection (SSI) rates was determined through logistic regression. The impact of variations in wound classification reporting on perceived outcomes was modelled by simulating observed-to-expected (O/E) ratios for SSI. RESULTS: In total, 27,376 patients were identified with significant heterogeneity in wound classification. In spite of clear guidelines prompting at least 'clean-contaminated' designation for HPB resections, 8% of all cases were coded as 'clean'. Contaminated [adjusted odds ratio (AOR): 1.39, P = 0.001] and dirty (AOR: 1.42, P = 0.02] cases were associated with higher odds of SSI, whereas clean-contaminated were not (P = 0.99). O/E ratios were highly sensitive to modest changes in wound classification. CONCLUSIONS: Perceived performance is affected by heterogeneous reporting of wound classification. As institutions work to improve outcomes and prepare for public reporting, it is imperative that all adhere to consistent reporting practices to provide accurate and reproducible outcomes.

Local ablative therapies and the effect on antitumor immune responses in pancreatic cancer - A review.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease, projected to rank as the second most prevalent cause of cancer-related mortality by 2030. Despite significant progress in advances in surgical techniques and chemotherapy protocols, the overall survival (OS) remains to be less than 10 % for all stages combined. In recent years, local ablative techniques have been introduced and utilized as additional therapeutic approaches for locally advanced pancreatic cancer (LAPC), with promising results with respect to local tumor control and OS. In addition to successful cytoreduction, there is emerging evidence that local ablation induces antitumor immune activity that could prevent or even treat distant metastatic tumors. The enhancement of antitumor immune responses could potentially make ablative therapy a therapeutic option for the treatment of metastatic PDAC. In this review, we summarize current ablative techniques used in the management of LAPC and their impact on systemic immune responses.