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Immunotherapy represents a paradigm shift in oncology treatment. The goal of immunotherapy is to overcome immunosuppression induced by a tumour and its microenvironment, thereby allowing the immune system to target and kill cancer cells. The immunotherapy era began when the first immune checkpoint inhibitor, ipilimumab, was approved for use almost a decade ago. This therapeutic approach is associated with distinct types of response, including processes such as pseudoprogression (ie, increased tumour burden via radiology, which is not accompanied by clinical deterioration) and hyperprogression (ie, rapid progression of the disease as a result of immunotherapy). In this Review, we focus on therapeutic approaches for patients who progress on immunotherapy. We review the different types of clinical responses associated with immunotherapy and describe treatment options for this population.

Pancreas cancer cells have a tendency to invade along nerves. Such cancerous nerve invasion (CNI) is associated with poor outcome; however, the exact mechanism that drives cancer cells to disseminate along nerves is unknown. Immunohistochemical analysis of human pancreatic ductal adenocarcinoma (PDAC) specimens showed overexpression of the L1 cell adhesion molecule (L1CAM) in cancer cells and in adjacent Schwann cells (SC) in invaded nerves. By modeling the neural microenvironment, we found that L1CAM secreted from SCs acts as a strong chemoattractant to cancer cells, through activation of MAP kinase signaling. L1CAM also upregulated expression of metalloproteinase-2 (MMP-2) and MMP-9 by PDAC cells, through STAT3 activation. Using a transgenic Pdx-1-Cre/KrasG12D /p53R172H (KPC) mouse model, we show that treatment with anti-L1CAM Ab significantly reduces CNI in vivo. We provide evidence of a paracrine response between SCs and cancer cells in the neural niche, which promotes cancer invasion via L1CAM secretion.

Nerve invasion frequently occurs in tumours and has traditionally been viewed as a passive process; however, recent studies have revealed active migration of cancer cells along axons (neural tracking). This Opinion article describes possible molecular mechanisms of neural tracking. The local extension of cancer cells along nerves is a frequent clinical finding for various tumours. Traditionally, nerve invasion was assumed to occur via the path of least resistance; however, recent animal models and human studies have revealed that cancer cells have an innate ability to actively migrate along axons in a mechanism called neural tracking. The tendency of cancer cells to track along nerves is supported by various cell types in the perineural niche that secrete multiple growth factors and chemokines. We propose that the perineural niche should be considered part of the tumour microenvironment, describe the molecular cues that facilitate neural tracking and suggest methods for its inhibition.

Although the pathogenic operations of cancer–nerve crosstalk (e.g., neuritogenesis, neoneurogensis, and perineural invasion—PNI) in the peripheral nervous system (PNS) during tumorigenesis, as well as the progression of all cancer types is continuing to emerge as an area of unique scientific interest and study, extensive, wide-ranging, and multidisciplinary investigations still remain fragmented and unsystematic. This is especially so in regard to the roles played by extracellular vesicles (EVs), which are lipid bilayer-enclosed nano- to microsized particles that carry multiple-function molecular cargos, facilitate intercellular communication in diverse processes. Accordingly, the biological significance of EVs has been greatly elevated in recent years, as there is strong evidence that they could contribute to important and possibly groundbreaking diagnostic and therapeutic innovations. This can be achieved and the pace of discoveries accelerated through cross-pollination from existing knowledge and studies regarding nervous system physiology and pathology, as well as thoroughgoing collaborations between oncologists, neurobiologists, pathologists, clinicians, and researchers. This article offers an overview of current and recent past investigations on the roles of EVs in cancer–nerve crosstalk, as well as in neural development, physiology, inflammation, injury, and regeneration in the PNS. By highlighting the mechanisms involved in physiological and noncancerous pathological cellular crosstalk, we provide hints that may inspire additional translational studies on cancer–nerve interplay.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers. It thrives in a nutrient-poor environment; however, the mechanisms by which PDAC cells undergo metabolic reprogramming to adapt to metabolic stress are still poorly understood. Here, we show that microRNA-135 is significantly increased in PDAC patient samples compared to adjacent normal tissue. Mechanistically, miR-135 accumulates specifically in response to glutamine deprivation and requires ROS-dependent activation of mutant p53, which directly promotes miR-135 expression. Functionally, we found miR-135 targets phosphofructokinase-1 (PFK1) and inhibits aerobic glycolysis, thereby promoting the utilization of glucose to support the tricarboxylic acid (TCA) cycle. Consistently, miR-135 silencing sensitizes PDAC cells to glutamine deprivation and represses tumor growth in vivo. Together, these results identify a mechanism used by PDAC cells to survive the nutrient-poor tumor microenvironment, and also provide insight regarding the role of mutant p53 and miRNA in pancreatic cancer cell adaptation to metabolic stresses. Pancreatic ductal adenocarcinoma must adapt to a nutrient-poor microenvironment. Here, the authors show that miR-135 accumulates in response to glutamine deprivation and inhibits aerobic glycolysis by targeting phosphofructokinase-1, thereby redirecting glucose carbon to the TCA cycle and allowing pancreatic cancer cells survival.

Immunohistochemistry (IHC) is the most widely used assay for identification of molecular biomarkers. However, IHC is time consuming and costly, depends on tissue-handling protocols, and relies on pathologists' subjective interpretation. Image analysis by machine learning is gaining ground for various applications in pathology but has not been proposed to replace chemical-based assays for molecular detection. To assess the prediction feasibility of molecular expression of biomarkers in cancer tissues, relying only on tissue architecture as seen in digitized hematoxylin-eosin (H&E)-stained specimens. This single-institution retrospective diagnostic study assessed the breast cancer tissue microarrays library of patients from Vancouver General Hospital, British Columbia, Canada. The study and analysis were conducted from July 1, 2015, through July 1, 2018. A machine learning method, termed morphological-based molecular profiling (MBMP), was developed. Logistic regression was used to explore correlations between histomorphology and biomarker expression, and a deep convolutional neural network was used to predict the biomarker expression in examined tissues. Positive predictive value (PPV), negative predictive value (NPV), and area under the receiver operating characteristics curve measures of MBMP for assessment of molecular biomarkers. The database consisted of 20 600 digitized, publicly available H&E-stained sections of 5356 patients with breast cancer from 2 cohorts. The median age at diagnosis was 61 years for cohort 1 (412 patients) and 62 years for cohort 2 (4944 patients), and the median follow-up was 12.0 years and 12.4 years, respectively. Tissue histomorphology was significantly correlated with the molecular expression of all 19 biomarkers assayed, including estrogen receptor (ER), progesterone receptor (PR), and ERBB2 (formerly HER2). Expression of ER was predicted for 105 of 207 validation patients in cohort 1 (50.7%) and 1059 of 2046 validation patients in cohort 2 (51.8%), with PPVs of 97% and 98%, respectively, NPVs of 68% and 76%, respectively, and accuracy of 91% and 92%, respectively, which were noninferior to traditional IHC (PPV, 91%-98%; NPV, 51%-78%; and accuracy, 81%-90%). Diagnostic accuracy improved given more data. Morphological analysis of patients with ER-negative/PR-positive status by IHC revealed resemblance to patients with ER-positive status (Bhattacharyya distance, 0.03) and not those with ER-negative/PR-negative status (Bhattacharyya distance, 0.25). This suggests a false-negative IHC finding and warrants antihormonal therapy for these patients. For at least half of the patients in this study, MBMP appeared to predict biomarker expression with noninferiority to IHC. Results suggest that prediction accuracy is likely to improve as data used for training expand. Morphological-based molecular profiling could be used as a general approach for mass-scale molecular profiling based on digitized H&E-stained images, allowing quick, accurate, and inexpensive methods for simultaneous profiling of multiple biomarkers in cancer tissues.

The tumor microenvironment (TME) includes a network of cancerous and non-cancerous cells, together with associated blood vessels, the extracellular matrix, and signaling molecules. The TME contributes to cancer progression during various phases of tumorigenesis, and interactions that take place within the TME have become targets of focus in cancer therapy development. Extracellular vesicles (EVs) are known to be conveyors of genetic material, proteins, and lipids within the TME. One of the hallmarks of cancer is its ability to reprogram metabolism to sustain cell growth and proliferation in a stringent environment. In this review, we provide an overview of TME EV involvement in the metabolic reprogramming of cancer and stromal cells, which favors cancer progression by enhancing angiogenesis, proliferation, metastasis, treatment resistance, and immunoevasion. Targeting the communication mechanisms and systems utilized by TME-EVs is opening a new frontier in cancer therapy.

Extracellular vesicles (EVs) transfer bioactive molecules between cells in a process reminiscent of enveloped viruses. EV cargo delivery is thought to occur by protein-mediated and pH-dependent membrane fusion of the EV and the cellular membrane. However, there is a lack of methods to identify the fusion proteins and resolve their mechanism. We developed and benchmarked an in vitro biophysical assay to investigate EV membrane fusion. The assay was standardized by directly comparing EV and viral fusion with liposomes. We show that EVs and retroviruses fuse with liposomes mimicking the membrane composition of the late endosome in a pH- and protein-dependent manner. Moreover, we directly visualize the stages of membrane fusion using cryo-electron tomography. We find that, unlike most retroviruses, EVs remain fusogenic after acidification and reneutralization. These results provide novel insights into the EV cargo delivery mechanism and an experimental approach to identify the EV fusion machinery.

Nurse practitioners (NPs) are increasingly integrated into surgical care teams, complementing traditional surgical roles. However, the relationship between their involvement and patient-reported outcome measures (PROMs), such as pain and anxiety, remains understudied. Purpose: To examine the types of care from NPs in surgical units during the perioperative period and evaluate their association with length of stay, pain, and anxiety. Methods: Our prospective comparative study in two surgical units at a tertiary medical center included 315 patients: 156 received care from NPs, and 159 received usual care. Data were collected at three time points: post-operative day one (T0), during hospitalization (T1), and 14 days post-discharge (T2). Measures included the Brief Pain Inventory, the Hospital Anxiety and Depression Scale, and an intervention checklist completed by the NPs. Findings: NPs performed primarily in-hospital interventions including care coordination (40%) and medication management (44%). Patients treated by NPs reported significantly lower in-hospital anxiety compared to usual care (p = 0.001). The length of stay and pain levels were not significantly associated with NP care. Discussion: NPs in surgical settings provide patient-centered care associated with lower in-hospital anxiety. Further research is recommended to validate these findings in diverse settings.