Safety and Efficacy of Oxaliplatin Pressurized Intraperitoneal Aerosolized Chemotherapy (PIPAC) in Colorectal and Appendiceal Cancer with Peritoneal Metastases: Results of a Multicenter Phase I Trial in the USA.

BACKGROUND: Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a laparoscopic locoregional treatment for peritoneal metastases (PM) from colorectal cancer (CRC) or appendiceal cancer (AC) in patients who cannot undergo cytoreductive surgery (CRS). While PIPAC has been studied in Europe and Asia, it has not been investigated in the USA. PATIENTS AND METHODS: We evaluated PIPAC with 90 mg/m2 oxaliplatin alone (cycle 1) and preceded by systemic chemotherapy with fluorouracil (5-FU) and leucovorin (LV) (cycle 2-3) as a multicenter prospective phase I clinical trial (NCT04329494). The primary endpoint was treatment-related adverse events (AEs). Secondary endpoints included survival and laparoscopic, histologic, and radiographic response. RESULTS: 12 patients were included: 8 with CRC and 4 with AC. Median prior chemotherapy cycles was 2 (interquartile range (IQR) 2-3). All patients were refractory to systemic oxaliplatin-based chemotherapy. Median peritoneal carcinomatosis index (PCI) was 28 (IQR 19-32). Six (50%) of twelve patients completed three PIPAC cycles. No surgical complications or dose-limiting toxicities were observed. Two patients developed grade 3 treatment-related toxicities (one abdominal pain and one anemia). Median overall survival (OS) was 12.0 months, and median progression-free survival (PFS) was 2.9 months. OS was correlated with stable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria but not with laparoscopic response by PCI or histologic response by peritoneal regression grading system (PRGS). CONCLUSIONS: This phase I trial in the USA demonstrated safety, feasibility, and early efficacy signal of PIPAC with oxaliplatin and chemotherapy in patients with PM from AC or CRC who are refractory to standard lines of systemic chemotherapy.

PIPAC for the Treatment of Gynecologic and Gastrointestinal Peritoneal Metastases: Technical and Logistic Considerations of a Phase 1 Trial.

BACKGROUND: Peritoneal metastases (PM) from ovarian, gastric, appendiceal, or colorectal origin can be treated via cytoreductive surgery with or without the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) for selected patients. Unfortunately, not all patients are candidates for aggressive surgical debulking. For these patients, pressurized intraperitoneal aerosolized chemotherapy (PIPAC) has emerged as an alternative method for intraperitoneal (IP) chemotherapy administration. This report presents the design and implementation of the first phase 1 trial to evaluate the safety and efficacy of PIPAC in the United States. METHODS: This is an ongoing prospective phase 1 clinical trial of PIPAC for patients who have histologically confirmed ovarian, uterine, gastric, appendiceal, or colorectal cancer with PM and have progressed to at least one evidence-based chemotherapeutic regimen. The trial has two clinical arms. The patients in arm 1 have gynecologic and gastric malignancies treated with IP cisplatin and doxorubicin, and the arm 2 patients have colorectal and appendiceal malignancies treated with intravenous fluorouracil and leucovorin followed by IP oxaliplatin. All the patients are monitored for dose-limiting toxicities and adverse events. RESULTS: Practical and technical considerations for the phase 1 PIPAC trial are presented. These considerations include patient selection, operating room setup, and technical details for successful aerosolized chemotherapy delivery. The phase 1 study results will be reported separately at completion of the trial. CONCLUSIONS: The PIPAC treatment is a feasible, minimally invasive approach that permits IP delivery of chemotherapy. Once completed, the ongoing phase 1 trial will help to provide safety and initial efficacy data.

Evaluating effectiveness of cognitive behavioral therapy within multimodal treatment for chronic groin pain after inguinal hernia repair.

INTRODUCTION: The development of chronic groin pain after inguinal hernia repair is a complex problem with many potential factors contributing to its development. Surgical options for alleviation of symptoms are limited and only performed by a few centers dedicated to its treatment. Opportunities to apply the principles of a prehabilitation program, including Cognitive Behavioral Therapy (CBT), aim to improve the surgical outcomes for this condition. METHODS AND PROCEDURES: A multi-disciplinary hernia team has implemented a clinical quality improvement (CQI) effort in an attempt to better measure and improve outcomes for patients suffering with chronic groin pain after inguinal hernia repair. Between April 2011 and August 2018, 129 patients (157 groins) underwent surgical treatment for chronic groin pain after inguinal hernia repair. Data were collected to compare outcomes for those undergoing preoperative CBT and patients who did not have CBT prior to their operation. RESULTS: Of 129 total patients, baseline demographics were similar in terms of gender, age, and BMI. In total, 27 patients (32 groins) underwent prehabilitation with CBT (20.93%). We found none of the patients who underwent preoperative CBT had new postoperative pain and all patient procedures were able to be performed on an outpatient basis. Overall, 15 (14.7%) patients had no improvement in symptoms after surgery from the non-CBT group, whereas there was improvement in chronic pain for all patients who underwent CBT. CONCLUSION: This attempt at process improvement demonstrated beneficial effects for patients who had CBT as part of a prehabilitation program prior to a surgical procedure to attempt to relieve groin pain after inguinal hernia repair. As with any CQI analysis, other factors may have contributed to these outcomes and these results may be different in another local environment.

A Reckless Guide to P-values : Local Evidence, Global Errors.

This chapter demystifies P-values, hypothesis tests and significance tests and introduces the concepts of local evidence and global error rates. The local evidence is embodied in this data and concerns the hypotheses of interest for this experiment, whereas the global error rate is a property of the statistical analysis and sampling procedure. It is shown using simple examples that local evidence and global error rates can be, and should be, considered together when making inferences. Power analysis for experimental design for hypothesis testing is explained, along with the more locally focussed expected P-values. Issues relating to multiple testing, HARKing and P-hacking are explained, and it is shown that, in many situations, their effects on local evidence and global error rates are in conflict, a conflict that can always be overcome by a fresh dataset from replication of key experiments. Statistics is complicated, and so is science. There is no singular right way to do either, and universally acceptable compromises may not exist. Statistics offers a wide array of tools for assisting with scientific inference by calibrating uncertainty, but statistical inference is not a substitute for scientific inference. P-values are useful indices of evidence and deserve their place in the statistical toolbox of basic pharmacologists.

Cortisol limits selected actions of synthetic glucocorticoids in the airway epithelium.

Cortisol, a physiologic glucocorticoid (GC), is essential for growth and differentiation of the airway epithelium. Epithelial function influences inflammation in chronic respiratory diseases. Synthetic GCs, including inhaled corticosteroids, exert anti-inflammatory effects in airway epithelium by transactivation of genes and by inhibition of proinflammatory cytokine release. We examined the effect of cortisol on the actions of synthetic GCs in the airway epithelium, demonstrating that cortisol acts like a partial agonist at the GC receptor (GR), limiting GC-induced GR-dependent transcription in the BEAS-2B human bronchial epithelial cell line. Cortisol also limited the inhibition of granulocyte macrophage colony-stimulating factor release by synthetic GCs in TNF-α-activated BEAS-2B cells. The relevance of these findings is supported by observations on tracheal epithelium obtained from mice treated for 5 d with systemic GC, showing limitations in selected GC effects, including inhibition of IL-6. Moreover, gene transactivation by synthetic GCs was compromised by standard air-liquid interface (ALI) growth medium cortisol concentration (1.4 µM) in the ALI-differentiated organotypic culture of primary human airway epithelial cells. These findings suggest that endogenous corticosteroids may limit certain actions of synthetic pharmacological GCs and contribute to GC insensitivity, particularly when corticosteroid levels are elevated by stress.-Prodanovic, D., Keenan, C. R., Langenbach, S., Li, M., Chen, Q., Lew, M. J., Stewart, A. G. Cortisol limits selected actions of synthetic glucocorticoids in the airway epithelium.

Preparing Cancer Patients and Family Caregivers for Lung Surgery: Development of a Multimedia Self-Management Intervention.

The surgical treatment of lung malignancies often results in persistent symptoms, psychosocial distress, and decrements in quality of life (QOL) for cancer patients and their family caregivers (FCGs). The potential benefits of providing patients and FCGs with preparatory education that begins in the preoperative setting have been explored in multiple medical conditions, with positive impact observed on postoperative recovery, psychological distress, and QOL. However, few studies have explored the benefits of preparatory educational interventions to promote self-management in cancer surgery, including lung surgery. This paper describes the systematic approach used in the development of a multimedia self-management intervention to prepare cancer patients and their FCGs for lung surgery. Intervention development was informed by (1) contemporary published evidence on the impact of lung surgery on patients and FCG, (2) our previous research that explored QOL, symptoms, and caregiver burden after lung surgery, (3) the use of the chronic care self-management model (CCM) to guide intervention design, and (4) written comments and feedback from patients and FCGs that informed intervention development and refinement. Pilot-testing of the intervention is in process, and a future randomized trial will determine the efficacy of the intervention to improve patient, FCG, and system outcomes.

Use of a mobile tower-based robot--The initial Xi robot experience in surgical oncology.

BACKGROUND AND OBJECTIVES: The da Vinci Xi platform provides expanded movement of the arms relative to the base, theoretically allowing increased versatility in complex multi-field or multi-quadrant surgery. We describe the initial Xi experience in oncologic surgery at a tertiary cancer center. METHODS: One hundred thirty unique robot-assisted procedures were performed using the Xi between 2014 and 2015, 112 of which were oncology surgeries. For procedures involving multiple quadrants, the robot was re-targeted. Complications were assessed according to Martin criteria and the Clavien-Dindo classification up to 90 days after operation. RESULTS: Thirteen different operations were performed in five oncology subspecialties (urology, gynecology, thoracic, hepatobiliary, and gastrointestinal surgery). Median operative times ranged from 183 min for nephroureterectomy to 543 min for esophagogastrectomy. Median estimated blood loss did not exceed 200 ml for any of the categorized procedures . No patients were transfused intraoperatively and no positioning injuries occurred. Conversions to open operation occurred in three cases (2.7%), though not related to complications or technical considerations. Overall complication rate was 26% with major complication rate of 4%. Readmissions were necessary in 11 (10%) patients. CONCLUSIONS: The da Vinci Xi can be safely assimilated into a surgical oncology program. The Xi offers versatility to various oncologic procedures with satisfactory complication and readmission rates.

Protease-activated receptor 2 (PAR2) protein and transient receptor potential vanilloid 4 (TRPV4) protein coupling is required for sustained inflammatory signaling.

G protein-coupled receptors of nociceptive neurons can sensitize transient receptor potential (TRP) ion channels, which amplify neurogenic inflammation and pain. Protease-activated receptor 2 (PAR(2)), a receptor for inflammatory proteases, is a major mediator of neurogenic inflammation and pain. We investigated the signaling mechanisms by which PAR(2) regulates TRPV4 and determined the importance of tyrosine phosphorylation in this process. Human TRPV4 was expressed in HEK293 cells under control of a tetracycline-inducible promoter, allowing controlled and graded channel expression. In cells lacking TRPV4, the PAR(2) agonist stimulated a transient increase in [Ca(2+)](i). TRPV4 expression led to a markedly sustained increase in [Ca(2+)](i). Removal of extracellular Ca(2+) and treatment with the TRPV4 antagonists Ruthenium Red or HC067047 prevented the sustained response. Inhibitors of phospholipase A(2) and cytochrome P450 epoxygenase attenuated the sustained response, suggesting that PAR(2) generates arachidonic acid-derived lipid mediators, such as 5',6'-EET, that activate TRPV4. Src inhibitor 1 suppressed PAR(2)-induced activation of TRPV4, indicating the importance of tyrosine phosphorylation. The TRPV4 tyrosine mutants Y110F, Y805F, and Y110F/Y805F were expressed normally at the cell surface. However, PAR(2) was unable to activate TRPV4 with the Y110F mutation. TRPV4 antagonism suppressed PAR(2) signaling to primary nociceptive neurons, and TRPV4 deletion attenuated PAR(2)-stimulated neurogenic inflammation. Thus, PAR(2) activation generates a signal that induces sustained activation of TRPV4, which requires a key tyrosine residue (TRPV4-Tyr-110). This mechanism partly mediates the proinflammatory actions of PAR(2).

N-glycosylation determines ionic permeability and desensitization of the TRPV1 capsaicin receptor.

The balance of glycosylation and deglycosylation of ion channels can markedly influence their function and regulation. However, the functional importance of glycosylation of the TRPV1 receptor, a key sensor of pain-sensing nerves, is not well understood, and whether TRPV1 is glycosylated in neurons is unclear. We report that TRPV1 is N-glycosylated and that N-glycosylation is a major determinant of capsaicin-evoked desensitization and ionic permeability. Both N-glycosylated and unglycosylated TRPV1 was detected in extracts of peripheral sensory nerves by Western blotting. TRPV1 expressed in HEK-293 cells exhibited various degrees of glycosylation. A mutant of asparagine 604 (N604T) was not glycosylated but did not alter plasma membrane expression of TRPV1. Capsaicin-evoked increases in intracellular calcium ([Ca(2+)](i)) were sustained in wild-type TRPV1 HEK-293 cells but were rapidly desensitized in N604T TRPV1 cells. There was marked cell-to-cell variability in capsaicin responses and desensitization between individual cells expressing wild-type TRPV1 but highly uniform responses in cells expressing N604T TRPV1, consistent with variable levels of glycosylation of the wild-type channel. These differences were also apparent when wild-type or N604T TRPV1-GFP fusion proteins were expressed in neurons from trpv1(-/-) mice. Capsaicin evoked a marked, concentration-dependent increase in uptake of the large cationic dye YO-PRO-1 in cells expressing wild-type TRPV1, indicative of loss of ion selectivity, that was completely absent in cells expressing N604T TRPV1. Thus, TRPV1 is variably N-glycosylated and glycosylation is a key determinant of capsaicin regulation of TRPV1 desensitization and permeability. Our findings suggest that physiological or pathological alterations in TRPV1 glycosylation would affect TRPV1 function and pain transmission.

A Memorizing and Generalizing Framework for Lifelong Person Re-Identification.

In this paper, we introduce a challenging yet practical setting for person re-identification (ReID) task, named lifelong person re-identification (LReID), which aims to continuously train a ReID model across multiple domains and the trained model is required to generalize well on both seen and unseen domains. It is therefore critical to learn a ReID model that can learn a generalized representation without forgetting knowledge of seen domains. In this paper, we propose a new MEmorizing and GEneralizing framework (MEGE) for LReID, which can jointly prevent the model from forgetting and improve its generalization ability. Specifically, our MEGE is composed of two novel modules, i.e., Adaptive Knowledge Accumulation (AKA) and differentiable Ranking Consistency Distillation (RCD). Taking inspiration from the cognitive processes in the human brain, we endow AKA with two special capacities, knowledge representation and knowledge operation by graph convolution networks. AKA can effectively mitigate catastrophic forgetting on seen domains while improving the generalization ability to unseen domains. By considering the ranking factor that is specifically important in ReID, RCD is designed to distill the ranking knowledge in a differentiable manner, which can further prevent the catastrophic forgetting. To supporting the study of LReID, we build a new and large-scale benchmark with two practical evaluation protocols that consider the metrics of non-forgetting and generalization. Experiments demonstrate that 1) our MEGE framework can effectively improve the performance on seen and unseen domains under the domain-incremental learning constraint, and that 2) the proposed MEGE outperforms state-of-the-art competitors by large margins.

Machine Learning Algorithm to Perform the American Society of Anesthesiologists Physical Status Classification.

OBJECTIVE: The American Society of Anesthesiologists (ASA) Physical Status (PS) Classification System defines perioperative patient scores ranging from 1 to 6 (healthy to brain dead, respectively). The scoring is performed and used by physician anesthesiologists and providers to classify surgical patients based on co-morbidities and various clinical characteristics. There is potentially a variability in scoring stemming from individual biases. The biases impact the prediction of operating times, length of stay in the hospital, anesthetic management, and billing. This study's purpose was to develop an automated system to achieve reproducible scoring. METHODS: A machine learning (ML) model was trained on already assigned ASA PS scores of 12,064 patients. The ML algorithm was automatically selected by Wolfram Mathematica (Wolfram Research, Champaign, IL) and tested with retrospective records not used in training. Manual scoring was performed by the anesthesiologist as part of the standard preoperative evaluation. Intraclass correlation coefficient (ICC) in R (version 4.2.2; R Development Core Team, Vienna, Austria) was calculated to assess the consistency of scoring. RESULTS: An ML model was trained on the data corresponding to 12,064 patients. Logistic regression was chosen automatically, with an accuracy of 70.3±1.0% against the training dataset. The accuracy against 1,999 patients (the test dataset) was 69.6±1.0%. The ICC for the comparison between ML and the anesthesiologists' ASA PS scores was greater than 0.4 ("fair to good"). CONCLUSIONS: We have shown the feasibility of applying ML to assess the ASA PS score within an oncology patient population. Though our accuracy was not very good, we feel that, as more data are mined, a valid foundation for refinement to ML will emerge.

Deep Learning for Instance Retrieval: A Survey.

In recent years a vast amount of visual content has been generated and shared from many fields, such as social media platforms, medical imaging, and robotics. This abundance of content creation and sharing has introduced new challenges, particularly that of searching databases for similar content - Content Based Image Retrieval (CBIR) - a long-established research area in which improved efficiency and accuracy are needed for real-time retrieval. Artificial intelligence has made progress in CBIR and has significantly facilitated the process of instance search. In this survey we review recent instance retrieval works that are developed based on deep learning algorithms and techniques, with the survey organized by deep feature extraction, feature embedding and aggregation methods, and network fine-tuning strategies. Our survey considers a wide variety of recent methods, whereby we identify milestone work, reveal connections among various methods and present the commonly used benchmarks, evaluation results, common challenges, and propose promising future directions.

Episodic, severe abdominal pain due to isolated jejunal Crohn's disease.

Small bowel Crohn's disease can present with episodic, relapsing, and remitting symptoms and delays in the diagnosis are common. We present a case of a young woman with three years of intermittent abdominal pain and nausea with negative previous evaluations. On presentation, inflammatory markers were elevated, and repeat imaging showed jejunal inflammation, with histopathological examination showing non-caseating granulomas of the small bowel consistent with Crohn's disease. This case highlights the importance of gastroenterologist recognizing the alarm signs in a patient with unexplained symptoms and adds to the literature on the clinical presentation of a rare diagnosis of isolated jejunal Crohn's disease.

Ligand-supported purification of the urotensin-II receptor.

A crucial limitation for structural and biophysical analysis of G protein-coupled receptors (GPCRs) is the inherent challenge of purifying and stabilizing these receptors in an active (agonist-bound) conformation. Peptide ligands, such as the vasoactive, cyclic hormone urotensin-II (U-II), may provide new purification tools, via high affinity, pseudo-irreversible binding suitable for ligand-based affinity purification. We show that the U-II receptor (UT) is resistant to desensitization as a result of low phosphorylation and diminished endocytosis. UT also displays an unusual proclivity to remain active with vasoconstriction sustained despite extensive washout of the ligand. To exploit these properties for ligand-supported purification, we modified the U-II ligand by attaching a biotin moiety and spacer arm to the N terminus, creating a novel affinity ligand (Bio-U-II) to interface with streptavidin media. Bio-U-II bound to UT with pharmacological properties analogous to those of the unmodified U-II ligand (high-affinity, pseudo-irreversible binding). The prebinding of Bio-U-II to UT (before exposure to detergent) facilitated specific capture of UT by stabilizing the receptor structure during solubilization with detergent. Solubilization of UT with the most compatible detergent, n-dodecyl ß-d-maltoside, was dependent on the critical micelle concentration, and Gα(q/11) protein was copurified with captured Bio-U-II-UT complexes. Furthermore, captured Bio-U-II-UT complexes were resistant to dissociation at elevated temperatures, suggesting that UT is relatively thermostable, making it an ideal candidate for future structural and biophysical studies. This work demonstrates the utility of pseudo-irreversible ligands to support the purification of a GPCR during detergent extraction, resulting in the first successful purification of the UT.

Multi-Component Mechanism of H2 Relaxin Binding to RXFP1 through NanoBRET Kinetic Analysis.

The peptide hormone H2 relaxin has demonstrated promise as a therapeutic, but mimetic development has been hindered by the poorly understood relaxin receptor RXFP1 activation mechanism. H2 relaxin is hypothesized to bind to two distinct ECD sites, which reorientates the N-terminal LDLa module to activate the transmembrane domain. Here we provide evidence for this model in live cells by measuring bioluminescence resonance energy transfer (BRET) between nanoluciferase-tagged RXFP1 constructs and fluorescently labeled H2 relaxin (NanoBRET). Additionally, we validate these results using the related RXFP2 receptor and chimeras with an inserted RXFP1-binding domain utilizing NanoBRET and nuclear magnetic resonance studies on recombinant proteins. We therefore provide evidence for the multi-component molecular mechanism of H2 relaxin binding to RXFP1 on the full-length receptor in cells. Also, we show the utility of NanoBRET real-time binding kinetics to reveal subtle binding complexities, which may be overlooked in traditional equilibrium binding assays.

Hypothermia Is Associated with Surgical Site Infection in Cytoreductive Surgery with Hyperthermic Intra-Peritoneal Chemotherapy.

BACKGROUND: Maintenance of peri-operative normothermia remains a global quality metric for hospitals. Hypothermia is associated with surgical site infections (SSIs) in colorectal surgery. Patients undergoing cytoreductive surgery (CRS) with hyperthermic intra-peritoneal chemotherapy (HIPEC) can experience multiple complications post-operatively. We sought to investigate the association of peri-operative hypothermia with SSIs in patients undergoing CRS/HIPEC at our institution. PATIENTS AND METHODS: Patients undergoing CRS/HIPEC from 2009-2017 were identified retrospectively from a prospectively collected institutional database. Hypothermia defined as less than 36.0°C in accordance with the Agency for Healthcare Research and Quality metric. Regression analyses were performed with SSIs diagnosed within 30 days post-operatively as the primary outcome. RESULTS: A total of 170 patients were identified, 14 (8.2%) of whom developed an SSI. Patients who developed an SSI experienced lower median temperatures (p = 0.027) and a greater percentage of operative time in hypothermia (p = 0.008). On a multivariable analysis adjusting for known risk factors for SSI, the percentage of operative time in hypothermia (odds ratio [OR] 1.04, 95% confidence interval [CI] 1.01-1.07, p = 0.008) was the only parameter associated with SSI within 30 days post-operatively. CONCLUSION: Hypothermia is associated with the development of SSIs in patients undergoing CRS/HIPEC. Our findings suggest that minimizing peri-operative temperatures to less than 36.0°C may decrease peri-operative SSI in this patient population.

Principles: when there should be no difference--how to fail to reject the null hypothesis.

It is common to perform experiments in which a 'success' is claimed when the null hypothesis is discarded. However, there is a category of experiment that has become important in which a success is when the null hypothesis is not rejected. Failing to discard the null hypothesis is different from proving it to be valid, a distinction that is particularly important in experiments in which any inadequacy of experimental design or implementation enhances the likelihood of a success. The appropriate analysis of such experiments tests for evidence of the validity of the null hypothesis rather than simply failing to find evidence against it.

Biased signalling from the glucocorticoid receptor: Renewed opportunity for tailoring glucocorticoid activity.

Recent landmark studies applying analytical pharmacology approaches to the glucocorticoid receptor (GR) have demonstrated that different ligands can cause differential activation of distinct GR-regulated genes. Drawing on concepts of signalling bias from the field of G protein-coupled receptor (GPCR) biology, we speculate that ligand-dependent differences in GR signalling can be considered analogous to GPCR biased signalling, and thus can be quantitatively analysed in a similar way. This type of approach opens up the possibility of using rational structure-based drug optimisation strategies to improve the therapeutic selectivity of glucocorticoid drugs to maximise their efficacy and minimise adverse effects.