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OBJECTIVE: To evaluate whether pathologic complete response (pCR) exclusively defines major pathologic response to treatment with improved survival. SUMMARY BACKGROUND DATA: pCR following trimodality therapy for esophagogastric adenocarcinoma is infrequent but associated with improved prognosis. Yet most clinical trials and correlative studies designate pCR as the primary endpoint. METHODS: We analyzed our prospectively maintained database for patients who underwent trimodality therapy for locally advanced esophageal adenocarcinoma between 1995 and 2017. Overall survival (OS) was examined by percentage treatment response (TR) in the primary tumor bed and pathologic nodal stage (ypN0) using Kaplan-Meier plots. Optimal thresholds of TR for differentiating patients in terms of OS were investigated with descriptive plots using restricted cubic spline functions; associations were quantified using Cox multivariable analysis. RESULTS: Among 788 patients, median follow-up was 37.5 months (range, 0.4–210.6); median OS was 48.3 months (95% CI, 42.2–58.8). Absence of residual nodal disease was independently associated with improved survival (P

Breast cancer is the major leading cause of cancer-related fatalities nationally and globally. There will be 287,850 new breast cancer cases and 43,250 breast cancer related deaths in the United States in 2022. The relapsed, treatment-resistant, undruggable, and incurable breast cancers are often associated with EGFR/HER2/K-RAS/SIAH pathway activation. The EGFR/HER2/K-RAS/SIAH pathway is a major tumor-driver whose hyperactivation is associated malignant tumor growth, multidrug-resistant phenotypes, early tumor relapse, and systematic metastasis. Seven-In-Absentia (SINA) homologues (SIAH) are extraordinarily evolutionarily-conserved E3 ubiquitin ligases that play a critical gatekeeper role downstream of the EGFR/HER2/K-RAS pathway. SIAH is a major tumor vulnerability that is ideally positioned to become an attractive target for innovative targeted therapy development against metastatic breast cancer (MBC). Prior studies have shown that tumor growth was abolished in malignant tumor cell lines such as MDA-MB-231, MDA-MB-468, MiaPaCa, A459, and HeLa following SIAH inhibition in xenograft models; however, the underpinning molecular mechanisms that give rise to this striking anti-EGFR/K-RAS and anticancer phenotype remain unclear. Specific objectives: to delineate the molecular mechanism(s) of why anti-SIAH2PD targeted therapy is so effective in impeding and eradicating the stage IV and aggressive tumors, we conducted reverse phase protein array (RPPA)-based kinomic analysis to delineate how major cancer signaling pathways and EGFR/HER2/K-RAS/SIAH-dependent signaling networks are rewired and remodeled in response to anti-SIAH2 targeted therapy. Brief statement of methods: About 300 proteins/phosphoproteins were quantititatively measured by the RPPA platform to identify new tumor vulnerabilities and actionable targets, compensatory signaling network activation/inhibition in response to anti-SIAH targeted therapies in five highly malignant cancer cell lines. Doxycycline (DOX)-inducible Tet-ON MDA-MB-231, MDA-MB-468, MiaPaCa, HeLa and A459 cell lines were amplified from single cell and DOX-induced SIAH2PD expression was confirmed. Each of the cell lines was then subjected to one of four experimental conditions: Tet-ON control cells without DOX induction (group A), Tet-ON control cells with DOX induction (group B), Tet-ON-SIAH2PD cancer cells without DOX-induction (no SIAH2PD inhibitor) (group C), Tet-ON-SIAH2PD cancer cells with DOX-induction (SIAH2PD inhibitor) (group D). Reverse Phase Protein Array (RPPA) in conjunction with Principal Component Analysis (PCA) was conducted to quantify fold-changes of proteins/phosphoproteins in response to SIAH inhibition. The ratios of D/C/B/A, D/C, D/B, C/A, and B/A were calculated using GAPDH normalized data. Summary of results: Supported by statistical analyses, we identified 6 unique phospho-proteins that were either up- or down-regulated in response to SIAHLoss-of-function. Many have known roles in controlling and regulating cell growth, cell death, NFκB signaling, stress response, DNA damage, and cell attachment pathways, supporting a tumor eradication phenotype in the absence of SIAH function in these cancer cell lines. Conclusion: Cancer landscape (CScape) functional protein pathway mapping has categorized the synergistic feedforward, feedback, and compensatory signaling pathway activation/inactivation in response to SIAH blockade in these EGFR/HER2/K-RAS-driven malignant human cell lines. Further validation analysis will be conducted to gain better insight into the global cancer pathway alterations to reveal the molecular mechanism(s) of why SIAH inhibition works so effectively to shut down malignant tumor growth in the preclinical models. Citation Format: Andrew P. Howell, Julia Wulfkuhle, Rosa I. Gallagher, Emanuel F. Petricoin, Amy H. Tang. The Use of Reverse Phase Protein Arrays (RPPA), Principal Component Analysis (PCA), and CScape Pathway Mapping to Identify New Tumor Vulnerability and Actionable Targets in Human Malignant Triple-Negative Breast cancer cell lines [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-08-13.

Objective: To evaluate the impact on trends in clinical presentation of acute, primary rhegmatogenous retinal detachments (RRD) from early to late phases of the COVID-19 pandemic. Methods: This study was a single-center, consecutive case series of 1,727 patients treated after vaccine availability (“late”; 3/29/21 to 9/26/21), corresponding time frame in previous year of pandemic (“early”; 3/30/20 to 9/27/20), and prior to pandemic (“pre”; 4/1/19 to 9/29/19). Primary outcome was proportion of patients presenting with macula-off RRD. Secondary outcomes included best-corrected visual acuity (BCVA) and primary proliferative vitreoretinopathy (PVR). Results: While macula-off RRD rates were significantly ( P < 0.0001) elevated in early and late cohorts compared to the pre cohort, only the early cohort showed a significant ( P < 0.0001) increase in both primary PVR presentation and complex RRD repair. Patients lost to follow-up in early cohort were significantly ( P < 0.0001) higher than others. Early cohort showed significantly ( P < 0.0001) worse final BCVA compared to others. Conclusion: Patients in late pandemic were less likely to exhibit clinical features of worse RRD disease and have improved visual outcomes compared to those in early pandemic. [ Ophthalmic Surg Lasers Imaging Retina 2023;54:78–83.]

Objective: We sought to define criteria associated with low lymph node metastasis risk in patients with submucosal (pT1b) gastric cancer from 3 Western and 3 Eastern countries. Summary Background Data: Accurate prediction of lymph node metastasis risk is essential when determining the need for gastrectomy with lymph node dissection following endoscopic resection. Under present guidelines, endoscopic resection is considered definitive treatment if submucosal invasion is only superficial, but this is not routinely assessed. Methods: Lymph node metastasis rates were determined for patient groups defined according to tumor pathological characteristics. Clinicopathological predictors of lymph node metastasis were determined by multivariable logistic regression and used to develop a nomogram in a randomly selected subset that was validated in the remainder. Overall survival was compared between Eastern and Western countries. Results: Lymph node metastasis was found in 701 of 3166 (22.1%) Eastern and 153 of 560 (27.3%) Western patients. Independent predictors of lymph node metastasis were female sex, tumor size, distal stomach location, lymphovascular invasion, and moderate or poor differentiation. Patients fulfilling the National Comprehensive Cancer Network guideline criteria, excluding the requirement that invasion not extend beyond the superficial submucosa, had a lymph node metastasis rate of 8.9% (53/594). Excluding moderately differentiated tumors lowered the rate to 3.4% (10/296). The nomogram's area under the curve was 0.690. Regardless of lymph node status, overall survival was better in Eastern patients. Conclusions: The lymph node metastasis rate was lowest in patients with well differentiated tumors that were 3 cm and lacked lymphovascular invasion. These criteria may be useful in decisions regarding endoscopic resection as definitive treatment for pT1b gastric cancer.

Objective: To study the incidence of intraoperative complications while collecting a vitreous sample for proteomic biomarker analyses during small-gauge pars plana vitrectomy (PPV). Methods: A retrospective case series was assembled from the surgical logs and charts of patients who underwent 23-, 25-, and 27-gauge PPV along with an undiluted vitreous biopsy. Primary surgical indication and detailed operative reports were reviewed. Complications specific to vitreous biopsy were assessed while complications related to vitrectomy in general without biopsy were not tabulated. Results: In 1190 eyes that underwent vitreous biopsy, the most common indications for PPV were rhegmatogenous retinal detachment (24.2%), epiretinal membrane (ERM) (21.7%), vitreous hemorrhage (11.0%), uveitis (8.3%), and macular hole (7.5%). An adequate sample of 0.5 cc to 1.0 cc was obtained in all cases. There was one sclerotomy break associated with biopsy, but no instances of lens touch, retinal contusion, retinal detachment, or intraocular hemorrhage. Conclusions: Undiluted vitreous biopsy obtained at the time of small-gauge vitrectomy is a generally safe procedure and may be considered for collection of samples for proteomic analysis. [ Ophthalmic Surg Lasers Imaging Retina 2023;54:32–36.]

A 75-year-old Caucasian woman presented with sudden-onset multifocal scotomas in her right eye's central vision for 1 day. There were subtle white intraretinal foveal lesions that correlated with patchy inner retinal hyperreflectivity on optical coherence tomography, suggestive of paracentral acute middle maculopathy. Initial cerebrovascular work-up was negative. Review of systems was positive for lethargy and jaw claudication. The sedimentation rate and c-reactive protein were elevated, but platelet count was normal. The patient was started on 60 mg oral prednisone daily and underwent bilateral temporal artery that confirmed the diagnosis of giant cell arteritis.

The multiscale nature of tropical cyclone (TC) intensity change under moderate vertical wind shear was explored through an ensemble of high-resolution simulations of Hurricane Gonzalo (2014). Ensemble intensity forecasts were characterized by large short-term (36-h) uncertainty, with a forecast intensity spread of over 20 m s−1, due to differences in the timing of rapid intensification (RI) onset. Two subsets of ensemble members were examined, referred to as early-RI and late-RI members. The two ensemble groups displayed significantly different vortex evolutions under the influence of a nearby upper-tropospheric trough and an associated dry-air intrusion. Mid-to-upper-tropospheric ventilation in late-RI members was linked to a disruption of inner-core diabatic heating, a more tilted vortex, and vortex breakdown, as the simulated TCs transitioned from a vorticity annulus toward a monopole structure. A column-integrated moist static energy (MSE) budget revealed the important role of horizontal advection in depleting MSE from the TC core, while mesoscale subsidence beneath the dry-air intrusion acted to dry a deep layer of the troposphere. Eventually, the dry-air intrusion retreated from late-RI members as vertical wind shear weakened, the magnitude of vortex tilt decreased, and late-RI members began to rapidly intensify, ultimately reaching a similar intensity as early-RI members. Conversely, the vortex structures of early-RI members were shown to exhibit greater intrinsic resilience to tilting from vertical wind shear, and early-RI members were able to fend off the dry-air intrusion relatively unscathed. The different TC intensity evolutions can be traced back to differences in the initial TC vortex structure and intensity. Significance Statement Despite recent advances, tropical cyclone intensity forecasts struggle to accurately predict episodes of rapid intensification. Such forecasts become increasingly challenging when a storm is embedded within an environment of moderate vertical wind shear. This study uses an ensemble of high-resolution simulations to examine how environmental influences can affect the tropical cyclone vortex and precipitation structure, which, in turn, modulate the intensity of the storm and the onset of rapid intensification. We propose a feedback that exists where slightly weaker and less resilient vortices are more susceptible to ventilation from dry, environmental air, aided in part by differential advection from the tilted circulation, resulting in a degradation of vortex organization and a delayed onset of rapid intensification.

Contemporary chronic total occlusion (CTO) percutaneous coronary intervention (PCI) incorporates wire escalation and dissection/re-entry recanalisation strategies.The purpose of the study was to investigate changes in collateral function after CTO PCI and to identify whether the mode of successful recanalisation influences collateral function regression.Patients scheduled for elective CTO PCI with evidence of viability in the CTO territory by noninvasive imaging were included in this study. After successful CTO PCI, the aortic pressure (Pa) and distal coronary artery wedge pressure (Pw) during balloon occlusion were measured, both in a resting state and during infusion of intravenous adenosine, allowing the calculation of the pressure-derived collateral pressure index at rest and hyperaemia (CPIEighty-one patients had physiological measurements at baseline and follow-up. In the final cohort the mean age was 64 years and 82% were male. The mean maximal stent diameter and total stent length were 3.2±0.5 mm and 68±31 mm, respectively. Successful strategies were antegrade wiring (64.2%), antegrade dissection re-entry (8.6%), and retrograde dissection re-entry (27.1%). Between the index procedure and follow-up, wedge pressure decreased from 34±11 mmHg to 21±8.5 mmHg (p0.01), respectively. FFRThere was a significant reduction in collateral flow over time, independent of the recanalisation technique.

In sub-Saharan Africa, sexually active adolescent girls and young women (AGYW) experience high rates of intimate partner violence (IPV) and low levels of contraceptive use, but the effect of IPV on contraceptive use is not well understood.In the Girl Power-Malawi study, AGYW aged 15-24 were recruited from 4 health centers in Lilongwe, Malawi, and followed for 1 year. At baseline, AGYW were assessed for IPV using the modified Conflict Tactics Scale. AGYW reported contraceptive method use at 6 and 12 months, characterized as barrier, non-barrier, or any modern method. Modified Poisson regression was implemented to estimate risk ratios (RRs) and 95% confidence intervals (CIs) to examine the effect of IPV on contraceptive use.One thousand AGYW were enrolled, and 954 non-pregnant participants were included. Baseline prevalence of IPV with the most recent partner was 35.5% (physical), 46.2% (sexual), and 76.9% (emotional). Baseline IPV did not affect contraceptive use at 6 months (aRR [95% CI]: physical 0.98 [0.91-1.05]; sexual 1.00 [0.94-1.07]; emotional 1.03 [0.94-1.12]) or 12 months (physical 0.95 [0.89-1.02]; sexual 0.96 [0.90-1.02]; emotional 0.98 [0.91-1.05]). None of the 3 IPV categories affected contraceptive use when the outcome was restricted to either barrier or non-barrier methods.In this cohort, IPV was not a key driver of contraceptive use in longitudinal analyses. Interventions are needed to address the alarming rates of IPV in this population, but addressing IPV alone might be insufficient to address low contraceptive use, and multifaceted youth-friendly health services might be necessary.

International audience; We propose a controllability method for the numerical solution of time-harmonic Maxwell's equations in their first-order formulation. By minimizing a quadratic cost functional, which measures the deviation from periodicity, the controllability method determines iteratively a periodic solution in the time domain. At each conjugate gradient iteration, the gradient of the cost functional is simply computed by running any time-dependent simulation code forward and backward for one period, thus leading to a non-intrusive implementation easily integrated into existing software. Moreover, the proposed algorithm automatically inherits the parallelism, scalability, and low memory footprint of the underlying time-domain solver. Since the time-periodic solution obtained by minimization is not necessarily unique, we apply a cheap post-processing filtering procedure which recovers the time-harmonic solution from any minimizer. Finally, we present a series of numerical examples which show that our algorithm greatly speeds up the convergence towards the desired time-harmonic solution when compared to simply running the time-marching code until the time-harmonic regime is eventually reached.

Recent behavioral research indicates that social media may be successfully integrated into weight loss interventions to mitigate the obesity epidemic that has been linked with type two diabetes, cardiovascular diseases, cancers, as well as poor psychological health. This study aimed to examine the content and characteristics of 100 most trending TikTok videos related to weight loss.This was a cross-sectional, descriptive study.Videos were analyzed for source, predominant theme, and inclusion of specific content. Independent two-tailed t-tests assessed the effect of content on number of comments, likes, and forwards garnered by the videos.More than 90% of the videos were consumer generated, indicating a missed opportunity by health professionals to use social media to provide accurate information regarding weight loss. Less than one-fifth of the videos were informational but significantly influenced the number of comments (P .001) and likes (P = .002). Videos mentioning benefits ((P .001) and speed of weight loss (P = .003) significantly influenced the number of forwards, whereas those that mentioned recipes (P = .005) and how to lose weight (P = .003) significantly affected the number of comments.The results underscore the need for further research to elucidate the effectiveness of social media in impacting weight loss, as well as how they may supplement traditional health promotion and behavior interventions for weight loss.

Background/aims A lack of knowledge exists as to how municipalities are meeting the rehabilitation needs of patients recovering from COVID-19. This poses a potential barrier when referring patients for rehabilitation. The aim of this study was to map and describe municipality-based rehabilitation services for patients recovering from COVID-19 in Denmark. Methods This was a cross-sectional, nation-wide survey. Key staff members from all 98 municipalities in Denmark were invited to participate. Participants had insight into the organisation and professional content of municipal rehabilitation. Structured telephone interviews were conducted by three interviewers between October and November 2020. The interview guide consisted of items that asked about the availability, content and organisation of municipality-based rehabilitation services. Results A total of 91 municipalities (93% response rate) participated in the study. Rehabilitation could be provided within pre-existing services in 98% of municipalities and 93% systematically assessed individual rehabilitation needs using a variety of measurement methods. All municipalities reported that they had services in place to provide functional rehabilitation (eg gait training) and over 90% provided physical, cognitive and lifestyle-related rehabilitation. In contrast, 70% could provide COVID-19 education and 64% psychological therapy. Overall, 32% of municipalities had not received referrals for COVID-19 rehabilitation. Of the 62 municipalities that had COVID-19 rehabilitation experience, 73% rated the degree to which they could deliver coherent and coordinated rehabilitation for patients with complex rehabilitation needs as high or very high. Conclusions Overall, Danish municipalities reported that pre-existing services are in place to provide relevant, individualised rehabilitation for patients recovering from COVID-19. Nonetheless, future efforts should ensure that patient education is established, in step with health care providers accumulating knowledge, as well as integrated referral pathways between sectors, to deliver rehabilitation to patients with complex needs. Further, implementation of a national data collection strategy would strengthen and inform future development of relevant services both nationally and internationally.

Bosworth fracture dislocations of the ankle are rare injuries of the ankle caused by extreme external rotation of the supinated foot where the proximal fibula fracture fragment is posteriorly dislocated and entrapped behind the posterior-lateral ridge of the tibia. This case series aims to document three such cases treated in our institution over a nine year period. We also provide a review of 129 cases in the existing literature.Medical records and relevant radiographs for each patient were analysed and collected from the time of presentation till the point of latest follow-up. During each clinic visit, all physical exam findings as well as all complications were recorded. The American Foot and Ankle Society (AOFAS) Hindfoot score was also tabulated for each patient at the point of latest review.Closed reduction was unsuccessful in all three patients, and all required open reduction. One patient had an uncomplicated recovery whilst the remaining two suffered significant soft tissue complications. One patient suffered severe soft tissue swelling preventing primary closure at the time of surgery, whilst another suffered post-operative wound dehiscence and infection. Eventually all fractures healed, and all three patients obtained satisfactory AOFAS scores.The diagnosis of Bosworth fracture dislocations of the ankle is often delayed or missed, due to its rare occurrence. Closed reduction is often unsuccessful, and early open reduction is required to avoid poor clinical outcomes due to severe soft tissue damage or even compartment syndrome.

To better understand the conditions that favor tropical cyclone (TC) rapid intensification (RI), this study assesses environmental and storm-scale characteristics that differentiate TCs that undergo RI from TCs that undergo slow intensification (SI). This comparison is performed between analog TC pairs that have similar initial intensity, vertical wind shear, and maximum potential intensity. Differences in the characteristics of RI and SI TCs in the North Atlantic and western North Pacific basins are evaluated by compositing and comparing data from the fifth-generation European Centre for Medium-Range Weather Forecasts (ECMWF) Re-Analysis (ERA5) and the Gridded Satellite (GridSat) dataset. In the period leading up to the start of RI, RI TCs tend to have a stronger and deeper vortex that is more vertically aligned than SI TCs. Additionally, surface latent heat fluxes are significantly larger in RI TCs prior to the intensity change period, compared to SI TCs. The largest surface latent heat flux differences are initially located to the left of shear; subsequently, upshear and right-of-shear differences amplify, resulting in a more symmetric distribution of surface latent heat fluxes in RI TCs. Increasing azimuthal symmetry of surface latent heat fluxes in RI TCs, together with an increasing azimuthal symmetry of horizontal moisture flux convergence, promote the upshear migration of convection in RI TCs. These differences, and their evolution before and during the intensity change period, are hypothesized to support the persistence and invigoration of upshear convection and, thus, a more symmetric latent heating pattern that favors RI.

Aim: Data are limited on PD-L1 expression and its association with overall survival (OS) in gastric cancer (GC) patients receiving routine care in different regions. Materials & methods: In a retrospective study, PD-L1 expression was assayed using the 22C3 pharmDx on GC tumor samples collected between 2003 and 2017 at South Korean and US cancer centers. PD-L1 positivity was defined as combined positive score (CPS) ≥1. The relationship between PD-L1 and OS was analyzed. Results: Of 574 GC tumor samples, 67.4% were CPS ≥1 (68.7% in Korean and 65.7% in US patients). PD-L1 expression was not associated with OS (adjusted hazard ratio: 0.94; 95% CI: 0.75–1.17). Conclusion: PD-L1 prevalence and its association with OS was similar between South Korean and US GC patients.

Objective-\ud \ud The impact of adjunctive manual thrombus aspiration (TA) in patients with stent thrombosis (ST) treated with percutaneous intervention has not been evaluated in the current era of potent P2Y12 agents and new-generation drug-eluting stents. We sought to assess the effect of TA using data from a large contemporary registry.\ud \ud Methods-\ud \ud The study population was derived from the Essex ST Investigation Registry (ESTHIR), which contains all consecutive cases of angiographically determined definite ST undergoing interventional treatment in a tertiary cardiac centre between November 2015 and June 2018. Propensity score matching was performed to match patients who underwent TA (TA group) to those who did not (n-TA group). The study endpoints were final TIMI flow and survival free of cardiovascular death (CD) or target lesion revascularisation (TLR).\ud \ud Results-\ud \ud A total of 128 ST patients were included in the present analysis. The mean age was 65 ± 11 years, and 84% were male. About 90% of the patients presented with STEMI, and 85% had very late ST. Seventy-two patients (56%) underwent TA. After propensity score matching, 30 patients were included in each study group. A higher rate of final TIMI III flow was observed in the TA group (TA vs n-TA group, 100% vs 83%), but this difference did not reach statistical significance (p = 0.052). At 1000 days of follow-up, survival free of CD or TLR was not different between the two groups (p = 0.8).\ud \ud Conclusion-\ud \ud In a propensity-matched population of ST patients undergoing PCI in a contemporary setting, TA was not associated with improved final TIMI flow or long-term cardiovascular outcomes.

Background “Self-care” for sexual and reproductive health (SRH) includes contraceptive methods and other supplies that people can use with or without the support of a healthcare provider. Self-administered tests, self-injection of injectable contraception, or self-removal of intrauterine devices (IUDs) can increase people’s access to and autonomy over their own SRH. Objectives of this study were to assess women’s current interest in and use of SRH self-care and explore key informants’ (KI) opinions of self-care, especially during the COVID-19 pandemic. Methods Data for this study came from female participants in the longitudinal Contraceptive Use Beyond ECHO (CUBE) study, and KIs, including healthcare providers, in South Africa and Zambia between September 2020 and June 2021. For this analysis, we used data from a participant phone survey (n = 537), and from in-depth interviews (IDIs) completed with a sub-sample of women (n = 39) and KIs (n = 36). Survey data were analyzed with descriptive statistics, and IDI data were analyzed using applied thematic analysis. Results Female survey participants in South Africa were more interested in learning about emergency contraceptive pills, subcutaneous injectable contraception, and CycleBeads, while Zambian participants wanted more information and access to condoms. However, in IDIs in both countries, women described minimal experience with self-care beyond condom use. In the Zambian KI IDIs, COVID-19 led to increased self-care counseling on subcutaneous injectable contraception and HIV self-testing. KIs who do not counsel on self-care were concerned that women may harm themselves or blame the provider for difficulties. Two KIs thought that women could possibly self-remove IUDs, but most expressed concerns. Reported barriers to self-care included COVID movement restrictions, transport costs, lack of accessible pharmacies, women’s low awareness, and possible stigma. Conclusions Women surveyed reported interest in learning more about SRH self-care methods and resources, but in IDIs did not report extensive previous use besides condoms. KIs described some concerns about women’s ability to use self-care methods. Counseling on and provision of self-care methods and supplies may have increased during the COVID-19 pandemic, but ensuring that self-care is more than just a temporary measure in health systems has the potential to increase access to SRH care and support women’s autonomy and healthcare needs.

Supplementary Video from Reprogrammed Schwann Cells Organize into Dynamic Tracks that Promote Pancreatic Cancer Invasion

Supplementary Data from Reprogrammed Schwann Cells Organize into Dynamic Tracks that Promote Pancreatic Cancer Invasion

Nerves are a component of the tumor microenvironment contributing to cancer progression, but the role of cells from nerves in facilitating cancer invasion remains poorly understood. Here we show that Schwann cells (SC) activated by cancer cells collectively function as tumor-activated Schwann cell tracks (TAST) that promote cancer cell migration and invasion. Nonmyelinating SCs form TASTs and have cell gene expression signatures that correlate with diminished survival in patients with pancreatic ductal adenocarcinoma. In TASTs, dynamic SCs form tracks that serve as cancer pathways and apply forces on cancer cells to enhance cancer motility. These SCs are activated by c-Jun, analogous to their reprogramming during nerve repair. This study reveals a mechanism of cancer cell invasion that co-opts a wound repair process and exploits the ability of SCs to collectively organize into tracks. These findings establish a novel paradigm of how cancer cells spread and reveal therapeutic opportunities.Significance:How the tumor microenvironment participates in pancreatic cancer progression is not fully understood. Here, we show that SCs are activated by cancer cells and collectively organize into tracks that dynamically enable cancer invasion in a c-Jun–dependent manner.See related commentary by Amit and Maitra, p. 2240.This article is highlighted in the In This Issue feature, p. 2221

Supplementary Figure from Reprogrammed Schwann Cells Organize into Dynamic Tracks that Promote Pancreatic Cancer Invasion

To evaluate the efficacy of chemotherapy in patients with microsatellite instability-high (MSI-high) gastric cancer.Although MSI-high gastric cancer is associated with superior prognosis, recent studies question the benefit of perioperative chemotherapy in this population.Locally advanced gastric adenocarcinoma patients who either underwent surgery alone or also received neoadjuvant, perioperative, or adjuvant chemotherapy between 2000-2018 were eligible. MSI status, determined by next generation sequencing or mismatch repair protein immunohistochemistry, was determined in 535 patients. Associations among MSI status, chemotherapy administration, and overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were assessed.In 535 patients, 82 (15.3%) had an MSI-high tumor and approximately 20% better OS, DSS, and DFS. Grade 1 (90-100%) pathological response to neoadjuvant chemotherapy was found in 0 of 40 (0%) MSI-high tumors versus 43 of 274 (16%) MSS. In the MSI-high group, the 3-year OS rate was 79% with chemotherapy versus 88% with surgery alone (P=0.48). In the MSS group, this was 61% versus 59%, respectively (P=0.96). After multivariable interaction analyses, patients with MSI-high tumors had superior survival compared with patients with MSS tumors whether given chemotherapy (HR 0.53, 95% CI 0.28-0.99) or treated with surgery alone (HR 0.15 vs. MSS, 95% CI 0.02-1.17).MSI-high locally advanced gastric cancer was associated with superior survival compared to MSS overall, despite worse pathological chemotherapy response. In patients with MSI-high gastric cancer who received chemotherapy, the survival rate was approximately 9% worse compared with surgery alone, but chemotherapy was not significantly associated with survival.

Purpose Plenty of studies have examined the long term effect of weight loss on bone mineral density. This study aimed to explore the effects of 10% weight loss on early changes in bone metabolism as well as the possible influencing factors. Methods Overweight and obese outpatients (BMI > 24.0 kg/m2) were recruited from the nutrition clinic and followed a calorie-restricted, high-protein, low-carbohydrate diet program. Dietary intake, body composition, serum procollagen type I N-propeptide (PINP), β-Crosslaps, PTH, 25(OH) VitD, a series of inflammatory cytokines and adipokines were measured for the participants before starting to lose weight and after 10% weight loss (NCT 04207879). Results A total of 75 participants were enrolled and 37 participants achieved a weight loss of at least 10%. It was found that PINP decreased (p = 0.000) and the β-Crosslaps increased (p = 0.035) in female participants. Decreases in PTH (p = 0.001), serum IL-2 (p = 0.013), leptin (p = 0.001) and increases in 25(OH) VitD (p = 0.001), serum ghrelin (p = 0.033) were found in 37 participants after 10% of their weight had been lost. Change in PINP was detected to be significantly associated with change in lean body mass (r = 0.418, p = 0.012) and change in serum ghrelin(r = − 0.374, p = 0.023). Conclusions Bone formation was suppressed and bone absorption was increased in female subjects after a 10% weight loss. Bone turnover was found to be associated with lean body mass and affected by the circulating ghrelin level.

Purpose To evaluate the effect of one full year of the coronavirus disease 2019 (COVID-19) pandemic on clinical presentation of acute, primary rhegmatogenous retinal detachment (RRD). Design Single-center, retrospective observational cohort study. Methods Patients were divided into two cohorts; consecutive patients treated for primary RRD during the COVID-19 pandemic (March 9, 2020 to March 7, 2021; pandemic cohort) and patients treated during the corresponding time in previous year (March 11, 2019 to March 8, 2020; control cohort). Main outcome measures Proportion of patients presenting with macula-involving (mac-off) or macula-sparring (mac-on) RRD. Results 952 patients in the pandemic cohort and 872 patients in the control cohort were included. Demographic factors were similar. Compared to the control cohort, significantly greater number of pandemic cohort patients presented with mac-off RRDs ([60.92%] pandemic, [48.17%] control, P = 0.0001) and primary proliferative vitreoretinopathy (PVR; [15.53%] pandemic, [6.9%] control, P = 0.0001). Pandemic cohort patients (10.81%) had significantly higher rates of lost to follow-up compared to control cohort (4.43%; P = 0.0001). Patients new to our clinic demonstrated significant increase in mac-off RRDs in the pandemic cohort (65.35%) compared to control cohort (50.40%; P = 0.0001). Pandemic cohort patients showed worse median final best-corrected visual acuity (BCVA; 0.30 logarithm of the minimum angle of resolution [logMAR]) compared to control cohort (0.18 logMAR; P = 0.0001). Conclusions Patients with primary RRD during the first year of the COVID-19 pandemic were more likely to have mac-off disease, present with primary PVR, be lost to follow-up, and have worse final BCVA outcomes.

The Memorial Sloan Kettering Cancer Center (MSK) nomogram combined both gastroesophageal junction (GEJ) and gastric cancer patients and was created in an era from patients who generally did not receive neoadjuvant chemotherapy. We sought to reevaluate the MSK nomogram in the era of multidisciplinary treatment for GEJ and gastric cancer.Using data on patients who underwent R0 resection for GEJ or gastric cancer between 2002 and 2016, the C-index of prediction for disease-specific survival (DSS) was compared between the MSK nomogram and the American Joint Committee on Cancer (AJCC) 8th edition staging system after segregating patients by tumor location (GEJ or gastric cancer) and neoadjuvant treatment. A new nomogram was created for the group for which both systems poorly predicted prognosis.During the study period, 886 patients (645 gastric and 241 GEJ cancer) underwent up-front surgery, and 999 patients (323 gastric and 676 GEJ) received neoadjuvant treatment. Compared with the AJCC staging system, the MSK nomogram demonstrated a comparable C-index in gastric cancer patients undergoing up-front surgery (0.786 vs 0.753) and a better C-index in gastric cancer patients receiving neoadjuvant treatment (0.796 vs 0.698). In GEJ cancer patients receiving neoadjuvant chemotherapy, neither the MSK nomogram nor the AJCC staging system performed well (C-indices 0.647 and 0.646). A new GEJ nomogram was created based on multivariable Cox regression analysis and was validated with a C-index of 0.718.The MSK gastric cancer nomogram's predictive accuracy remains high. We developed a new GEJ nomogram that can effectively predict DSS in patients receiving neoadjuvant treatment.

Purpose: In patients with locally advanced esophageal adenocarcinoma, response to neoadjuvant therapy strongly predicts survival, but robust molecular predictors of response have been lacking. We therefore sought to discover meaningful predictors of response in these patients. Experimental Design: We retrospectively identified all patients with adenocarcinoma of the lower esophagus or gastroesophageal junction who (i) were treated with multimodality therapy with curative intent at our institution from 2014 through 2020 and (ii) underwent prospective sequencing by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets. Clinicopathologic and genomic data were analyzed to identify potential genomic features, somatic alterations, and oncogenic pathways associated with treatment response. Results: In total, 237 patients were included. MDM2 amplification was independently associated with poor response to neoadjuvant therapy [OR, 0.10 (95% confidence interval, 0.01–0.55); P = 0.032], when accounting for significant clinicopathologic variables, including clinical stage, tumor grade, and chemotherapy regimen. Moreover, TP53 pathway alterations, grouped according to inferred severity of TP53 dysfunction, were significantly associated with response to neoadjuvant therapy (P = 0.004, q = 0.07). Patients with MDM2 amplifications or truncating biallelic TP53 mutations had similar outcomes in terms of poor responses to neoadjuvant therapy and, consequently, shorter progression-free survival, compared with patients with TP53 pathway wild-type tumors. Thus, worsening TP53 dysfunction was directly correlated with worse outcomes. Conclusions: MDM2 amplification and TP53 status are associated with response to therapy in patients with esophageal adenocarcinoma. Given the dearth of actionable targets in esophageal adenocarcinoma, MDM2 inhibition, in combination with cytotoxic chemotherapy, may represent an important therapeutic strategy to overcome treatment resistance and improve outcomes in these patients.

Nootropics (smart drugs) are used by students to enhance cognitive performance which have been reported times in recent years. However, some of the nootropics are central nervous system stimulants which are very likely to lead to addiction or complications such as vomiting and dizziness. Are there nootropics that can improve learning behavior while having potential positive effect on health? Here, we reported that Atomoxetine (ATX) has sex-specific effect on prolonging the life span of female Drosophila melanogaster. Further study indicated that ATX enhanced female resistance to heat stress and their vertical climbing ability, but it did decrease the number of eggs laid. ATX increased food-intake and sleep time both of females and males, and significantly reduced the 24h spontaneous activity of females and males. Our results present the sex dimorphic effect of ATX on life span regulation in Drosophila, and support further research on the beneficial role of ATX and the mechanisms in other animal models.

FBP1-associated proteins identified by tandem affinity purification and mass spectrometry

Supplementary Data from The Role of the TP53 Pathway in Predicting Response to Neoadjuvant Therapy in Esophageal Adenocarcinoma

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Background: Mesothelin is overexpressed in several malignancies and is purportedly a specific marker of malignant transformation. In this pilot study, we investigated whether tissue and serum mesothelin are potential markers of neoplastic progression in Barrett's esophagus (BE) and in esophageal adenocarcinoma (EAC).Methods: Mesothelin expression was retrospectively evaluated in normal, BE, and EAC tissue from surgically resected esophageal specimens (n = 125). In addition, soluble mesothelin-related peptide (SMRP) levels were measured in serum.Results: Normal esophageal mucosa did not express mesothelin. BE tissue with high-grade dysplasia specifically expressed mesothelin, whereas BE tissue with low-grade or without dysplasia did not. Fifty-seven (46%) EAC tumors were positive for mesothelin. EAC tumors with BE expressed mesothelin more often than those without BE (58% vs. 35%, P = 0.01). SMRP levels were elevated in 70% of EAC patients (mean = 0.89 nmol/L; range: 0.03–3.77 nmol/L), but not in patients with acid reflux and/or BE.Conclusions: Mesothelin is commonly expressed in BE-associated EAC. On the basis of this pilot study, a prospective study is under way to evaluate tissue and serum mesothelin which are potential markers of neoplastic progression in BE and in EAC (NCT01393483).Impact: Current surveillance methods in Barrett's esophagus are invasive and neither cost-effective nor sensitive. This pilot study suggests that serum mesothelin is a marker of neoplastic transformation in BE and may provide a noninvasive method to improve identification of malignant transformation. Cancer Epidemiol Biomarkers Prev; 21(3); 482–6. ©2012 AACR.

LC gene signature classifier and gene list

TMA data for ASCL1 and S100 of 173 LCs

Assessment of the effectiveness of IQGAP1 depletion and the effect of gemcitabine on the pERK1/2 levels in the PDAC patient samples.