Cross-cultural evaluation of the Michigan Hand Outcomes Questionnaire: a systematic review.

This systematic review aims to provide a comprehensive synthesis and in-depth analysis of the quality of the different cross-cultural versions of the MHQ. This study was conducted using Pubmed, Web of Science, CINAHL and SCOPUS databases to identify cross-cultural validation studies of the MHQ. Methodological quality, quality of evidence and criteria for good measurement properties of these studies were applied for each psychometric property. Quality assessment and data extraction were performed independently by two reviewers according to the COnsensus-based Standards for selection of health Measurement INstruments (COSMIN) guidelines. A total of 493 articles were identified, of which 22 were included and 20 were analysed.Of the six properties analysed, responsiveness and hypothesis testing for construct validity had the highest methodological quality and quality of evidence, and met the criteria for good measurement properties. The lowest quality properties were measurement error and internal consistency. The different cross-cultural versions of the MHQ were found to be reliable, valid and able to detect clinical change. The lack of development of measurement error, formulation of an a priori hypothesis or structural validity affects the detection of small clinical changes and their discriminative capacity.

Hypertension and Risk of Endometrial Cancer: A Pooled Analysis in the Epidemiology of Endometrial Cancer Consortium (E2C2).

BACKGROUND: The incidence rates of endometrial cancer are increasing, which may partly be explained by the rising prevalence of obesity, an established risk factor for endometrial cancer. Hypertension, another component of metabolic syndrome, is also increasing in prevalence, and emerging evidence suggests that it may be associated with the development of certain cancers. The role of hypertension independent of other components of metabolic syndrome in the etiology of endometrial cancer remains unclear. In this study, we evaluated hypertension as an independent risk factor for endometrial cancer and whether this association is modified by other established risk factors. METHODS: We included 15,631 endometrial cancer cases and 42,239 controls matched on age, race, and study-specific factors from 29 studies in the Epidemiology of Endometrial Cancer Consortium. We used multivariable unconditional logistic regression models to estimate ORs and 95% confidence intervals (CI) to evaluate the association between hypertension and endometrial cancer and whether this association differed by study design, race/ethnicity, body mass index, diabetes status, smoking status, or reproductive factors. RESULTS: Hypertension was associated with an increased risk of endometrial cancer (OR, 1.14; 95% CI, 1.09-1.19). There was significant heterogeneity by study design (Phet < 0.01), with a stronger magnitude of association observed among case-control versus cohort studies. Stronger associations were also noted for pre-/perimenopausal women and never users of postmenopausal hormone therapy. CONCLUSIONS: Hypertension is associated with endometrial cancer risk independently from known risk factors. Future research should focus on biologic mechanisms underlying this association. IMPACT: This study provides evidence that hypertension may be an independent risk factor for endometrial cancer.

TTCC-2019-02: real-world evidence of first-line cetuximab plus paclitaxel in recurrent or metastatic squamous cell carcinoma of the head and neck.

Objectives: The aim of this study was to confirm the efficacy of the ERBITAX scheme (paclitaxel 80 mg/m2 weekly and cetuximab 400 mg/m2 loading dose, and then 250 mg/m2 weekly) as first-line treatment for patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) who are medically unfit for cisplatin-based (PT) chemotherapy. Materials and methods: This retrospective, non-interventional study involved 16 centers in Spain. Inclusion criteria were to have started receiving ERBITAX regimen from January 2012 to December 2018; histologically confirmed SCCHN including oral cavity, oropharynx, hypopharynx, and larynx; age ≥18 years; and platinum (PT) chemotherapy ineligibility due to performance status, comorbidities, high accumulated dose of PT, or PT refractoriness. Results: A total of 531 patients from 16 hospitals in Spain were enrolled. The median age was 66 years, 82.7% were male, and 83.5% were current/former smokers. Patients were ineligible to receive PT due to ECOG 2 (50.3%), comorbidities (32%), PT cumulative dose ≥ 225 mg/m2 (10.5%), or PT refractoriness (7.2%). Response rate was 37.7%. Median duration of response was 5.6 months (95% CI: 4.4-6.6). With a median follow-up of 8.7 months (95% CI: 7.7-10.2), median PFS and OS were 4.5 months (95% CI: 3.9-5.0) and 8.9 months (95% CI: 7.8-10.3), respectively. Patients treated with immunotherapy after ERBITAX had better OS with a median of 29.8 months compared to 13.8 months for those who received other treatments. The most common grade ≥ 3 toxicities were acne-like rash in 36 patients (6.8%) and oral mucositis in 8 patients (1.5%). Five (0.9%) patients experienced grade ≥ 3 febrile neutropenia. Conclusion: This study confirms the real-world efficacy and tolerability of ERBITAX as first-line treatment in recurrent/metastatic SCCHN when PT is not feasible. Immunotherapy after treatment with ERBITAX showed remarkable promising survival, despite potential selection bias.

LAP1 supports nuclear adaptability during constrained melanoma cell migration and invasion.

Metastasis involves dissemination of cancer cells away from a primary tumour and colonization at distal sites. During this process, the mechanical properties of the nucleus must be tuned since they pose a challenge to the negotiation of physical constraints imposed by the microenvironment and tissue structure. We discovered increased expression of the inner nuclear membrane protein LAP1 in metastatic melanoma cells, at the invasive front of human primary melanoma tumours and in metastases. Human cells express two LAP1 isoforms (LAP1B and LAP1C), which differ in their amino terminus. Here, using in vitro and in vivo models that recapitulate human melanoma progression, we found that expression of the shorter isoform, LAP1C, supports nuclear envelope blebbing, constrained migration and invasion by allowing a weaker coupling between the nuclear envelope and the nuclear lamina. We propose that LAP1 renders the nucleus highly adaptable and contributes to melanoma aggressiveness.

Protein Supplementation with Short Peptides Prevents Early Muscle Mass Loss after Roux-en-Y-Gastric Bypass.

Introduction: A significant reduction in fat-free mass (FFM) following bariatric surgery (BS) has been reported, and adequate protein intake is recommended for FFM preservation. Current guidelines of nutritional management after BS recommend complex protein (CP) compounds. However, Roux-en-Y-gastric bypass (RYGB) has a negative impact on CP digestion, leading to protein malabsorption. At present, there is no data regarding the impact of early supplementation with short peptide-based (SPB) or hydroxy methylbutyrate (HMB)-enriched formulas on the evolution of the FFM after the BS. Aim: The aim of this study is to evaluate the effect of nutritional products based on CP, HBM-enriched, or SPB formulas on the FFM of patients that undergo RYGB. Material and methods: This is a prospective interventional study, including three groups of patients (according to the type of protein product) as candidates for BS, recruited between December 2021 and April 2022, matched by age, gender, and BMI. All patients underwent evaluations at baseline and one month post-BS, including: medical history, physical and anthropometric evaluation, bioimpedance, and biochemical analysis. Results: A total of 60 patients were recruited: 63% women, mean age 43.13 ± 9.4 years, and BMI 43.57 ± 4.1 kg/m2. The % of FFM loss from total weight loss (TWL) was significantly lower in the SPB group than CP and HMB groups despite the major %TWL in this group (40.60 ± 17.27 in CP, 34.57 ± 13.15 in HMB, and 19.14 ± 9.38 in SPB, p < 0.001). TWL% was 9.98 ± 1.82 vs. 9.83 ± 2.71 vs. 13.56 ± 4.30, p < 0.001, respectively. Conclusion: In our study, the SPB supplementation prevented almost 50% FFM lost from the TWL than the CP- or HMB-enriched compounds at one month post-BS. These results are significant in the setting of muscle mass preservation after the BS, and have the potential to change the current guidelines for the management of nutritional supplementation after BS.

Risk Factors, Radiological and Clinical Outcomes in Subclinical and Clinical Pituitary Apoplexy.

BACKGROUND: Pituitary apoplexy (PA) can be symptomatic, namely acute apoplexy (APA), or asymptomatic or subclinical (SPA). OBJECTIVE: To describe the clinical characteristics and evolution of the patients with APA compared to SPA Patients and methods: Retrospective, longitudinal database analysis. RESULTS: We identified 58 patients with PA, and 37 accomplished the inclusion criteria (17 men, median age 47.7 years). A total of 29 (78.4%) had APA (17 underwent surgery, and 12 were conservatively managed), and 8 (21.6%) had SPA. The presence of non-functioning pituitary adenoma (NFPA) odds ratio (OR): 29.36 (95% confidence interval (CI): 1.86-462.36) and the largest size OR 1.10 (95% CI: 1.01-1.2) elevated the risk of having surgery. Hypopituitarism developed in 35.1% without significant differences between APA and SPA. In non-surgical patients, adenoma volume shrunk spontaneously at one year magnetic resonance imaging (MRI), without statistical differences between the conservatively treated and SPA group. CONCLUSIONS: APA is more frequent in larger NFPAs, and this subset of patients has a higher risk of surgery. Hypopituitarism is quite frequent even in patients with SPA, and, therefore, long-term follow-up is mandatory. In the non-surgical group, the pituitary tumour shrinkage is clinically relevant after one year of PA. Consequently, surgery indication in NFPA should be delayed and reassessed if patients remain asymptomatic.

Tissue-Specific Human Extracellular Matrix Scaffolds Promote Pancreatic Tumour Progression and Chemotherapy Resistance.

Over 80% of patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed at a late stage and are locally advanced or with concurrent metastases. The aggressive phenotype and relative chemo- and radiotherapeutic resistance of PDAC is thought to be mediated largely by its prominent stroma, which is supported by an extracellular matrix (ECM). Therefore, we investigated the impact of tissue-matched human ECM in driving PDAC and the role of the ECM in promoting chemotherapy resistance. Decellularized human pancreata and livers were recellularized with PANC-1 and MIA PaCa-2 (PDAC cell lines), as well as PK-1 cells (liver-derived metastatic PDAC cell line). PANC-1 cells migrated into the pancreatic scaffolds, MIA PaCa-2 cells were able to migrate into both scaffolds, whereas PK-1 cells were able to migrate into the liver scaffolds only. These differences were supported by significant deregulations in gene and protein expression between the pancreas scaffolds, liver scaffolds, and 2D culture. Moreover, these cell lines were significantly more resistant to gemcitabine and doxorubicin chemotherapy treatments in the 3D models compared to 2D cultures, even after confirmed uptake by confocal microscopy. These results suggest that tissue-specific ECM provides the preserved native cues for primary and metastatic PDAC cells necessary for a more reliable in vitro cell culture.

Cytokine Profile in Children with Severe Multisystem Inflammatory Syndrome Related to the Coronavirus Disease 2019.

The multisystem inflammatory syndrome in children (MIS-C) is a novel and concerning entity related to severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection. Although MIS-C has been the subject of intensive research efforts, its pathophysiology and optimal treatment remain elusive. We studied the clinical features, laboratory findings, and immunoinflammatory profiles of seven children prospectively admitted to a pediatric intensive care unit (PICU) during the first wave of the pandemic. All patients had immunoglobulin (Ig)-G against SARS-CoV-2, four of seven patients had both IgM and IgG, and in one of the 7 SARS-CoV-2 was detected in a respiratory sample. All patients received intravenous fluid boluses (median: 15 mL/kg) and norepinephrine. The most common form of respiratory support was supplemental oxygen via nasal cannula. None of the patients needed mechanical ventilation. The cardiovascular system was frequently involved. All patients had an elevated troponin-I (median: 107.3 ng/L). Four out of seven patients had coronary artery abnormalities, and two of seven had both abnormal electrocardiogram (EKG) findings and evidence of left ventricular dysfunction on echocardiogram. Ig levels and complement function were normal. Peripheral blood phenotyping with flow cytometry showed decreased T-cell numbers at the expense of CD8+ T-cells. Cytokine profiling showed a heterogeneous increase in interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-18, IL-2Ra, IL-10, and IL-1Ra that tended to normalize after treatment. Our study shows that children with MIS-C have elevated plasma levels of pro- and anti-inflammatory cytokines in the acute phase of the disease without other relevant immunologic disturbances. These findings suggest the presence of a mixed antagonist response syndrome (MARS) similar to that present in pediatric sepsis. Combining a meticulous differential diagnosis with cautiously coordinated immunomodulatory therapy and high-quality supportive care can help clinicians avoid causing iatrogenic harm in patients with MIS-C.

The Impact of Bariatric Surgery on the Muscle Mass in Patients with Obesity: 2-Year Follow-up.

PURPOSE: Bariatric surgery (BS) induces a significant and sustained weight loss in patients with severe obesity (SO). Nevertheless, apart from significantly reducing body fat, fat-free mass (FFM) might also be lost. At present, there is little and controversial data in the literature regarding the impact of BS on FFM. In recent years, bioimpedance (BIA) has emerged as a reliable test to assess body composition easily to use in the daily clinical practice. On the bases, the aim of the present study is to evaluate the impact of BS on the FFM, evaluated by means of BIA. MATERIAL AND METHODS: This is a prospective, observational study, including consecutive patients with SO that underwent BS between February 2018 and February 2019 at our center. At baseline, 1, 6, 12, and 24 months after the BS, all the patients underwent complete medical history, physical and anthropometric evaluation, and body composition assessment by means of BIA (using Bodystat QuadScan4000®). RESULTS: Eighty-five patients with SO were recruited, 72.9% females, aged 45.54 ± 9.98 years, pre-BS BMI 43.87 ± 6.52 kg/m2. FFM significantly decreased continuously after BS at all timepoints. The loss of FFM 24 months post-BS accounted for approximately 21.71 ± 13.9% of the total weight loss, and was independent of BS technique or protein metabolism. Pre-BS HOMA-IR and FFM were independent predictors of FFM at 24 months. CONCLUSIONS: Significant and early loss of FFM in patients with SO that undergo BS was seen, not related to protein metabolism parameters or the BS technique used, suggesting an independent mechanism.

The amoeboid state as part of the epithelial-to-mesenchymal transition programme.

Cell migration is essential for many biological processes, while abnormal cell migration is characteristic of cancer cells. Epithelial cells become motile by undergoing epithelial-to-mesenchymal transition (EMT), and mesenchymal cells increase migration speed by adopting amoeboid features. This review highlights how amoeboid behaviour is not merely a migration mode but rather a cellular state - within the EMT spectra - by which cancer cells survive, invade and colonise challenging microenvironments. Molecular biomarkers and physicochemical triggers associated with amoeboid behaviour are discussed, including an amoeboid associated tumour microenvironment. We reflect on how amoeboid characteristics support metastasis and how their liabilities could turn into therapeutic opportunities.

Aggressive Pituitary Macroadenoma Treated With Capecitabine and Temozolomide Chemotherapy Combination in a Patient With Nelson's Syndrome: A Case Report.

Nelson's syndrome is considered a severe side effect that can occur after a total bilateral adrenalectomy in patients with Cushing's disease. It usually presents with clinical manifestations of an enlarging pituitary tumor including visual and cranial nerve alterations, and if not treated, can cause death through local brain compression or invasion. The first therapeutic option is surgery but in extreme cases of inaccessible or resistant aggressive pituitary tumors; the off-label use of chemotherapy with capecitabine and temozolomide can be considered. However, the use of this treatment is controversial due to adverse events, lack of complete response, and inability to predict results. We present the case of a 48-year-old man diagnosed with Nelson's syndrome with prolonged partial response and significant clinical benefit to treatment with capecitabine and temozolomide.

Shrinkage by the third month predicts long-term response of macroprolactinoma after cabergoline.

OBJECTIVE: Transsphenoidal surgery (TSS) is mainly indicated in prolactinomas when dopamine agonist treatment fails. However, there is no established early predictor of cabergoline (CBG) response. The present study was aimed to identify predictors of CBG resistance in order to select patients who may benefit from early TSS. DESIGN: Retrospective longitudinal study. METHODS: We reviewed the medical record of patients diagnosed with prolactinoma after 2010. Inclusion criteria: macroprolactinomas under CBG treatment with serial prolactin levels and MRI before treatment and 3 and 12 months afterwards. The main outcome was tumour size shrinkage ≥ 50% (using the two largest diameters in sagittal view) after 12 months of CBG (TS_50). The capacity of the most important clinical and biochemical variables in predicting the main outcome was examined. RESULTS: A total of 185 prolactinomas where included: 124 (67.0%) were microadenomas and 61 (33.0%) were macroadenomas of which 27 patients meet de inclusion criteria; median age (42.5 years; (IQR: 28.0)). The median follow-up was (67.5 months; (IQR: 30.2)). Ten patients (37.0%) underwent surgery after more than 1 year of CBG. The volume reduction at the first MRI (3-4 months) was the unique valuable predictor: (OR: 1.16 (95% CI: 1.02-1.32)) of TS_50. A tumour volume shrinkage of ≥ 30% in the first 3-4 months of CBG therapy predicts TS_50 with an AUC (0.95 (CI: 0.76-0.99)). CONCLUSION: Tumour shrinkage in the first 3-4 months after starting treatment with CBG is a good tool for predicting the long-term response and can help clinicians to take more appropriated and personalized decisions.

General Spanish population normative data analysis for the EORTC QLQ-C30 by sex, age, and health condition.

PURPOSE: General population normative data for the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire facilitates interpretation of data assessed from cancer patients. This study aims to present normative data of the general Spanish population. METHODS/PATIENTS: Data were obtained from a prior larger study collecting EORTC QLQ-C30 norm data across 15 countries. Data were stratified by sex and age groups (18-39, 40-49, 50-59, 60-69 and > 70 years). Sex and age distribution were weighted according to population distribution statistics. Sex- and age-specific normative values were analysed separately, as were participants with versus those without health conditions. Multiple linear regression was used to estimate the association of each of the EORTC QLQ-C30 scales with the determinants age, sex, sex-by-age interaction term, and health condition. RESULTS: In total, 1,165 Spanish individuals participated in the study. Differences were found by sex and age. The largest sex-related differences were seen in fatigue, emotional functioning, and global QOL (Quality of Life), favouring men. The largest age differences were seen in emotional functioning, insomnia, and pain, with middle-aged groups having the worst scores. Those > 60 years old scored better than those < 60 years old on all scales except for physical functioning. Participants with no health conditions scored better in all QLQ-C30 domains. CONCLUSIONS: The present study highlights differences in HRQOL between specific sex/age strata and especially between people with and without a health condition in the general Spanish population. These factors must be considered when comparing general population HRQOL data with that of cancer patients.

A preclinical pipeline to evaluate migrastatics as therapeutic agents in metastatic melanoma.

BACKGROUND: Metastasis is a hallmark of cancer and responsible for most cancer deaths. Migrastatics were defined as drugs interfering with all modes of cancer cell invasion and thus cancers' ability to metastasise. First anti-metastatic treatments have recently been approved. METHODS: We used bioinformatic analyses of publicly available melanoma databases. Experimentally, we performed in vitro target validation (including 2.5D cell morphology analysis and mass spectrometric analysis of RhoA binding partners), developed a new traceable spontaneously metastasising murine melanoma model for in vivo validation, and employed histology (haematoxylin/eosin and phospho-myosin II staining) to confirm drug action in harvested tumour tissues. RESULTS: Unbiased and targeted bioinformatic analyses identified the Rho kinase (ROCK)-myosin II pathway and its various components as potentially relevant targets in melanoma. In vitro validation demonstrated redundancy of several RhoGEFs upstream of RhoA and confirmed ROCK as a druggable target downstream of RhoA. The anti-metastatic effects of two ROCK inhibitors were demonstrated through in vivo melanoma metastasis tracking and inhibitor effects also confirmed ex vivo by digital pathology. CONCLUSIONS: We proposed a migrastatic drug development pipeline. As part of the pipeline, we provide a new traceable spontaneous melanoma metastasis model for in vivo quantification of metastasis and anti-metastatic effects by non-invasive imaging.

Canagliflozin: A New Therapeutic Option in Patients That Present Postprandial Hyperinsulinemic Hypoglycemia after Roux-en-Y Gastric Bypass: A Pilot Study.

INTRODUCTION: Roux-en-Y gastric bypass (RYGB) is the most common surgical procedure for morbid obesity. However, it can present serious late complications, like postprandial hyperinsulinemic hypoglycemia (PHH). Recent data suggested an increase in intestinal SGLT-1 after RYGB. However, there is no data on the inhibition of SGLT-1 to prevent PHH in patients with prior RYBG. On this basis, we aimed to evaluate (a) the effect of canagliflozin 300 mg on the response to 100 g glucose overload (oral glucose tolerance test [OGTT]); (b) the pancreatic response after intra-arterial calcium stimulation in the context of PHH after RYGB. MATERIALS AND METHODS: This is a prospective pilot study including patients (n = 21) with PHH after RYGB, matched by age and gender with healthy controls (n = 5). Basal OGTT and after 2 weeks of daily 300 mg of canagliflozin was performed in all cases. In addition, venous sampling after intra-arterial calcium stimulation of the pancreas was performed in 10 cases. RESULTS: OGTT after canagliflozin showed a significant reduction of plasma glucose levels (minute 30: 161.5 ± 36.22 vs. 215.9 ± 58.11 mg/dL; minute 60: 187.46 ± 65.88 vs. 225.9 ± 85.60 mg/dL, p < 0.01) and insulinemia (minute 30: 95.6 ± 27.31 vs. 216.35 ± 94.86 mg/dL, p = 0.03; minute 60: 120.85 ± 94.86 vs. 342.64 ± 113.32 mIU/L, p < 0.001). At minute 180, a significant reduction (85.7%) of the rate of hypoglycemia was observed after treatment with canagliflozin (p < 0.00001). All cases presented normal pancreatic response after intra-arterial calcium administration. CONCLUSION: Canagliflozin (300 mg) significantly decreased glucose absorption and prevented PHH after 100 g OGTT in patients with RYGB. Our results suggest that canagliflozin could be a new therapeutic option for patients that present PHH after RYGB.

Candidemia Diagnosis With T2 Nuclear Magnetic Resonance in a PICU: A New Approach.

OBJECTIVES: Early diagnosis of invasive Candida infections is a challenge for pediatricians, intensivists, and microbiologists. To fill this gap, a new nanodiagnostic method has been developed using manual application of T2 nuclear magnetic resonance to detect Candida species. The aim of this study was to evaluate, prospectively, the usefulness as a tool diagnosis of the T2Candida panel in pediatric patients admitted at the PICU compared with blood culture. DESIGN: This is a prospective, observational, and unicentric study to compare T2Candida results with simultaneous blood cultures for candidemia diagnose. SETTING: This study was carried out in a 1,300-bed tertiary care hospital with a 16-bed medical-surgical PICU. PATIENTS: Sixty-three patients from 0 to 17 years old were enrolled in this study, including those undergoing solid organ transplantation (kidney, liver, pulmonary, multivisceral, intestinal, and heart) and hematopoietic stem cell transplantation. MEASUREMENTS AND MAIN RESULTS: Seven patients were positive by the T2Candida test. Only two of them had the simultaneous positive blood culture. T2Candida yielded more positive results than blood cultures. CONCLUSIONS: T2Candida might be useful for the diagnosis of candidemia in PICUs. The prevalence of candidemia might be underestimated in this pediatric population. The use of this diagnostic tool in these units may help clinicians to start adequate and timely antifungal treatments.

Analysis of Lymphotoxin Alpha Expression in Human Retina and Generation of Expression Vectors to Functional Characterization of Polymorphisms in the Tumor Necrosis Factor Locus.

With the evolution of new genomic sequencing technologies an important amount of genomic data has been provided. As a consequence of this, many gene polymorphisms have been shown to be significantly associated with different disorders. Many strategies have been implemented to reveal the role of having more than one allele at a specific locus and their involvement in the illnesses. Site-directed mutagenesis is one of the most common strategies to understand the regulatory regions of genes and the relationship between the protein structure and its function. Here, we describe the analysis of lymphotoxin alpha expression in human retina and the generation of expression vectors to functional characterization of polymorphisms in the tumor necrosis factor locus using pCEFL-Flag expression vector and transfection assays in COS-1 cell line.

WNT11-FZD7-DAAM1 signalling supports tumour initiating abilities and melanoma amoeboid invasion.

Melanoma is a highly aggressive tumour that can metastasize very early in disease progression. Notably, melanoma can disseminate using amoeboid invasive strategies. We show here that high Myosin II activity, high levels of ki-67 and high tumour-initiating abilities are characteristic of invasive amoeboid melanoma cells. Mechanistically, we find that WNT11-FZD7-DAAM1 activates Rho-ROCK1/2-Myosin II and plays a crucial role in regulating tumour-initiating potential, local invasion and distant metastasis formation. Importantly, amoeboid melanoma cells express both proliferative and invasive gene signatures. As such, invasive fronts of human and mouse melanomas are enriched in amoeboid cells that are also ki-67 positive. This pattern is further enhanced in metastatic lesions. We propose eradication of amoeboid melanoma cells after surgical removal as a therapeutic strategy.

Cancer Burden Is Controlled by Mural Cell-ß3-Integrin Regulated Crosstalk with Tumor Cells.

Enhanced blood vessel (BV) formation is thought to drive tumor growth through elevated nutrient delivery. However, this observation has overlooked potential roles for mural cells in directly affecting tumor growth independent of BV function. Here we provide clinical data correlating high percentages of mural-ß3-integrin-negative tumor BVs with increased tumor sizes but no effect on BV numbers. Mural-ß3-integrin loss also enhances tumor growth in implanted and autochthonous mouse tumor models with no detectable effects on BV numbers or function. At a molecular level, mural-cell ß3-integrin loss enhances signaling via FAK-p-HGFR-p-Akt-p-p65, driving CXCL1, CCL2, and TIMP-1 production. In particular, mural-cell-derived CCL2 stimulates tumor cell MEK1-ERK1/2-ROCK2-dependent signaling and enhances tumor cell survival and tumor growth. Overall, our data indicate that mural cells can control tumor growth via paracrine signals regulated by ß3-integrin, providing a previously unrecognized mechanism of cancer growth control.

Myosin II Reactivation and Cytoskeletal Remodeling as a Hallmark and a Vulnerability in Melanoma Therapy Resistance.

Despite substantial clinical benefit of targeted and immune checkpoint blockade-based therapies in melanoma, resistance inevitably develops. We show cytoskeletal remodeling and changes in expression and activity of ROCK-myosin II pathway during acquisition of resistance to MAPK inhibitors. MAPK regulates myosin II activity, but after initial therapy response, drug-resistant clones restore myosin II activity to increase survival. High ROCK-myosin II activity correlates with aggressiveness, identifying targeted therapy- and immunotherapy-resistant melanomas. Survival of resistant cells is myosin II dependent, regardless of the therapy. ROCK-myosin II ablation specifically kills resistant cells via intrinsic lethal reactive oxygen species and unresolved DNA damage and limits extrinsic myeloid and lymphoid immunosuppression. Efficacy of targeted therapies and immunotherapies can be improved by combination with ROCK inhibitors.