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Metastases are initiated by disseminated tumor cells (DTCs) that colonize distant organs. Growing evidence suggests that the microenvironment of the primary tumor primes DTCs for dormant or proliferative fates. However, the manner in which this occurs remains poorly understood. Here, using the Window for High-Resolution Intravital Imaging of the Lung (WHRIL), we study the live lung longitudinally and follow the fate of individual DTCs that spontaneously disseminate from orthotopic breast tumors. We find that spontaneously DTCs have increased levels of retention, increased speed of extravasation, and greater survival after extravasation, compared to experimentally metastasized tumor cells. Detailed analysis reveals that a subset of macrophages within the primary tumor induces a pro-dissemination and pro-dormancy DTC phenotype. Our work provides insight into how specific primary tumor microenvironments prime a subpopulation of cells for expression of proteins associated with dissemination and dormancy. The understanding of the mechanisms underlying the ability of disseminated tumor cells (DTCs) to form metastasis is incomplete. Here, by using high-resolution intravital imaging of the murine lung to track the fate of breast-derived DTCs, the authors show that macrophages within the primary tumor induce a pro-dissemination and pro-dormancy phenotype in tumor cells, favouring their extravasation in the lung.

Cancer stem cells (CSCs) play an important role during metastasis, but the dynamic behavior and induction mechanisms of CSCs are not well understood. Here, we employ high-resolution intravital microscopy using a CSC biosensor to directly observe CSCs in live mice with mammary tumors. CSCs display the slow-migratory, invadopod-rich phenotype that is the hallmark of disseminating tumor cells. CSCs are enriched near macrophages, particularly near macrophage-containing intravasation sites called Tumor Microenvironment of Metastasis (TMEM) doorways. Substantial enrichment of CSCs occurs on association with TMEM doorways, contributing to the finding that CSCs represent >60% of circulating tumor cells. Mechanistically, stemness is induced in non-stem cancer cells upon their direct contact with macrophages via Notch-Jagged signaling. In breast cancers from patients, the density of TMEM doorways correlates with the proportion of cancer cells expressing stem cell markers, indicating that in human breast cancer TMEM doorways are not only cancer cell intravasation portals but also CSC programming sites. Intravital imaging reveals macrophage-driven de novo induction of cancer stem cells in vivo, and their dramatic enrichment on dissemination through TMEM doorways. These findings provide a mechanism for the validated ability of TMEM doorway density to be prognostic for distant recurrence of metastatic tumors in breast cancer patients.

Purpose Adding pembrolizumab to neoadjuvant chemotherapy (NAC) for triple-negative breast cancer (TNBC) improves pathologic complete response (pCR) rates and event-free survival. The impact of adding immunotherapy to NAC on surgical outcomes is unknown. This study compares 90-day post-surgical complications (PSCs) and time to adjuvant treatment among patients undergoing NAC for TNBC with and without immunotherapy. Methods Patients treated with NAC alone or with immunotherapy (NAC-I) for stage I–III TNBC between 2018 and 2022 were retrospectively identified at a single academic institution. Kruskal–Wallis rank sum and Fisher's exact tests compared patient sociodemographic and clinical characteristics. Multivariable logistic regression determined odds ratios (OR) predicting PSCs. Results Of 54 patients, 29 received NAC alone and 25 received NAC-I. Compared to NAC patients, NAC-I patients had more advanced stage tumors (p = 0.038), and had slightly higher rates of mastectomy with reconstruction (p = 0.193). 72.0% of NAC-I patients experienced a pCR, compared with 44.8% of NAC patients (p = 0.193). There were 10 PSCs (34.5%) in NAC patients compared to 9 PSCs (36.0%) in NAC-I patients (p > 0.99). Regression analysis demonstrated no association of PSCs with NAC-I (OR 0.83, 95% CI 0.19–3.60). Time to adjuvant therapy was shorter for NAC-I patients (28 days vs 36 days, p = 0.013). Conclusions Patients with TNBC receiving NAC-I have higher pCR rates and do not appear to have added 90-day PSCs or delays to adjuvant therapy despite trending toward more extensive surgical procedures compared to NAC alone. Larger studies are needed to further evaluate the surgical safety of immunotherapy.

[...]one patient was readmitted because of a splenic infarct, managed conservatively, and discharged home. [...]in a series of 85 consecutive LSG patients, Triantafyllidis et al.4 observed that of the three patients who experienced a leak (presenting on POD 5, 10, and 13), none were identified by routine UGIS performed on POD 3. [...]our data confirm the safety in omitting routine UGIS, and we will perform the study only when clinically indicated by leak physiology.

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is a rising cause of skin and soft tissue infections over the last decade with potentially serious complications. In this article, we describe a case of a large scalp and post-auricular abscess complicated by bacteremia. This is a case of a 73-year-old female who presented with altered mental status was found to have two fluctuant scalp abscesses, bacteremia with necrosis. The patient was promptly treated with intravenous antibiotics, multiple operative debridements without calvarial periosteum involvement defects requiring split-thickness skin grafts for wound closure. This case highlights the severity of a CA-MRSA skin infection in an atypical location.

Metastases are initiated by disseminated tumor cells (DTCs) that depart from the primary tumor and colonize target organs. Growing evidence suggests that the microenvironment of the primary tumor lesion primes DTCs to display dormant or proliferative fates in target organs. However, the manner in which events taking place in the primary tumor influence DTC fate, sometimes long after dissemination, remains poorly understood. With the advent of a novel intravital imaging technique called the Window for High-Resolution Intravital Imaging of the Lung (WHRIL), we have, for the first time, been able to study the live lung longitudinally and follow the fate of individual DTCs that spontaneously disseminate from orthotopic breast tumors. We find, across several models, a high rate of success for tumor cells to complete the initial steps of the metastatic cascade in the secondary site, including retention of DTCs in the lung vasculature, speed of extravasation, and survival after extravasation. Importantly, initiation of metastatic growth was controlled primarily by a rate-limiting step that occurred post-extravasation and at the stage of the conversion of single DTCs from a dormant to a proliferative state. Detailed analysis of these events revealed that, even before dissemination, a subset of macrophages within the primary tumor induces, in tumor cells that are about to disseminate, the expression of proteins that regulate a pro-dissemination (MenaINV) and pro-dormancy (NR2F1) phenotype. Surprisingly, if cancer cells are intravenously injected, the rate limiting stages of MenaINV-associated extravasation, dormancy, and other parameters, are lost or altered in a way that impacts how DTCs progress through the metastatic cascade. Our work provides novel insight into how specific primary tumor microenvironments prime a subpopulation of cells for dissemination and dormancy. We also propose that dissecting mechanisms of metastasis, or testing anti-metastatic therapies, may yield results of limited application if derived from models that do not follow spontaneous dissemination. Competing Interest Statement Dr. Julio Aguirre-Ghiso (a Co-author in this article) is a scientific Co-Founder of, Scientific Advisory Board Member, and equity owner in the private company, HiberCell LLC. In addition, Dr. Aguirre-Ghiso receives financial compensation as a consultant for HiberCell LLC. HiberCell LLC. is a Mount Sinai spin-out company focused on the research and development of therapeutics that prevent or delay the recurrence of cancer. Footnotes * https://www.dropbox.com/s/10jksjx2ijjy1hg/Movie%201%20Intravascular%20Tumor%20Cell.avi?dl=0 * https://www.dropbox.com/s/w66acc0mxv5ysqu/Movie%202%20Extravascular%20Tumor%20Cell.avi?dl=0

ABSTRACT Cancer stem cells (CSCs) play an important role during metastasis, but the dynamic behavior and induction mechanisms of CSCs are not well understood. We employed high-resolution intravital microscopy using a CSC biosensor to directly observe CSCs in live mice with mammary tumors. CSCs display the slow-migratory, invadopod-rich phenotype that is the hallmark of disseminating tumor cells. CSCs are enriched near macrophages, particularly near macrophage-containing intravasation sites called Tumor Microenvironment of Metastasis (TMEM) doorways. A dramatic enrichment of CSCs occurs on association with TMEM doorways, contributing to the finding that CSCs represent ∼>60% of circulating tumor cells. Mechanistically, stemness is induced in non-stem cancer cells upon their direct contact with macrophages via Notch signaling. In breast cancers from patients, the density of TMEM doorways correlates strongly with the proportion of cancer cells expressing stem cell markers, indicating that in human breast cancer TMEM doorways are not only cancer cell intravasation portals but also CSC programming sites. One Sentence Summary Intravital imaging reveals macrophage-mediated induction of cancer stem cells in vivo and their dramatic enrichment on dissemination through TMEM doorways. Competing Interest Statement The authors have declared no competing interest. * GLOSSARY SORE6>GFP cancer stem cell reporter construct (Fig S1A) minCMV>GFP minCMV control construct SORE6-GFP fluorescent protein product of SORE6>GFP construct SORE6+ same as SORE6-GFP SORE6- tumor cells containing the SORE6>GFP construct but not expressing fluorescent protein product (SORE-GFP), due to lack of stem transcription factors activity CSC Cancer stem-like cell

BackgroundThe decision between definitive radio(chemo)therapy (RCT) or a surgical strategy, i. e. surgery ± adjuvant radio(chemo)therapy for optimal treatment of oropharyngeal cancer is highly debated. Human papillomavirus(HPV)-related tumours are a distinct entity associated with p16 overexpression. While this represents a major prognostic factor, its predictive significance remains unknown.ResultsAmong 183 consecutive unselected patients treated between 2009 and 2013 with a state-of-the-art surgical procedure ± adjuvant radio(chemo)therapy or definitive RCT including intensity-modulated radiotherapy, 3‑year disease-free survival (DFS) was 74 vs. 57%, respectively (p = 0.007). When focusing on p16+ patients (49%), there was no significant difference in tumour control rate between surgery ± radio(chemo)therapy and the definitive RCT group (3-year DFS 83 vs. 82%, respectively; p = 0.48). However, delayed severe dysphagia was significantly lower in favour of definitive RCT: 35 vs. 4%, respectively; p = 0.0002.ConclusionOur results highlight distinct outcomes after definitive RCT or initial surgical treatment according to p16 status, which should thus be considered during the decision process.