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Metabolic rewiring is often considered an adaptive pressure limiting metastasis formation; however, some nutrients available at distant organs may inherently promote metastatic growth. We find that the lung and liver are lipid-rich environments. Moreover, we observe that pre-metastatic niche formation increases palmitate availability only in the lung, whereas a high-fat diet increases it in both organs. In line with this, targeting palmitate processing inhibits breast cancer-derived lung metastasis formation. Mechanistically, breast cancer cells use palmitate to synthesize acetyl-CoA in a carnitine palmitoyltransferase 1a-dependent manner. Concomitantly, lysine acetyltransferase 2a expression is promoted by palmitate, linking the available acetyl-CoA to the acetylation of the nuclear factor-kappaB subunit p65. Deletion of lysine acetyltransferase 2a or carnitine palmitoyltransferase 1a reduces metastasis formation in lean and high-fat diet mice, and lung and liver metastases from patients with breast cancer show coexpression of both proteins. In conclusion, palmitate-rich environments foster metastases growth by increasing p65 acetylation, resulting in a pro-metastatic nuclear factor-kappaB signaling., Metabolické přepojení je často považováno za adaptivní tlak omezující tvorbu metastáz; Některé živiny dostupné ve vzdálených orgánech však mohou ze své podstaty podporovat metastatický růst. Zjistili jsme, že plíce a játra jsou prostředí bohatá na lipidy. Navíc pozorujeme, že premetastatická tvorba niky zvyšuje dostupnost palmitátu pouze v plicích, zatímco strava s vysokým obsahem tuku jej zvyšuje v obou orgánech. V souladu s tím cílené zpracování palmitátů inhibuje tvorbu plicních metastáz odvozených od rakoviny prsu. Mechanicky buňky rakoviny prsu používají palmitát k syntéze acetyl-CoA způsobem závislým na karnitin palmitoyltransferáze 1a. Současně je exprese lysin acetyltransferázy 2a podporována palmitátem, který spojuje dostupný acetyl-CoA s acetylací podjednotky jaderného faktoru-kappaB p65. Delece lysin acetyltransferázy 2a nebo karnitin palmitoyltransferázy 1a snižuje tvorbu metastáz u myší s chudou a vysokotučnou dietou a metastázy plic a jater u pacientek s karcinomem prsu vykazují koexpresi obou proteinů. Závěrem lze říci, že prostředí bohaté na palmitáty podporuje růst metastáz zvýšením acetylace p65, což vede k signalizaci prometastatického jaderného faktoru-kappaB.

The gut and the liver are characterized by mutual interactions between both organs, the microbiome, diet and other environmental factors. The sum of these interactions is conceptualized as the gut–liver axis. In this Review we discuss the gut–liver axis, concentrating on the barriers formed by the enterohepatic tissues to restrict gut-derived microorganisms, microbial stimuli and dietary constituents. In addition, we discuss the establishment of barriers in the gut and liver during development and their cooperative function in the adult host. We detail the interplay between microbial and dietary metabolites, the intestinal epithelium, vascular endothelium, the immune system and the various host soluble factors, and how this interplay establishes a homeostatic balance in the healthy gut and liver. Finally, we highlight how this balance is disrupted in diseases of the gut and liver, outline the existing therapeutics and describe the cutting-edge discoveries that could lead to the development of novel treatment approaches.

The gut and the liver are characterized by mutual interactions between both organs, the microbiome, diet and other environmental factors. The sum of these interactions is conceptualized as the gut-liver axis. In this Review we discuss the gut-liver axis, concentrating on the barriers formed by the enterohepatic tissues to restrict gut-derived microorganisms, microbial stimuli and dietary constituents. In addition, we discuss the establishment of barriers in the gut and liver during development and their cooperative function in the adult host. We detail the interplay between microbial and dietary metabolites, the intestinal epithelium, vascular endothelium, the immune system and the various host soluble factors, and how this interplay establishes a homeostatic balance in the healthy gut and liver. Finally, we highlight how this balance is disrupted in diseases of the gut and liver, outline the existing therapeutics and describe the cutting-edge discoveries that could lead to the development of novel treatment approaches.In this Review, Pabst and colleagues discuss the gut-liver axis, with an emphasis on the establishment and regulation of structural and functional barriers, dynamics within the axis (immune responses and microbiome) and clinical implications.

In whole breast and regional nodal irradiation (WB + RNI), breathhold increases organ at risk (OAR) sparing. WB + RNI is usually performed in supine position, because positioning materials obstruct beam paths in prone position. Recent advancements allow prone WB + RNI (pWB + RNI) with increased sparing of OARs compared to supine WB + RNI. We evaluate positional and dosimetrical impact of repeated breathhold (RBH) and failure to breathhold (FTBH) in pWB + RNI. Twenty left-sided breast cancer patients were scanned twice in breathhold (baseline and RBH) and once free breathing (i.e. FTBH). Positional impact was evaluated using overlap index (OI) and Dice similarity coefficient (DSC). Dosimetrical impact was assessed by beam transposition from the baseline plan. Mean OI and DSC ranges were 0.01–0.98 and 0.01–0.92 for FTBH, and 0.73–1 and 0.69–1 for RBH. Dosimetric impact of RBH was negligible. FTBH significantly decreased minimal dose to CTV WBI, level II and the internal mammary nodes, with adequate mean doses. FTBH significantly increased heart, LAD, left lung and esophagus dose. OI and DSC for RBH and FTBH show reproducible large ROI positions. Small ROIs show poor overlap. FTBH maintained adequate target coverage but increased heart, LAD, ipsilateral lung and esophagus dose. RBH is a robust technique in pWB + RNI. (Clinicaltrials.gov: NCT05179161, registered 05/01/2022).

In node positive breast cancer patients who are treated with neoadjuvant systemic therapy, axillary staging and treatment is still a topic of debate. This multicenter study will contribute to evidence-based guidelines with regard to the oncologic safety and impact on quality of life of less vs. more invasive axillary staging and treatment strategies.Background: Node positive breast cancer (cN+) patients with an axillary pathologic complete response after neoadjuvant systemic therapy (NST) are not expected to benefit from axillary lymph node dissection (ALND). Therefore, less invasive axillary staging procedures have been introduced to establish response-guided treatment. However, evidence is lacking with regard to their oncologic safety and impact on quality of life (QoL). We hypothesize that if response-guided treatment is given, less invasive staging procedures are non-inferior to standard ALND in terms of oncologic safety, and superior to standard ALND in terms of QoL. Patients and Methods: MINIMAX is a Dutch multicenter registry study that includes patients with cN1-3M0 unilateral invasive breast cancer, who receive NST, followed by axillary staging and treatment according to local protocols. In a retrospective registry of +/- 4000 patients, the primar y endpoint is oncologic safety at 5 and 10 years (disease-free, breast-cancer-specific and overall survival, and axillary recurrence rate). In a prospective multicenter registry, the primar y endpoints are QoL at 1 and 5 years, and we aim to verify the 5-year oncologic safety. With an estimated 5-year disease-free survival of 72.5% and anticipated loss to follow-up of 10%, a sample size of 549 is needed to have 80% power to detect non-infer iority (with a 10% margin) of less invasive staging procedures. Conclusion: In cN+ patients treated with NST, less invasive axillary staging procedures are already implemented globally. Evidence is needed to support the assumed oncologic safety and superior QoL of such procedures. This study will contribute to evidence-based guidelines. (C) 2021 The Authors. Published by Elsevier Inc.

Surgery has been historically the preferred primary treatment for patients with well-differentiated thyroid carcinoma and for selected locoregional recurrences. Adjuvant therapy with radioactive iodine is typically recommended for patients with an intermediate to high risk of recurrence. Despite these treatments, locally advanced disease and locoregional relapses are not infrequent. These patients have a prolonged overall survival that may result in long periods of active disease and the possibility of requiring subsequent treatments. Recently, many new options have emerged as salvage therapies. This review offers a comprehensive discussion and considerations regarding surgery, active surveillance, radioactive iodine therapy, ultrasonography-guided percutaneous ablation, external beam radiotherapy, and systemic therapy for well-differentiated thyroid cancer based on relevant publications and current reference guidelines. We feel that the surgical member of the thyroid cancer management team is empowered by being aware and facile with all management options. ispartof: CANCERS vol:15 issue:3 ispartof: location:Switzerland status: published

A good understanding of the MRI anatomy of the rectum and its surroundings is pivotal to ensure high-quality diagnostic evaluation and reporting of rectal cancer. With this pictorial review, we aim to provide an image-based overview of key anatomical concepts essential for treatment planning, response evaluation and post-operative assessment. These concepts include the cross-sectional anatomy of the rectal wall in relation to T-staging; differences in staging and treatment between anal and rectal cancer; landmarks used to define the upper and lower boundaries of the rectum; the anatomy of the pelvic floor and anal canal, the mesorectal fascia, peritoneum and peritoneal reflection; and guides to help discern different pelvic lymph node stations on MRI to properly stage regional and non-regional rectal lymph node metastases. Finally, this review will highlight key aspects of post-treatment anatomy, including the assessment of radiation-induced changes and the evaluation of the post-operative pelvis after different surgical resection and reconstruction techniques.

Background In recent years, the use of Indocyanine Green (ICG) fluorescence-guided surgery during open and laparoscopic procedures has exponentially expanded across various clinical settings. The European Association of Endoscopic Surgery (EAES) initiated a consensus development conference on this topic with the aim of creating evidence-based statements and recommendations for the surgical community. Methods An expert panel of surgeons has been selected and invited to participate to this project. Systematic reviews of the PubMed, Embase and Cochrane libraries were performed to identify evidence on potential benefits of ICG fluorescence-guided surgery on clinical practice and patient outcomes. Statements and recommendations were prepared and unanimously agreed by the panel; they were then submitted to all EAES members through a two-rounds online survey and results presented at the EAES annual congress, Barcelona, November 2021. Results A total of 18,273 abstracts were screened with 117 articles included. 22 statements and 16 recommendations were generated and approved. In some areas, such as the use of ICG fluorescence-guided surgery during laparoscopic cholecystectomy, the perfusion assessment in colorectal surgery and the search for the sentinel lymph nodes in gynaecological malignancies, the large number of evidences in literature has allowed us to strongly recommend the use of ICG for a better anatomical definition and a reduction in post-operative complications. Conclusions Overall, from the systematic literature review performed by the experts panel and the survey extended to all EAES members, ICG fluorescence-guided surgery could be considered a safe and effective technology. Future robust clinical research is required to specifically validate multiple organ-specific applications and the potential benefits of this technique on clinical outcomes.

(1) Background: Paramagnetic seeds are a safe alternative for the wire-guided localisation of non-palpable breast lesions, but can also be applied for non-breast lesions. This study presents the experience with a paramagnetic seed, MagSeed® (Endomagnetics Ltd., Cambridge, UK, CE-registered and FDA-cleared), in an academic and non-academic breast centre. (2) Methods: Multicentre, retrospective analysis of 374 consecutive patients who underwent surgery after paramagnetic seed localisation (MSL) between 2018 and 2020. Indications for localisation included non-palpable breast lesions (n = 356), lymph nodes (n = 15) or soft tissue lesions (n = 3). The primary outcome was feasibility and the rate of positive section margins. The secondary outcome was predictive factors for positive section margins. (3) Results: The accurate excision of high-risk breast lesions, lymph nodes and soft tissue lesions was seen in 91.07% (n = 56). Positive section margins were observed in 7.86% (n = 25) after breast conserving surgery for invasive or ductal carcinoma in situ (DCIS) (n = 318). Invasive breast cancer associated with DCIS (p = 0.043) and the size of DCIS (p < 0.001) were significantly correlated with the positive section margins. (4) Conclusion: This study confirms the feasibility of MSL, as well as the higher risk for positive margins in cases of breast carcinoma with associated DCIS. Soft tissue lesions and lymph nodes associated with other malignancies, e.g., melanoma, can also be localised with paramagnetic seeds. This offers perspectives for future applications, such as the de-escalation of axillary treatment in breast cancer. ispartof: Cancers vol:14 issue:24 ispartof: location:Switzerland status: published

Introduction: Skin-sparing mastectomy (SSM) with immediate breast reconstruction is the ideal treatment for interested and suitable patients with extensive ductal carcinoma in situ (DCIS). There is no guideline to indicate on how large DCIS the procedure can be performed safely. The primary target of this study was to define the oncological safety of SSM in extensive pure DCIS. The secondary target was to find predictive factors for DCIS upstaging to invasive disease.Materials and methods: A total of 71 consecutive patients with extensive pure DCIS and undergoing SSM with immediate latissimus dorsi (LD) breast reconstruction were retrospectively evaluated. Results: The median size of DCIS lesion in preoperative imaging was 60 mm, the median weight of mastectomy specimen was 350 g, and the median resection margin (RM) was 2.0 mm. A total of 20 patients (28%) had an RM less than 0.5 mm and nine patients (13%) had ink positive margins. Six patients having positive RM underwent reoperation. A total of 29 patients (41%) presented invasive cancer foci in final histopathological assessment and nine patients (13%) had an axillary metastasis. Adjuvant therapy was given to 23 patients presenting invasive cancer. There were no local recurrences or distant metastases (0%, 95% confidence interval 0-0.051) during the mean follow-up of 71 mo. None of the factors evaluated predicted upstaging to invasive disease.Conclusions: SSM with immediate breast reconstruction in patients with extensive DCIS is oncologically safe even when the margins are close or positive. Additional invasive foci and solitary axillary lymph node metastases are frequent but do not worsen the outcome. (c) 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Ectopic adipose tissues (EAT) are present adjacent to many organs and have predominantly been described in overweight and obesity. They have been suggested to be related to fatty acid overflow and to have harmful effects. The objective of this semi-comprehensive review is to explore whether EAT may play a supportive role rather than interfering with its function, when the adjacent organ is challenged metabolically and functionally. EAT are present adhered to different tissues or organs, including lymph nodes, heart, kidney, ovaries and joints. In this review, we only focused on epicardial, perinodal, and peritumoral fat since these locations have been studied in more detail. Evidence was found that EAT volume significantly increased, associated with chronic metabolic challenges of the corresponding tissue. In vitro evidence revealed transfer of fatty acids from peritumoral and perinodal fat to the adjacent tissue. Cytokine expression in these EAT is upregulated when the adjacent tissue is challenged. In these tissues, glycolysis is enhanced, whereas fatty acid oxidation is increased. Together with more direct evidence, this shows that glucose is oxidized to a lesser degree, but used to support anabolic metabolism of the adjacent tissue. In these situations, browning occurs, resulting from upregulation of anabolic metabolism, stimulated by uncoupling proteins 1 and 2 and possibly 3. In conclusion, the evidence found is fragmented but the available data support the view that accumulation and browning of adipocytes adjacent to the investigated organs or tissues may be a normal physiological response promoting healing and (patho)physiological growth.

Background: There is a trend towards de-escalating axillary staging and treatment in breast cancer patients. On account of neoadjuvant systemic therapy, node-positive breast cancer patients can achieve a pathological complete response of the axilla. It is hypothesized that these patients do not benefit from an axillary lymph node dissection (ALND), and thus may be spared the risk of severe post-surgical morbidity. In an effort to omit standard ALND, less invasive axillary staging procedures are being implemented to establish response-guided treatment. However, it is unclear which less invasive staging procedure is most accurate, and long-term data are missing with regard to their oncologic safety. Summary: This article provides an overview of the literature on currently used less invasive axillary staging procedures, the accuracy and feasibility of these procedures in clinical practice, important issues concerning axillary treatment, and issues to be addressed in ongoing or future studies. Key messages: More evidence is needed regarding the safety of replacing standard ALND by less invasive axillary staging procedures in terms of long-term prognosis. These less invasive staging procedures not only serve to select patients who may benefit from treatment de-escalation, but also to select patients who may benefit from treatment escalation.

Ectopic adipose tissues (EAT) are present adjacent to many organs and have predominantly been described in overweight and obesity. They have been suggested to be related to fatty acid overflow and to have harmful effects. The objective of this semi-comprehensive review is to explore whether EAT may play a supportive role rather than interfering with its function, when the adjacent organ is challenged metabolically and functionally. EAT are present adhered to different tissues or organs, including lymph nodes, heart, kidney, ovaries and joints. In this review, we only focused on epicardial, perinodal, and peritumoral fat since these locations have been studied in more detail. Evidence was found that EAT volume significantly increased, associated with chronic metabolic challenges of the corresponding tissue. In vitro evidence revealed transfer of fatty acids from peritumoral and perinodal fat to the adjacent tissue. Cytokine expression in these EAT is upregulated when the adjacent tissue is challenged. In these tissues, glycolysis is enhanced, whereas fatty acid oxidation is increased. Together with more direct evidence, this shows that glucose is oxidized to a lesser degree, but used to support anabolic metabolism of the adjacent tissue. In these situations, browning occurs, resulting from upregulation of anabolic metabolism, stimulated by uncoupling proteins 1 and 2 and possibly 3. In conclusion, the evidence found is fragmented but the available data support the view that accumulation and browning of adipocytes adjacent to the investigated organs or tissues may be a normal physiological response promoting healing and (patho)physiological growth.

Advanced personalized immunotherapies still have to overcome several biomedical and technical limitations before they become a routine cancer treatment in spite of recent achievements. In adoptive cell therapy (ACT), the capacity to obtain adequate numbers of therapeutic T cells in the patients following ex vivo treatment should be improved. Moreover, the time and costs to produce these T cells should be reduced. In this work, inverse opal (IOPAL) 3D hydrogels consisting of poly(ethylene) glycol (PEG) covalently combined with heparin were engineered to resemble the environment of lymph nodes, where T cells get activated and proliferate. The introduction of an IOPAL strategy allowed a precise control on the porosity of the hydrogels, providing an increase in the proliferation of primary human CD4+ T cells, when compared with state-of-the-art expansion systems. Additionally, the IOPAL hydrogels also showed a superior expansion compared to hydrogels with the same composition, but without the predetermined pore structure. In summary, we have shown the beneficial effect of having an IOPAL architecture in our 3D hydrogels to help achieving large numbers of cells, while maintaining the desired selected phenotypes required for ACT., We acknowledge D. P. Rosenblatt for proofreading this manuscript and “Servei de Microscòpia” from UAB for assistance in the confocal microscopy. This work has been developed inside the “Materials Science” PhD program of UAB. The authors are grateful for the financial support received from the Spanish Government (PID2020-115296RA-I00, PID2019-105622RBI00, and the “Ramón y Cajal” program (RYC-2017-22614)), the Networking Research Center on Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN) through the projects “Alycia” (No. BBN18PI01) and “Gels4ACT” (No. BBN20PIV02), as well as CSIC for a JAE Intro fellowship. The work was funded as well by the Max Planck Society through the Max Planck Partner Group “Dynamic Biomimetics for Cancer Immunotherapy” in collaboration with the Max Planck for Medical Research (Heidelberg, Germany). This research was also supported by the European Union's Horizon 2020 research and innovation programme H2020-MSCA-COFUND-2016 (DOC-FAM, grant agreement no. 754397). ICMAB-CSIC acknowledges support from the Severo Ochoa programme for centres of excellence in R&D (FUNFUTURE, CEX2019-000917-S)., With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000917-S).

Blood vessel endothelial cells (ECs) have long been known to modulate inflammation by regulating immune cell trafficking, activation status and function. However, whether the heterogeneous EC populations in various tissues and organs differ in their immunomodulatory capacity has received insufficient attention, certainly with regard to considering them for alternative immunotherapy. Recent single-cell studies have identified specific EC subtypes that express gene signatures indicative of phagocytosis or scavenging, antigen presentation and immune cell recruitment. Here we discuss emerging evidence suggesting a tissue-specific and vessel type-specific immunomodulatory role for distinct subtypes of ECs, here collectively referred to as 'immunomodulatory ECs' (IMECs). We propose that IMECs have more important functions in immunity than previously recognized, and suggest that these might be considered as targets for new immunotherapeutic approaches. ispartof: NATURE REVIEWS IMMUNOLOGY vol:22 issue:9 pages:576-588 ispartof: location:England status: published

Background The optimal timing of surgery following chemoradiotherapy (CRT) is controversial. This trial aimed to assess disease recurrence and survival rates between patients with locally advanced rectal adenocarcinoma (LARC) who underwent total mesorectal excision (TME) after a waiting interval of 8 weeks or less (classic interval; CI) versus more than 8 weeks (long interval; LI) following preoperative CRT. Methods This was a phase III, single-centre, randomized clinical trial. Patients with LARC situated within 12 cm of the anal verge (T3–T4 or N+ disease) were randomized to undergo TME within or after 8 weeks after CRT. Results Between January 2006 and January 2017, 350 patients were randomized, 175 to each group. As of February 2022, the median follow-up time was 80 (6–174) months. Among the 322 included patients (CI, 159; LI, 163) the cumulative incidence of locoregional recurrence at 5 years was 10.1 per cent in the CI group and 6.9 per cent in the LI group (P = 0.143). The cumulative incidence of distant metastasis at 5 years was 30.8 per cent in the CI group and 18.6 per cent in the LI group (sub-HR = 1.78; 95 per cent c.i. 1.14 to 2.78, P = 0.010). The disease-free survival (DFS) in each group was 59.7 and 69.9 per cent respectively (P = 0.157), and overall survival (OS) rates at 5 years were 73.6 versus 77.9 per cent (P = 0.476). Conclusion Incidence of distant metastasis decreased with an interval between CRT and surgery exceeding 8 weeks, but this did not impact on DFS or OS. Registration number NCT03287843 (http://www.clinicaltrials.gov).

At the interface between the innate and adaptive immune system, dendritic cells (DCs) play key roles in tumour immunity and hold a hitherto unrealized potential for cancer immunotherapy. Here we review the role of distinct DC subsets in the tumour microenvironment, with special emphasis on conventional type 1 DCs. Integrating new knowledge of DC biology and advancements in cell engineering, we provide a blueprint for the rational design of optimized DC vaccines for personalized cancer medicine., Dendritic cells (DCs) have been explored as a promising strategy for cancer immunotherapy. In this Perspective, the authors discuss the different types of DCs and their therapeutic potential in the context of vaccines for personalized cancer therapy.

Purpose of Review To review current practice in MRI-based nodal staging in rectal cancer and assess the associated evidence. Recent Findings Nodal staging is less accurate than other MRI-detected prognostic markers such as circumferential resection margin status, extramural venous invasion and T stage. Previous research has focused on matching MRI and pathology findings but crucially N stage has never been shown to have prognostic importance on MRI. Recent pathological evidence suggests that tumour deposits may be more important than nodal status and these can be clearly distinguished from nodal metastases on MRI. Summary Nodal staging on MRI is prognostically inaccurate. MRI staging should move away from TNM to focus on those radiological markers which can be proved to have prognostic accuracy. Tumour deposits should be reported separately to lymph node metastases on both histopathology and imaging. Research is underway confirming their prognostic importance on MRI.

This systematic review and meta-analysis pools data from studies in the neoadjuvant setting on axillary pathologic complete response rates for different breast cancer subtypes in patients with initial clinically node-positive disease.Importance An overview of rates of axillary pathologic complete response (pCR) for all breast cancer subtypes, both for patients with and without pathologically proven clinically node-positive disease, is lacking. Objective To provide pooled data of all studies in the neoadjuvant setting on axillary pCR rates for different breast cancer subtypes in patients with initially clinically node-positive disease. Data Sources The electronic databases Embase and PubMed were used to conduct a systematic literature search on July 16, 2020. The references of the included studies were manually checked to identify other eligible studies. Study Selection Studies in the neoadjuvant therapy setting were identified regarding axillary pCR for different breast cancer subtypes in patients with initially clinically node-positive disease (ie, defined as node-positive before the initiation of neoadjuvant systemic therapy). Data Extraction and Synthesis Two reviewers independently selected eligible studies according to the inclusion criteria and extracted all data. All discrepant results were resolved during a consensus meeting. To identify the different subtypes, the subtype definitions as reported by the included articles were used. The random-effects model was used to calculate the overall pooled estimate of axillary pCR for each breast cancer subtype. Main Outcomes and Measures The main outcome of this study was the rate of axillary pCR and residual axillary lymph node disease after neoadjuvant systemic therapy for different breast cancer subtypes, differentiating studies with and without patients with pathologically proven clinically node-positive disease. Results This pooled analysis included 33 unique studies with 57 531 unique patients and showed the following axillary pCR rates for each of the 7 reported subtypes in decreasing order: 60% for hormone receptor (HR)-negative/ERBB2 (formerly HER2)-positive, 59% for ERBB2-positive (HR-negative or HR-positive), 48% for triple-negative, 45% for HR-positive/ERBB2-positive, 35% for luminal B, 18% for HR-positive/ERBB2-negative, and 13% for luminal A breast cancer. No major differences were found in the axillary pCR rates per subtype by analyzing separately the studies of patients with and without pathologically proven clinically node-positive disease before neoadjuvant systemic therapy. Conclusions and Relevance The HR-negative/ERBB2-positive subtype was associated with the highest axillary pCR rate. These data may help estimate axillary treatment response in the neoadjuvant setting and thus select patients for more or less invasive axillary procedures.Question What are the rates of axillary pathologic complete response (pCR) for different breast cancer subtypes in patients with initially clinically node-positive breast cancer? Findings This systematic review and meta-analysis, including 33 unique studies with 57 531 unique patients, showed that the hormone receptor (HR)-negative/ERBB2-positive subtype was associated with the highest axillary pCR rate (60%). The remaining subtypes were associated with the following axillary pCR rates in decreasing order: 59% for ERBB2-positive, 48% for triple-negative, 45% for HR-positive/ERBB2-positive, 35% for luminal B, 18% for HR-positive/ERBB2-negative, and 13% for luminal A breast cancer. Meaning These data can help estimate axillary treatment response in the neoadjuvant setting and thus select patients for more or less invasive axillary procedures.

Mechanisms by which advanced glycation end products (AGEs) contribute to type 1 diabetes (T1D) pathogenesis are poorly understood. Since life-long pharmacotherapy with alagebrium chloride (ALT) slows progression to experimental T1D, we hypothesized that acute ALT therapy delivered prediabetes, may be effective. However, in female, non-obese diabetic (NODShiLt) mice, ALT administered prediabetes (day 50–100) did not protect against experimental T1D. ALT did not decrease circulating AGEs or their precursors. Despite this, pancreatic β-cell function was improved, and insulitis and pancreatic CD45.1+ cell infiltration was reduced. Lymphoid tissues were unaffected. ALT pre-treatment, prior to transfer of primed GC98 CD8+ T cell receptor transgenic T cells, reduced blood glucose concentrations and delayed diabetes, suggesting islet effects rather than immune modulation by ALT. Indeed, ALT did not reduce interferon-γ production by leukocytes from ovalbumin-pre-immunised NODShiLt mice and NODscid recipients given diabetogenic ALT treated NOD splenocytes were not protected against T1D. To elucidate β-cell effects, NOD-derived MIN6N8 β-cell major histocompatibility complex (MHC) Class Ia surface antigens were examined using immunopeptidomics. Overall, no major changes in the immunopeptidome were observed during the various treatments with all peptides exhibiting allele specific consensus binding motifs. As expected, longer MHC Class Ia peptides were captured bound to H-2Db than H-2Kb under all conditions. Moreover, more 10–12 mer peptides were isolated from H-2Db after AGE modified bovine serum albumin (AGE-BSA) treatment, compared with bovine serum albumin (BSA) or AGE-BSA+ALT treatment. Proteomics of MIN6N8 cells showed enrichment of processes associated with catabolism, the immune system, cell cycling and presynaptic endocytosis with AGE-BSA compared with BSA treatments. These data show that short-term ALT intervention, given prediabetes, does not arrest experimental T1D but transiently impacts β-cell function.

Contains fulltext : 238902.pdf (Publisher’s version ) (Closed access) AIMS: Tumour deposits (TDs) are an important prognostic marker in colorectal cancer. However, the classification, and inclusion in staging, of TDs has changed significantly in each tumour-node-metastasis (TNM) edition since their initial description in TNM-5, and terminology remains controversial. Expert consensus is needed to guide the future direction of precision staging. METHODS AND RESULTS: A modified Delphi consensus process was used. Statements were formulated and sent to participants as an online survey. Participants were asked to rate their agreement with each statement on a five-point Likert scale and also to suggest additional statements for discussion. These responses were circulated together with anonymised comments, and statements were modified prior to carrying out a second online round. Consensus was set at 70%. Overall, 32 statements reached consensus. There were concerns that TDs were currently incorrectly placed in the TNM system and that their prognostic importance was being underestimated. There were concerns regarding interobserver variation and it was felt that a clearer, more reproducible definition of TDs was needed. CONCLUSIONS: Our main recommendations are that the number of TDs should be recorded even if lymph node metastases (LNMs) are also present and that nodules with evidence of origin [extramural venous invasion (EMVI), perineural invasion (PNI), lymphatic invasion (LI)] should still be categorised as TDs and not excluded, as TNM-8 specifies. Whether TDs should continue to be included in the N category at all is controversial, and did not achieve consensus; however, participants agreed that TDs are prognostically worse than LNMs and the N1c category is suboptimal, as it does not reflect this.

The European SocieTy for Radiation and Oncology -Advisory Committee on Radiation Oncology Practice (ESTRO-ACROP) endorsed a project to provide guidelines (GL) for the identification and delineation of clinically negative lymph-nodal stations (LNs) involved in upper gastrointestinal clinical scenarios. The presented GL is focused on preoperative (or definitive) setting. The project aim is to improve the consistency of clinical target volume (CTV) delineation by providing: a description of the anatomical boundaries of the LNs; a radiological computed tomography-based atlas depicting the LNs areas; a free, web-based, interactive example case for independent training of radiation oncologists on LNs delineation according to the presented GL, by both qualitative and quantitative analysis (through the FALCON EduCase platform). This project was carried out with the intention to facilitate and improve uniformity of future upper gastrointestinal guidelines on nodal CTV delineation. We report methodology and results from the collaboration of a working group panel selected by the ESTRO-ACROP. ispartof: RADIOTHERAPY AND ONCOLOGY vol:164 pages:92-97 ispartof: location:Ireland status: published

ObjectiveEndoscopic mucosal biopsies of primary gastric cancers (GCs) are used to guide diagnosis, biomarker testing and treatment. Spatial intratumoural heterogeneity (ITH) may influence biopsy-derived information. We aimed to study ITH of primary GCs and matched lymph node metastasis (LNmet).DesignGC resection samples were annotated to identify primary tumour superficial (PTsup), primary tumour deep (PTdeep) and LNmet subregions. For each subregion, we determined (1) transcriptomic profiles (NanoString ‘PanCancer Progression Panel’, 770 genes); (2) next-generation sequencing (NGS, 225 gastrointestinal cancer-related genes); (3) DNA copy number profiles by multiplex ligation-dependent probe amplification (MLPA, 16 genes); and (4) histomorphological phenotypes.ResultsNanoString profiling of 64 GCs revealed no differences between PTsup1 and PTsup2, while 43% of genes were differentially expressed between PTsup versus PTdeep and 38% in PTsup versus LNmet. Only 16% of genes were differently expressed between PTdeep and LNmet. Several genes with therapeutic potential (eg IGF1, PIK3CD and TGFB1) were overexpressed in LNmet and PTdeep compared with PTsup. NGS data revealed orthogonal support of NanoString results with 40% mutations present in PTdeep and/or LNmet, but not in PTsup. Conversely, only 6% of mutations were present in PTsup and were absent in PTdeep and LNmet. MLPA demonstrated significant ITH between subregions and progressive genomic changes from PTsup to PTdeep/LNmet.ConclusionIn GC, regional lymph node metastases are likely to originate from deeper subregions of the primary tumour. Future clinical trials of novel targeted therapies must consider assessment of deeper subregions of the primary tumour and/or metastases as several therapeutically relevant genes are only mutated, overexpressed or amplified in these regions.

The eighth edition of the American Joint Committee on Cancer (AJCC8) staging manual has major changes in oral squamous cell carcinoma (OSCC). We searched PubMed, OvidMedline, Scopus, and Web of Science for studies that examined the performance of AJCC8 in OSCC. A total of 40 808 patients were included in the studies of our meta-analysis. A hazard ratio (HR) of 1.87 (95%CI 1.78-1.96) was seen for stage II, 2.65 (95%CI 2.51-2.80) for stage III, 3.46 (95%CI 3.31-3.61) for stage IVa, and 7.09 (95%CI 4.85-10.36) for stage IVb. A similar gradual increase in risk was noted for the N classification. For the T classification, however, there was a less clear variation in risk between T3 and T4. AJCC8 provides a good risk stratification for OSCC. Future research should examine the proposals introduced in the published studies to further improve the performance of AJCC8.

Objective: The aim of this study was to perform a systematic review and meta-analysis to assess the accuracy of different surgical axillary staging procedures compared with ALND.Summary of Background Data: Optimal axillary staging after neoadjuvant systemic therapy (NST) in node-positive breast cancer is an area of controversy. Several less invasive procedures, such as sentinel lymph node biopsy (SLNB), marking axillary lymph node with radioactive iodine seed (MARI), and targeted axillary dissection (a combination of SLNB and a MARI-like procedure), have been proposed to replace the conventional axillary lymph node dissection (ALND) with its concomitant morbidity.Methods: PubMed and Embase were searched for studies comparing less invasive surgical axillary staging procedures to ALND to identify axillary burden after NST in patients with pathologically confirmed node-positive breast cancer (cNthorn). A meta-analysis was performed to compare identification rate (IFR), false-negative rate (FNR), and negative predictive value (NPV).Results: Of 1132 records, 20 unique studies with 2217 patients were included in quantitative analysis: 17 studies on SLNB, 1 study on MARI, and 2 studies on a combination procedure. Overall axillary pathologic complete response rate was 37%. For SLNB, pooled rates of IFR and FNR were 89% and 17%. NPV ranged from 57% to 86%. For MARI, IFR was 97%, FNR 7%, and NPV 83%. For the combination procedure, IFR was 100%, FNR ranged from 2% to 4%, and NPV from 92% to 97%.Conclusion: Axillary staging by a combination procedure consisting of SLNB with excision of a pre-NST marked positive lymph node appears to be most accurate for axillary staging after NST. More evidence from prospective multicenter trials is needed to confirm this.

Epithelial Ovarian cancer (EOC) is the most lethal gynecological malignancy and has limited curative therapeutic options. Immunotherapy for EOC is promising, but clinical efficacy remains restricted to a small percentage of patients. Several lines of evidence suggest that the low response rate might be improved by combining immunotherapy with carboplatin and paclitaxel, the standard-of-care chemotherapy for EOC. Here, we assessed the immune contexture of EOC tumors, draining lymph nodes, and peripheral blood mononuclear cells during carboplatin/paclitaxel chemotherapy. We observed that the immune contexture of EOC patients is defined by the tissue of origin, independent of exposure to chemotherapy. Summarized, draining lymph nodes were characterized by a quiescent microenvironment composed of mostly non-proliferating naïve CD4 + T cells. Circulating T cells shared phenotypic features of both lymph nodes and tumor-infiltrating immune cells. Immunologically ‘hot’ ovarian tumors were characterized by ICOS, GITR, and PD-1 expression on CD4 + and CD8 + cells, independent of chemotherapy. The presence of PD-1 + cells in tumors prior to, but not after, chemotherapy was associated with disease-specific survival (DSS). Accordingly, we observed high MHC-I expression in tumors prior to chemotherapy, but minimal MHC-I expression in tumors after neoadjuvant chemotherapy, even though there were no differences in the number of tumor-infiltrating lymphocytes (TIL) in both groups. We therefore speculate that the TIL influx into the chemotherapy tumor microenvironment may be a consequence of the general inflammatory nature of chemotherapy-experienced tumors. Strategies to upregulate MHC-I during or after neoadjuvant chemotherapy may thus improve treatment outcome in these patients.

Melanoma is an immunogenic neoplasm infiltrated by T cells, although these adaptive T cells usually fail to eradicate the tumor. Plasmacytoid dendritic cells (PDCs) are potent regulators of the adaptive immune response and can eliminate melanoma cells via TLR-mediated effector functions. The PDC compartment is maintained by progressively restricted bone marrow progenitors. Terminally differentiated PDCs exit the bone marrow into the circulation, then home to lymph nodes and inflamed peripheral tissues. Infiltration by PDCs is documented in various cancers. However, their role within the melanoma immune contexture is not completely known. We found that in locoregional primary cutaneous melanoma (PCM), PDC infiltration was heterogeneous, occurred early, and was recurrently localized at the invasive margin, the site where PDCs interact with CD8+ T cells. A reduced PDC density was coupled with an increased Breslow thickness and somatic mutations at the NRAS p.Q61 codon. Compared with what was seen in PCM, high numbers of PDCs were found in regional lymph nodes, as also identified by in silico analysis. In contrast, in metastatic melanoma patients, PDCs were mostly absent in the tumor tissues and were significantly reduced in the circulation, particularly in the advanced M1c group. Exposure of circulating PDCs to melanoma cell supernatant (SN-mel) depleted of extracellular vesicles resulted in significant PDC death. SN-mel exposure also resulted in a defect of PDC differentiation from CD34+ progenitors. These findings indicate that soluble components released by melanoma cells support the collapse of the PDC compartment, with clinical implications for refining TLR agonist–based trials.

Background: The Z0011 trial initiated a paradigm shift in the axillary treatment of breast cancer patients with a positive sentinel lymph node biopsy (SLNB), disregarding patients with a positive ultrasound-guided lymph node biopsy (UGLNB). We examined whether relevant differences exist between these patients to determine if the conclusions of the ACOSOG Z0011 trial are applicable to UGLNB-positive patients. Methods: Patients diagnosed with invasive breast cancer in the Netherlands between January 2008 and December 2014 were selected from the Netherlands Cancer Registry. Results: A total of 11,820 cases were included: 9149 cases in the SLNB group and 2671 in the UGLNB group. Multivariate analyses showed that UGLNB-positive patients were older (p

Background Thyroid lobectomy is the preferred option for small, unifocal papillary thyroid carcinoma. Involvement of the central neck lymph nodes is an indication for total thyroidectomy plus central neck dissection. We aimed to verify if frozen section examination of ipsilateral central neck nodes can identify the subgroup of patients scheduled for thyroid lobectomy intraoperatively who could benefit of more extensive initial operative treatment. Methods Ninety-four consenting patients with clinically unifocal cN0 papillary thyroid carcinoma underwent thyroid lobectomy plus ipsilateral central neck dissection with frozen section examination. If the frozen section examination was positive for metastases, a completion thyroidectomy and a bilateral central neck dissection were accomplished during the same procedure. Results Frozen section examination identified occult nodal metastases in 25 of the 94 patients who then underwent immediate completion thyroidectomy and bilateral central neck dissection. Overall, central neck node metastases were found at final histology in 35 cases: occult micrometastases were observed in additional 9 patients and nodal metastases ≥2 mm in additional 1 patient. Conclusion Intraoperative assessment of nodal status obtained with ipsilateral central neck dissection and frozen section examination is able to change the extent of thyroidectomy in about one-fourth of patients scheduled for thyroid lobectomy. Frozen section examination appears a safe and effective strategy to decrease the need of a second-step completion procedure and, theoretically, the risk of recurrence.

OBJECTIVE This study aim to investigate the feasibility and the cardiac and lung-sparing value of Deep Inspiration Breath-Hold (DIBH) technique compared to the Free Breathing (FB) technique among left-sided breast cancer patients who underwent chest-wall, level 3 +/- level 1-2 axillary, supraclavicular and the internal mammary nodes (IMN) irradiation. METHODS Ten patients who underwent the modified radical mastectomy and were treated with adjuvant radiotherapy were included in this study. All patients underwent CT simulation during FB and DIBH. Audiovisual guidance was used. Target volumes included chest-wall and regional nodes. The treatment plans and dose-volume histograms that were created on both CT scans were used to compare doses to heart, ventricle, left anterior descending artery (LAD) and lung. RESULTS The mean heart dose was reduced from 6,4 Gy to 3,3 Gy using DIBH technique. Heart V20, V30 and V40 and maximum dose were significantly decreased in the DIBH plans compared to FB. For LAD coronary artery, there was a significant reduction in mean dose from 42,5 Gy to 20,5 Gy in DIBH plans. There was a significant reduction in mean dose to the ipsilateral lung (ilung); V5, V10, V20 in DIBH plans. CONCLUSION Patients with locally advanced left-sided breast cancer require additional attention to improve heart and lung sparing to reduce late cardiovascular events and secondary cancer risks. DIBH technique led to significant reductions in heart, ventricle, LAD, left lung DVH parameters without compromising the dose coverage to PTV in patients treated with chest-wall and lymphatic irradiation, including IMN.

Background and aims: Stage II cancer of the tongue is mostly managed surgically both locally and regionally. However, indications for postoperative radiotherapy and reconstructive options vary between centers. This paper aims to describe differences in treatment in a geographically homogenous cohort. Methods: A retrospective comparison was made between two cohorts of clinical T2N0 tongue cancer from Finland and Sweden. The Finnish cohort included 75 patients and the Swedish 54. All patients had curative intent of treatment and no previous head and neck cancer. Data analyzed consisted of pathological stage, size and thickness of tumor, frequency of reconstruction, radiotherapy delivered, and survival. Results: The Finnish cohort included a higher proportion of patients managed with reconstructive surgery (67%) than the Swedish cohort (0%), p

Background Marking the axilla with radioactive iodine seed and sentinel lymph node (SLN) biopsy have been proposed for axillary staging after neoadjuvant systemic therapy in clinically node‐positive breast cancer. This study evaluated the identification rate and detection of residual disease with combined excision of pretreatment‐positive marked lymph nodes (MLNs) together with SLNs. Methods This was a multicentre retrospective analysis of patients with clinically node‐positive breast cancer undergoing neoadjuvant systemic therapy and the combination procedure (with or without axillary lymph node dissection). The identification rate and detection of axillary residual disease were calculated for the combination procedure, and for MLNs and SLNs separately. Results At least one MLN and/or SLN(s) were identified by the combination procedure in 138 of 139 patients (identification rate 99·3 per cent). The identification rate was 92·8 per cent for MLNs alone and 87·8 per cent for SLNs alone. In 88 of 139 patients (63·3 per cent) residual axillary disease was detected by the combination procedure. Residual disease was shown only in the MLN in 20 of 88 patients (23 per cent) and only in the SLN in ten of 88 (11 per cent), whereas both the MLN and SLN contained residual disease in the remainder (58 of 88, 66 per cent). Conclusion Excision of the pretreatment‐positive MLN together with SLNs after neoadjuvant systemic therapy in patients with clinically node‐positive disease resulted in a higher identification rate and improved detection of residual axillary disease., Replacing axillary lymph node dissection with less invasive axillary staging procedures in patients with clinically node‐positive breast cancer treated with neoadjuvant systemic therapy is debated. Implementation of several different less invasive procedures is ongoing at some centres. In this cohort, the identification rate and detection of residual disease of combined excision of the pretreatment‐positive marked lymph node with the sentinel lymph nodes were evaluated, and compared with excising only the marked lymph node or the sentinel lymph nodes alone. Combination superior

Preoperative differentiation between limited (pN1; 1–3 axillary metastases) and advanced (pN2–3; ≥4 axillary metastases) nodal disease can provide relevant information regarding surgical planning and guiding adjuvant radiation therapy. The aim was to evaluate the diagnostic performance of preoperative axillary ultrasound (US) and breast MRI for differentiation between pN1 and pN2–3 in clinically node-positive breast cancer. A total of 49 patients were included with axillary metastasis confirmed by US-guided tissue sampling. All had undergone breast MRI between 2008–2014 and subsequent axillary lymph node dissection. Unenhanced T2-weighted MRI exams were reviewed by two radiologists independently. Each lymph node on the MRI exams was scored using a confidence scale (0–4) and compared with histopathology. Diagnostic performance parameters were calculated for differentiation between pN1 and pN2–3. Interobserver agreement was determined using Cohen’s kappa coefficient. At final histopathology, 67.3% (33/49) and 32.7% (16/49) of patients were pN1 and pN2–3, respectively. Breast MRI was comparable to US in terms of accuracy (MRI reader 1 vs US, 71.4% vs 69.4%, p = 0.99; MRI reader 2 vs US, 73.5% vs 69.4%, p = 0.77). In the case of 1–3 suspicious lymph nodes, pN2–3 was observed in 30.4% on US (positive predictive value (PPV) 69.6%) and in 22.2–24.3% on MRI (PPV 75.7–77.8%). In the case of ≥4 suspicious lymph nodes, pN1 was observed in 33.3% on US (negative predictive value (NPV) 66.7%) and in 38.5–41.7% on MRI (NPV 58.3–61.5%). Interobserver agreement was considered good (k = 0.73). In clinically node-positive patients, the diagnostic performance of axillary US and breast MRI is comparable and limited for accurate differentiation between pN1 and pN2–3. Therefore, there seems no added clinical value of preoperative breast MRI regarding nodal staging in patients with positive axillary US.

Annexin A1 (AnxA1) modulates neutrophil life span and bone marrow/blood cell trafficking thorough activation of formyl-peptide receptors (FPRs). Here, we investigated the effect of exogenous AnxA1 on haematopoiesis in the mouse. Treatment of C57BL/6 mice with recombinant AnxA1 (rAnxA1) reduced the granulocyte–macrophage progenitor (GMP) population in the bone marrow, enhanced the number of mature granulocytes Gr-1+Mac-1+ in the bone marrow as well as peripheral granulocytic neutrophils and increased expression of mitotic cyclin B1 on hematopoietic stem cells (HSCs)/progenitor cells (Lin−Sca-1+c-Kit+: LSK). These effects were abolished by simultaneous treatment with Boc-2, an FPR pan-antagonist. In in vitro studies, rAnxA1 reduced both HSC (LSKCD90lowFLK-2−) and GMP populations while enhancing mature cells (Gr1+Mac1+). Moreover, rAnxA1 induced LSK cell proliferation (Ki67+), increasing the percentage of cells in the S/G2/M cell cycle phases and reducing Notch-1 expression. Simultaneous treatment with WRW4, a selective FPR2 antagonist, reversed the in vitro effects elicited by rAnxA1. Treatment of LSK cells with rAnxA1 led to phosphorylation of PCLγ2, PKC, RAS, MEK, and ERK1/2 with increased expression of NFAT2. In long-term bone marrow cultures, rAnxA1 did not alter the percentage of LSK cells but enhanced the Gr-1+Mac-1+ population; treatment with a PLC (U73122), but not with a PKC (GF109203), inhibitor reduced rAnxA1-induced phosphorylation of ERK1/2 and Elk1. Therefore, we identify here rAnxA1 as an inducer of HSC/progenitor cell differentiation, favouring differentiation of the myeloid/granulocytic lineage, via Ca2+/MAPK signalling transduction pathways.

PURPOSE: A recent research shows an increasing recognition that organisms not traditionally considered infectious in nature contribute to disease processes. Propionibacterium acnes (P. acnes) is a gram-positive, aerotolerant anaerobe prevalent in the sebaceous gland-rich areas of the human skin. A ubiquitous slow-growing organism with the capacity to form biofilm, P. acnes, recognized for its role in acne vulgaris and medical device-related infections, is now also linked to a number of other human diseases. While bacterial culture and molecular techniques are used to investigate the involvement of P. acnes in such diseases, definitive demonstration of P. acnes infection requires a technique (or techniques) sensitive to the presence of biofilms and insensitive to the presence of potential contamination. Fortunately, there are imaging techniques meeting these criteria, in particular, fluorescence in situ hybridization and immunofluorescence coupled with confocal laser scanning microscopy, as well as immunohistochemistry.METHODS: Our literature review considers a range of microscopy-based studies that provides definitive evidence of P. acnes colonization within tissue from a number of human diseases (acne vulgaris, degenerative disc and prostate disease and atherosclerosis), some of which are currently not considered to have an infectious etiology.RESULTS/CONCLUSION: We conclude that P. acnes is an opportunistic pathogen with a likely underestimated role in the development of various human diseases associated with significant morbidity and, in some cases, mortality. As such, these findings offer the potential for new studies aimed at understanding the pathological mechanisms driving the observed disease associations, as well as novel diagnostic strategies and treatment strategies, particularly for degenerative disc disease. These slides can be retrieved under Electronic Supplementary Material.

This systematic review and meta-analysis pools data from studies in the neoadjuvant setting on axillary pathologic complete response rates for different breast cancer subtypes in patients with initial clinically node-positive disease.Importance An overview of rates of axillary pathologic complete response (pCR) for all breast cancer subtypes, both for patients with and without pathologically proven clinically node-positive disease, is lacking. Objective To provide pooled data of all studies in the neoadjuvant setting on axillary pCR rates for different breast cancer subtypes in patients with initially clinically node-positive disease. Data Sources The electronic databases Embase and PubMed were used to conduct a systematic literature search on July 16, 2020. The references of the included studies were manually checked to identify other eligible studies. Study Selection Studies in the neoadjuvant therapy setting were identified regarding axillary pCR for different breast cancer subtypes in patients with initially clinically node-positive disease (ie, defined as node-positive before the initiation of neoadjuvant systemic therapy). Data Extraction and Synthesis Two reviewers independently selected eligible studies according to the inclusion criteria and extracted all data. All discrepant results were resolved during a consensus meeting. To identify the different subtypes, the subtype definitions as reported by the included articles were used. The random-effects model was used to calculate the overall pooled estimate of axillary pCR for each breast cancer subtype. Main Outcomes and Measures The main outcome of this study was the rate of axillary pCR and residual axillary lymph node disease after neoadjuvant systemic therapy for different breast cancer subtypes, differentiating studies with and without patients with pathologically proven clinically node-positive disease. Results This pooled analysis included 33 unique studies with 57 531 unique patients and showed the following axillary pCR rates for each of the 7 reported subtypes in decreasing order: 60% for hormone receptor (HR)-negative/ERBB2 (formerly HER2)-positive, 59% for ERBB2-positive (HR-negative or HR-positive), 48% for triple-negative, 45% for HR-positive/ERBB2-positive, 35% for luminal B, 18% for HR-positive/ERBB2-negative, and 13% for luminal A breast cancer. No major differences were found in the axillary pCR rates per subtype by analyzing separately the studies of patients with and without pathologically proven clinically node-positive disease before neoadjuvant systemic therapy. Conclusions and Relevance The HR-negative/ERBB2-positive subtype was associated with the highest axillary pCR rate. These data may help estimate axillary treatment response in the neoadjuvant setting and thus select patients for more or less invasive axillary procedures.Question What are the rates of axillary pathologic complete response (pCR) for different breast cancer subtypes in patients with initially clinically node-positive breast cancer? Findings This systematic review and meta-analysis, including 33 unique studies with 57 531 unique patients, showed that the hormone receptor (HR)-negative/ERBB2-positive subtype was associated with the highest axillary pCR rate (60%). The remaining subtypes were associated with the following axillary pCR rates in decreasing order: 59% for ERBB2-positive, 48% for triple-negative, 45% for HR-positive/ERBB2-positive, 35% for luminal B, 18% for HR-positive/ERBB2-negative, and 13% for luminal A breast cancer. Meaning These data can help estimate axillary treatment response in the neoadjuvant setting and thus select patients for more or less invasive axillary procedures.

Background: Completion lymph node dissection (CLND) in sentinel node (SN) positive melanoma patients leads to substantial morbidity and costs, while only approximately 20% have a metastasis in non-sentinel nodes (NSNs). The aim of this study was to investigate if the biomarkers S-100B and Lactate Dehydrogenase (LDH) are associated with NSN positivity, to identify patients in whom CLND could safely be omitted.Methods: All SN positive patients who underwent CLND at the University Medical Centre Groningen between January 2004 and January 2015 were analysed. Patient and tumor characteristics, and serum S-100B and LDH values measured the day before CLND were statistically tested for their association with NSN positivity.Results: NSN positivity was found in 20.6% of the 107 patients undergoing CLND. Univariate analysis revealed male gender (p = 0.02), melanoma of the lower extremity (p = 0.05), Breslow thickness (p = 0.004), ulceration (p = 0.04), proportion of involved SNs (p = 0.045) and S-100B value (p = 0.01) to be associated with NSN positivity. LDH level was not significantly associated with positive NSNs (p = 0.39). In multivariable analysis, S-100B showed to have the strongest association with NSN positivity, within its reference interval of 0.20 mu g/I (p = 0.02, odds ratio 5.71, 95% confidence interval 1.37-23.87).Conclusion: In this study, the preoperatively measured S-100B value is the strongest predictor for NSN positivity in patients planned for CLND. Fluctuations of the S-100B level within the reference interval might give important clues about residual tumor load. Although further validation will be needed, this new closer look of S-100B could be of value in patient selection for CLND in the future. (C) 2016 Elsevier Ltd. All rights reserved.

This review summarizes current applications and clinical utility of diffusion-weighted imaging (DWI) for rectal cancer and in addition provides a brief overview of more recent developments (including intravoxel incoherent motion imaging, diffusion kurtosis imaging, and novel postprocessing tools) that are still in more early stages of research. More than 140 papers have been published in the last decade, during which period the use of DWI have slowly moved from mainly qualitative (visual) image interpretation to increasingly advanced methods of quantitative analysis. So far, the largest body of evidence exists for assessment of tumour response to neoadjuvant treatment. In this setting, particularly the benefit of DWI for visual assessment of residual tumour in post-radiation fibrosis has been established and is now increasingly adopted in clinics. Quantitative DWI analysis (mainly the apparent diffusion coefficient) has potential, both for response prediction as well as for tumour prognostication, but protocols require standardization and results need to be prospectively confirmed on larger scale. The role of DWI for further clinical tumour and nodal staging is less well-defined, although there could be a benefit for DWI to help detect lymph nodes. Novel methods of DWI analysis and post-processing are still being developed and optimized; the clinical potential of these tools remains to be established in the upcoming years.

Vesicular stomatitis virus (VSV) is an insect-transmitted rhabdovirus that is neurovirulent in mice. Upon peripheral VSV infection, CD169+ subcapsular sinus (SCS) macrophages capture VSV in the lymph, support viral replication, and prevent CNS neuroinvasion. To date, the precise mechanisms controlling VSV infection in SCS macrophages remain incompletely understood. Here, we show that Toll-like receptor-7 (TLR7), the main sensing receptor for VSV, is central in controlling lymph-borne VSV infection. Following VSV skin infection, TLR7−/− mice display significantly less VSV titers in the draining lymph nodes (dLN) and viral replication is attenuated in SCS macrophages. In contrast to effects of TLR7 in impeding VSV replication in the dLN, TLR7−/− mice present elevated viral load in the brain and spinal cord highlighting their susceptibility to VSV neuroinvasion. By generating novel TLR7 floxed mice, we interrogate the impact of cell-specific TLR7 function in anti-viral immunity after VSV skin infection. Our data suggests that TLR7 signaling in SCS macrophages supports VSV replication in these cells, increasing LN infection and may account for the delayed onset of VSV-induced neurovirulence observed in TLR7−/− mice. Overall, we identify TLR7 as a novel and essential host factor that critically controls anti-viral immunity to VSV. Furthermore, the novel mouse model generated in our study will be of valuable importance to shed light on cell-intrinsic TLR7 biology in future studies. CA extern

Purpose Image guided adaptive brachytherapy (IGABT) for cervical cancer improves pelvic control and survival across all stages. Improvement in pelvic control is larger in advanced stages, but improvement in survival is similar across stages. This paper analyzes the patterns of failure in the RetroEMBRACE cohort to investigate this discrepancy. Methods and Materials 731 patients from 12 institutions treated with chemoradiation therapy and magnetic resonance imaging or computed tomography–based IGABT were evaluated. The pattern of failure at time of first relapse was analyzed. Results Three hundred twenty-five failures (single and synchronous) occurred in 222 of 731 patients (30%). Among the 325 failures, 9% were local and 6% regional. Pelvic (local or regional) failures made up 13%, paraaortic node (PAN) 9%, systemic 21%, and distant (systemic + PAN) 24%. Of the 222 patients with treatment failure, 21% had pelvic failure alone, 57% had distant failure alone, and 23% had both pelvic and distant failure. Of all failures that occurred, 40% to 50% occurred in the first year, with a further 20% to 30% occurring in the second year. Although local, regional, and PAN failure tended to plateau after year 3, systemic failure continued to occur up to year 10. Conclusions Implementation of IGABT has changed the patterns of relapse after chemoradiation therapy for cervical cancer. The predominant failure after IGABT is systemic, whereas the predominant failure with conventional brachytherapy is pelvic. Effective treatments to eradicate micrometastases in PAN and distant organs are needed in addition to IGABT and chemoradiation therapy to maximize local, regional, PAN, and systemic control and improve survival.

Background: Clinical nodal (cN) staging is a key element in treatment decisions in patients with esophageal cancer (EC). The reliability of cN status regarding the effect on response and survival after neoadjuvant chemoradiotherapy (nCRT) with esophagectomy was evaluated in determining the up- and downstaged pathological nodal (pN) status after surgery alone. Material and methods: From a prospective database, we included all 395 EC patients who had surgery with curative intent with or without nCRT between 2000 and 2015. All patients were staged by a standard pretreatment protocol: 16-64 mdCT, 18 F-FDG-PET or 18 F-FDG-PET/CT and EUS ± FNA. After propensity score matching on baseline clinical tumor and nodal (cT/N) stage and histopathology, a surgery-alone and nCRT group (each N = 135) were formed. Clinical and pathological N stage was scored as equal (cN = pN), downstaged (cN > pN) or upstaged (cN p value Results: The surgery-alone and nCRT group did not differ in cT/N status. Pathologic examination revealed equal staging (32 vs. 27%), nodal up (43 vs. 16%) and downstaging (25 vs. 56%), respectively (p p = .002) and lymph-angioinvasion (p = .016) in surgery-alone, and upper abdominal cN metastases (p = .012) and lymph node ratio (p = .034) in the nCRT group. Conclusions: Despite modern staging methods, correct cN staging remains difficult in EC. Nodal overstaging (cN > pN) occurred more often than understaging impeding an adequate assessment of pathologic complete response and prognosis after nCRT. Preoperative assessment of true nodal response after nCRT in EC remains difficult with clinical nodal upstaging (16% vs. 43%) and downstaging (56% vs. 25%) after nCRT and surgery alone, respectively.

Background: In light of the evolving landscape of adjuvant therapy in melanoma and the recently confirmed absent survival benefit of completion lymph node dissection (CLND), it becomes important to explore possible consequences of omitting CLND, and whether it is possible to adequately stratify positive sentinel node (SN) patients solely based on information retrieved from the melanoma up to the sentinel lymph node biopsy (SLNB).Methods: A retrospective cohort from nine European Organization for Research and Treatment of Cancer Melanoma Group centres was used. Patients were staged based on SLNB and CLND result according to the American Joint Committee on Cancer (AJCC) criteria and stratified by ulceration and SN tumour burden. These were incorporated in Cox regression models. Predictive ability was assessed using Harrell's concordance index (c-index) and the Akaike information criterion (AIC).Results: In total, 1015 patients were eligible. CLND led to upstaging in N-category in 19% and in AJCC stage in 5-6%. The model incorporating only ulceration and SN tumour burden performed equally well as the model incorporating substages after CLND. The model incorporating substages based on SLNB had the lowest predictive ability. Stratifying by ulceration and SN tumour burden resulted in four positive SN groups from which low-, intermediate- and high-risk prognostic classes could be derived.Conclusions: Adequate stratification of positive SN patients was possible based on ulceration and SN tumour burden category. The identification of low-, intermediate- and high-risk patients could guide adjuvant therapy in clinical practice. Omitting CLND seems to have little consequences. (C) 2018 Elsevier Ltd. All rights reserved.