Explore the vast range of titles available.

The drivers and the specification of CD4 + T cell differentiation in the tumor microenvironment and their contributions to tumor immunity or tolerance are incompletely understood. Using models of pancreatic ductal adenocarcinoma (PDA), we show that a distinct subset of tumor-infiltrating dendritic cells (DC) promotes PDA growth by directing a unique T H -program. Specifically, CD11b + CD103 − DC predominate in PDA, express high IL-23 and TGF-β, and induce FoxP3 neg tumor-promoting IL-10 + IL-17 + IFNγ +  regulatory CD4 + T cells. The balance between this distinctive T H program and canonical FoxP3 +  T REGS is unaffected by pattern recognition receptor ligation and is modulated by DC expression of retinoic acid. This T H -signature is mimicked in human PDA where it is associated with immune-tolerance and diminished patient survival. Our data suggest that CD11b + CD103 − DC promote CD4 + T cell tolerance in PDA which may underscore its resistance to immunotherapy. Pancreatic ductal adenocarcinoma is characterized by a highly immunosuppressive tumour microenvironment. Here, the authors show that specialized subsets of tumour-infiltrating dendritic cells induce distinct CD4 + T cell programs and specifically identify a CD103 – CD11b + subset which induces tumor-promoting FoxP3 – Type-1 regulatory T cells.

BackgroundThis study aimed to identify the results of the quality assessment and the learning curve of robot-assisted minimally invasive McKeown esophagectomy (RAMIE-MK).MethodsThe study retrospectively reviewed the data of 400 consecutive patients with esophageal cancer who underwent RAMIE-MK by a single surgeon from November 2015 to March 2019. Cumulative summation analysis of the learning curve was performed. The patients were divided into decile cohorts of 40 cases to minimize demographic deviations and to maximize the power of detecting statistically significant changes in performance.ResultsThe 90-day mortality rate for all the patients was 0.5% (2 cases). The authors’ experience was divided into the ascending phase (40 cases), the plateau phase (175 cases), and the descending phase (185 cases). After 40 cases, significant improvements in operative time (328 vs. 251 min; P = 0.019), estimated blood loss (350 vs. 200 ml; P = 0.031), and conversion rates (12.5% vs. 2.5%; P < 0.001) were observed. After 80 cases, a decrease in the rates of anastomotic leakage (22.5% vs. 8.1%; P = 0.001) and vocal cord palsy (31.3% vs. 18.4%; P = 0.024) was observed. The number of harvested lymph nodes increased after 40 cases (13 vs. 23; P < 0.001), especially for lymph nodes along the recurrent laryngeal nerve (3.0 vs. 6.0; P < 0.001).ConclusionsThe learning phase of RAMIE-MK consists of 40 cases, and quality outcomes can be improved after 80 procedures. Several turning points related to the optimization of surgical outcomes can be used as benchmarks for surgeons performing RAMIE-MK.

While next-generation sequencing (NGS) is used to guide therapy in patients with metastatic lung adenocarcinoma (LUAD), use of NGS to determine pathologic LN metastasis prior to surgery has not been assessed. To bridge this knowledge gap, we performed NGS using MSK-IMPACT in 426 treatment-naive patients with clinical N2-negative LUAD. A multivariable logistic regression model that considered preoperative clinical and genomic variables was constructed. Most patients had cN0 disease (85%) with pN0, pN1, and pN2 rates of 80%, 11%, and 9%, respectively. Genes altered at higher rates in pN-positive than in pN-negative tumors were STK11 ( p  = 0.024), SMARCA4 ( p  = 0.006), and SMAD4 ( p  = 0.011). Fraction of genome altered ( p  = 0.037), copy number amplifications ( p  = 0.001), and whole-genome doubling ( p  = 0.028) were higher in pN-positive tumors. Multivariable analysis revealed solid tumor morphology, tumor SUVmax, clinical stage, SMARCA4 and SMAD4 alterations were independently associated with pathologic LN metastasis. Incorporation of clinical and tumor genomic features can identify patients at risk of pathologic LN metastasis; this may guide therapy decisions before surgical resection.

Macrophages are cells of the innate immune system involved in critical activities such as maintaining tissue homeostasis and immune surveillance. Pro-inflammatory macrophages M1 are responsible for the inflammatory response, while M2 macrophages are associated with the immunosuppressive repair phase of tissue remodeling. Most cancers are associated with chronic inflammation, and a high number of macrophages in tumors have been associated with tumor progression. Much effort has been made in elucidating the mechanisms through which macrophages contribute to tumor development, yet much less is known about the initial mechanisms by which tumors modify macrophages. Our work has focused on identifying the mechanisms by which macrophages from tumor hosts are modified by tumors. We have shown that peritoneal macrophages are significantly altered in mice bearing advanced mammary tumors and are not M1 or M2 polarized, but express a mixture of both transcriptional programs. These macrophages are less differentiated and more prone to apoptosis, resulting in increased myelopoiesis as a compensation to regenerate macrophage progenitors in the marrow. Macrophages in the tumor microenvironment are also neither M1 nor M2 cells and through a display of different mechanisms are even more impaired than their peripheral counterparts. Finally, systemic blood monocytes, precursors of tissue macrophages, are also altered in tumor bearers and show a mixed program of pro- and anti-inflammatory functions. We conclude that there is evidence for local and systemic immune impairment in tumor hosts.

The drivers and the specification of CD4 T cell differentiation in the tumor microenvironment and their contributions to tumor immunity or tolerance are incompletely understood. Using models of pancreatic ductal adenocarcinoma (PDA), we show that a distinct subset of tumor-infiltrating dendritic cells (DC) promotes PDA growth by directing a unique T -program. Specifically, CD11b CD103 DC predominate in PDA, express high IL-23 and TGF-β, and induce FoxP3 tumor-promoting IL-10 IL-17 IFNγ regulatory CD4 T cells. The balance between this distinctive T program and canonical FoxP3 T is unaffected by pattern recognition receptor ligation and is modulated by DC expression of retinoic acid. This T -signature is mimicked in human PDA where it is associated with immune-tolerance and diminished patient survival. Our data suggest that CD11b CD103 DC promote CD4 T cell tolerance in PDA which may underscore its resistance to immunotherapy.

IntroductionDouble lumen tube (DLT) intubation is used for lung isolation but is not without disadvantages including increased intubation time, anesthesia expertise, risk of airway trauma, and costs over single lumen tube (SLT) intubation. SLT intubation with CO2 insufflation can be used as an alternative for lung isolation. We reviewed our experience with this technique during thoracoscopic surgery.MethodsWe performed a retrospective review of a prospectively maintained IRB-approved database from 2009 to 2018. Operations were performed with CO2 insufflation up to 15 mmHg. Indications for surgery, operative details, intraoperative complications, pathology, and postoperative complications were reviewed.ResultsWe identified 123 patients (70 females [57%]) with a median age of 40 years (range 16–80 years) and a median BMI of 26.2 kg/m2 (range 15–59 kg/m2) that underwent minimally invasive thoracoscopic procedures with this technique. Procedures included: mediastinal mass resection or biopsy (41%), sympathectomy (37%), wedge resection (10%), first rib resection (6%), diaphragm plication (2%), segmentectomy (2%), decortication (2%), pleural biopsy (2%), and pericardial cyst resection (1%). Median operative time was 90 min (range 25–584 min) and median intraoperative blood loss was 10 mL (range 2–200 mL). Intraoperative hemodynamic parameters were obtained at procedure start, 1 h after CO2 insufflation, and at procedure completion: we observed significant changes in heart rate and systolic blood pressure (P = 0.027 and P < 0.001, respectively) although clinically inconsequential. Mean end-tidal CO2 1 h after insufflation was 36.6 ± 4.5 mmHg. There were no intraoperative complications and no conversions to a DLT. Median length of stay was 1 day (range 0–14 days). Five complications (4%) were observed and no mortalities.ConclusionsSLT intubation and CO2 insufflation is a feasible and safe alternative to DLT intubation for lung isolation. This can be a useful strategy to accomplish lung isolation for some thoracoscopic procedures, in particular when expertise for DLT placement is unavailable.

Stage IV non-small cell lung cancer (NSCLC) accounts for 35 to 40% of newly diagnosed cases of NSCLC. The oligometastatic state—≤5 extrathoracic metastatic lesions in ≤3 organs—is present in ~25% of patients with stage IV disease and is associated with markedly improved outcomes. We retrospectively identified patients with extrathoracic oligometastatic NSCLC who underwent primary tumor resection at our institution from 2000 to 2018. Event-free survival (EFS) and overall survival (OS) were estimated using the Kaplan–Meier method. Factors associated with EFS and OS were determined using Cox regression. In total, 111 patients with oligometastatic NSCLC underwent primary tumor resection; 87 (78%) had a single metastatic lesion. Local consolidative therapy for metastases was performed in 93 patients (84%). Seventy-seven patients experienced recurrence or progression. The five-year EFS was 19% (95% confidence interval (CI), 12–29%), and the five-year OS was 36% (95% CI, 27–50%). Factors independently associated with EFS were primary tumor size (hazard ratio (HR), 1.15 (95% CI, 1.03–1.29); p = 0.014) and lymphovascular invasion (HR, 1.73 (95% CI, 1.06–2.84); p = 0.029). Factors independently associated with OS were neoadjuvant therapy (HR, 0.43 (95% CI, 0.24–0.77); p = 0.004), primary tumor size (HR, 1.18 (95% CI, 1.02–1.35); p = 0.023), pathologic nodal disease (HR, 1.83 (95% CI, 1.05–3.20); p = 0.033), and visceral-pleural invasion (HR, 1.93 (95% CI, 1.10–3.40); p = 0.022). Primary tumor resection represents an important treatment option in the multimodal management of extrathoracic oligometastatic NSCLC. Encouraging long-term survival can be achieved in carefully selected patients, including those who received neoadjuvant therapy and those with limited intrathoracic disease.

During the last two decades, next-generation sequencing (NGS) has played a key role in enhancing non-small cell lung cancer treatment paradigms through the application of “targeted therapy” in advanced and metastatic disease. The use of specific tyrosine kinase inhibitors in patients with oncogenic driver alterations, such as EGFR, ALK, ROS1, BRAF V600E, MET, and NTRK mutations, among others, has changed treatment approaches and improved outcomes in patients with late-stage disease. Although NGS technology has mostly been used in the setting of systemic therapy to identify targets, response to therapy, and mechanisms of resistance, it has multiple potential applications for patients with earlier-stage disease, as well. In this review, we discuss the emerging role of NGS technologies to better understand tumor biology in patients with non-small cell lung cancer who are undergoing surgery with curative intent. In this patient cohort, we examine tumor heterogeneity, the underlying tumor genomics associated with lung adenocarcinoma subtypes, the prediction of recurrence after complete surgical resection, the use of plasma circulating tumor DNA for detection of early cancers and monitoring for minimal residual disease, the differentiation of separate primaries from intrapulmonary metastases, and the use of NGS to guide induction and adjuvant therapies.

Thermal injury is associated with an increased risk of abdominal complications such as ischemia, infarction and pneumatosis intestinalis (PI). PI is characterized by gas in the intestinal wall and, when diagnosed it can signify the presence of a life-threatening condition. We present a case of a patient who survived 75% total body surface area burns complicated by ischemic bowel that initially presented as extensive PI. This patient was emergently taken to the operating room and underwent a subtotal colectomy and small bowel resection for ischemic bowel. Prompt diagnosis and successful management of the underlying condition ultimately contributed to the patient's survival. The presence of peritonitis or abdominal distension, portomesenteric venous gas and lactic acidosis should prompt immediate surgical intervention in the post-burn period.

Measures to facilitate this goal include: the establishment of a framework to monitor and assess the burden of stroke (and its risk factors) and stroke services at a national level; the implementation of integrated population-level and individual-level prevention strategies for people at any increased risk of cerebrovascular disease, with emphasis on early detection and control of hypertension; planning and delivery of acute stroke care services, including the establishment of stroke units with access to reperfusion therapies for ischaemic stroke and workforce training and capacity building (and monitoring of quality indicators for these services nationally, regionally, and globally); the promotion of interdisciplinary stroke care services, training for caregivers, and capacity building for community health workers and other health-care providers working in stroke rehabilitation; and the creation of a stroke advocacy and implementation ecosystem that includes all relevant communities, organisations, and stakeholders. Introduction The global burden of stroke is huge: in 2020, stroke was the second leading cause of death (6·6 million deaths) and the third leading cause of disability (responsible for 143 million disability-adjusted life-years [DALYs]) after neonatal disorders (in children) and ischaemic heart disease (in adults).1,2 Alarmingly, evidence suggests that the incidence of stroke in younger individuals (ie, people younger than 55 years) is increasing worldwide.3 The absolute number of people affected by stroke, which includes those who die or remain disabled, has almost doubled in the past 30 years.1 Most of the contemporary stroke burden—86% of global deaths and 89% of global DALYs lost because of stroke in 2020—is in low-income and middle-income countries (LMICs),1 and the burden of stroke is increasing faster in LMICs than in high-income countries (HICs).1 Stroke is also a leading cause of depression and dementia, which are other common non-communicable diseases (NCDs).4,5 Little progress has been made by most countries towards Sustainable Development Goal (SDG) 3.4—reducing premature mortality from NCDs by a third between 2015 and 2030.6 Achieving SDG 3.4 worldwide, which would in turn facilitate the achievement of nine other SDGs,7 would require an additional US$140 billion of spending on NCD interventions from 2023–30, but could help to avert 39 million deaths and generate $2·7 trillion in net economic benefits (with benefits outweighing costs by a factor of 19:1).6 Given that the incidence of stroke rises with age, the combination of growing populations and ageing demographics is likely to result in large increases in global deaths and disability in the future unless major improvements occur in population prevention programmes that reduce the risk of stroke.8 Thus, pragmatic solutions to reduce the burden of stroke and related NCDs are urgently needed to save lives and improve brain health, quality of life, and socioeconomic productivity globally.8–11 Key messages Multiple factors contribute to the high burden of stroke in low-income and middle-income countries, including undetected and uncontrolled hypertension, lack of easily accessible, high-quality health services, insufficient attention to and investment in prevention, air pollution, population growth, unhealthy lifestyles (eg, poor diet, smoking, sedentary lifestyle, obesity), an earlier age of stroke onset and greater proportion of haemorrhagic strokes than in high-income countries, and the burden of infectious diseases resulting in competition for limited healthcare resources. Major facilitators include professional stroke organisations and networks that could advocate and build capacity for stroke care and research, and universal health coverage that can facilitate population-wide access to evidence-based care (pre-hospital care, acute care, rehabilitation, and prevention).