Cancer recurrence after surgery remains an unresolved clinical problem
. Myeloid cells derived from bone marrow contribute to the formation of the premetastatic microenvironment, which is required ...for disseminating tumour cells to engraft distant sites
. There are currently no effective interventions that prevent the formation of the premetastatic microenvironment
. Here we show that, after surgical removal of primary lung, breast and oesophageal cancers, low-dose adjuvant epigenetic therapy disrupts the premetastatic microenvironment and inhibits both the formation and growth of lung metastases through its selective effect on myeloid-derived suppressor cells (MDSCs). In mouse models of pulmonary metastases, MDSCs are key factors in the formation of the premetastatic microenvironment after resection of primary tumours. Adjuvant epigenetic therapy that uses low-dose DNA methyltransferase and histone deacetylase inhibitors, 5-azacytidine and entinostat, disrupts the premetastatic niche by inhibiting the trafficking of MDSCs through the downregulation of CCR2 and CXCR2, and by promoting MDSC differentiation into a more-interstitial macrophage-like phenotype. A decreased accumulation of MDSCs in the premetastatic lung produces longer periods of disease-free survival and increased overall survival, compared with chemotherapy. Our data demonstrate that, even after removal of the primary tumour, MDSCs contribute to the development of premetastatic niches and settlement of residual tumour cells. A combination of low-dose adjuvant epigenetic modifiers that disrupts this premetastatic microenvironment and inhibits metastases may permit an adjuvant approach to cancer therapy.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Patients with non–small-cell lung cancer were randomly assigned to three cycles of chemotherapy with or without nivolumab, an anti–PD-1 antibody. Event-free survival was longer with nivolumab than ...without it (31.6 months vs. 20.8 months), and the percentage of patients with a pathological complete response was 24.0% and 2.2%, respectively.
We conducted a phase I trial of neoadjuvant nivolumab, a monoclonal antibody to the programmed cell death protein 1 checkpoint receptor, in patients with resectable non–small cell lung cancer. We ...analyzed perioperative outcomes to assess the safety of this strategy.
Patients with untreated stage I-IIIA non–small cell lung cancer underwent neoadjuvant therapy with 2 cycles of nivolumab (3 mg/kg), 4 and 2 weeks before resection. Patients underwent invasive mediastinal staging as indicated and post-treatment computed tomography. Primary study end points were safety and feasibility of neoadjuvant nivolumab followed by pulmonary resection. Data on additional surgical details were collected through chart review.
Of 22 patients enrolled, 20 underwent resection. One was unresectable; another had small cell histologic subtype. There were no delays to surgical resection. Median time from first treatment to surgery was 33 (range, 17-43) days. There were 15 lobectomies, 2 pneumonectomies, 1 bilobectomy, 1 sleeve lobectomy, and 1 wedge resection. Of 13 procedures attempted via a video-assisted thoracoscopic surgery or robotic approach, 7 (54%) required thoracotomy. Median operative time was 228 (range, 132-312) minutes; estimated blood loss was 100 (range, 25-1000) mL; length of hospital stay was 4 (range, 2-17) days. There was no operative mortality. Morbidity occurred in 10 of 20 patients (50%). The most common postoperative complication was atrial arrhythmia (6/20; 30%). Major pathologic response was identified in 9 of 20 patients (45%).
Neoadjuvant therapy with nivolumab was not associated with unexpected perioperative morbidity or mortality. More than half of the video-assisted thoracoscopic surgery/robotic cases were converted to thoracotomy, often because of hilar inflammation and fibrosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective To study causes and implications of intraoperative conversion to thoracotomy during video-assisted thoracoscopic surgery (VATS) lobectomy. Methods We performed an institutional review of ...patients undergoing lobectomy for known or suspected lung cancer with root cause analysis of every conversion from VATS to open thoracotomy. Results Between 2004 and 2012, 1227 patients underwent lobectomy. Of these, 517 procedures (42%) were completed via VATS, 87 procedures (7%) were converted to open procedures, and 623 procedures (51%) were performed via planned thoracotomy. Patients undergoing thoracotomy were younger and had a higher incidence of prior lung cancers. Planned thoracotomy and conversion group patients had higher clinical T stage than patients in the VATS group, whereas the planned thoracotomy group had higher pathologic stage than patients in the other groups. Postoperative complications were more frequent in patients in the conversion group (46%) than in the VATS group (23%; P < .001), but similar to the open group (42%; P = .56). Validating a previous classification of causes for conversion, 22 out of 87 conversions (25%) were due to vascular causes, 56 conversions (64%) were for anatomy (eg, adhesions or tumor size), and 8 conversions (9%) were the result of lymph nodes. No specific imaging variables predicted conversion. Within the conversion groups, emergent (20 out of 87; 23%) and planned (67 out of 87; 77%) conversion groups were similar in patient and tumor characteristics and incidence of perioperative morbidity. The conversion rate for VATS lobectomy dropped from 21 out of 74 (28%), to 29 out of 194 (15%), to 37 out of 336 (11%) ( P < .001) over 3-year intervals. Over the same periods, the proportion of operations started via VATS increased significantly. Conclusions With increasing experience, a higher proportion of lobectomy operations can be completed thoracoscopically. VATS should be strongly considered as the initial approach for the majority of patients undergoing lobectomy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The extraordinary demands of managing the COVID-19 pandemic has disrupted the world’s ability to care for patients with thoracic malignancies. As a hospital’s COVID-19 population increases and ...hospital resources are depleted, the ability to provide surgical care is progressively restricted, forcing surgeons to prioritize among their cancer populations. Representatives from multiple cancer, surgical, and research organizations have come together to provide a guide for triaging patients with thoracic malignancies as the impact of COVID-19 evolves as each hospital.
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