Tertiary lymphoid structures critical for prognosis in endometrial cancer patients

B-cells play a key role in cancer suppression, particularly when aggregated in tertiary lymphoid structures (TLS). Here, we investigate the role of B-cells and TLS in endometrial cancer (EC). Single cell RNA-sequencing of B-cells shows presence of naïve B-cells, cycling/germinal center B-cells and antibody-secreting cells. Differential gene expression analysis shows association of TLS with L1CAM overexpression. Immunohistochemistry and co-immunofluorescence show L1CAM expression in mature TLS, independent of L1CAM expression in the tumor. Using L1CAM as a marker, 378 of the 411 molecularly classified ECs from the PORTEC-3 biobank are evaluated, TLS are found in 19%. L1CAM expressing TLS are most common in mismatch-repair deficient (29/127, 23%) and polymerase-epsilon mutant EC (24/47, 51%). Multivariable Cox regression analysis shows strong favorable prognostic impact of TLS, independent of clinicopathological and molecular factors. Our data suggests a pivotal role of TLS in outcome of EC patients, and establishes L1CAM as a simple biomarker

Neoadjuvant immune checkpoint blockade in women with mismatch repair deficient endometrial cancer: a phase I study

Neoadjuvant immune checkpoint blockade (ICB) has shown unprecedented activity in mismatch repair deficient (MMRd) colorectal cancers, but its effectiveness in MMRd endometrial cancer (EC) remains unknown. In this investigator-driven, phase I, feasibility study (NCT04262089), 10 women with MMRd EC of any grade, planned for primary surgery, received two cycles of neoadjuvant pembrolizumab (200 mg IV) every three weeks. A pathologic response (primary objective) was observed in 5/10 patients, with 2 patients showing a major pathologic response. No patient achieved a complete pathologic response. A partial radiologic response (secondary objective) was observed in 3/10 patients, 5/10 patients had stable disease and 2/10 patients were non-evaluable on magnetic resonance imaging. All patients completed treatment without severe toxicity (exploratory objective). At median duration of follow-up of 22.5 months, two non-responders experienced disease recurrence. In-depth analysis of the loco-regional and systemic immune response (predefined exploratory objective) showed that monoclonal T cell expansion significantly correlated with treatment response. Tumour-draining lymph nodes displayed clonal overlap with intra-tumoural T cell expansion. All pre-specified endpoints, efficacy in terms of pathologic response as primary endpoint, radiologic response as secondary outcome and safety and tolerability as exploratory endpoint, were reached. Neoadjuvant ICB with pembrolizumab proved safe and induced pathologic, radiologic, and immunologic responses in MMRd EC, warranting further exploration of extended neoadjuvant treatment

Tertiary lymphoid structures critical for prognosis in endometrial cancer patients

B-cells play a key role in cancer suppression, particularly when aggregated in tertiary lymphoid structures (TLS). Here, we investigate the role of B-cells and TLS in endometrial cancer (EC). Single cell RNA-sequencing of B-cells shows presence of naive B-cells, cycling/germinal center B-cells and antibody-secreting cells. Differential gene expression analysis shows association of TLS with L1CAM overexpression. Immunohistochemistry and co-immunofluorescence show L1CAM expression in mature TLS, independent of L1CAM expression in the tumor. Using L1CAM as a marker, 378 of the 411 molecularly classified ECs from the PORTEC-3 biobank are evaluated, TLS are found in 19%. L1CAM expressing TLS are most common in mismatch-repair deficient (29/127, 23%) and polymerase-epsilon mutant EC (24/47, 51%). Multivariable Cox regression analysis shows strong favorable prognostic impact of TLS, independent of clinicopathological and molecular factors. Our data suggests a pivotal role of TLS in outcome of EC patients, and establishes L1CAM as a simple biomarker.Tertiary lymphoid structures (TLS) are associated with a reduced risk of cancer recurrence and improved response to immune checkpoint blockade in several tumor types. Here the authors identify L1CAM as a marker for mature TLS and show that the presence of TLS is associated with favorable prognosis in patients with endometrial cancer from the PORTEC-3 trial.Biological, physical and clinical aspects of cancer treatment with ionising radiatio

Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy

Cystatin C (CyC), a secreted cysteine protease inhibitor, has unclear biological functions. Many patients exhibit elevated plasma CyC levels, particularly during glucocorticoid (GC) treatment. This study links GCs with CyC’s systemic regulation by utilizing genome-wide association and structural equation modeling to determine CyC production genetics in the UK Biobank. Both CyC production and a polygenic score (PGS) capturing predisposition to CyC production were associated with increased all-cause and cancer-specific mortality. We found that the GC receptor directly targets CyC, leading to GC-responsive CyC secretion in macrophages and cancer cells. CyC-knockout tumors displayed significantly reduced growth and diminished recruitment of TREM2+ macrophages, which have been connected to cancer immunotherapy failure. Furthermore, the CyC-production PGS predicted checkpoint immunotherapy failure in 685 patients with metastatic cancer from combined clinical trial cohorts. In conclusion, CyC may act as a GC effector pathway via TREM2+ macrophage recruitment and may be a potential target for combination cancer immunotherapy.publishedVersio

Impact of Residency Training Level on the Surgical Quality Following General Surgery Procedures

OBJECTIVE To investigate the safety of surgical performance by residents of different training level performing common general surgical procedures. METHODS Data were consecutively collected from all patients undergoing general surgical procedures such as laparoscopic cholecystectomy, laparoscopic appendectomy, inguinal, femoral and umbilical hernia repair from 2005 to 2011 at the Department of Surgery of the University Hospital of Zurich, Switzerland. The operating surgeons were grouped into junior residents, senior residents and consultants. The comprehensive complication index (CCI) representing the overall number and severity of all postoperative complications served as primary safety endpoint. A multivariable linear regression analysis was used to analyze differences between groups. Additionally, we focused on the impact of senior residents assisting junior residents on postoperative outcome comparing to consultants. RESULTS During the observed time, 2715 patients underwent a general surgical procedure. In 1114 times, a senior resident operated and in 669 procedures junior residents performed the surgery. The overall postoperative morbidity quantified by the CCI was for consultants 5.0 (SD 10.7), for senior residents 3.5 (8.2) and for junior residents 3.6 (8.3). After adjusting for possible confounders, no difference between groups concerning the postoperative complications was detected. There is also no difference in postoperative complications detectable if junior residents were assisted by consultants then if assisted by senior residents. DISCUSSION Patient safety is ensured in general surgery when performed by surgical junior residents. Senior residents are able to adopt the role of the teaching surgeon in charge without compromising patients' safety

Cardiac Hemangioma in the Left Ventricular Septum

Background Primary cardiac tumors are an exceedingly rare benign group of tumors that may remain asymptomatic for a prolonged duration or could lead to significant clinical events

Tertiary lymphoid structures critical for prognosis in endometrial cancer patients

B-cells play a key role in cancer suppression, particularly when aggregated in tertiary lymphoid structures (TLS). Here, we investigate the role of B-cells and TLS in endometrial cancer (EC). Single cell RNA-sequencing of B-cells shows presence of naive B-cells, cycling/germinal center B-cells and antibody-secreting cells. Differential gene expression analysis shows association of TLS with L1CAM overexpression. Immunohistochemistry and co-immunofluorescence show L1CAM expression in mature TLS, independent of L1CAM expression in the tumor. Using L1CAM as a marker, 378 of the 411 molecularly classified ECs from the PORTEC-3 biobank are evaluated, TLS are found in 19%. L1CAM expressing TLS are most common in mismatch-repair deficient (29/127, 23%) and polymerase-epsilon mutant EC (24/47, 51%). Multivariable Cox regression analysis shows strong favorable prognostic impact of TLS, independent of clinicopathological and molecular factors. Our data suggests a pivotal role of TLS in outcome of EC patients, and establishes L1CAM as a simple biomarker. Tertiary lymphoid structures (TLS) are associated with a reduced risk of cancer recurrence and improved response to immune checkpoint blockade in several tumor types. Here the authors identify L1CAM as a marker for mature TLS and show that the presence of TLS is associated with favorable prognosis in patients with endometrial cancer from the PORTEC-3 trial

Cystatin C is glucocorticoid-responsive, directs recruitment of Trem2+ macrophages and predicts failure of cancer immunotherapy

Cystatin C (CyC) is a secreted cysteine protease inhibitor and its biological functions remain insufficiently characterized. Plasma CyC is elevated in many patients, especially when receiving glucocorticoid (GC) treatment. Endogenous GCs are essential for life and are appropriately upregulated in response to systemic stress. Here we empirically connect GCs with systemic regulation of CyC. We used genome-wide association and structural equation modeling to determine the genetics of the latent trait CyC production in UK Biobank. CyC production and a polygenic score (PGS) capturing germline predisposition to CyC production predicted elevated all-cause and cancer-specific mortality. We then demonstrated that CyC is a direct target of GC receptor, with GC-responsive CyC secretion exhibited by macrophages and cancer cells. Using isogenic CyC-knockout tumors, we discovered a markedly attenuated tumor growth in vivo and found abrogated recruitment of Trem2+ macrophages, which have been previously linked to failure of cancer immunotherapy. Finally, we showed that the CyC-production PGS predicted checkpoint immunotherapy failure in a combined clinical trial cohort of 685 metastatic cancer patients. Taken together, our results demonstrate that CyC may be a direct effector of GC-induced immunosuppression, acting through recruitment of Trem2+ macrophages, and therefore could be a target for combination cancer immunotherapy