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.

B cells critical for outcome in high grade serous ovarian carcinoma.

Recent work has shown evidence for the prognostic significance of tumor infiltrating B cells (B-TIL) in high grade serous ovarian carcinoma (HGSOC), the predominant histological subtype of ovarian cancer. However, it remains unknown how the favorable prognosis associated with B-TIL relates to the current standard treatments of primary debulking surgery (PDS) followed by chemotherapy or (neo-)adjuvant chemotherapy (NACT) combined with interval debulking surgery. To address this, we analyzed the prognostic impact of B-TIL in relationship to primary treatment and tumor infiltrating T cell status in a highly homogenous cohort of HGSOC patients. This analysis involved a combined approach utilizing histological data and high-dimensional flow cytometry analysis. Our findings indicate that while HGSOC tumors pre-treated with NACT are infiltrated with tumor-reactive CD8+ and CD4+ TIL subsets, only B-TIL and IgA plasma blasts confer prognostic benefit in terms of overall survival. Importantly, the prognostic value of B-TIL and IgA plasma blasts was not restricted to patients treated with NACT, but was also evident in patients treated with PDS. Together, our data point to a critical prognostic role for B-TIL in HGSOC patients independent of T cell status, suggesting that alternative treatment approaches focused on the activation of B cells should be explored for HGSOC.

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. Case Presentation A 64-year-old female patient underwent echocardiography prior to elective knee surgery due to the presence of palpitations and dyspnea. This revealed the existence of a mass located on the left side of the interventricular septum, which was resected successfully. Conclusion Surgical resection represents the primary therapeutic approach for the management of cardiac hemangiomas. Failure to perform timely resection may elevate the risk of developing total atrioventricular block and experiencing sudden death.

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.

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.

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.