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MDSCs in breast cancer tissues

Relationship between MDSCs and breast cancer stemness

Myeloid-derived suppressor cells (MDSC) contribute to immune suppression in cancer, but the mechanisms through which they drive metastatic progression are not fully understood. In this study, we show how MDSC convey stem-like qualities to breast cancer cells that coordinately help enable immune suppression and escape. We found that MDSC promoted tumor formation by enhancing breast cancer cell stem-like properties as well as by suppressing T-cell activation. Mechanistic investigations indicated that these effects relied upon cross-talk between the STAT3 and NOTCH pathways in cancer cells, with MDSC inducing IL6-dependent phosphorylation of STAT3 and activating NOTCH through nitric oxide leading to prolonged STAT3 activation. In clinical specimens of breast cancer, the presence of MDSC correlated with the presence of cancer stem-like cells (CSC) and independently predicted poor survival outcomes. Collectively, our work revealed an immune-associated mechanism that extrinsically confers cancer cell stemness properties and affects patient outcome. We suggest that targeting STAT3-NOTCH cross-talk between MDSC and CSC could offer a unique locus to improve cancer treatment, by coordinately targeting a coupled mechanism that enables cancer stemness and immune escape. Cancer Res; 76(11); 3156–65. ©2016 AACR.

Correlations between CD33, ALDH1A1 and IL6 transcripts in patients with breast cancer

MDSC phenotype and suppressor activity

Supplementary tables: Supplementary Table 1. Patient characteristics (All 3 cohorts) Supplementary Table 2. shRNA Sequences and Real-time PCR primers Supplementary Table 3. Multivariate analysis of overall survival (All 3 cohorts) Supplementary Table 4. Multivariate analysis of overall survival (Cohort 1, HER2+ patients) Supplementary Table 5. Multivariate analysis of overall survival (Cohorts 2 and 3, random patients)

Supplementary Figure 1 MDSC phenotype and suppressor activity Supplementary Figure 2 MDSCs in breast cancer tissues Supplementary Figure 3 Relationship between MDSCs and breast cancer stemness Supplementary Figure 4 MDSCs produce NO and IL-6 and induce tumor STAT3 phosphorylation Supplementary Figure 5 Correlations between CD33, ALDH1A1 and IL6 transcripts in patients with breast cancer

The standard method for nodal staging in breast cancer (BC) patients after neoadjuvant chemotherapy (NAC) is sentinel lymph node biopsy (SLNB) with a radioisotope (RI) injection. However, SLNB after NAC results in high false-negative rates (FNR), and the RI method is restricted by nuclear medicine unit dependency. These limitations resulted in the development of the superparamagnetic iron oxide (SPIO) method, reducing FNR and presenting a comparable detection rate. This bi-institutional cohort comparison study aimed to assess the efficacy of SPIO and radioisotope SNLB in BC patients after NAC using Propensity Score Matching (PSM) analysis. The study group comprised 508 patients who underwent SLNB after NAC for ycT1-4N0M0 BC between 2013 and 2021 in two high volume centers. Data were retrieved from prospectively conducted databases. In the SPIO group, the median of retrieved sentinel lymph nodes (SLNs) was significantly higher than in the RI group (3 vs. 2; p < 0.0001). The SPIO method was associated with a significantly higher chance of retrieving at least three lymph nodes when compared to the RI method (71% vs. 11.3%; p < 0.0001). None of the analyzed demographic and clinical variables had a statistically significant influence on the efficacy of SLNs retrieval in the RI group, while in the SPIO group, patients with ≥three harvested SLNs had lower weight and decreased BMI. Based on this PSM analysis, SPIO-guided SLNB allowed the efficient retrieval and detection of SLNs in BC patients after NAC compared to RI.

Sentinel lymph node biopsy (SLNB) is a well-established procedure for staging clinically node-negative early breast cancer (BC). Superparamagnetic iron oxide (SPIO) demonstrated efficacy for nodal identification using a magnetic probe after local retroaeroal interstitial injection. Its benefits lie in its flexibility, which is an essential property in the global setting, where access to the isotope is difficult. To the best of our knowledge, this is the first study to evaluate the feasibility and safety of the SPIO for SLNB in BC patients treated with neoadjuvant chemotherapy (NAC). Seventy-four female patients were included. The median time of lymph node retrieval was 20 min. The median number of resected sentinel nodes (SNs) was 4. SN was detected in all patients. No serious adverse event was observed. SPIO in identifying SN in BC patients after NAC is feasible and oncologically safe.

The Epstein-Barr virus (EBV) may directly cause the development of EBV-associated gastric cancer (EBVaGC). The prevalence of EBVaGC ranges from 4% to 18%, with a 2-fold higher frequency in males, and in tumors arising in the gastric cardia or corpus and 4 times higher frequency in gastric stump carcinoma. The vast majority of EBVaGC are lymphoepithelioma-like carcinomas. Despite extensive nodal involvement and distant metastases at initial diagnosis, EBVaGC seems to be a distinct etiologic entity with a favorable prognosis. However, the lymphoepithelioma-like carcinomas subtype in EBVaGC cannot be recognized in the current molecular classifications. Neither is there an association between EBV positivity and survival of patients after curative gastrectomy if they received standard adjuvant chemotherapy, nor EBV positivity and prediction of response to neoadjuvant platinum/5-FU-based chemotherapy. Alterations in chemokines and PD-L1 provide theoretical justification for clinical evaluation of immune checkpoint therapy in EBVaGC. Moreover, a higher degree of host immune response was demonstrated in EBVaGC. The current histologic and molecular GC classification does not influence clinical practice. Further research is expected to find convenient methods to assess gastric subtypes in day-to-day practice and to tailor therapy to improve overall survival.

Background. The erector spinae plane (ESP) block has recently been shown to effectively alleviate postoperative pain and reduce opioid consumption in breast surgery patients. However, data are still limited concerning the quality of recovery in patients following this procedure.Methods. This study was a randomized controlled trial (RCT) performed in a university hospital. We randomly allocated patients to one of three groups: ESP, SHAM, and control (CON). Procedures in the ESP and SHAM blocks were performed ipsilaterally with 0.375% ropivacaine or 0.9% saline (0.4 mL/kg). Our primary outcome was the assessment of the patient’s improvement with quality-of-recovery 40 (QoR-40) a day after surgery. Other outcome assessments included postoperative pain evaluation on the visual analog scale (VAS), 24-hour opioid consumption with patient-controlled analgesia (PCA), time to the first opioid demand, and global satisfaction with perioperative treatment. Results. Overall, patients in the ESP group had improved QoR-40 compared to the CON group, 186 [177–193] vs. 175 [165–183] (medians and interquartile ranges). Pain severity was significantly higher in the CON group compared to the ESP group at hours 2 (38 [23–53] vs. 20 [7–32]) and 4 (30 [18–51] vs. 19 [7–25]). Moreover, we observed lower oxycodone consumption after 24 hours with the PCA pump between the ESP (4 [2–8] mg) and the CON (9.5 [5–19]) groups. Patients in the CON group used PCA sooner than those in the ESP group. Participants in the ESP group were more satisfied with treatment than those in the CON group. We found no statistical difference between SHAM and the other groups. Conclusions. Compared to the CON group, the ESP block improved the quality of recovery, alleviated pain intensity, and lowered opioid consumption in patients undergoing breast surgery. However, we did not observe this superiority in comparison with the SHAM group. Trial registration: NCT04726878

Surgical quality assurance is a key element of gastric cancer treatment. The Maruyama Computer Program (MCP) allows to predict lymph node involvement in stations no. 1-16. The aim of the current study was to evaluate the accuracy of the MCP predictions in GC patients treated with neoadjuvant chemotherapy (nCTH) followed by gastrectomy with adequate lymphadenectomy.101 patients who underwent preoperative nCTH followed by D2 gastrectomy with curative intent were analysed. The response to nCTH was measured using the tumour regression grade system.Test sensitivity, specificity, PPV, NPV and accuracy of the MCP were 92%, 33%, 41%, 89%, and 53%, respectively. In patients with response to nCTH, number of false positive (FP) results was significantly higher than in patients who did not respond to nCTH both in the N1 (56.3% vs 28.9%, p 0.0001) and in the N2 (59% vs 41%, p 0.0001) trier. The risk for FP results was 6 times higher in N1 (OR = 6.50, 95%CI: 3.91-10.82,; p 0.0001) and N2 (OR = 5.84, 95%CI: 2.85-11.96; p 0.0001) triers. In patients with intestinal type GC, the risk for FP results was 4 times higher than in other histologic types of GC in both N1 (OR = 4.23, 95%CI: 2.58-6.95; p 0.0001) and N2 (OR = 4.23, 95%CI: 2.02-9.62; p = 0.0002) triers.MCP predictions in the GC patients treated with nCTH have low specificity due to significantly high number of FP results. Noticeably low accuracy level of predictions indicate a need for new prediction models, based on Laurén classification, since it may provide some information on expected regression grade.

Background: Proximal gastric resection (PGR) is rarely used in western countries because of frequent postoperative reflux and uncommon diagnosis of early gastric cancer (GC). Objectives: We hypothesized that the PGR with an anti-reflux procedure may be an attractive option even in advanced proximal GC after downstaging with the neo-adjuvant chemotherapy. Method: A novel technique of end-to-side esophago-gastrostomy with the posterior wall of the gastric stump and partial neo-fundoplication to prevent reflux symptoms has been introduced. An observational retrospective study was undertaken to evaluate early and late outcomes of the innovative technique in patients with advanced proximal GC after neoadjuvant chemotherapy. Results: Twenty consecutive patients with the diagnosis of loco-regionally advanced GC, localized in the subcardiac region or proximal upper third of the stomach, were selected for the study. Eleven (55%) patients completed preoperative neo-adjuvant chemotherapy. The mean postoperative hospitalization time was 13.3 (± 8.3) days. There was one postoperative in-hospital death due to acute circulatory insufficiency. The mean comprehensive complication index was 11.94 (±24.82). Two patients were diagnosed with a complete pathological response (ypT0N0). Median survival was 41.8 (95% CI 27.9–41.8) months. The 5-year survival rate was 42%. At a median follow-up of 26 months, reflux symptoms were present in 7 (35%) patients who had to use antireflux medication. Anastomotic stenosis was observed in 1 patient during the follow-up. Mean scores of reflux symptoms on medication were not significantly different to those in patients without medication. The Overall Satisfaction Score for patients on medication was 7.57 ± 1.92, whereas it was 8.83 ± 1.34 (p = 0.2; Student t test) for those with no medication. Conclusions: Proximal gastrectomy is feasible and may be safely used in patients with advanced GC after neo-adjuvant chemotherapy with acceptable survival. Posterior esophago-gastrostomy with partial neo-fundoplication reduces the postoperative reflux, while patients with persistent reflux symptoms can be effectively treated with an antireflux therapy.

In some breast cancer (BC) patients, an examination of lymph nodes dissected during sentinel lymph node biopsy (SLNB) demonstrates a presence of metastatic lesions and extracapsular extension (ECE) in a SLN. This study aimed to evaluate clinical relevance of ECE in BC patients. This is a retrospective analysis of 891 patients with cancer metastases to SLN, referred to supplementary axillary lymph node dissection (ALND), hospitalized between Jan 2007 and Dec 2017. Clinical and epidemiological data was evaluated. Long-term treatment outcomes were analysed. In 433 (48.6%) patients, cancer metastases were limited to the SLN (group I), in 61 (6.8%) patients the SLN capsule was exceeded focally (≤ 1 mm—group II). In 397 (44.6%) patients, a more extensive ECE was found (> 1 mm—group III). Metastases to non-sentinel lymph nodes (nSLNs) were diagnosed in 27.0% patients from group I, 44.3% patients from group II and in 49.6% patients from group III. No statistically significant differences were observed in long-term treatment outcomes for compared groups. The presence of ECE is accompanied by a higher stage of metastatic lesions in the lymphatic system. The differences in this respect were statistically significant, when compared to the group of ECE(−) patients. ECE, regardless of its extent, did not impact the long-term treatment results. ECE remains an indication for supplementary ALND and for other equivalent cancer treatment procedures, regardless of ECE size.

Although mastectomy could lead to a decrease in sexual performance among patients, only a handful of studies focused on the psychological and sexual behavioral aspects after the surgery. Research on post-mastectomy sexuality has focused mainly on female subjects but barely on lesbian, gay, bisexual, transgender, queer (LGBTQ), and male patients. This narrative review aimed to explore the importance of sexuality after mastectomy from a LGBTQ perspective. Each sexual minority group has been addressed individually. In general, sexual and gender minority breast cancer (BC) patients undergoing bilateral mastectomy expect a complex treatment plan in terms of physical and emotional outcomes. Bilateral mastectomy or top surgery for masculinization reasons was reported to be the most popular procedure among transmen, which resulted in a significant improvement in the quality of life. Heterosexual and lesbian female patients are willing to undergo mastectomy after repeated lumpectomies or to avoid radiation, despite potential post-operative somatic and quality-of-life complications. Transwomen would seek gender-affirming surgery to improve physical satisfaction and psychological well-being. There is not enough evidence for non-oncological reasons and consequences of mastectomy in gay men and cisgender heterosexual men. Establishing the awareness of the sexuality impact of mastectomy will allow the implementation of tailored perioperative psychological care.

Breast implantation (BI) is the most common plastic surgery worldwide performed among women. Generally, BI is performed both in aesthetic and oncoplastic procedures. Recently, the prevalence of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) or breast implant illness (BII) has aroused concerns. As a result, several countries, like Australia, Korea or the United Kingdom, introduced national registries dedicated to the safety and quality of BI surgeries. This narrative review aimed to focus on the clinical challenges, management and the current state of knowledge of BI. Both short and long-term outcomes of BI are determined by various alternatives and differences, which surgeons must consider during the planning and performing breast augmentation along with further complications or risk of reoperation. Proper preoperative decisions and aspects of surgical technique emerged to be equally important. The number of performed breast reconstructions is increasing, providing the finest aesthetic results and improving patient’s quality of life. Choice of prosthesis varies according to individual preferences and anatomical variables. A newly diagnosed cases of BIA-ALCL with lacking data on prevention, diagnosis, and treatment are placing it as a compelling medical challenge. Similarly, BII remains one of the most controversial subjects in reconstructive breast surgery due to unspecified diagnostic procedures, and recommendations.

Peritoneal metastases (PM) of gastric cancer (GC) are characterized by a particularly poor prognosis, with median survival time of 6 months, and virtually no 5-year survival reported. Conversion therapy for GC is defined as a surgical treatment aiming at an R0 resection after systemic chemotherapy for tumours that were originally unresectable (or marginally resectable) for technical and/or oncological reasons. The aim of the present study was to evaluate early and late outcomes in GC patients with PM who underwent the cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) after neoadjuvant (conversion) chemotherapy. Thirty patients with stage IV GC underwent CRS plus HIPEC. Severe grade III/IV (Clavien-Dindo classification) complications occurred in 13 (43%) patients. The Comprehensive Complication Index (CCI) ranged from 8.7 to 100 (median, 42.4). In the multivariate survival analysis, ypT2 and P3 (according to the Japanese classification of the PM severity) were favourable and adverse prognostic factors p = 0.031 and o = 0.035, respectively. Estimated 1- and 3-year survival was 73.9% and 36.6%, respectively. The median survival was 19.3 months. Conclusion: Conversion surgery, including extended gastrectomy and multi-organ resections followed by HIPEC performed after systemic chemotherapy therapy for GC with PM is justified in downstaged patients with ypT2 and limited (less than P3) PM.

Aim of the study: Intraoperative radiotherapy (IORT) may improve outcome of surgical treatment of recurrent colorectal cancer (CRC). The aim of this study is to determine the feasibility, safety and long-term results of surgical treatment of recurrent CRC with orthovolt IORT. Material and methods: Fifty-nine consecutive CRC patients with local recurrence (LR), undergoing surgery, were included in the retrospective analysis of prospectively collected data. The modified Wanebo classification was used to stage LR (Tr). Twenty-five (43%) patients received IORT using INTRABEAM® PRS 500. The complications were classified according to the Clavien-Dindo classification. Results: There were 32 males and 27 females, with a median age of 63 years. Multi-visceral resections were performed in 37 (63%) patients. Median hospitalization time after surgery with IORT was 7 days. One (1.7%) in-hospital postoperative death was reported. Grade 3/4 postoperative complications were found in 11 (19%) patients. Intraoperative radiotherapy had no effect on the postoperative hospitalization time, morbidity and mortality. Median survival after R0 resection was 32 months. Complete resection (R0), no synchronous liver metastases (M0), and no lateral and posterior pelvic wall involvement, were significant predictors of improved survival. Stage of LR was found to be an independent prognostic factor in the multivariate analysis (p = 0.03); Cox regression model). In patients with LR stage < Tr5, a 3-year overall survival (OS) rate was 52%. Conclusions : Combination of surgical resection and orthovolt IORT is a safe and feasible procedure that does not increase the risk of postoperative complications or prolongs the hospital stay. Despite aggressive surgery supported by IORT, the advanced stage of LR is a limiting factor of long-term survival.