Prognostic Relevance of Tumor-Infiltrating Immune Cells in Cervix Squamous Cell Carcinoma.

There exists a variety of studies about tumor-infiltrating immune cells (TIICs) in cervical cancer, but their prognostic value in correlation with the histopathological subtype has never been investigated. Therefore, the aim of this study was to quantify TIICs in a panel of 238 sporadic cervical cancers and investigate the correlation with cervical cancer subtype and patient survival. TIICs levels were significantly increased in the subgroup of CSCC (191 samples) in comparison to CAC (47 samples). In CSCC, TIICs' infiltration showed a negative correlation with age, FIGO stage and with the histone protein modification H3K4me3. Moreover, in CAC, it was positively correlated with p16 and with the glucocorticoid receptor and inversely correlated with the MDM2 protein and with H3K4me3. Interestingly, immune infiltration was an independent positive prognosticator for disease-free survival (DFS) in patients with CSCC, those bearing tumors with the strongest TIICs infiltration showing the better DFS. Altogether, the present study provides a differentiated overview of the relations between TIIC levels and prognosis in patients with CSCC vs. patients with CAC.

Elderly and Patients with Large Breast Volume Have an Increased Risk of Seroma Formation after Mastectomy-Results of the SerMa Pilot Study.

The collective of the SerMa pilot study included 100 cases of primary breast cancer or Carcinoma in situ who had undergone a mastectomy procedure with or without reconstruction of the breast using an implant or expander at Augsburg University Hospital between 12/2019 and 12/2022. The study aimed to investigate possible causes of seroma formation; reported here are the clinicopathological correlations between seroma formation and tumor biology and surgical procedures. Seroma occurred significantly more often in patients with older age (median patient age in cases with seroma was 73 years vs. 52 years without seroma; p < 0.001). In addition, patients with larger mastectomy specimen were significantly more likely to develop seroma (median ablation weight in cases with seroma 580 g vs. 330 g without seroma; p < 0.001). Other significant parameters for seroma formation were BMI (p = 0.005), grading (p = 0.015) and tumor size (p = 0.036). In addition, with insertion of implant or expander, a seroma occurred significantly less frequently (p < 0.001). In a binary logistic regression, age in particular was confirmed as a significant risk factor. In contrast, tumor biological characteristics, number of lymph nodes removed or affected showed no significant effect on seroma formation. The present study shows the need for patient education about the development of seroma in particular in older patients and patients with large breast volumes within the preoperative surgical clarification. These clinicopathological data support the previously published results hypothesizing that seroma formation is related to autoimmune/inflammatory processes and will be tested on a larger collective in the planned international multicenter SerMa study.

Cytoplasmic Localization of Thyroid Hormone Receptor (TR) Alpha and Nuclear Expression of Its Isoform TRα2 Determine Survival in Breast Cancer in Opposite Ways.

The aim of this retrospective study was to assess the respective prognostic values of cytoplasmic and nuclear TRα, TRα1, and TRα2 expression in breast cancer (BC) tissue samples and correlate the results with clinico-pathological parameters. In 249 BC patients, the expression patterns of general TRα and the α1 and α2 isoforms were evaluated via immuno-histochemistry. Prognosis-determining aspects were calculated via univariate, as well as multivariate, analysis. Univariate Cox-regression analysis revealed no association between nuclear TRα expression and overall survival (OS) (p = 0.126), whereas cytoplasmic TRα expression was significantly correlated with a poor outcome for both OS (p = 0.034) and ten-year survival (p = 0.009). Strengthening these results, cytoplasmic TRα was found to be an independent marker of OS (p = 0.010) when adjusted to fit clinico-pathological parameters. Analyses of the TRα-subgroups revealed that TRα1 had no prognostic relevance, whereas nuclear TRα2 expression was positively associated with OS (p = 0.014), ten-year survival (p = 0.029), and DFS (p = 0.043). Additionally, nuclear TRα2 expression was found to be an independent positive prognosticator (p = 0.030) when adjusted to fit clinico-pathological parameters. Overall, our results support the hypothesis that subcellular localization of TRα and its isoforms plays an important role in the carcinogenesis and prognosis of breast cancer. Cytoplasmic TRα expression correlates with more aggressive disease progression, whereas nuclear TRα2 expression appears to be a protective factor. These data may help us to prioritize high-risk BC subgroups for possible targeted tumor therapy.

Th2/Th17 cell associated cytokines found in seroma fluids after breast cancer surgery.

PURPOSE: The development of a seroma after breast cancer surgery is a common postoperative complication seen after simple mastectomy and axillary surgery. We could recently demonstrate that breast cancer patients undergoing a simple mastectomy with subsequent seroma formation developed a T-helper cell increase within the aspirated fluid measured by flow cytometry. The same study revealed a Th2 and/or a Th17 immune response in peripheral blood and seroma fluid of the same patient. Based on these results and within the same study population, we now analyzed the Th2/Th17 cell associated cytokine content as well as the best known clinical important cytokine IL-6. METHODS: Multiplex cytokine measurements (IL-4, IL-5, IL-13, IL-10, IL-17, and IL-22) were done on 34 seroma fluids (Sf) after fine needle aspiration of patients who developed a seroma after a simple mastectomy. Serum of the same patient (Sp) and that of healthy volunteers (Sc) were used as controls. RESULTS: We found the Sf to be highly cytokine rich. Almost all analyzed cytokines were significantly higher in abundance in the Sf compared to Sp and Sc, especially IL-6, which promotes Th17 differentiation as well as suppresses Th1 differentiation in favor of Th2 development. CONCLUSION: Our Sf cytokine measurements reflect a local immune event. In contrast, former study results on T-helper cell populations in both Sf and Sp tend to demonstrate a systemic immune process.

Recommendations for the diagnosis and treatment of patients with early breast cancer: update 2023.

PURPOSE OF REVIEW: In recent years, the therapy of breast carcinoma has evolved at a rapid pace. Therapies from metastasis are pushing into the (neo)adjuvant treatment of breast carcinoma at ever shorter intervals. RECENT FINDINGS: Biomarker-based therapeutic approaches became more and more en vogue to guide (neo)adjuvant endocrine therapy and chemotherapy. SUMMARY: This article reviews recent data developments in early breast cancer (EBC) and current recommendations in diagnosis and therapy.

Prognostic Relevance of Nuclear Receptors in Relation to Peritumoral Inflammation and Tumor Infiltration by Lymphocytes in Breast Cancer.

The prognostic impact of tumor-infiltrating lymphocytes (TILs) is intensively investigated in breast cancer (BC). It is already known that triple-negative breast cancer (TNBC), the most aggressive type of BC, has the highest percentage of TILs. In addition, there is an influence of steroid hormone receptor expression (type I nuclear receptors) on TIL subpopulations in breast cancer tissue. The link between type II nuclear receptors and the level of TILs is unclear. Therefore, the aim of this study was to quantify TILs in a panel of 264 sporadic breast cancers and investigate the correlation of TIL levels with type I and II nuclear receptors expression. TIL levels were significantly increased in the subgroup of TNBC. By contrast, they decreased in estrogen (ER)- or progesterone receptor (PR)-positive cases. Moreover, TIL levels were correlated with type II nuclear receptors, including PPARγ, with a significant inverse correlation of the nuclear form (r = −0.727, p < 0.001) and a weak positive correlation of the cytoplasmic form (r = 0.202, p < 0.002). Surprisingly, BC cases with a TIL Salgado score of >15% showed a significantly decreased overall survival. In addition, peritumoral inflammation was also quantified in BC tissue samples. In our cohort, although the level of peritumoral inflammation was not correlated with OS, it determined the prognostic value of ER, PR, and PPARγ in BC. Altogether, the present study provides a differentiated overview of the relations between nuclear receptor expression, TIL levels, peritumoral inflammation, and prognosis in BC.

Cytoplasmic Colocalization of RXRα and PPARγ as an Independent Negative Prognosticator for Breast Cancer Patients.

Retinoid X receptor α (RXRα) is a nuclear receptor (NR) which functions as the primary heterodimeric partner of other NRs including the peroxisome proliferator-activated receptor γ (PPARγ). We previously reported that, in breast cancers (BC), the subcellular localization of these two receptors was strongly associated with patient prognosis. In the present work, we investigated the prognosis value of the combined cytoplasmic expression of RXRα and PPARγ using a retrospective cohort of 250 BC samples. Patients with tumors expressing both NRs in tumor cell cytoplasm exhibited a significant shorter overall (OS) and disease-free survival (DFS). This was also observed for patients with stage 1 tumors. Cox univariate analysis indicated that patients with tumors coexpressing RXRα and PPARγ in the cytoplasm of tumor cells have a decreased 5 y OS rate. Cytoplasmic co-expression of the two NRs significantly correlated with HER2 positivity and with NCAD and CD133, two markers of tumor aggressiveness. Finally, in Cox multivariate analysis, the co-expression of RXRα and PPARγ in the cytoplasm appeared as an independent OS prognosticator. Altogether, this study demonstrates that the cytoplasmic co-expression of RXRα and PPARγ could be of relevance for clinicians by identifying high-risk BC patients, especially amongst those with early and node-negative disease.

The Role of Chemokines in Cervical Cancers.

Both clinical-pathological and experimental studies have shown that chemokines play a key role in activating the immune checkpoint modulator in cervical cancer progression and are associated with prognosis in tumor cell proliferation, invasion, angiogenesis, chemoresistance, and immunosuppression. Therefore, a clear understanding of chemokines and immune checkpoint modulators is essential for the treatment of this disease. This review discusses the origins and categories of chemokines and the mechanisms that are responsible for activating immune checkpoints in cervical dysplasia and cancer, chemokines as biomarkers, and therapy development that targets immune checkpoints in cervical cancer research.

Evolution of the Use of Completion Axillary Lymph Node Dissection in Patients with T1/2N0M0 Breast Cancer and Tumour-Involved Sentinel Lymph Nodes Undergoing Mastectomy: A Cohort Study.

BACKGROUND: In breast cancer, completion axillary lymph node dissection (cALND) was previously recommended for patients with at least one tumour-affected sentinel lymph node (SLN). Several prospective trials predominantly in patients undergoing breast-conserving surgery showed no benefit and increased arm morbidity with this procedure. We report the influence of these trials on clinical practice of patients undergoing mastectomy. METHODS: We analysed prospectively collected data from patients with primary invasive breast cancer treated at German breast cancer units between January 2008 and December 2015. Time trends of cALND rates were analysed in patients undergoing mastectomy for T1/2N0M0 breast cancer with one or two tumour-involved SLNs. Multivariable logistic regression was used to determine factors influencing the decision not to perform cALND. RESULTS: Among the entire study cohort of 166,074 patients treated at 179 breast cancer units, 4093 patients (2%) had T1/2N0M0 breast cancer with one or two tumour-involved SLNs and underwent mastectomy. cALND rates decreased from 89.9% in 2010 to 55.5% in 2015 (p < 0.001). Rates decreased from 82% to 8% in patients with micrometastatic SLN disease and from 93% to 63% in those with macrometastasis (p < 0.001). In multivariable analysis, factors associated with omission of cALND were treatment at a general, nonacademic hospital, pT1 status, older age, higher number of removed SLNs, fewer tumour-affected SLNs, and SLN micrometastasis (all p < 0.001). CONCLUSIONS: Despite limited evidence from prospective trials relating to the omission of cALND specifically in patients undergoing mastectomy, our nationwide data show that use of cALND decreased in these patients in routine clinical practice.

Which patients with sentinel node-positive breast cancer after breast conservation still receive completion axillary lymph node dissection in routine clinical practice?

PURPOSE: In the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial, patients with 1 or 2 tumour-involved sentinel lymph nodes (SLNs) gained no benefit from completion axillary lymph dissection (cALND). We examined implementation of evidence from this trial into routine clinical management. METHODS: Data were included from patients diagnosed with primary breast cancer in German breast cancer units between 2008 and 2015 and analysed retrospectively from a prospective maintained database. Descriptive analyses assessed time-trend changes in axillary surgery. Factors associated with cALND in patients with 1 or 2 positive SLNs were identified using multivariable logistic regression analysis. RESULTS: Overall, 179 breast cancer units provided data for 188,909 patients, of whom 13,741 (7.3%) had pT1/2cN0M0 invasive breast cancer with 1 or 2 tumour-involved SLNs and underwent breast-conserving surgery and adjuvant radiotherapy. cALND use decreased from 94.6% in 2008 to 46.9% in 2015 (p < 0.001). In multivariable analyses, the following factors were associated with cALND: fewer removed SLNs; two tumour-affected SLNs; younger age; lower annual case volume per hospital; higher tumour grade and lymphovascular invasion. No statistically significant influence was detected for hormone receptor or HER2 status. CONCLUSION: In our cohort, 7.3% of patients with primary breast cancer met the ACOSOG Z0011 inclusion criteria and could potentially have been spared the morbidity of cALND. cALND tended to be performed in patients with a higher axillary tumour burden. This study shows a shift towards less extensive axillary surgery through rapid implementation of new clinical trial evidence into routine clinical practice.

Attitudes of Nurses Toward Disability and Treatment in Space-Occupying Middle Cerebral Artery Stroke.

BACKGROUND: Attitudes toward the degree of acceptable disability and the importance of aphasia are critical in deciding on decompressive hemicraniectomy (DHC) in space-occupying middle cerebral artery stroke (SOS). The attitudes of nurses deserve strong attention, because of their close interaction with patients during acute stroke treatment. METHODS: This is a multicenter survey among 627 nurses from 132 hospitals in Germany. Questions address the acceptance of disability, importance of aphasia, and the preferred treatment in the hypothetical case of SOS. RESULTS: Modified Rankin Scale (mRS) scores of 1 and 2 were considered acceptable by the majority of all respondents (89.7%). A mRS of 3, 4, and 5 was considered acceptable by 60.0, 15.5, and 1.6%, respectively. DHC was indicated as the treatment of choice in 31.4%. Every third participant considered the presence of aphasia important for treatment decision (33.3%). Older respondents more often refrained from DHC, irrespective of the presence of aphasia (dominant hemisphere p = 0.001, non-dominant hemisphere p = 0.004). Differences regarding acceptable disability and treatment decision were dependent on age, sex, and having relatives with stroke. CONCLUSION: Most German nurses indicate moderately severe disability after SOS not to be acceptable, without emphasizing the presence of aphasia. The results call for greater scientific efforts in order to find reliable predictors for outcome after SOS.