Is the CTS5 a helpful decision-making tool in the extended adjuvant therapy setting?

PURPOSE: The Clinical Treatment Score post-5 years (CTS5) is an easy-to-use tool estimating the late distant recurrence (LDR) risk in patients with hormone receptor-positive breast cancer after 5 years of endocrine therapy (ET). Apart from evaluating the prognostic value and calibration accuracy of CTS5, the aim of this study is to clarify if this score is able to identify patients at higher risk for LDR who will benefit from extended ET. METHODS: Prognostic power, calibration, and predictive value of the CTS5 was tested in patients of the prospective ABCSG-06 and -06a trials (n = 1254 and 860 patients, respectively). Time to LDR was analyzed with Cox regression models. RESULTS: Higher rates of LDR in the years five to ten were observed in high- and intermediate-risk patients compared to low-risk patients (HR 4.02, 95%CI 2.26-7.15, p < 0.001 and HR 1.93, 95%CI 1.05-3.56, p = 0.035). An increasing continuous CTS5 was associated with increasing LDR risk (HR 2.23, 95% CI 1.74-2.85, p < 0.001). Miscalibration of CTS5 in high-risk patients could be observed. Although not reaching significance, high-risk patients benefitted the most from prolonged ET with an absolute reduction of the estimated 5-year LDR of - 6.1% (95%CI - 14.4 to 2.3). CONCLUSION: The CTS5 is a reliable prognostic tool that is well calibrated in the lower and intermediate risk groups with a substantial difference of expected versus observed LDR rates in high-risk patients. While a numerical trend in favoring prolonged ET for patients with a higher CTS5 was found, a significantly predictive value for the score could not be confirmed. CLINICAL TRIAL REGISTRATION: ABCSG-06 trial (NCT00309491), ABCSG-06A7 1033AU/0001 (NCT00300508).

Differential immunomodulatory effects of epirubicin/cyclophosphamide and docetaxel in breast cancer patients.

BACKGROUND: Epirubicin/cyclophosphamide (EC) and docetaxel (D) are commonly used in a sequential regimen in the neoadjuvant treatment of early, high-risk or locally advanced breast cancer (BC). Novel approaches to increase the response rate combine this treatment with immunotherapies such as PD-1 inhibition. However, the expected stimulatory effect on lymphocytes may depend on the chemotherapy backbone. Therefore, we separately compared the immunomodulatory effects of EC and D in the setting of a randomized clinical trial. METHODS: Tumor and blood samples of 154 patients from the ABCSG-34 trial were available (76 patients received four cycles of EC followed by four cycles of D; 78 patients get the reverse treatment sequence). Tumor-infiltrating lymphocytes, circulating lymphocytes and 14 soluble immune mediators were determined at baseline and at drug change. Furthermore, six BC cell lines were treated with E, C or D and co-cultured with immune cells. RESULTS: Initial treatment with four cycles of EC reduced circulating B and T cells by 94% and 45%, respectively. In contrast, no comparable effects on lymphocytes were observed in patients treated with initial four cycles of D. Most immune mediators decreased under EC whereas D-treatment resulted in elevated levels of CXCL10, urokinase-type plasminogen activator (uPA) and its soluble receptor (suPAR). Accordingly, only the exposure of BC cell lines to D induced similar increases as compared to E. While treatment of BC cells with E was associated with cell shrinkage and apoptosis, D induced cell swelling and accumulation of cells in G2 phase. CONCLUSION: The deleterious effect of EC on lymphocytes indicates strong immunosuppressive properties of this combination therapy. D, in contrast, has no effect on lymphocytes, but triggers the secretion of stimulatory proteins in vivo and in vitro, indicating a supportive effect on the immune system. Underlying differences in the induced cell death might be causal. These divergent immunomodulatory effects of epirubicin/cyclophosphamide and docetaxel should be considered when planning future combinations with immunotherapies in breast cancer.

Emergence of immune-related adverse events correlates with pathological complete response in patients receiving pembrolizumab for early triple-negative breast cancer.

Based upon results of the KEYNOTE-522 trial and following approval by regulatory authorities, the addition of pembrolizumab to chemotherapy is now the standard-of-care for the treatment of early triple-negative breast cancer (eTNBC) (Clinical stage II-III). Pembrolizumab is a programmed cell death protein 1 monoclonal antibody, known to cause immune-related adverse events (irAEs) in a significant subset of patients. Real-world data on incidence, type and treatment strategies of irAEs in the setting of eTNBC treatment are sparse. In this multicenterretrospective analysis, we characterized real-world incidence of irAEs and treatment outcomes such as pathological complete response (pCR) from the combination of pembrolizumab and chemotherapy as neoadjuvant treatment for eTNBC. We found a rate of irAEs of all grades of 63.9% and of 20% for irAEs of grade 3 or higher. In the overall population, a pCR rate of 57.1% was observed. The emergence of irAEs correlated significantly with pCR (72.2% versus 30.8%; p =.03). Discontinuation of neoadjuvant chemotherapy before week 12 correlated significantly with a lower pCR rate. To our knowledge, this is the first study evaluating the real-world efficacy and safety of a neoadjuvant combination of chemotherapy and pembrolizumab in eTNBC, demonstrating a significant correlation between irAEs and pCR. Early discontinuation of neoadjuvant therapy due to AEs resulted in a lower pCR rate.

The Impact of Adjuvant Radiotherapy on Immediate Prepectoral Implant-Based Breast Reconstruction.

BACKGROUND: Immediate prepectoral implant-based breast reconstruction (IBBR) rates have increased in recent years owing to improved cosmetic and psychological benefits. However, there is a lack of studies regarding complications rates following adjuvant radiotherapy (RT) among patients undergoing immediate prepectoral IBBR. METHODS: We conducted a retrospective monocentric analysis of a cohort of consecutively treated patients who underwent NSM following immediate prepectoral IBBR at our institution between March 2017 and November 2021. Patient demographics, quality of life, complication rates, and oncological safety were evaluated in the RT and non-RT groups. Data analysis was performed using IBM SPSS Version 24 (IMB Corp., Armonk, NY, USA). RESULTS: A total of 98 patients were examined: 70 were assigned to have prepectoral IBBR without RT and 28 to the group who had prepectoral IBBR with RT. There was a statistically significant difference in overall capsular contracture rate between the RT and non-RT group (18% vs. 4.3%, p=0.04). The total implant loss in the cohort was 4% (10.7% vs. 1.4%, p=0.05). We obtained a high percentages of all BREAST-Q categories in both groups; however, satisfaction with the breast and sexual well-being was higher in the non-RT group. The three-year overall survivals were 97.4% in the RT group and 98.5% in the non-RT group. CONCLUSION: Our findings showed that patients in the RT group had a higher rate of capsular contracture and implant loss than those in the non-RT group. However, complication rates were within acceptable range and with accurate preoperative information patients have more benefits from immediate reconstruction showing excellent overall quality of life irrespectively of radiation. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Ptotic versus Nonptotic Breasts in Nipple-sparing Mastectomy and Immediate Prepectoral Breast Reconstruction.

In recent years, nipple-sparing mastectomy followed by implant-based breast reconstruction has gained popularity due to improved cosmetic and psychological benefits. However, patients with ptotic breasts remain the main challenge for surgeons, owing to the potential risk of postoperative complications. Methods: A retrospective chart review was performed for patients who underwent nipple-sparing mastectomy and prepectoral implant-based breast reconstruction between March 2017 and November 2021. Patient demographics, incidence of complications, and quality of life assessed using the BREAST-Q questionnaire were compared between the two different incisions [inverted-T for ptotic versus inframammary fold (IMF) for nonptotic breasts]. Results: A total of 98 patients were examined: 62 in the IMF cohort and 36 in the inverted-T cohort. The results demonstrated equivalence in the safety metrics between the two groups, including hematoma (p=0.367), seroma (p=0.552), infection (P = 1.00), skin necrosis (P = 1.00), local recurrence (P = 1.00), implant loss (P = 0.139), capsular contracture (P = 1.00), and nipple-areolar complex necrosis (P = 0.139). The BREAST-Q scores were equally high in both groups. Conclusion: Our results suggest that inverted-T incision for ptotic breasts is a safe modality with similar complication rates and high aesthetic results compared with IMF incision for nonptotic breasts. A higher rate of nipple-areolar complex necrosis in the inverted-T group, although not significant, should be considered during careful preoperative planning and patient selection.

Fistula-Associated Anal Adenocarcinoma: A 20-Year Single-Center Experience.

BACKGROUND: Fistula-associated anal adenocarcinoma (FAAC) is a rare consequence in patients with long-standing perianal fistulas. A paucity of data are available for this patient collective, making clinical characterization and management of this disease difficult. OBJECTIVE: This study aimed to describe a single-center experience with FAAC patients, their clinical course, and histopathological and molecular pathological characterization. METHODS: All patients receiving surgery for an anal fistula in 1999-2019 at a tertiary university referral hospital were included in this retrospective analysis. Patients with FAAC were eligible for histopathological analysis, including immunohistochemistry and molecular profiling. RESULTS: This study included 1004 patients receiving surgical treatment for an anal fistula, of whom 242 had an underlying inflammatory bowel disease (IBD). Ten patients were diagnosed with a fistula-associated anal carcinoma (1.0%), and six of these patients had an FAAC (0.6%). The mean overall survival of FAAC patients was 24 ± 3 months. FAAC immunohistochemistry revealed positive staining for CK20, CDX2 and MUC2, while stainings for CK5/6 and CK7 were negative. All FAAC specimens revealed microsatellite stability. Molecular profiling detected mutations in 35 genes, with the most frequent mutations being TP53, NOTCH1, NOTCH3, ATM, PIK3R1 and SMAD4. CONCLUSION: FAAC is rare but associated with poor clinical outcome. Tissue acquisition is crucial for early diagnosis and therapy and should be performed in long-standing, non-healing, IBD-associated fistulas in particular. The immunophenotype of FAAC seems more similar to the rectal-type mucosa than the anal glands.

Prepectoral Versus Subpectoral Implant-Based Breast Reconstruction: A Systemic Review and Meta-analysis.

BACKGROUND: Implant-based breast reconstruction (IBBR) remains the standard and most popular option for women undergoing breast reconstruction after mastectomy worldwide. Recently, prepectoral IBBR has resurged in popularity, despite limited data comparing prepectoral with subpectoral IBBR. METHODS: A systematic search of PubMed and Cochrane Library from January 1, 2011 to December 31, 2021, was performed following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) reporting guidelines, data were extracted by independent reviewers. Studies that compared prepectoral with subpectoral IBBR for breast cancer were included. RESULTS: Overall, 15 studies with 3,101 patients were included in this meta-analysis. Our results showed that patients receiving prepectoral IBBR experienced fewer capsular contractures (odds ratio [OR], 0.54; 95% confidence interval [CI], 0.32-0.92; P = 0.02), animation deformity (OR, 0.02; 95% CI, 0.00-0.25; P = 0.002), and prosthesis failure (OR, 0.58; 95% CI, 0.42-0.80; P = 0.001). There was no significant difference between prepectoral and subpectoral IBBR in overall complications (OR, 0.83; 95% CI, 0.64-1.09; P = 0.19), seroma (OR, 1.21; 95% CI, 0.59-2.51; P = 0.60), hematoma (OR, 0.76; 95% CI, 0.49-1.18; P = 0.22), infection (OR, 0.87; 95% CI, 0.63-1.20; P = 0.39), skin flap necrosis (OR, 0.70; 95% CI, 0.45-1.08; P = 0.11), and recurrence (OR, 1.31; 95% CI, 0.52-3.39; P = 0.55). Similarly, no significant difference was found in Breast-Q scores between the prepectoral and subpectoral IBBR groups. CONCLUSIONS: The results of our systematic review and meta-analysis demonstrated that prepectoral, implant-based, breast reconstruction is a safe modality and has similar outcomes with significantly lower rates of capsular contracture, prosthesis failure, and animation deformity compared with subpectoral, implant-based, breast reconstruction.

Duration of Adjuvant Aromatase-Inhibitor Therapy in Postmenopausal Breast Cancer.

BACKGROUND: For postmenopausal women with hormone-receptor-positive breast cancer, the most effective duration for adjuvant therapy with an aromatase inhibitor remains unclear. METHODS: In this prospective, phase 3 trial, we randomly assigned postmenopausal women with hormone-receptor-positive breast cancer who had received 5 years of adjuvant endocrine therapy to receive the aromatase inhibitor anastrozole for an additional 2 years (2-year group, receiving a total of 7 years) or an additional 5 years (5-year group, receiving a total of 10 years). The primary end point was disease-free survival. The primary analysis included all the patients who were still participating in the trial and who had no recurrence 2 years after randomization (i.e., when treatment in the 2-year group had ended). Secondary end points were overall survival, contralateral breast cancer, second primary cancer, and clinical bone fracture. RESULTS: Among the 3484 women who were enrolled in the trial, 3208 remained in the trial without disease progression after the first 2 years of extended anastrozole treatment following randomization. Among these women, disease progression or death occurred in 335 women in each treatment group in the primary-analysis set at 8 years (hazard ratio, 0.99; 95% confidence interval [CI], 0.85 to 1.15; P = 0.90). No between-group differences occurred in most secondary end points, and subgroup analyses did not indicate differences in any particular subgroup. The risk of clinical bone fracture was higher in the 5-year group than in the 2-year group (hazard ratio, 1.35; 95% CI, 1.00 to 1.84). CONCLUSIONS: In postmenopausal women with hormone-receptor-positive breast cancer who had received 5 years of adjuvant endocrine therapy, extending hormone therapy by 5 years provided no benefit over a 2-year extension but was associated with a greater risk of bone fracture. (Funded by AstraZeneca and the Austrian Breast and Colorectal Cancer Study Group; ABCSG-16/SALSA ClinicalTrials.gov number, NCT00295620.).

Short-term outcome after ventral hernia repair using self-gripping mesh in sublay technique - A retrospective cohort analysis.

BACKGROUND: Hernia repair in sublay technique is widely accepted for ventral hernias, as it appears to be advantageous in terms of complication and recurrence rates. Self-gripping meshes are increasingly used for hernia repair with retromuscular mesh positioning. However, real-life data on the safe use in that specific indication are still lacking. The purpose of this study is the evaluation of short-term postoperative outcome of self-gripping versus conventional non-self-gripping meshes in sublay hernia repair. MATERIALS AND METHODS: This retrospective analysis assessed patients undergoing ventral hernia repair in sublay technique between January 2011 and July 2018 at the Department of Surgery, Medical University of Vienna. 244 consecutive patients were eligible for final analysis. Patients were grouped according to the utilized mesh. Baseline characteristics and peri-as well as postoperative outcome was assessed. RESULTS: There was no significant difference in baseline characteristics between the two groups. Median follow-up was 11 months (IQR 3-30). The overall complication rate (28.3% versus 13.7%, p = 0.005) due to an increased rate of seromas (17.3% versus 6.8%, p = 0.013) and surgical site infections (12.6% versus 4.3%, p = 0.021) was significantly higher in patients with a self-gripping mesh. Significantly more patients with a self-gripping mesh needed a surgical intervention (21.3% versus 9.4%, p = 0.011). CONCLUSION: In sublay ventral hernia repair, the use of self-gripping meshes is associated with a higher overall complication rate and an increased rate of complication-associated surgical interventions when compared to non-self-gripping mesh placements.

Circulating biomarkers of cell death.

Numerous disease states are associated with cell death. For many decades, apoptosis and accidental necrosis have been assumed to be the two ways how a cell can die. The recent discovery of additional cell death processes such as necroptosis, ferroptosis or pyroptosis revealed a complex interplay between cell death mechanisms and diseases. Depending on the particular cell death pathway, cells secrete distinct molecular patterns, which differ between cell death types. This review focusses on released molecules, detectable in the blood flow, and their potential role as circulating biomarkers of cell death. We elucidate the molecular background of different biomarkers and give an overview on their correlation with disease stage, therapy response and prognosis in patients.

Adjuvant Bisphosphonate Therapy in Postmenopausal Breast Cancer.

OPINION STATEMENT: Bone health and breast cancer are two connected subjects, because breast cancer patients have a higher prevalence of osteopenia/osteoporosis and reduced bone health parameters than healthy woman of the same age. Therefore, the positive effect of adjuvant bisphosphonate therapy plays an important role in breast cancer treatment. Several randomized trials have studied bisphosphonates in the adjuvant setting in postmenopausal woman and demonstrated their potential to prevent treatment-induced bone loss. The prevention of fractures and the subsequent preservation of patients' quality of life are important arguments for the use of adjuvant bisphosphonates in postmenopausal breast cancer patients. In addition, trials of adjuvant bone-targeted agents showed a reduction of recurrences in and outside bone and an improved outcome in patients treated with bisphosphonates.

Optimal duration of adjuvant endocrine therapy: how to apply the newest data.

BACKGROUND: The benefit of 5 years of adjuvant endocrine therapy for women with hormone receptor-positive (HR+) breast cancer (BC) is beyond discussion. Nevertheless, the risk of recurrence of luminal BC persists for 15 years or more after diagnosis. Consequently, approaches of extended adjuvant therapy have been investigated in large clinical trials, with the ultimate aim of further reducing the risk of recurrence in patients with HR+ BC. METHODS: A review of recently published trial data is presented to provide a solid basis for discussion. A discussion of the side effects of long-term endocrine treatment, multigenetic tests aiming to identify patients at particular risk, and an outlook for further promising targets are additional aims of this review. CONCLUSION: Extended adjuvant therapy seems beneficial in reducing distant relapse and contralateral BC for a selected group of patients with HR+ BC, particularly if aromatase inhibitors (AIs) are used after initial tamoxifen therapy. However, patients with lower risk of recurrence and initial AI therapy may suffer more from side effects than benefit from extended therapy.

Impact of Neoadjuvant Chemotherapy on Clinical Risk Scores and Survival in Patients with Colorectal Liver Metastases.

BACKGROUND: Several clinical risk scores for patients with colorectal liver metastases (CLM) were established in cohorts of patients undergoing liver resection (LR) without neoadjuvant chemotherapy (NAC). The purpose of the study was to evaluate the predictive values of four common risk scores in the setting of NAC and the impact of score changes during NAC. METHODS: Risk scores (Fong, Nordlinger, Nagashima, and Konopke) were retrospectively calculated for 336 patients undergoing LR for CLM, including 109 patients without and 227 patients with NAC. In patients with NAC, the scores were calculated before and after NAC. RESULTS: In patients without NAC (n = 109), all risk scores except the Konopke score showed a significant correlation with disease-free survival (DFS). Only the Nagashima score also was predictive for overall survival (OS). In patients with NAC (n = 227), all scores except the Konopke score were predictive for DFS and OS before and after NAC. Score changes in the Fong and the Nagashima score showed a significant correlation with DFS and OS. CONCLUSIONS: Nagashima score was the most universally applicable score and predicted prognosis in all tested scenarios.