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Background: Duration of surgery is a main cost factor of surgical training. The purpose of this analysis of operative times for laparoscopic cholecystectomies (LC) was to quantify the extra time and related costs in regards to the surgeons' experience in the operating room (OR). Methods: All LC performed between January 01, 2005 and December 31, 2008 in 46 hospitals reporting to the database of the Swiss Association for Quality Management in Surgery (AQC) were analyzed ( n = 10,010). Four levels of seniority were specified: resident (R), junior consultant (JC), senior consultant (SC), and attending surgeon (AS). The differences in operative time according to seniority were investigated in a multivariable log-linear and median regression analysis controlling for possible confounders. The OR costs were calculated by using a full cost rate in a teaching hospital. Results: A total of 9,208 LC were available for analysis; 802 had to be excluded due to missing data ( n = 212) or secondary major operations ( n = 590). Twenty-eight percent of the LC were performed by R as teaching operations ( n = 2,591). Compared with R, the multivariable analysis of operative time showed a median difference of −2.5 min (−9.0; 4.8) for JC and −18 min (−25; −11) for SC and −28 min (−35; −10) for AS, respectively. The OR minute costs were €17.57, resulting in incremental costs of €492 (159; 615) per operation in case of tutorial assistance. Conclusions: The proportion of LC performed as tutorial assistance for R remains low. Surgical training in the OR causes relevant case-related extra time and therefore costs. [ABSTRACT FROM AUTHOR]

Lymphomas associated with breast implants are rare, and the majority of these are anaplastic large-cell lymphomas of T-cell origin. Very uncommonly B-cell lymphomas associated with implants have been described, and examples of invasive disease are even less commonly reported. This report discusses one such 72-year-old patient who presented with pain and concerns about implant rupture on imaging. Histopathology demonstrated an invasive EBV + large B-cell lymphoma associated with bilateral silicone implants inserted 20 years previously. This was managed with implant explantation, capsulectomy and adjuvant chemotherapy., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: There remains uncertainty regarding the optimal extent of initial surgery and management of recurrent disease in medullary thyroid cancer (MTC). We aim to describe the patterns of disease recurrence and outcomes of the reoperative surgery in a cohort of consecutively treated patients at a specialized tertiary referral center., Patients and Methods: A retrospective cohort study of 235 surgically treated patients with MTC at a tertiary referral center was performed using prospectively collected data., Results: In the study period 1986-2022, 235 patients underwent surgery for MTC. Of these, 45 (19%) patients had reoperative surgery for cervical nodal recurrence at a median (range) 2.1 (0.3-16) years following the index procedure. After a median follow-up of 4 years, 38 (84%) patients remain free of structural cervical recurrence, although 15 (33%) underwent 2 or more reoperative procedures. No long-term complications occurred after reoperative surgery. Local cervical recurrence was independently predicted by pathologically involved nodal status (OR 5.10, P = .01) and failure to achieve biochemical cure (OR 5.0, P = .009). Local recurrence did not adversely affect overall survival and was not associated with distant recurrence (HR 0.93, P = .83). Overall survival was independently predicted by high pathological grade (HR 10.0, P = .002) and the presence of metastatic disease at presentation (HR 8.27, P = 0018)., Conclusion: Loco-regional recurrence in MTC does not impact overall survival, or the development of metastatic disease, demonstrating the safety of the staged approach to the clinically node-negative lateral neck. When recurrent disease is technically resectable, reoperative surgery can be undertaken with minimal morbidity in a specialized center and facilitates structural disease control., (© The Author(s) 2023. Published by Oxford University Press.)

Context: Management of sporadic medullary thyroid microcarcinoma smaller than 1 cm (micro-MTC) is controversial because of conflicting reports of prognosis. As these cancers are often diagnosed incidentally, they pose a management challenge when deciding on further treatment and follow-up., Objective: We report the outcomes of surgically managed sporadic micro-MTC in a specialist endocrine surgery and endocrinology unit and identify associations for recurrence and disease-specific survival in this population., Methods: Micro-MTCs were identified from a prospectively maintained surgery database, and slides were reviewed to determine pathological grade. The primary end points were recurrence, time to recurrence and disease-specific survival. Prognostic factors assessed included size, grade, lymph node metastasis (LNM), and postoperative calcitonin., Results: From 1995 to 2022, 64 patients were diagnosed with micro-MTC with 22 excluded because of hereditary disease. The included patients had a median age of 60 years, tumor size of 4 mm, and 28 (67%) were female. The diagnosis was incidental in 36 (86%) with 4 (10%) being high grade, 5 (12%) having LNM and 9 (21%) having elevated postoperative calcitonin. Over a 6.6-year median follow-up, 5 (12%) developed recurrence and 3 (7%) died of MTC. High grade and LNM were associated with 10-year survival estimates of 75% vs 100% for low grade and no LNM (hazard ratio = 831; P < .01). High grade, LNM, and increased calcitonin were associated with recurrence (P < .01). Tumor size and type of surgery were not statistically significantly associated with recurrence or survival. No patients with low grade micro-MTC and normal postoperative calcitonin developed recurrence., Conclusion: Most sporadic micro-MTCs are detected incidentally and are generally associated with good outcomes. Size is not significantly associated with outcomes. Using grade, LNM, and postoperative calcitonin allows for the identification of patients at risk of recurrence to personalize management., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Lymph node metastasis in thyroid cancer is common and associated with an increased risk of locoregional recurrence (LRR). Although therapeutic central neck dissection is well established, prophylactic central node dissection (pCND) for microscopic occult nodal involvement is controversial and recommendations are based on low-level evidence. The potential benefits of pCND such as reducing LRR and re-operation, refining staging, and improving surveillance are enthusiastically debated and the decision to perform pCND must be weighed up against the increased risks of complications., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: This is the first randomized trial to evaluate the efficacy of intraoperative cholangiography (IOC) and magnetic resonance cholangiopancreatography (MRCP) in patients with suspected CBDS., Methods: This unblinded, multicenter RCT was conducted at five swiss hospitals. Eligibility criteria were suspected CBDS. Patients were randomized to IOC and laparoscopic cholecystectomy (LC), followed by endoscopic retrograde cholangiopancreatography (ERCP) if needed, or MRCP followed by ERCP if needed, and LC. Primary outcome was length of stay (LOS), secondary outcomes were cost, stone detection, and complication rates., Results: 122 Patients were randomised to the IOC Group (63) or the MRCP group (59). Median LOS for the IOC and the MRCP groups were 4 days IQR [3, 6] and [4, 6], with an estimated increase of LOS of 1.2 days in the MRCP group (p = 0.0799) in the linear model. Median cost in the IOC and MRCP groups were 10 473 Swiss Francs (CHF) and 10 801 CHF, respectively (p = 0.694). CBDS were found in 24 and 12 patients in the IOC and the MRCP groups, respectively (p = 0.0387). The complication rate did not differ between both groups., Conclusion: There is equipoise between both pathways. IOC has a significantly higher diagnostic yield than MRCP., Trial Registration: Clinicaltrials.gov identifier NCT02351492: Radiological Investigation of Bile Duct Obstruction (RIBO)., (Copyright © 2022 International Hepato-Pancreato-Biliary Association Inc. All rights reserved.)

Background: The mortality rate is low in endocrine surgery, making it a difficult outcome to use for quality improvement in individual units. Lessons from population data sets are of value in improving outcomes. Data from the Australian and New Zealand Audit of Surgical Mortality (ANZASM) were used here to understand and elucidate potential systems issues that may contribute to preventable deaths., Methods: ANZASM data relating to 30-day mortality after thyroidectomy, parathyroidectomy, and adrenalectomy from 2009 to 2020 were reviewed. Mortality rates were calculated using billing data. Thematic analysis of independent assessor reports was conducted to produce a coding framework., Results: A total of 67 deaths were reported, with an estimated mortality rate of 0.03-0.07 per cent (38 for thyroidectomy (0.03-0.06 per cent), 16 for parathyroidectomy (0.03-0.06 per cent), 13 for adrenalectomy (0.15-0.33 per cent)). Twenty-seven deaths (40 per cent) were precipitated by clinically significant adverse events, and 18 (27 per cent) were judged to be preventable by independent ANZASM assessors. Recurrent themes included inadequate preoperative assessment, lack of anticipation of intraoperative pitfalls, and failure to recognize and effectively address postoperative complications. Several novel themes were reiterated, such as occult ischaemic heart disease associated with death after parathyroid surgery, unexpected intraoperative difficulties from adrenal metastasis, and complications due to anticoagulation therapy after thyroid surgery., Conclusion: This study represents a large-scale national report of deaths after endocrine surgery and provides insights into these rare events. Although the overall mortality rate is low, 27 per cent of deaths involved systems issues that were preventable following independent peer review., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd.)

Plasticity delineates cancer subtypes with more or less favourable outcomes. In breast cancer, the subtype triple-negative lacks expression of major differentiation markers, e.g., estrogen receptor α (ERα), and its high cellular plasticity results in greater aggressiveness and poorer prognosis than other subtypes. Whether plasticity itself represents a potential vulnerability of cancer cells is not clear. However, we show here that cancer cell plasticity can be exploited to differentiate triple-negative breast cancer (TNBC). Using a high-throughput imaging-based reporter drug screen with 9 501 compounds, we have identified three polo-like kinase 1 (PLK1) inhibitors as major inducers of ERα protein expression and downstream activity in TNBC cells. PLK1 inhibition upregulates a cell differentiation program characterized by increased DNA damage, mitotic arrest, and ultimately cell death. Furthermore, cells surviving PLK1 inhibition have decreased tumorigenic potential, and targeting PLK1 in already established tumours reduces tumour growth both in cell line- and patient-derived xenograft models. In addition, the upregulation of genes upon PLK1 inhibition correlates with their expression in normal breast tissue and with better overall survival in breast cancer patients. Our results indicate that differentiation therapy based on PLK1 inhibition is a potential alternative strategy to treat TNBC., (© 2022. The Author(s).)

Background: Percutaneous cholecystostomy (PC) is a treatment option for acute cholecystitis (AC) in cases where cholecystectomy (CCY) is not feasible due to limited health conditions. The use of PC remains questionable. The aim was to retrospectively analyse the outcome of patients after PC., Methods: All patients who underwent PC for AC at a tertiary referral hospital over 10 years were included. Descriptive statistics, analysed mortality with and without CCY after PC, and a multivariable logistic regression for potential confounder and a landmark sensitivity analysis for immortal time bias were used., Results: Of 158 patients, 79 were treated with PC alone and 79 had PC with subsequent CCY. Without CCY, 48% (38 patients) died compared to 9% with CCY. In the multivariable analysis CCY was associated with 85% lower risk of mortality. The landmark analysis was compatible with the main analyses. Direct PC-complications occurred in 17% patients. Histologically, 22/75 (29%) specimens showed chronic cholecystitis, and 76% AC., Conclusion: Due to the high mortality rate of PC alone, performing up-front CCY is proposed. PC represents no definitive treatment for AC and should remain a short-term solution because of the persistent inflammatory focus. According to these findings, almost all specimens showed persistent inflammation., (Copyright © 2021 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Stromal infiltration is associated with poor prognosis in human colon cancers. However, the high heterogeneity of human tumor-associated stromal cells (TASCs) hampers a clear identification of specific markers of prognostic relevance. To address these issues, we established short-term cultures of TASCs and matched healthy mucosa-associated stromal cells (MASCs) from human primary colon cancers and, upon characterization of their phenotypic and functional profiles in vitro and in vivo, we identified differentially expressed markers by proteomic analysis and evaluated their prognostic significance. TASCs were characterized by higher proliferation and differentiation potential, and enhanced expression of mesenchymal stem cell markers, as compared to MASCs. TASC triggered epithelial-mesenchymal transition (EMT) in tumor cells in vitro and promoted their metastatic spread in vivo, as assessed in an orthotopic mouse model. Proteomic analysis of matched TASCs and MASCs identified a panel of markers preferentially expressed in TASCs. The expression of genes encoding two of them, calponin 1 (CNN1) and tropomyosin beta chain isoform 2 (TPM2), was significantly associated with poor outcome in independent databases and outperformed the prognostic significance of currently proposed TASC markers. The newly identified markers may improve prognostication of primary colon cancers and identification of patients at risk.

Background: Ovarian cancer (OC) is the fifth most common malignant female cancer with a high mortality, mainly because of aggressive high-grade serous carcinomas (HGSOC), but also due to absence of specific early symptoms and effective detection strategies. The CXCL12-CXCR4 axis is considered to have a prognostic impact and to serve as potential therapeutic target. Therefore we investigated the role of pCXCR4 and CXCR4 expression of the tumor cells and of tumor infiltrating immune cells (TIC) in high-grade serous OC and their association with the recurrence-free (RFS) and overall survival (OS)., Methods: A tissue microarray of 47 primary high grade ovarian serous carcinomas and their recurrences was stained with primary antibodies directed against CXCR4 and pCXCR4. Beside the evaluation of the absolute tumor as well as TIC expression in primary and recurrent cancer biopsies the corresponding ratios for pCXCR4 and CXCR4 were generated and analyzed. The clinical endpoints were response to chemotherapy, OS as well as RFS., Results: Patients with a high pCXCR4/CXCR4 TIC ratio in primary cancer biopsies showed a significant longer RFS during the first two years (p = 0.025). However, this effect was lost in the long-term analysis including a follow-up period of 5 years (p = 0.128). Interestingly, the Multivariate Cox regression analysis showed that a high pCXCR4/CXCR4 TIC ratio in primary cancer independently predicts longer RFS (HR 0.33; 95CI 0.13 - 0.81; p = 0.015). Furthermore a high dichotomized distribution of CXCR4 positive tumor expression in recurrent cancer biopsies showed a significantly longer 6-month RFS rate (p = 0.018) in comparison to patients with low CXCR4 positive tumor expression. However, this effect was not independent of known risk factors in a Multivariate Cox regression (HR 0.57; 95CI 0.24 - 1.33; p = 0.193)., Conclusions: To the best of our knowledge we show for the first time that a high pCXCR4/CXCR4 TIC ratio in primary HGSOC biopsies is indicative for better RFS and response to chemotherapy., Highlights: • We observed a significant association between high pCXCR4/CXCR4 TIC ratio and better RFS in primary cancer biopsies, especially during the early postoperative follow-up and independent of known risk factors for recurrence. • High CXCR4 tumor expression in recurrent HGSOC biopsies might be indicative for sensitivity to chemotherapy. We found evidence that at the beginning of the disease (early follow-up) the role of the immune response seems to be the most crucial factor for progression. On the other hand in recurrent/progressive disease the biology of the tumor itself becomes more important for prognosis. • We explored for the first time the predictive and prognostic role of pCXCR4/CXCR4 TIC ratio in high-grade serous ovarian cancer., (© 2022. The Author(s).)

Background: Concern regarding suboptimal cure rates has led to some endocrine surgery units abandoning focused parathyroidectomy for primary hyperparathyroidism in favor of open bilateral neck exploration or making intraoperative parathyroid hormone estimation mandatory in focused parathyroidectomy. This study explores whether focused parathyroidectomy for radiologically localized primary hyperparathyroidism without intraoperative parathyroid hormone is still a valid approach., Methods: Retrospective review of a tertiary referral endocrine surgery unit database. All parathyroidectomies for primary hyperparathyroidism over 6 years (2013-2019) were included. Lithium-induced hyperparathyroidism, reoperations, familial disease, and concurrent thyroid surgery were excluded. Characteristics and outcomes for focused parathyroidectomy and open bilateral neck exploration were compared by intention-to-treat and treatment delivered. Persistence and recurrence, conversions and complications were analyzed as endpoints., Results: A total of 2,828 parathyroidectomies were performed and 2,421 analyzed. By intention to treat there were 1,409 focused parathyroidectomies and 1,012 open bilateral neck explorations. Focused parathyroidectomy patients were younger: 63 vs 66 years (P < .01); however, gender (77%, 79% female), preoperative peak serum calcium (2.72, 2.70 mmol/L [P = .23]), and serum parathyroid hormone (11.5, 11.0 pmol/L [P = .52]) did not differ. In total, 229 (16.3%) focused parathyroidectomies were converted to open bilateral neck exploration. Multiple gland disease was confirmed in 54.5% of converted patients. Median follow-up was 41 months (3-60 months). Persistence or recurrence requiring reoperation totaled 2.2% and did not differ between focused parathyroidectomy and open bilateral neck exploration in either intention to treat or final treatment analyses. Complications occurred in 1.2% of focused parathyroidectomy and 3.2% open bilateral neck exploration (P < .01)., Conclusions: In experienced hands and with a ready-selective approach to conversion, focused parathyroidectomy based on concordant imaging and without intraoperative parathyroid hormone may deliver equivalent cure rates to open bilateral neck exploration with significantly fewer complications. Focused parathyroidectomy without intraoperative parathyroid hormone should therefore be maintained in the endocrine surgeon's armamentarium., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The aim of this study was to compare the risk of complications and recurrence between oncoplastic and conventional breast surgery., Methods: This is a retrospective analysis of a consecutive series of 436 patients with stage I-III breast cancer who underwent surgery at the University Hospital of Basel between 2011 and 2018., Results: The nipple/skin-sparing mastectomy (NSM/SSM) group showed significantly more delayed wound healing (32.7 vs. 5.8%, p < 0.001) and skin necrosis (13.9 vs. 1.9%, p = 0.020) compared to conventional mastectomy (CM), which corresponded to significantly higher odds of short-term complications (OR 2.34, 95% CI 1.02-5.35, p = 0.044). The incidence rate of long-term morbidity in oncoplastic breast-conserving surgery (OBCS) was significantly higher compared to conventional breast-conserving surgery (CBCS; 25.5 vs. 11.3 per 100 patient years [PY], p < 0.001), in particular concerning chronic pain (13.3 vs. 6.6, p = 0.011) and lymphedema (4.1 vs. 0.4, p = 0.003). Seroma as a long-term morbidity occurred more often in the CM group compared to the NSM/SSM group (5.8 vs. 0.5 per 100 PY, p = 0.004). Patients received adjuvant treatment earlier after CM compared to NSM/SSM (HR 1.83, 95% CI 1.05-3.19, p = 0.034). There were no significant differences in the incidence of positive margins nor in the odds of recurrence after OBCS versus CBCS and after NSM/SSM versus CM., Conclusions: Even though the present study confirmed expected differences in complications and morbidity, it suggested that oncoplastic surgery is oncologically safe. Patients undergoing NSM/SSM should be followed closely to allow early detection and treatment of frequently associated complications and ensure timely start of adjuvant therapy., Competing Interests: W.P.W. has received research support from Takeda Pharmaceuticals International via Swiss Group for Clinical Cancer Research (SAKK), honoraria/consultation from Genomic Health, Inc., USA, and support for conferences and meetings from Sandoz, Genomic Health, Medtronic, Novartis Oncology, and Pfizer. J.L. has received personal fees for his work by the Department of Breast Surgery, University Hospital of Basel. C.K. has received research support from Roche, Tessaro, Genomic Health, Pfizer, Astra Zeneca, GSK, and Lilly., (Copyright © 2020 by S. Karger AG, Basel.)

Since colorectal cancer (CRC) remains one of the most common malignancies, a tremendous amount of studies keep taking place in this field. Over the past 25 years, a notable part of the scientific community has focused on the association between the immune system and colorectal cancer. A variety of studies have shown that high densities of infiltrating CD8+ T-cells are associated with improved disease-free and overall survival in CRC. Stromal cell-derived factor-1 (SDF-1) is a protein that regulates leukocyte trafficking and is variably expressed in several healthy and malignant tissues. There is strong evidence that SDF-1 has a negative prognostic impact on a variety of solid tumors. However, the existing data do not provide sufficient evidence that the expression of SDF-1 has an influence on CRC. Knowing nowadays, that the microenvironment plays a crucial role in the development of cancer, we hypothesized that the expression of SDF-1 in CRC could influence the prognostic significance of CD8+ T-cells, as an indicator of the essential role of the immune microenvironment in cancer development. Therefore, we explored the combined prognostic significance of CD8+ T-cell density and SDF-1 expression in a large CRC collective. We analyzed a tissue microarray of 613 patient specimens of primary CRCs by immunohistochemistry (IHC) for the CD8 + T-cells density and the expression of SDF-1 by tumor cells and tumor-infiltrating immune cells. Besides, we analyzed the expression of SDF-1 at the RNA level in The Cancer Genome Atlas cohort. We found that the combined high CD8+ T-cell infiltration and expression of SDF-1 shows a favorable 5-year overall survival rate (66%; 95% CI 48-79%) compared to tumors showing a high expression of CD8+ T-cell only (55%; 95% CI 45-64%; p = 0.0004). After stratifying the patients in nodal negative and positive groups, we found that the prognostic significance of CD8+ T-cell density in nodal positive colorectal cancer depends on SDF-1 expression. Univariate and multivariate Hazard Cox regression survival analysis considering the combination of both markers revealed that the combined high expression of SDF-1 and CD8+ T-cell density was an independent, favorable, prognostic marker for overall survival (HR = 0.34, 95% CI 0.17-0.66; p = 0.002 and HR = 0.45, 95% CI 0.23-0.89; p = 0.021, respectively). In our cohort there was a very weak correlation between SDF-1 and CD8+ T-cells (r s  = 0.13, p = 0.002) and in the trascriptomic expression of these two immune markers display a weak correlation (r s  = 0.28, p < 0.001) which was significantly more pronounced in stage III cancers (r s  = 0.40, p < 0.001). The combination of high CD8+ T-cell density and expression of SDF-1 represents an independent, favorable, prognostic condition in CRC, mostly in patients with stage III disease.

The incidence of thyroid cancer is rapidly increasing, mostly due to the overdiagnosis and overtreatment of differentiated thyroid cancer (TC). The increasing use of potent preclinical models, high throughput molecular technologies, and gene expression microarrays have provided a deeper understanding of molecular characteristics in cancer. Hence, molecular markers have become a potent tool also in TC management to distinguish benign from malignant lesions, predict aggressive biology, prognosis, recurrence, as well as for identification of novel therapeutic targets. In differentiated TC, molecular markers are mainly used as an adjunct to guide management of indeterminate nodules on fine needle aspiration biopsies. In contrast, in advanced thyroid cancer, molecular markers enable targeted treatments of affected signalling pathways. Identification of the driver mutation of targetable kinases in advanced TC can select treatment with mutation targeted tyrosine kinase inhibitors (TKI) to slow growth and reverse adverse effects of the mutations, when traditional treatments fail. This review will outline the molecular landscape and discuss the impact of molecular markers on diagnosis, surveillance and treatment of differentiated, poorly differentiated and anaplastic follicular TC.

Background/aim: To investigate whether teaching procedures and surgical experience are associated with surgical site infection (SSI) rates., Methods: This prospective cohort study of patients undergoing general, orthopedic trauma and vascular surgery procedures was done between 2012 and 2015 at two tertiary care hospitals in Switzerland/Europe., Results: Out of a total of 4560 patients/surgeries, 1403 (30.8%) were classified as teaching operations. The overall SSI rate was 5.1% (n = 233). Teaching operations (OR 0.78, 95% CI 0.57-1.07, p = 0.120), junior surgeons (OR 0.80, 95% CI 0.55-1.15, p = 0.229) and surgical experience (OR 0.997, 95% CI 0.982-1.012, p = 0.676) were overall not independently associated with the odds of SSI. However, for surgeons' seniority and experience, these associations depended on the duration of surgery., Conclusions: In procedures of shorter and medium duration, teaching procedures and junior as well as less experienced surgeons are not independently associated with increased odds of SSI., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Single-cell analyses have revealed extensive heterogeneity between and within human tumours 1-4 , but complex single-cell phenotypes and their spatial context are not at present reflected in the histological stratification that is the foundation of many clinical decisions. Here we use imaging mass cytometry 5 to simultaneously quantify 35 biomarkers, resulting in 720 high-dimensional pathology images of tumour tissue from 352 patients with breast cancer, with long-term survival data available for 281 patients. Spatially resolved, single-cell analysis identified the phenotypes of tumour and stromal single cells, their organization and their heterogeneity, and enabled the cellular architecture of breast cancer tissue to be characterized on the basis of cellular composition and tissue organization. Our analysis reveals multicellular features of the tumour microenvironment and novel subgroups of breast cancer that are associated with distinct clinical outcomes. Thus, spatially resolved, single-cell analysis can characterize intratumour phenotypic heterogeneity in a disease-relevant manner, with the potential to inform patient-specific diagnosis.

Objectives: Analysis of tumor immune infiltration has been suggested to outperform tumor, node, metastasis staging in predicting clinical course of colorectal cancer (CRC). Infiltration by cells expressing OX40, a member of the tumor necrosis factor receptor family, or CD16, expressed by natural killer cells, monocytes, and dendritic cells, has been associated with favorable prognosis in patients with CRC. We hypothesized that assessment of CRC infiltration by both OX40+ and CD16+ cells might result in enhanced prognostic significance., Methods: Colorectal cancer infiltration by OX40 and CD16 expressing cells was investigated in 441 primary CRCs using tissue microarrays and specific antibodies, by immunohistochemistry. Patients' survival was evaluated by Kaplan-Meier and log-rank tests. Multivariate Cox regression analysis, hazard ratios, and 95% confidence intervals were also used to evaluate prognostic significance of OX40+ and CD16+ cell infiltration., Results: Colorectal cancer infiltration by OX40+ and CD16+ cells was subclassified into 4 groups with high or low infiltration levels in all possible combinations. High levels of infiltration by both OX40+ and CD16+ cells were associated with lower pT stage, absence of peritumoral lymphocytic (PTL) inflammation, and a positive prognostic impact. Patients bearing tumors with high infiltration by CD16+ and OX40+ cells were also characterized by significantly longer overall survival, as compared with the other groups. These results were confirmed by analyzing an independent validation cohort., Conclusions: Combined infiltration by OX40+ and CD16+ immune cells is an independent favorable prognostic marker in CRC. The prognostic value of CD16+ immune cell infiltration is significantly improved by the combined analysis with OX40+ cell infiltration.

Purpose: Ovarian carcinoma (OC) is the most lethal female genital cancer. After a primary curative surgical approach followed by chemotherapy, a fraction of the patients recur with chemoresistant disease. Data indicate a favorable therapeutic effect of tumor-infiltrating neutrophils (TIN) in OC. Our aim was to investigate the prognostic role of CD66b expression, corresponding to neutrophilic infiltration for recurrence-free survival (RFS) and overall survival (OS) in patients with OC., Methods: A collective of 47 primary serous ovarian carcinoma and their matching recurrences were processed and stained with CD66b using immunohistochemistry. Tumors from patients with RFS of more than 6 months were defined as chemosensitive. Statistical analysis of CD66b expression was performed to assess the clinical endpoints., Results: High density of CD66b expressing neutrophils in primary carcinoma was associated with chemosensitivity (p = 0.014) and longer RFS (p = 0.001). Univariate analysis identified high density of CD66b expressing neutrophils as a predictor for favorable RFS (HR 0.41, 95% CI 0.22-0.76, p < 0.005). Residual disease > 2 cm (HR 3.67, 95% CI 1.62-8.31, p < 0.002) and higher number of chemotherapy cycles (HR 1.28, 95% CI 1.05-1.55, p < 0.013) were associated with worse RFS. Multivariate analysis showed that high density of CD66b expressing neutrophils (HR 0.22, 95% CI 0.10-0.48, p < 0.001) and residual disease > 2 cm (HR 3.69, 95% CI 1.43-9.53, p < 0.007) were independent predictors of RFS but had no impact on OS., Conclusion: High CD66b neutrophil density in primary high-grade OC predicts good response to initial chemotherapy and longer recurrence-free survival independent of known risk factors.

Background: Surgical site infections (SSIs) are common surgical complications that lead to increased costs. Depending on payer type, however, they do not necessarily translate into deficits for every hospital., Objective: We investigated how surgical site infections (SSIs) influence the contribution margin in 2 reimbursement systems based on diagnosis-related groups (DRGs)., Methods: This preplanned observational health cost analysis was nested within a Swiss multicenter randomized controlled trial on the timing of preoperative antibiotic prophylaxis in general surgery between February 2013 and August 2015. A simulation of cost and income in the National Health Service (NHS) England reimbursement system was conducted., Results: Of 5,175 patients initially enrolled, 4,556 had complete cost and income data as well as SSI status available for analysis. SSI occurred in 228 of 4,556 of patients (5%). Patients with SSIs were older, more often male, had higher BMIs, compulsory insurance, longer operations, and more frequent ICU admissions. SSIs led to higher hospital cost and income. The median contribution margin was negative in cases of SSI. In SSI cases, median contribution margin was Swiss francs (CHF) -2045 (IQR, -12,800 to 4,848) versus CHF 895 (IQR, -2,190 to 4,158) in non-SSI cases. Higher ASA class and private insurance were associated with higher contribution margins in SSI cases, and ICU admission led to greater deficits. Private insurance had a strong increasing effect on contribution margin at the 10th, 50th (median), and 90th percentiles of its distribution, leading to overall positive contribution margins for SSIs in Switzerland. The NHS England simulation with 3,893 patients revealed similar but less pronounced effects of SSI on contribution margin., Conclusions: Depending on payer type, reimbursement systems with DRGs offer only minor financial incentives to the prevention of SSI.

Background: Long-duration surgery requires repeated administration of antimicrobial prophylaxis (amp). Amp "redosing" reduces incidence of surgical site infections (SSI) but is frequently omitted. Clinical relevance of redosing timing needs to be investigated. Here, we evaluated the effects of compliance with amp redosing and its timing on SSI incidence in prolonged duration surgery., Methods: Data from >9000 patients undergoing visceral, trauma, or vascular surgery with elective or emergency treatment in two tertiary referral Swiss hospitals were analyzed. All patients had to receive amp preoperatively and redosing, if indicated. Antibiotics used were cefuroxime (1.5 or 3 g, if weight >80 kg), or cefuroxime and metronidazole (1.5 and 0.5 g, or 3 and 1 g doses, if weight >80 kg). Alternatively, in cases of known or suspected allergies, vancomycin (1 g), gentamicin (4 mg/Kg), and metronidazole or clindamycin (300 mg) with or without ciprofloxacin (400 mg) were used. Association of defined parameters, including wound class, ASA scores, and duration of operation, with SSI incidence was explored., Results: In the whole cohort, SSI incidence significantly correlated with duration of surgery (ρ = 0.73, p = 0.031). In 593 patients undergoing >240 min long interventions, duration of surgery was the only parameter significantly (p < 0.001) associated with increased SSI risk, whereas wound class, ASA scores, treatment areas, and emergency versus elective hospital entry were not. Redosing significantly reduced SSI incidence as shown by multivariate analysis (OR 0.60, 95% CI 0.37-0.96, p = 0.034), but exact timing had no significant impact., Conclusions: Long-duration surgery associates with higher SSI incidence. Irrespective of its exact timing, amp redosing significantly decreases SSI risk.

Background: Triple-negative breast cancer (TNBC) represents about 10-20% of all invasive breast cancers and is associated with a poor prognosis. The nectin cell adhesion protein 4 (Nectin-4) is a junction protein involved in the formation and maintenance of cell junctions. Nectin-4 has previously shown to be expressed in about 60% of TNBC as well as in TNBC metastases, but to be absent in normal breast tissue, which makes it a potential specific target for TNBC therapy. Previous studies have shown an association of Nectin-4 protein expression with worse prognosis in TNBC in a small patient cohort. The aim of our study was to explore the role of Nectin-4 in TNBC and confirm its impact on survival in a larger TNBC patient cohort. Material and Methods: We performed immunohistochemical staining for Nectin-4 on a tissue microarray encompassing 148 TNBC cases with detailed clinical annotation and outcomes data. Results: A high expression of Nectin-4 was present in 86 (58%) of the 148 TNBC cases. In multivariate survival analysis, high expression of Nectin-4 was associated with a significantly better overall survival when compared with low expression of Nectin-4 ( p < 0.001). Nectin-4-high expression was also significantly associated with a lower tumor stage ( p = 0.025) and pN0 lymph node stage ( p = 0.034). Conclusion: Our results confirm that expression of Nectin-4 serves as a potential prognostic marker in TNBC and is associated with a significantly better overall survival. In addition, Nectin-4 represents a potential target in TNBC, and its role in molecular defined breast cancer subtype should be investigated in larger patient cohorts., (Copyright © 2019 Zeindler, Soysal, Piscuoglio, Ng, Mechera, Isaak, Weber, Muenst and Kurzeder.)

Colorectal cancer (CRC) is a leading cause of cancer-related death. Conventional chemotherapeutic regimens have limited success rates, and a major challenge for the development of novel therapies is the lack of adequate in vitro models. Nonmalignant mesenchymal and immune cells of the tumor microenvironment (TME) are known to critically affect CRC progression and drug responsiveness. However, tumor drug sensitivity is still evaluated on systems, such as cell monolayers, spheroids, or tumor xenografts, which typically neglect the original TME. Here, it is investigated whether a bioreactor-based 3D culture system can preserve the main TME cellular components in primary CRC samples. Freshly excised CRC fragments are inserted between two collagen scaffolds in a "sandwich-like" format and cultured under static or perfused conditions up to 3 d. Perfused cultures maintain tumor tissue architecture and densities of proliferating tumor cells to significantly higher extents than static cultures. Stromal and immune cells are also preserved and fully viable, as indicated by their responsiveness to microenvironmental stimuli. Importantly, perfusion-based cultures prove suitable for testing the sensitivity of primary tumor cells to chemotherapies currently in use for CRC. Perfusion-based culture of primary CRC specimens recapitulates TME key features and may allow assessment of tumor drug response in a patient-specific context., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: The Rearranged during Transfection (RET) protein is overexpressed in a subset of Estrogen Receptor (ER) positive breast cancer, with both signalling pathways functionally interacting. This cross-talk plays a pivotal role in the resistance of breast cancer cells to anti-endocrine therapies, and RET expression is assumed to correlate with poor prognosis based on findings in small patient cohorts. The aim of our study was to investigate the impact of RET expression on patient outcome in human breast cancer., Methods: We performed an immunohistochemical analysis of RET protein expression on a tissue microarray encompassing 990 breast cancer patients and correlated its expression with clinicopathological parameters and survival data., Results: Expression of RET was detected in 409 out of 990 cases (41.3%). RET and ER expression significantly correlated (p < 0.0001). The Luminal B HER2-positive subtype showed the highest expression rate (48.9%). In univariate and multivariate survival analyses, RET expression had no impact on overall survival., Conclusion: We confirmed the co-expression of RET and ER, but we did not find RET expression to be an independent prognostic factor in human breast cancer. Clinical trials with newly developed RET inhibitors are needed to evaluate if RET inhibition has a beneficial impact on patient survival in ER positive breast cancer.

Background: Surgical drains are widely used despite limited evidence in their favor. This study describes the associations between drains and surgical site infections (SSI)., Methods: This prospective observational double center study was performed in Switzerland between February 2013 and August 2015., Results: The odds of SSI in the presence of drains were increased in general (OR 2.41, 95%CI 1.32-4.30, p = 0.004), but less in vascular and not in orthopedic trauma surgery. In addition to the surgical division, the association between drains and SSI depended significantly on the duration of surgery (p = 0.01) and wound class (p = 0.034). Furthermore, the duration of drainage (OR 1.24, 95%CI 1.15-1.35, p < 0.001), the number (OR 1.74, 95%CI 1.09-2.74, p = 0.019) and type of drains (open versus closed: OR 3.68, 95%CI 1.88, 6.89, p < 0.001) as well as their location (overall p = 0.002) were significantly associated with SSI., Conclusions: The general use of drains is discouraged. However, drains may be beneficial in specific surgical procedures., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Surgical site infections (SSI) are a major cause of morbidity and mortality in surgical patients. Postoperative and total hospital length of stay (LOS) are known to be prolonged by the occurrence of SSI. Preoperative LOS may increase the risk of SSI. This study aims at identifying the associations of pre- and postoperative LOS in hospital and intensive care with the occurrence of SSI., Methods: This observational cohort study includes general, orthopedic trauma and vascular surgery patients at two tertiary referral centers in Switzerland between February 2013 and August 2015. The outcome of interest was the 30-day SSI rate., Results: We included 4596 patients, 234 of whom (5.1%) experienced SSI. Being admitted at least 1 day before surgery compared to same-day surgery was associated with a significant increase in the odds of SSI in univariate analysis (OR 1.65, 95% CI 1.25-2.21, p < 0.001). More than 1 day compared to 1 day of preoperative hospital stay did not further increase the odds of SSI (OR 1.08, 95% CI 0.77-1.50, p = 0.658). Preoperative admission to an intensive care unit (ICU) increased the odds of SSI as compared to hospital admission outside of an ICU (OR 2.19, 95% CI 0.89-4.59, p = 0.057). Adjusting for potential confounders in multivariable analysis weakened the effects of both preoperative admission to hospital (OR 1.38, 95% CI 0.99-1.93, p = 0.061) and to the ICU (OR 1.89, 95% CI 0.73-4.24, p = 0.149)., Conclusion: There was no significant independent association between preoperative length of stay and risk of SSI while SSI and postoperative LOS were significantly associated.

Background: Optimal resource utilization in high-cost environments like operating theatres is fundamental in today's cost constrained health care systems. Interruptions of the surgical workflow, i.e. microcomplications (MC), lead to prolonged procedure times and higher costs and can be indicative of surgical mistakes. Reducing MC can improve operating room efficiency and prevent intraoperative complications. We, therefore, aimed to evaluate the impact of a high-resolution standardized laparoscopic cholecystectomy protocol (HRSL) on operative time and intraoperative interruptions in a teaching hospital., Methods: HRSL consisted of a detailed stepwise protocol for the procedure, supported by a teaching video, both to be reviewed as mandatory preparation by each team member before surgery. Audio-video records of laparoscopic cholecystectomies were reviewed regarding type, frequency and duration of MC before and after implementation of HRSL., Results: Thirty-nine (20 control and 19 HRSL) audio-video records of laparoscopic cholecystectomies with a total duration of 51.36 h (28.92 pre 22.44 post) were reviewed. The majority of operations (86%) were performed by teams who had completed less than 10 procedures together previously. Communication-related interruptions and instrument changes accounted for the majority of MC. Median frequency and duration of MC were 95 events/h and 15.6 min/h, respectively, of surgery pre-intervention. With HRSL this was reduced to 76 events/h and 10.6 min/h of operating. In multivariable analysis, HRSL was an independent predictor for shorter delay and lower frequency of MC [percentage decrease 27% (95% CI 18-35%), resp. 30% (95% CI 19-40%)]. Procedure-related risk factors for the longer delay due to MC in multivariable analysis were less experience of the surgeon and intraoperative adhesiolysis., Conclusions: HRSL is effective in reducing delays due to MC in a teaching institution with limited team experience. These findings should be tested in larger potentially cluster-randomized controlled trials. The trial has been registered with clinicaltrials.gov: NCT03329859.

Purpose: Indications for nipple-sparing mastectomy (NSM) have broadened to include the risk reducing setting and locally advanced tumors, which resulted in a dramatic increase in the use of NSM. The Oncoplastic Breast Consortium consensus conference on NSM and immediate reconstruction was held to address a variety of questions in clinical practice and research based on published evidence and expert panel opinion., Methods: The panel consisted of 44 breast surgeons from 14 countries across four continents with a background in gynecology, general or reconstructive surgery and a practice dedicated to breast cancer, as well as a patient advocate. Panelists presented evidence summaries relating to each topic for debate during the in-person consensus conference. The iterative process in question development, voting, and wording of the recommendations followed the modified Delphi methodology., Results: Consensus recommendations were reached in 35, majority recommendations in 24, and no recommendations in the remaining 12 questions. The panel acknowledged the need for standardization of various aspects of NSM and immediate reconstruction. It endorsed several oncological contraindications to the preservation of the skin and nipple. Furthermore, it recommended inclusion of patients in prospective registries and routine assessment of patient-reported outcomes. Considerable heterogeneity in breast reconstruction practice became obvious during the conference., Conclusions: In case of conflicting or missing evidence to guide treatment, the consensus conference revealed substantial disagreement in expert panel opinion, which, among others, supports the need for a randomized trial to evaluate the safest and most efficacious reconstruction techniques.

Background: Ovarian carcinoma (OC) is the fifth most common female cancer and mostly diagnosed at an advanced stage. Surgical debulking is usually followed by adjuvant platinum-based chemotherapy. Only few biomarkers are known to be related to chemosensitivity. OX40 is a TNF receptor member and expressed on activated CD4+ and CD8+ T cells. It is known that OX40 signaling promotes survival and responds to various immune cells of the innate and adaptive immune system. Therefore we investigated the indicative value of OX40 expression for recurrence and survival in OC., Methods: A tissue microarray of biopsies of mostly high-grade primary serous OC and matched recurrences of 47 patients was stained with OX40. Recurrence within 6 months of the completion of platinum-based chemotherapy was defined as chemoresistance., Results: Chemosensitivity correlated significantly with high OX40 positive immune cell density in primary cancer biopsies (p = 0.027). Furthermore patients with a higher OX40 expression in recurrent cancer biopsies showed a better outcome in recurrence free survival (RFS) (p = 0.017) and high OX40 expression was associated with chemosensitivity (p = 0.008). OX40 positive TICI in recurrent carcinomas significantly correlated with IL-17 positive tumor infiltrating immune cells in primary carcinomas (r s  = 0.34; p = 0.023). Univariate cox regression analysis revealed a significant longer RFS and higher numbers of chemotherapy cycles for high OX40 tumor cell expression in recurrent cancer biopsies (HR 0.39, 95%CI 0.16-0.94, p = 0.036 and 1.28, 95%CI 1.05-1.55; p = 0.013)., Conclusion: High OX40 expression in OC is correlated with chemosensitivity and improved RFS in OC. Patients might therefore benefit from a second line therapy.

Background: Routine preoperative blood work is not recommended but selected biochemical markers may predict the risk of surgical site infection (SSI). This study examines the association between preoperative biochemical markers and the risk of SSI., Methods: This observational cohort study, nested in a randomized controlled trial, was conducted at two tertiary referral centers in Switzerland., Results: 122 (5.8%) of 2093 patients experienced SSI. Preoperative increasing levels of albumin (OR 0.93), CRP (OR 1.34), hemoglobin (OR 0.87) and eGFR (OR 0.90) were significantly associated with the odds of SSI. The same accounts for categorized parameters. The highest area under the curve from ROC curves was 0.62 for albumin. Positive predictive values ranged from 6.4% to 9.5% and negative predictive values from 94.8% to 95.7%. The association of CRP, mildly and moderately decreased eGFR and hemoglobin with the odds of SSI remained significant on multivariate analysis., Conclusions: Our results do not support generally delaying elective surgery based on preoperative blood results. However, it may be considered in situations with potentially severe sequelae of SSI., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Tutorial assistance is related to extra time and cost, and the hospitals' financial compensation for this activity is under debate. We therefore aimed at quantifying the extra time and resulting cost required to train one surgical resident in the operating theatre for board certification in Switzerland as an example of a training curriculum involving several surgical subspecialties. Additionally, we intended to quantify the percentage of tutorial assistance., Methods: We analysed 200,700 operations carried out between 2008 and 2012. Median duration of procedure categories was calculated according to four different seniority levels. The extra time if the procedure was performed by residents, and resulting cost were analysed. The percentage of procedures carried out by residents as compared to more experienced surgeons was assessed over time., Results: On average, residents performed about a third of all operations including typical teaching procedures like appendectomies. An increase in duration and cost of well-defined procedures categories, e.g. cholecystectomies was demonstrated if a resident performed the procedure. In less well-defined categories, residents seemed to perform less difficult procedures than senior consultants resulting in shorter durations of surgery., Conclusions: The financial impact of tutorial assistance is important, and solutions need to be found to compensate for this activity. The low percentage of procedures performed by trainees may make it difficult to fulfil requirements for board certification within a reasonable period of time. This should be addressed within the training curriculum.

Background: Pregnancy at early age is the most significant modifiable factor which consistently decreases lifetime breast cancer risk. However, the underlying mechanisms haven't been conclusively identified. Studies in mice suggest a reduction in progesterone-receptor (PR) sensitive epithelial cells as well as a downregulation of the Wnt signaling pathway as being one of the main mechanisms for the protective effect of early pregnancy. The aim of our study was to validate these findings in humans., Methods: We collected benign breast tissue of 125 women who had been stratified according to age at first pregnancy and the occurrence of subsequent breast cancer, and performed immunohistochemistry for PR, Wnt4 and the Wnt-target Versican., Results: The number of PR positive epithelial cells was significantly lower in the group of women with early pregnancy and no subsequent breast cancer compared to the group of nulliparous women with subsequent invasive breast cancer (p = 0.0135). In women with early pregnancy, expression of Versican and Wnt4 was significantly lower compared to nulliparous women (p = 0.0036 and p = 0.0241 respectively), and Versican expression was also significant lower compared to women with late pregnancy (p < 0.0001)., Discussion: Our results confirm prior observations in mice and suggest a role of downregulation of epithelial Wnt signaling in the protective effect of early pregnancy in humans. This results in a decreased proliferation of stem/progenitor cells; therefore, the Wnt signaling pathway may represent a potential target for breast cancer prevention in humans.

Background: The lymph node status represents a major prognostic factor in colorectal cancer. However, it was demonstrated that neoadjuvant chemoradiotherapy (CRT) decreases the numbers of lymph nodes in the specimen. Several studies describe less than 12 lymph nodes in the resected specimen of rectal cancer patients after neoadjuvant radiation. This meta-analysis quantifies the influence of neoadjuvant CRT or radiotherapy (RT) only on the lymph node yield in rectal cancer patients., Methods: We performed a systematic review and searched PubMed, EMBASE and the Cochrane Library without any language restriction from 1st of January 1980 until 31st March 2015. Two reviewers examined all publications independently and extracted the relevant data if the study assessed lymph node counts or positive lymph node yields of patients who received neoadjuvant treatment compared with patients who did not receive neoadjuvant treatment. Meta-analyses were conducted to quantify the mean difference in lymph node yield., Results: A total of 34 articles (including 37 datasets) were included in the meta-analyses. Neoadjuvant CRT resulted in a mean reduction of 3.9 lymph nodes (95% confidence interval [CI] 3.7-4.1) and an average reduction in harvested positive lymph nodes of 0.7 (95% CI 0.2-1.2) compared with patients who received no neoadjuvant therapy. Individuals who received neoadjuvant RT had, in average, 2.1 lymph node less (95% CI 1.7-2.5) resected compared with their counterparts who received no neoadjuvant treatment., Conclusions: Neoadjuvant CRT or RT only in rectal cancer patients leads to a decrease in lymph node harvest of approximately four and two lymph nodes, respectively. We therefore stress the importance of intensifying all efforts from involved subspecialities (i.e. surgeons and pathologists) to reach the benchmark harvest of 12 resected lymph nodes according to current guidelines., (Copyright © 2016 Elsevier Ltd. All rights reserved.)