The single-cell pathology landscape of breast cancer.

Single-cell analyses have revealed extensive heterogeneity between and within human tumours1-4, 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 cytometry5 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.

Management of Medullary Thyroid Cancer: Patterns of Recurrence and Outcomes of Reoperative Surgery.

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.

Unexpected deaths after endocrine surgery: learning from rare events using a national audit of surgical mortality.

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.

High ratio of pCXCR4/CXCR4 tumor infiltrating immune cells in primary high grade ovarian cancer is indicative for response to chemotherapy.

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.

Persistent acute cholecystitis after cholecystostomy - increased mortality due to treatment approach?

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.

Efficacy of intraoperative cholangiography versus preoperative magnetic resonance cholangiography in patients with intermediate risk for common bile duct stones.

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).

Tumor Infiltration by OX40+ Cells Enhances the Prognostic Significance of CD16+ Cell Infiltration in Colorectal Cancer.

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.

Infiltration by myeloperoxidase-positive neutrophils is an independent prognostic factor in breast cancer.

PURPOSE: Myeloperoxidase (MPO) is an enzyme secreted by neutrophil granulocytes as a result of phagocytosis during inflammation. In colorectal cancer, tumour infiltration by MPO expressing cells has been shown to be independently associated with a favourable prognosis. In this study, we explored the role of MPO-positive cell infiltration and its prognostic significance in invasive breast cancer. METHODS: We performed immunohistochemical staining for MPO on multiple tissue microarrays comprising a total of 928 human breast cancer samples with detailed clinical-pathological annotation and outcome data. RESULTS: MPO-positive cell infiltration (≥ 5 cells/tissue punch) was found in 150 (16%) of the 928 evaluable breast cancer cases. In univariate survival analyses, infiltration by MPO-positive cells was associated with a significantly better overall survival (p < 0.001). In subset univariate analyses, the infiltration by MPO-positive cells was associated with significantly better overall survival in the Luminal B/HER2-negative subtype (p = 0.005), the HER2 enriched subtype (p = 0.011), and the Triple Negative subtype (p < 0.001). In multivariate analysis, MPO expression proved to be an independent prognostic factor for improved overall survival (p < 0.001). CONCLUSIONS: This is the first study to show that infiltration of MPO-positive cells is an independent prognostic biomarker for improved overall survival in human breast cancer.

Expression of RET is associated with Oestrogen receptor expression but lacks prognostic significance in breast cancer.

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.

Antimicrobial Prophylaxis Redosing Reduces Surgical Site Infection Risk in Prolonged Duration Surgery Irrespective of Its Timing.

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.

Oncoplastic Breast Consortium consensus conference on nipple-sparing mastectomy.

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.

High OX40 expression in recurrent ovarian carcinoma is indicative for response to repeated chemotherapy.

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.

High-resolution standardization reduces delay due to workflow disruptions in laparoscopic cholecystectomy.

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.

Associations of Hospital Length of Stay with Surgical Site Infections.

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.

Tutorial Assistance for Board Certification in Surgery: Frequency, Associated Time and Cost.

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.

MPO density in primary cancer biopsies of ovarian carcinoma enhances the indicative value of IL-17 for chemosensitivity.

BACKGROUND: Cancer of the ovary is mostly discovered at a late stage and cannot be removed by surgery alone. Therefore surgery is usually followed by adjuvant chemotherapy. However, few reliable biomarkers exist to predict response to chemotherapy of ovarian cancer. Previously, we could demonstrate that IL-17 density is indicative for chemosensitivity. This study focuses on the predictive value of myeloperoxidase (MPO) concerning response to chemotherapy of ovarian cancer. METHODS: Biopsies of mostly high-grade primary serous ovarian carcinomas and their matched recurrences were stained with MPO after fixation in formalin and embedding in paraffin. For this staining the technique of tissue-microarray was used. Recurrence within 6 months of the completion of platinum-based chemotherapy was defined as chemoresistance as previously publised. Data for MPO could be analyzed in 92 biopsies. RESULTS: MPO and IL-17 positive immune cells correlated significantly in biopsies of primary and recurrent carcinomas (r s = 0.41; p = 0.004 and r s = 0.40; p = 0.007, respectively). MPO expression alone did not predict response to chemotherapy, but in multivariate cox regression analysis including age, residual disease, number of chemotherapy cycles, FIGO classification and combined categorized MPO and IL-17 cell densities of primary cancer biopsies, the combination of both immune markers was an independent prognostic factor for recurrence-free survival (p = 0.013, HR = .23, 95CI = 0.07-0.73). There was no chemoresistant patient in the subgroup of MPO + IL-17+, neither in primary nor in recurrent cancer biopsies. CONCLUSIONS: High MPO positive cell density enhances the indicative value of IL-17 for response to chemotherapy in ovarian carcinoma. Although, these results have to be validated in a larger cohort.

A Nod to the Nodes: An Overview of the Role of Central Neck Dissection in the Management of Papillary Thyroid Carcinoma.

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.

Natural History and Predictive Factors of Outcome in Medullary Thyroid Microcarcinoma.

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.

Identification of TPM2 and CNN1 as Novel Prognostic Markers in Functionally Characterized Human Colon Cancer-Associated Stromal Cells.

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.

A high-throughput drug screen reveals means to differentiate triple-negative breast cancer.

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.