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Papillary thyroid cancer is associated with lymph node metastasis and tumor recurrence that need repeated surgery, entailing surgical challenges with a high risk of complications such as nerve damage and bleeding. Magseed is a metal coil used to detect non-palpable lesions and is an established modality in breast cancer surgery. In this case series, we explore the feasibility of Magseed in metastasis surgery of papillary thyroid cancer. Under the guidance of ultrasonography, Magseed is injected into the target tissue and intraoperatively detected with a handheld magnetometer probe, Sentimag®. Five patients with recurrence of papillary thyroid cancer were operated on with focused Magseed-guided localization. All patients had repeated surgery and radioiodine treatments. Four of the patients had lymph node metastasis hidden in the fibrosis, and one patient had recurrent tumor tissue on the left side of the larynx. Magseed was easy to use, safe, and precise in detecting the target tissue., Competing Interests: Declaration of competing interest All authors do not have any financial and personal relationships with other people or organizations that could inappropriately influence (bias) this work., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer in adults, presents significant challenges owing to its resistance to conventional therapies. Standard treatment primarily revolves around surgical methods, particularly nephrectomy, which is critical for managing localized diseases. Despite recent advancements, the metastatic potential of ccRCC necessitates ongoing vigilance in postoperative monitoring to manage and detect disease recurrence. Recent shifts in treatment paradigms, especially with the integration of molecular patterns in ccRCC, have enabled the development of targeted therapies. Immune checkpoint and tyrosine kinase inhibitors (TKIs) have become central to managing metastatic ccRCC, offering new hope through improved survival outcomes. Recent studies have corroborated this by demonstrating the benefits of combining these therapies., Case Presentation: This report discusses a case study of a patient with high-grade ccRCC and thyroid metastases initially deemed non-resectable. The combination of immunotherapy and TKIs reduced tumor size, transforming the thyroid metastasis to a resectable state., Conclusion: This case highlights significant advancements in treatment approaches and the critical in the management of ccRCC, underscoring the necessity for continuous adaptation of clinical practices to incorporate new therapeutic developments., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

The parathyroid cell is a vital regulator of extracellular calcium levels, operating through the secretion of parathyroid hormone (PTH). Despite its importance, the regulation of PTH secretion remains complex and not fully understood, representing a unique interplay between extracellular and intracellular calcium, and hormone secretion. One significant challenge in parathyroid research has been the difficulty in maintaining cells ex vivo for in-depth cellular investigations. To address this issue, we introduce a novel platform for parathyroid cell transplantation and noninvasive in vivo imaging using the anterior chamber of the eye as a transplantation site. We found that parathyroid adenoma tissue transplanted into the mouse eye engrafted onto the iris, became vascularized, and retained cellular composition. Transplanted animals exhibited elevated PTH levels, indicating a functional graft. With in vivo confocal microscopy, we were able to repetitively monitor parathyroid graft morphology and vascularization. In summary, there is a pressing need for new methods to study complex cellular processes in parathyroid cells. Our study provides a novel approach for noninvasive in vivo investigations that can be applied to understand parathyroid physiology and pathology under physiological and pathological conditions. This innovative strategy can deepen our knowledge on parathyroid function and disease., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The relationships between parathyroid hormone (PTH) secretion and parathyroid cell membrane potential, including the identities and roles of K + channels that regulate and/or modulate membrane potential are not well defined. Here we have used Western blot/immunohistochemistry as well as patch-clamp and perifusion techniques to identify and localize specific K + channels in parathyroid cells and to investigate their roles in the control of membrane potential and PTH secretion. We also re-investigated the relationship between membrane potential and exocytosis. We showed that in single human parathyroid cells K + current is dependent on at least two types of Ca 2+ -activated K + channels: a small-conductance Ca 2+ -activated K + channel (K SK ) and a large-conductance voltage and Ca 2+ -activated K + channel (K BK ). These channels were sensitive to specific peptide blocking toxins including apamin, charybdotoxin, and iberiotoxin. These channels confer sensitivity of the membrane potential in single cells to high extracellular K + , TEA, and peptide toxins. Blocking of K BK potently inhibited K + channel current, and K BK was shown to be expressed in the plasma membrane of parathyroid cells. In addition, when using the capacitance technique as an indicator of exocytosis, clamping the parathyroid cell at -60 mV prevented exocytosis, whereas holding the membrane potential at 0 mV facilitated it. Taken together, the results show that human parathyroid cells have functional K BK and K SK channels but the data presented herein suggest that K BK /K SK channels likely contribute to the maintenance of the membrane potential, and that membrane potential, per se, modulates exocytosis independently of [Ca 2+ ] i ., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Planning for return to work (RTW) is relevant among sub-groups of metastatic breast cancer (mBC) survivors. RTW and protective factors for RTW in patients with mBC were determined., Methods: Patients with mBC, ages 18-63 years, were identified in Swedish registers, and data were collected starting 1 year before their mBC diagnosis. The prevalence of working net days (WNDs) (>90 and >180) during the year after mBC diagnosis (y1) was determined. Factors associated with RTW were assessed using regression analysis. The impact of contemporary oncological treatment of mBC on RTW and 5-year mBC-specific survival was compared between those diagnosed in 1997-2002 and 2003-2011., Results: Of 490 patients, 239 (48.8%) and 189 (36.8%) had >90 and >180 WNDs, respectively, during y1. Adjusted odds ratios (AORs) of WNDs >90 or >180 during y1 were significantly higher for patients with age ≤50 years (AOR 180  = 1.54), synchronous metastasis (AOR 90  = 1.68, AOR 180  = 1.67), metastasis within 24 months (AOR 180  = 1.51), soft tissue, visceral, brain as first metastatic site (AOR 90  = 1.47) and sickness absence <90 net days in the year before mBC diagnosis, suggesting limited comorbidities (AOR 90  = 1.28, AOR 180  = 2.00), respectively. Mean (standard deviation) WNDs were 134.9 (140.1) and 161.3 (152.4) for patients diagnosed with mBC in 1997-2002 and 2003-2011, respectively (p = 0.046). Median (standard error) mBC-specific survivals were 41.0 (2.5) and 62.0 (9.6) months for patients diagnosed with mBC in 1997-2002 and 2003-2011, respectively (p < 0.001)., Conclusions: RTW of more than 180 WNDs was associated with younger age, early development of metastases and limited comorbidities during the year before the diagnosis of mBC. Patients diagnosed with mBC in 2003 or later had more WNDs and better survival than those diagnosed earlier., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Accumulating evidence indicates that tumor-associated macrophages promote tumor progression and that high macrophage infiltration is correlated with advanced tumor stages and poor prognosis in breast cancer. GATA binding protein 3 (GATA-3) is a differentiation marker related to differentiated states in breast cancer. In this study, we explore how the extent of MI relates to GATA-3 expression, hormonal status, and the differentiation grade of breast cancer. To examine breast cancer in early development, we selected 83 patients that were treated with radical breast-conserving surgery (R0), without lymph node metastases (N0) or distant metastases (M0), with and without postoperative radiotherapy. Immunostaining of M2-macrophage-specific antigen CD163 was used to detect tumor-associated macrophages, and macrophage infiltration was estimated semi-quantitatively into no/low, moderate, and high infiltration. The macrophage infiltration was compared to GATA-3, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), and Ki-67 expression in cancer cells. GATA-3 expression is associated with ER and PR expression but inversely correlated to macrophage infiltration and Nottingham histologic grade. High macrophage infiltration in advanced tumor grade was associated with low GATA-3 expression. The disease-free survival is inversely related to Nottingham histologic grade in patients having tumors with no/low macrophage infiltration, a difference that is not found in patients with moderate/high macrophage infiltration. These findings indicate that macrophage infiltration might impact the differentiation, malignant behavior, and prognosis of breast cancer, regardless of the morphological and hormonal states of the cancer cells in the primary tumor., Competing Interests: NO authors have competing interests., (Copyright: © 2023 Oda et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: To investigate the association between p53 expression in tumor cells and intratumoral macrophage infiltration in muscle-invasive urinary bladder cancer (MIBC) in relation to clinical and pathological variables and outcomes after radical cystectomy., Methods: Tumor specimens of the primary tumor from patients treated with radical cystectomy for MIBC were immunostained with the M2-macrophage-specific marker CD163 and the cell cycle protein p53. The expression of these markers was analyzed in relation to patients´ and tumor characteristics and outcome., Results: Out of 100 patients with urinary bladder cancer (UBC) pathological stage T1-4 N0-3 M0, 77% were men. The patients had a median age of 69 years and 80% had nonorgan-confined tumors (pT3-4). Lymph node metastasis was found in 42 (42%) of all patients. P53-positive expressions were found in 63 (63%) patients. Strong macrophage infiltration in the tumor microenvironment was shown in 74 (74%) patients. Combinations of CD163/p53 status were as follows: CD163+/p53+, 50%; CD163+/p53-, 24%; CD163-/p53+, 13%; and CD163-/p53-, 13%. Patients with CD163+/P53+ had higher proportions of organ-confined tumors., Conclusions: In the present series of patients with MIBC treated with cystectomy, we found that high CD163+ macrophage infiltration in the tumor micro-environment often was combined with p53+ cancer cells. This simultaneous expression of p53 by tumor cells and increased infiltration of M2-macrophages in the tumor microenvironment was associated with improved CSS, which might indicate a possible protective effect of M2 macrophages in p53+ tumors. Further investigations are needed to explore the biological relation between mutational burden and immune profile in MIBC., Competing Interests: Conflict of interest The authors have no conflict of interest., (Copyright © 2022. Published by Elsevier Inc.)

The clinical significance of thyroglobulin (Tg) expression in papillary thyroid cancer (PTC) has not been systematically explored in relation to the Ki-67 index, lymph node ratio (LNR), or other conventional prognostic predictors. In this retrospective study of 327 patients with PTC, we investigated the immunohistochemical expression of Tg in both primary tumors and their matching lymph node metastases in relation to the Ki-67 index, LNR, and clinical data. Tumoral Tg immunoreactivity was inversely correlated to the Ki-67 index and tumor recurrence. The Ki-67 index was higher in lymph node metastases (mean 4%) than in the primary tumors (mean 3%). Reduced Tg expression, estimated as 0-25% Tg positive tumor cells, was more common in lymph node metastases compared to primary tumors. In addition to advanced metastatic burden (defined as N1b stage and LNR ≥ 21%), low Tg expression (0-25% positive tumor cells) in lymph node metastases had a significant prognostic impact with shorter recurrence-free survival. These findings support the potential value of histopathological assessment of Tg expression and Ki-67 index in lymph node metastases as complementary predictors to anticipate the prognosis of PTC patients better., (© 2023. The Author(s).)

Objective: The aims of this study were to explore if the ambulatory fludrocortisone suppression test (FST) was safe, accurate and cost-effective., Context: The diagnosis of primary aldosteronism (PA) remains time-consuming and complex. The FST is used to confirm PA, but it is an in-patient test due to potentially serious complications such as hypokalemia. In Stockholm, FST has been performed since 2005 as an ambulatory procedure., Design: This is a retrospective study including all patients investigated with FST in four hospitals in Stockholm, Sweden, during 2005-2019., Patients/measurements: In total, 156 cases of ambulatory FST (FSTamb) and 15 cases of in-patient FST (FSTin) were included. FSTamb and FSTin were compared regarding health costs, clinical characteristics and laboratory results., Results: No difference was found in the outcomes of FSTamb and FSTin. No severe complications were reported in FSTamb patients. No difference was found in the median value for plasma potassium on Day 5 between the two groups. Only three patients (1.9%) in the FSTamb had to repeat the test due to incomplete intake of medications. FSTamb and FSTin were equally accurate. The cost of performing FSTamb was at least 50% lower compared with FSTin ($2400 vs. $5200 per patient). The time needed for FSTamb was 60 min of physician's time and 150 min of nurse's time which were lower than the 5 days in FSTin., Conclusions: Ambulatory FST is safe and accurate and can be performed with significantly less healthcare costs compared to FSTin., (© 2022 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

The aim of the study was to compare 3 blood sampling methods, including capillary blood sampling, for determining Tamoxifen (TAM), Z-endoxifen (END), and 4-hydroxytamoxifen (4HT) concentrations. High performance liquid chromatography-mass spectrometry was used to quantify concentrations of TAM, END, and 4HT in plasma, venous blood, and capillary blood samples of 16 participants on TAM therapy for breast cancer. The rhelise kit was used for capillary sampling. Calibration curves using 13 C-labeled analogs of TAM, END, and 4HT as internal standards were used for quantifications. A capillary sampling kit was used successfully for all participants. Mean TAM concentrations did not differ significantly in the 3 types of samples. Mean END and 4HT concentrations did differ significantly between capillary and venous blood samples, possibly related to photodegradation in the internal standards prior to use or degradation products with chromatographic retention times similar to the metabolites. TAM, END, and 4HT concentrations were relatively stable when stored for 14 days at 8 °C and 20 °C. Therapeutic drug monitoring of TAM using an innovative kit and capillary blood sampling is feasible. Preliminary data from this study will aid in developing a multicenter, randomized clinical trial of personalized TAM dose monitoring and adjustments, with the goal of enhancing the quality-of-life and outcomes of patients with breast cancer.Clinical Trial Identification: EudraCT No 2017-000641-44., (© 2022. The Author(s).)

Background: The N stage in papillary thyroid cancer (PTC) is an important prognostic factor based on anatomical localization of cervical lymph nodes (LNs) only and not the extent of lymphatic metastasis. In this retrospective study, the clinical significance of lymph node ratio (LNR) and tumor cell proliferation in relation to the conventional classification of PTC was explored., Methods: Patients diagnosed with PTC at the Karolinska University Hospital in Stockholm, Sweden, during the years 2009-2011 were included. The LNR, defined as the number of metastatic LNs divided by the total number of LNs investigated, and the Ki-67 index were analyzed in relation to clinical data., Results: The median number of LN removed was 16 with the following N stage distribution: N0 (26%), N1a (45%), and N1b (29%). A Ki-67 index of ≥3% was significantly correlated with the presence of metastases and tumor recurrence with a sensitivity of 50% and specificity of 80% (p = 0.015). Lymph node ratio ≥21% was related to tumor recurrence with sensitivity of 89% and specificity of 70% (p = 0.006). Patients with LN metastases in the lateral cervical compartment only had significantly lower LNR (14.5%) compared to those with both central and lateral cervical metastases (39.5%) (p = 0.004) and exhibited no tumor recurrence. Increased Ki-67 index was significantly related to LNR ≥21% (p = 0.023) but was not associated with N stage., Conclusions: The Ki-67 proliferation index and LNR may better reflect the malignant behavior of PTC compared to the anatomical classification of LN metastases solely.

Rarely, salivary gland tumors such as mucoepidermoid carcinoma, mammary analogue secretory carcinoma and mucinous carcinoma arise as primary tumors from ectopic or metaplastic salivary gland tissue adjacent to or within the thyroid gland. We report for the first time a case of primary salivary acinic cell carcinoma (AcCC) adjacent to the thyroid gland in a 71-year-old female patient with Crohns disease and a previous history of malignant melanoma. Following the development of a nodule adjacent to the left thyroid lobe, a fine-needle aspiration biopsy was reported as consistent with a follicular lesion of undetermined significance (Bethesda III). A left-sided hemithyroidectomy was performed. A circumscribed lesion measuring 33 mm was noted adjacent to the thyroid and trapping parathyroid, it was composed of solid nests and glands with microcystic and follicular patterns. The tumor was negative for thyroid, parathyroid and paraganglioma markers, but positive for pan-cytokeratins, CK7, CD10, CD117, androgen receptor and HNF-beta. A metastasis of a thyroid-like renal cell carcinoma was suspected but ruled out, and the patient had no evident lesions on extensive radiology of the urogenital, pulmonary and GI tracts. Based on the morphology, a diagnosis of AcCC was suggested, and confirmed with DOG1 and PAS-diastase staining. Molecular analyses pinpointed a constitutional ASXL1 variant of uncertain significance, but no fusion events. The patient had no radiological or clinical evidence of parotid, submandibular or sublingual tumors postoperatively, and the excised lesion was therefore assumed to be a primary tumor. We here detail the morphological and immunophenotypic profile of this previously undescribed perithyroidal tumor.

Cell-cell fusion is a normal biological process playing essential roles in organ formation and tissue differentiation, repair and regeneration. Through cell fusion somatic cells undergo rapid nuclear reprogramming and epigenetic modifications to form hybrid cells with new genetic and phenotypic properties at a rate exceeding that achievable by random mutations. Factors that stimulate cell fusion are inflammation and hypoxia. Fusion of cancer cells with non-neoplastic cells facilitates several malignancy-related cell phenotypes, e.g ., reprogramming of somatic cell into induced pluripotent stem cells and epithelial to mesenchymal transition. There is now considerable in vitro, in vivo and clinical evidence that fusion of cancer cells with motile leucocytes such as macrophages plays a major role in cancer metastasis. Of the many changes in cancer cells after hybridizing with leucocytes, it is notable that hybrids acquire resistance to chemo- and radiation therapy. One phenomenon that has been largely overlooked yet plays a role in these processes is polyploidization. Regardless of the mechanism of polyploid cell formation, it happens in response to genotoxic stresses and enhances a cancer cell's ability to survive. Here we summarize the recent progress in research of cell fusion and with a focus on an important role for polyploid cells in cancer metastasis. In addition, we discuss the clinical evidence and the importance of cell fusion and polyploidization in solid tumors., Competing Interests: Conflict-of-interest statement: Dr. Tim Spary received salary (not related to the submitted work) from Novintum Bioscience Ltd, London, England. The other authors have no conflict of interest., (©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.)

Mutations of the Telomerase reverse transcriptase ( TERT ) gene promoter are recurrently found in follicular thyroid carcinoma (FTC) and follicular tumors of uncertain malignant potential (FT-UMP), but nearly never in follicular thyroid adenoma (FTA). We, therefore, believe these mutations could signify malignant potential. At our department, postoperative TERT promoter mutational testing of FT-UMPs was implemented in 2014, with a positive mutation screening leading to vigilant follow-up and sometimes adjuvant treatment. To date, we screened 51 FT-UMPs and compared outcomes to 40 minimally invasive FTCs (miFTCs) with known TERT genotypes. Eight FT-UMPs (16%) displayed TERT promoter mutations, of which four cases underwent a completion lobectomy at the discretion of the patient, and a single patient also opted in for radioiodine (RAI) treatment. Three mutation-positive patients developed distant metastases, registered in one patient receiving a completion lobectomy and in two patients with no additional treatment. Three out of four patients who received additional surgery, including the RAI-treated patient, are still without metastatic disease. We conclude that FT-UMPs with TERT promoter mutations harbor malignant potential and exhibit at least similar recurrence rates to TERT - promoter-mutated miFTCs. Mutational screening should constitute a cornerstone analysis in the histopathological work-up of FT-UMPs., Competing Interests: The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Breast cancer (BC) intrinsic subtype classification is based on the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and proliferation marker Ki-67. The expression of these markers depends on both the genetic background of the cancer cells and the surrounding tumor microenvironment. In this study, we explore macrophage traits in cancer cells and intra-tumoral M2-macrophage infiltration (MI) in relation to intrinsic subtypes in non-metastatic invasive BC treated with breast conserving surgery, with and without postoperative radiotherapy (RT). Immunostaining of M2-macrophage-specific antigen CD163 in cancer cells and MI were evaluated, together with ER, PR, HER2, and Ki-67-expression in cancer cells. The tumors were classified into intrinsic subtypes according to the ESMO guidelines. The immunostaining of these markers, MI, and clinical data were analyzed in relation to ipsilateral local recurrence (ILR) as well as recurrence-free (RFS) and disease-free specific (DFS) survival. BC intrinsic subtypes are associated with T-stage, Nottingham Histologic Grade (NHG), and MI. Macrophage phenotype in cancer cells is significantly associated with NHG3-tumors. Significant differences in macrophage infiltration were observed among the intrinsic subtypes of pT1-T2 stage BC. Shorter RFS was observed in luminal B HER2neg tumors after RT, suggesting that this phenotype may be more resistant to irradiation. Ki-67-expression was significantly higher in NHG3 and CD163-positive tumors, as well as those with moderate and high MI. Cancer cell ER expression is inversely related to MI and thus might affect the clinical staging and assessment of BC.

Follicular neoplasms of the thyroid gland are most often characterized by follicular-patterned thyrocytes with a neutrally stained cytoplasm, while a minority of cases present with oncocytic differentiation (Hürthle cell tumors). Exceedingly rare variants with a clear cell phenotype have also been reported, both as clear cell follicular thyroid adenomas (ccFTAs) and clear cell follicular carcinomas (ccFTCs). We present a patient with a 30-mm lesion in the thyroid isthmus in which the preoperative cytology proposed a follicular tumor. On postoperative histopathological evaluation, the tumor surprisingly displayed uniform clear-cell differentiation. No nuclear features suggestive of papillary thyroid carcinoma were observed, and differential diagnoses such as medullary thyroid carcinoma, metastatic renal cell, and parathyroid carcinoma were ruled out. The histological investigation revealed intracapsular collections of tumor cells displaying a debatable relation to the surrounding capsule and blood vessels, and the final diagnosis was a follicular tumor of uncertain malignant potential (FT-UMP) as defined by the WHO 2017 classification. As subsets of FT-UMPs with TERT promoter mutations do recur as advanced malignant tumors, a sequencing analysis was undertaken but could not identify TERT promoter mutations at position C228 or C250. To our knowledge, no previous literature has described a clear cell phenotype in an FT-UMP. We therefore advocate that endocrine pathologists should be aware of this entity in addition to ccFTAs and ccFTCs.

Purpose: We investigated the effects of alterations in the biological markers p14, p53, p21, and p16 in relation to tumour cell proliferation, T-category, N- category, lymphovascular invasion, and the ability to predict prognosis in patients with muscle-invasive bladder cancer (MIBC) treated with cystectomy and, if applicable, chemotherapy., Materials and Methods: We prospectively studied patients with urinary bladder cancer pathological stage pT1 to pT4 treated with cystectomy, pelvic lymph node dissection and postoperative chemotherapy. Tissue microarrays from paraffin-embedded cystectomy tumour samples were examined for expression of immunostaining of p14, p53, p21, p16 and Ki-67 in relation to other clinical and pathological factors as well as cancer-specific survival., Results: The median age of the 110 patients was 70 years (range 51-87 years), and 85 (77%) were male. Pathological staging was pT1 to pT2 (organ-confined) in 28 (25%) patients and pT3 to pT4 (non-organ-confined) in 82 (75%) patients. Lymph node metastases were found in 47 patients (43%). P14 expression was more common in tumours with higher T-stages (P = 0.05). The expression of p14 in p53 negative tumours was associated with a significantly shorter survival time (P=0.003). Independently of p53 expression, p14 expression was associated with an impaired response to chemotherapy (P=0.001). The expression of p21 in p53 negative tumours was associated with significantly decrease levels of tumour cell proliferation detected as Ki-67 expression (P=0.03)., Conclusions: The simultaneous expression of the senescence markers involved in the p53-pathway shows a more relevant correlation to the pathological outcome of MIBC than each protein separately. P14 expression in tumours with non-altered (p53-) tumours is associated with poor prognosis. P14 expression is associated with impaired response to chemotherapy. P21 expression is related to decreased tumour cell proliferation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Follicular thyroid adenomas (FTAs) and carcinomas (FTCs), collectively the most common thyroid neoplasms, constitute a significant clinical challenge since histological evidence of invasive behaviour is required for a malignant diagnosis. Small subsets of FTAs relapse as manifest malignant FTCs, indicating that histology is not always adequate to predict malignant potential. Lately, recurrent mutations in the promoter of the Telomerase reverse transcriptase (TERT) gene have been coupled to FTCs, whereas FTAs usually lack this aberrancy. We describe three patients with follicular thyroid tumours in which TERT promoter mutational screening was employed as part of the clinical work-up to pinpoint malignant potential. In two retrospective analyses of seemingly benign lesions, the detected mutations predicted future skeletal metastases, and in one prospective case, the mutational screening led to a different clinical management of the afflicted patient. We therefore consider TERT promoter mutational screening an adjunct tool of value in equivocal cases.

Purpose: Cancer cell fusion with macrophages results in highly tumorigenic hybrids that acquire genetic and phenotypic characteristics from both maternal cells. Macrophage traits, exemplified by CD163 expression, in tumor cells are associated with advanced stages and poor prognosis in breast cancer (BC). In vitro data suggest that cancer cells expressing CD163 acquire radioresistance., Methods: Tissue microarray was constructed from primary BC obtained from 83 patients treated with breast-conserving surgery, 50% having received postoperative radiotherapy (RT) and none of the patients had lymph node or distant metastasis. Immunostaining of CD163 in cancer cells and macrophage infiltration (MI) in tumor stroma were evaluated. Macrophage:MCF-7 hybrids were generated by spontaneous in vitro cell fusion. After irradiation (0, 2.5 and 5 Gy γ-radiation), both hybrids and their maternal MCF-7 cells were examined by clonogenic survival., Results: CD163-expression by cancer cells was significantly associated with MI and clinicopathological data. Patients with CD163-positive tumors had significantly shorter disease-free survival (DFS) after RT. In vitro generated macrophage:MCF-7 hybrids developed radioresistance and exhibited better survival and colony forming ability after radiation compared to maternal MCF-7 cancer cells., Conclusions: Our results suggest that macrophage phenotype in tumor cells results in radioresistance in breast cancer and shorter DFS after radiotherapy.

Telomerase reverse transcriptase ( TERT ) promoter mutations have been linked to adverse clinical parameters in thyroid cancer, but TERT -expressing tumours are not always mutated. Little is known regarding other TERT -related genetic aberrations. To delineate the role of TERT gene aberrancies in follicular thyroid tumours, 95 follicular carcinomas (FTCs), 43 follicular adenomas (FTAs) and 33 follicular tumours of uncertain malignant potential (FT-UMPs) were collected. The tumours were assayed for TERT expression, TERT promoter mutations, TERT promoter hypermethylation and TERT gene copy number (CN) alterations and the results were compared to clinical parameters. Cases with mutation, detectable mRNA expression, CN gain or hypermethylation were classified as TERT aberrant, and these aberrancies were regularly found in FTC and FT-UMP but uncommonly found in FTA. In total, 59% FTCs and 63% FT-UMPs exhibited one or more of these TERT gene aberrancies. Moreover, 24 out of 28 FTCs (86%) with TERT expression displayed an evident TERT gene aberration, and statistics showed an increased risk for relapse in FTCs with TERT expression, CN gain or hypermethylation. We conclude that TERT expression in follicular thyroid tumours is coupled to promoter mutations, CN gain and increased promoter methylation. The molecular similarities regarding TERT aberrations between the FTC and FT-UMP groups indicate that a significant subset of FT-UMP cases may display future recurrences. TERT aberrancies are thus promising as future additional markers for determining malignant potential of follicular thyroid tumours., (© 2018 Society for Endocrinology.)

Background: Tumor-associated macrophages (TAMs) constitute a subset of nonneoplastic cells in tumor stroma and influence cancer progression in solid tumors. The clinical significance of TAMs in urinary bladder cancer (UBC) is controversial., Methods: We prospectively studied 103 patients with stage pT1-T4 UBC treated with cystectomy and pelvic lymph node dissection. Tumor sections were immunostained with M2-specific macrophage marker CD163 and proliferation marker Ki-67. The expression of these markers in cancer cells as well as macrophage infiltration (MI) in tumor stroma was analyzed in relation to clinical data and outcome., Results: The mean rate of CD163 and Ki-67 expressed by cancer cells were 35% and 78%, respectively. With borderline significance, MI was associated with lower rate of lymph node metastasis (P = 0.06). CD163 expression in cancer cells was proportional to MI (P<0.014). Patients with CD163-positive tumors and strong MI had significantly longer cancer-specific survival (CSS) (76 months), compared to patient with CD163-positive tumors and weak MI (28 months) (P = 0.02)., Conclusions: M2-specific MI tends to be inversely correlated with LN metastasis and improved CSS in UBC. MI might have protective impact in CD163-positive tumors. Expression of CD163 in cancer cells is significantly correlated with MI and might have a tumor promoting impact., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: To investigate the possibility of detecting sentinel lymph nodes (SNs) in patients with urinary bladder cancer (BCa) intra-operatively and whether the histopathological status of the identified SNs reflected that of the lymphatic field., Patients and Methods: We studied 103 patients with BCa pathological stage T1-T4 who were treated with cystectomy and pelvic lymph node (LN) dissection during 2005-2011 at the Department of Urology, Linköping University Hospital. Radioactive tracer Nanocoll 70 MBq and blue dye were injected into the bladder wall around the primary tumour before surgery. SNs were detected ex vivo during the operation with a handheld Geiger probe (Gamma Detection System; Neoprobe Corp., Dublin, OH, USA). All LNs were formalin-fixed, sectioned three times, mounted on slides and stained with haematoxylin and eosin. An experienced uropathologist evaluated the slides., Results: The mean age of the patients was 69 years, and 80 (77%) were male. Pathological staging was T1-12 (12%), T2-20 (19%), T3-48 (47%) and T4-23 (22%). A mean (range) number of 31 (7-68) nodes per patient were examined, totalling 3 253 nodes. LN metastases were found in 41 patients (40%). SNs were detected in 83 of the 103 patients (80%). Sensitivity and specificity for detecting metastatic disease by SN biopsy (SNB) varied between LN stations, with average values of 67% and 90%, respectively. LN metastatic density (LNMD) had a significant prognostic impact; a value of ≥8% was significantly related to shorter survival. Lymphovascular invasion (LVI) occurred in 65% of patients (n = 67) and was significantly associated with shorter cancer-specific survival (P < 0.001)., Conclusion: We conclude that SNB is not a reliable technique for peri-operative localization of LN metastases during cystectomy for BCa; however, LNMD has a significant prognostic value in BCa and may be useful in the clinical context and in BCa oncological and surgical research. LVI was also found to be a prognostic factor., (© 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.)

Cell fusion is a natural biological process in normal development and tissue regeneration. Fusion between cancer cells and macrophages results in hybrids that acquire genetic and phenotypic characteristics from both maternal cells. There is a growing body of in vitro and in vivo data indicating that this process also occurs in solid tumors and may play a significant role in tumor progression. However, investigations of the response of macrophage:cancer cell hybrids to radiotherapy have been lacking. In this study, macrophage:MCF-7 hybrids were generated by spontaneous in vitro cell fusion. After irradiation, both hybrids and their maternal MCF-7 cells were treated with 0 Gy, 2.5 Gy and 5 Gy γ-radiation and examined by clonogenic survival and comet assays at three time points (0 h, 24 h, and 48 h). Compared to maternal MCF-7 cells, the hybrids showed increased survival fraction and plating efficiency (colony formation ability) after radiation. The hybrids developed less DNA-damage, expressed significantly lower residual DNA-damage, and after higher radiation dose showed less heterogeneity in DNA-damage compared to their maternal MCF-7 cells. To our knowledge this is the first study that demonstrates that macrophage:cancer cell fusion generates a subpopulation of radioresistant cells with enhanced DNA-repair capacity. These findings provide new insight into how the cell fusion process may contribute to clonal expansion and tumor heterogeneity. Furthermore, our results provide support for cell fusion as a mechanism behind the development of radioresistance and tumor recurrence., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no conflicts of interests.

Background: Cell fusion is a natural process in normal development and tissue regeneration. Fusion between cancer cells and macrophages generates metastatic hybrids with genetic and phenotypic characteristics from both maternal cells. However, there are no clinical markers for detecting cell fusion in clinical context. Macrophage-specific antigen CD163 expression in tumor cells is reported in breast and colorectal cancers and proposed being caused by macrophages-cancer cell fusion in tumor stroma. The purpose of this study is to examine the cell fusion process as a biological explanation for macrophage phenotype in breast., Methods: Monocytes, harvested from male blood donor, were activated to M2 macrophages and co-cultured in ThinCert transwell system with GFP-labeled MCF-7 cancer cells. MCF7/macrophage hybrids were generated by spontaneous cell fusion, isolated by fluorescence-activated cell sorting and confirmed by fluorescence microscopy, short tandem repeats analysis and flow cytometry. CD163 expression was evaluated in breast tumor samples material from 127 women by immunohistochemistry., Results: MCF-7/macrophage hybrids were generated spontaneously at average rate of 2 % and showed phenotypic and genetic traits from both maternal cells. CD163 expression in MCF-7 cells could not be induced by paracrine interaction with M2-activated macrophages. CD163 positive cancer cells in tumor sections grew in clonal collection and a cutoff point >25 % of positive cancer cells was significantly correlated to disease free and overall survival., Conclusions: In conclusion, macrophage traits in breast cancer might be caused by cell fusion rather than explained by paracrine cellular interaction. These data provide new insights into the role of cell fusion in breast cancer and contributes to the development of clinical markers to identify cell fusion.

Background: We studied patients treated with radical cystectomy for locally advanced bladder cancer to compare the results of both preoperative positron emission tomography/computed tomography (PET/CT) and conventional CT with the findings of postoperative histopathological evaluation of lymph nodes., Methods: Patients who had bladder cancer and were candidates for cystectomy underwent preoperative PET/CT using 18-fluorodeoxyglucose (FDG) and conventional CT. The results regarding lymph node involvement were independently evaluated by two experienced radiologists and were subsequently compared with histopathology results, the latter of which were reassessed by an experienced uropathologist (HO)., Results: There were 54 evaluable patients (mean age 68 years, 47 [85%] males and 7 [15%] females) with pT and pN status as follows: < pT2-14 (26%), pT2-10 (18%), and > pT2-30 (56%); pN0 37 (69%) and pN+ 17 (31%). PET/CT showed positive lymph nodes in 12 patients (22%), and 7 of those cases were confirmed by histopathology; the corresponding results for conventional CT were 11 (20%) and 7 patients (13%), respectively. PET/CT had 41% sensitivity, 86% specificity, 58% PPV, and 76% NPV, whereas the corresponding figures for conventional CT were 41%, 89%, 64%, and 77%. Additional analyses of the right and left side of the body or in specified anatomical regions gave similar results., Conclusions: In this study, PET/CT and conventional CT had similar low sensitivity in detecting and localizing regional lymph node metastasis in bladder cancer.

The scavenger receptor, CD163, is a macrophage-specific marker. Recent studies have shown that CD163 expression in breast and rectal cancer cells is associated with poor prognosis. This study was conducted to evaluate the relationship between CD163 expression as a macrophage trait in cancer cells, and macrophage infiltration and its clinical significance in colorectal cancer. Immunostaining of CD163 and macrophage infiltration were evaluated in paraffin-embedded specimens, earlier analyzed for CD31, D2-40 and S-phase fraction, from primary tumors and normal colorectal mucosa of 75 patients with colorectal carcinoma. The outcomes were analyzed in relation to clinical-pathological data. CD163 expression was positive in cancer cells in 20 % of colorectal cancer patients and was related to advanced tumor stages (P = 0.008) and unfavorable prognosis (p = 0.001). High macrophage infiltration was related to shorter survival and positive CD163 expression in tumor cells. The prognostic impact of macrophage infiltration was independent of tumor stage and CD163 expression in cancer cells (p = 0.034). The expression of macrophage phenotype in colorectal cancer cells is associated with macrophage density in tumor stroma and lower survival rates. Macrophage infiltration has an independent prognostic impact on mortality in colorectal cancer. In accordance with previous experimental studies, these findings provide new insights into the role of macrophages in colorectal cancer.

Background: The transmembrane adapter protein, DAP12, transduces activation signals for several arrays of receptors, including human signal-regulatory protein, DAP12-associating lectin-1, triggering receptor expressed on myeloid cells-1, -2, and -3, in natural killer cells, granulocytes, monocytes/macrophages, and dendritic cells. The macrophage-specific antigen, Cluster of Differentiation 163 (CD163), is expressed in breast and colorectal cancers and is associated with early cancer recurrence and poor prognosis. It was recently shown that fusion between intestinal tumor cells and macrophages results in nuclear reprogramming with hybrid transcripts from both cells of origin. The role of DAP12 in the fusion process is not known. This study investigates the expression of DAP12 in BRC cells, and its relation to other macrophage traits and to the clinical progression of disease., Materials and Methods: Immunostaining of DAP12 and CD163 was performed and evaluated in paraffin-embedded specimens from 132 patients with BRC. The outcomes were analyzed in relation to clinicopathological data., Results: DAP12 expression in cancer cells was positive in 66 percent of the cancers and was associated with high tumor grade (P = .015), and with liver (P = .047) and skeletal (P = .067), but not with lung metastases (P = 1.00). Patients with BRC expressing DAP12 had poor prognosis, with higher recurrence rates of skeletal (P = .018) and liver metastases (P = .047), and shorter survival time (P = .0060)., Conclusion: We suggest that macrophage traits in BRC cells facilitate the metastatic process and that DAP12 expression might promote metastatic homing to bone and liver tissues., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Aims: To determine the possible advantage of intra-arterial injection of methylene blue with a view to improving lymph node recovery in postoperative examination of colorectal cancer specimens., Methods and Results: Thirty-two colorectal cancer specimens were assigned randomly to either dissection with intra-arterial methylene blue injection or to routine dissection (without methylene blue injection). Immediately postoperatively, the specimens in the staining group were injected intra-arterially with methylene blue dye. The two procedures were compared with respect to the number of lymph nodes recovered. The number of recovered lymph nodes was significantly higher in the intra-arterial methylene blue injection group than in the group investigated with routine procedures (P<0.0001)., Conclusion: The intra-arterial methylene blue injection method is fairly easy to use postoperatively and increases significantly the number of lymph nodes recovered in colorectal cancer specimens., (© 2011 Blackwell Publishing Limited.)

Macrophages are a heterogeneous cell population of the myeloid linage derived from monocytes. These cells show two different polarization states, M1 and M2 macrophages in response to different micro environmental signals. Tumor associated macrophages (TAM) represent the M2 type and promote tumor progression. These cells express antigens that more or less are specific for macrophages like: CD14, CD68, MAC387, CD163, and DAP12. In a series of recent studies it is shown that cancer cells may express these antigens and CD163, MAC387 and DAP12 may be expressed by e.g. breast cancer cells. Thus, 48% of the breast cancers expressed CD163 that is a scavenger receptor normally expressed by macrophages alone. The corresponding figure for rectal cancer is 31%. The expression of CD163 is correlated to early distant recurrence in breast cancer and local recurrence in rectal cancer and reduced survival time in both conditions. Expression of macrophage antigens in breast- and colorectal-cancers may have a prognostic relevance in clinical praxis. One explanation to these findings is that resemblance with macrophages may indicate a more invasive phenotype due to genetic exchange between the primary tumor cells and associated macrophages. This is further supported by the finding that expression of DAP12, a macrophage fusion receptor, in breast cancer is associated with an advanced tumor grade and higher rates of skeletal and liver metastases and overall shorter distant recurrence free survival. Another explanation to the changed phenotype is a genetic exchange between the cells by exosome-mediated transfer.

Expression of the macrophage antigen CD163 in breast cancer cells is recently shown to be related to early distant recurrence and shortened survival. In this study, 163 patients with rectal cancer, included in the Swedish rectal cancer trial and followed up for a median of 71 months, were examined for the expression of CD163 in the primary tumors. The cancer cells expressed CD163 in the primary tumors in 23% (n = 32) of the patients. In pretreatment biopsies from 101 patients, 10 had CD163-positive cancers and these patients had earlier local recurrence (p < 0.044) and reduced survival time (p < 0.045) compared with those with CD163-negative tumors. When studying surgical specimens from 61 patients randomized to preoperative irradiation (5 x 5 Gy delivered in 1 week), it was found that 31% were CD163 positive whereas the corresponding figure was only 17% for 78 patients who were nonirradiated (p < 0.044), which tentatively may be consistent with X-rays inducing fusion. In CD163-positive tumors there was a reduced apoptotic activity as measured with the Termina deoxynucleotidyl Transferase Biotin-dUTP Nick End Labeling (TUNEL) technique (p = 0.018). There tended also to be an increased proliferation activity measured as an expression of Ki-67 non significant (NS). It is concluded that primary rectal cancers may express CD-163, and this phenotypic macrophage trait is related to early local recurrence, shorter survival time and reduced apoptosis. Furthermore, the expression of CD163 is more common after irradiation.

Cells of the monocyte/macrophage lineage are important for tumour cell migration, invasion and metastasis. Fusion between macrophages and cancer cells in animal models in vitro and in vivo causes hybrids with increased metastatic potential. Primary breast cancer cells were characterized for macrophage antigens to test if phenotypic resemblance to macrophages is related to early distant recurrence. Immunostaining for CD163, MAC387 and CD68 was performed in a breast cancer tissue micro array from 127 patients consequently followed up for a median of 13 years. Tumour-associated macrophages expressed all 3 antigens. The breast cancers expressed CD163 to 48%, MAC387 to 14% while CD68 was not expressed. TGF-beta staining intensity was positively related to both CD163 and MAC387 expression. Expression of CD163 in the cancer cells was compared to their DNA ploidy, Nottingham Histological Grade, TNM-stage, node state, presence of estrogen receptors and occurrence of distant metastases and survival. Cancers of a more advanced histological grade expressed CD163 to a higher extent. Cells expressing MAC387 were more common in cancers with a high proportion of CD163 positive cells. Multivariate analysis showed that expression of the macrophage antigen CD163 in breast cancer cells has a prognostic impact on the occurrence of distant metastases and reduced patient survival time., ((c) 2008 Wiley-Liss, Inc.)

Background: Molecular typing of Helicobacter spp. in clinical biopsy specimens has become increasingly important. By means of nested polymerase chain reaction (PCR) amplification and Southern blot analysis of the PCR amplicons, we have shown that Helicobacter spp. DNA is present in human gallstones. In this study we have investigated the possibility of using multiple displacement amplification (MDA) of isolated gallstone DNA and pyrosequencing analysis for the molecular identification of Helicobacter spp., Materials and Methods: DNA isolated from the nucleus of 33 human gallstones and one control strain were used in a MDA assay. Subsequently, pyrosequencing analysis was performed either directly on MDA-DNA using primers flanking the Helicobacter spp. 16S rDNA variable V3 region or on PCR amplicons derived from broad-range primers flanking the 16S rDNA variable V3, V4, and V9 regions., Results: Pyrosequencing analysis of 16S rDNA derived from MDA-DNA revealed that Helicobacter spp.-like DNA was present in 25 of 33 (approximately 76%) gallstones. Using an H. pylori-specific Southern blot analysis, Helicobacter spp.-like DNA was present in 20 of 33 [approximately 61%] of the gallstones. Using MDA-DNA directly in pyrosequencing analysis, Helicobacter spp.-like DNA was present in 13 of 33 [approximately 39%] gallstones., Conclusions: We conclude that multiple displacement amplification combined with pyrosequencing enables a rapid and accurate molecular typing of Helicobacter spp. from small and precious biopsy specimens.

Gallbladder cancer is a rare disease with poor prognosis and short survival time. The condition is usually associated with gallstones and predominantly affects women. We have taken data from the National Cancer Register and the Cause of Death Register in Sweden and studied the annual incidence of and mortality due to gallbladder cancer from 1988 to 1997. Incidence has declined during this period, which may be explained by a high rate of cholecystectomies in Sweden between 1950 and 1970. Prognosis has traditionally been poor, with a median survival time of 3.5 months, which might be explained by the fact that the disease usually is diagnosed at an advanced stage. Epidemiological figures show that prognosis may have improved during the past decade. In several retrospective studies, mainly from Japan, better results with longer survival times are reported after extended surgery. In a small group of 11 patients with gallbladder cancer, Nevin grade II-V, who underwent extended surgery at The University Hospital in Linköping, there are no signs of recurrent disease in 10 patients after a follow-up of 1-8 years.