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Background Investigation of lymph node micrometastasis (mN) of gastric cancer has been focused on either T1 disease or T1-4N0 disease. Yet, it is unclear whether standard management algorithm toward poorly differentiated gastric cancer (PDGC) is more vulnerable to existence of mN, given its inherently biological aggressiveness, as compared with other histological types. Patients and methods A surgical series (n = 3456) of gastric cancer categorized by histological differentiation was enrolled to analyze survival stratification. Of them, a cohort of T1-T4 N0 PDGC (n = 100) were subjected to cytokeratin immunohistochemistry, a surrogate of mN. Results Cancer-specific survival by AJCC8 staging system could be nicely differentiated in both well-/moderately differentiated and signet ring cell types, while those between stage IA versus IB (p = 0.105), and stage IB versus IIA (p = 0.141) in PDGC could not. Thirteen (13%) out of 100 node-negative PDGC cases exhibited mN, with 5, 2, 5 and 1 cases occurring in T1, T2, T3, and T4 stage, respectively, without identifiable contributing factors. Prognostic performance of AJCC8 working upon PDGC became more discriminative by incorporating mN, as hazard ratio of stage IIIC referenced to stage IA increased from 43 to 78. Conclusion Defective discriminative survival of PDGC by standard staging algorithm prompted us to survey mN occurring in T1-T4N0 PDGC. The prognostic performance of AJCC8 working upon PDGC was enhanced by incorporating mN. As so, we recommend documentation of mN exclusively on node-negative PDGC that helps unveil stage migration phenomenon and switch to appropriate adjuvant therapy in need.

Detection of nodal micrometastasis (tumor size: 0.2–2.0 mm) is challenging for pathologists due to the small size of metastatic foci. Since lymph nodes with micrometastasis are counted as positive nodes, detecting micrometastasis is crucial for accurate pathologic staging of colorectal cancer. Previously, deep learning algorithms developed with manually annotated images performed well in identifying micrometastasis of breast cancer in sentinel lymph nodes. However, the process of manual annotation is labor intensive and time consuming. Multiple instance learning was later used to identify metastatic breast cancer without manual annotation, but its performance appears worse in detecting micrometastasis. Here, we developed a deep learning model using whole-slide images of regional lymph nodes of colorectal cancer with only a slide-level label (either a positive or negative slide). The training, validation, and testing sets included 1963, 219, and 1000 slides, respectively. A supercomputer TAIWANIA 2 was used to train a deep learning model to identify metastasis. At slide level, our algorithm performed well in identifying both macrometastasis (tumor size > 2.0 mm) and micrometastasis with an area under the receiver operating characteristics curve (AUC) of 0.9993 and 0.9956, respectively. Since most of our slides had more than one lymph node, we then tested the performance of our algorithm on 538 single-lymph node images randomly cropped from the testing set. At single-lymph node level, our algorithm maintained good performance in identifying macrometastasis and micrometastasis with an AUC of 0.9944 and 0.9476, respectively. Visualization using class activation mapping confirmed that our model identified nodal metastasis based on areas of tumor cells. Our results demonstrate for the first time that micrometastasis could be detected by deep learning on whole-slide images without manual annotation.

AIM Minimal residual disease (MRD) is the net result of the biological properties of disseminated tumour cells and the effect of the immune system and treatment to eliminate them. The aim of this work is to report the changes in MRD status and immune function (lymphocyte count) after FOLFOX chemotherapy, and the outcome in Stage III colon cancer patients. METHOD This study is a prospective, single-centre observational study. Lymphocyte counts were determined prior to and 1, 2 and 3 months after the completion of chemotherapy. Circulating tumour cells (CTCs) and bone marrow micrometastases were determined using immunocytochemistry with anticarcinoembryonic antigen prior to and 1 month after chemotherapy. MRD was classified as negative (Group I), micrometastasis positive only (Group II) and CTC positive (Group III). Changes in lymphocyte counts and MRD subtype following chemotherapy and relapse-free progression were analysed. RESULTS Of the total of 185 patients, 83 (44.9%) relapsed. The risk of relapse significantly increased from Groups I to III (p

Chenlu Liang, Liuyi Li, Meizhen Zhu, Jiejie Hu, Yang Yu Department of Breast Tumor Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, People’s Republic of ChinaCorrespondence: Yang YuDepartment of Breast Tumor Surgery, Zhejiang Cancer Hospital, No. 1, Banshan Road, Hangzhou, 310022, Zhejiang Province, People’s Republic of ChinaTel/Fax +86 571 8812 2011Email yuyangkaiyu@163.comPurpose: The results of large randomised trials have changed the treatment strategy of axillary lymph nodes. Axillary lymph node dissection (ALND) can be avoided in some patients with one to two sentinel lymph nodes (SLNs) metastasis based on final paraffin section (FPS) results which called into question the need for intraoperative frozen section (FS). This study aims to assess the guiding value of the number of positive SLN detected via FS for intraoperative ALND.Patients and Methods: This study retrospectively analyzed data from 3303 patients with breast cancer who underwent SLN biopsy between 2015 and 2019. Combined with the FPS results, FS sensitivity, specificity, and false negative rate (FNR) were calculated and the difference in the number of positive SLNs between FS and FPS was analyzed.Results: The overall FNR of FS was 23.21%, which was 76.47% in isolated tumor cells, 62.28% in micrometastasis, and 12.09% in macrometastatic disease. The size of SLN metastasis were significantly associated with a higher FNR (p< 0.001). The accuracy rate of the number of positive SLNs detected via FS was 92.62%. Human epidermal growth factor receptor 2 (HER2) (p< 0.03) and Ki67 (p< 0.02) were significant factors affecting the accuracy rate.Conclusion: FS is a effective method for SLN biopsy, ALND can be avoided in patients with one or two positive SLNs detected via FS.Keywords: breast neoplasms, sentinel lymph node, frozen section, false negative rate, axillary lymph node dissection

Shuli Hu,1 Man Luo,2 Yaling Li1 1Department of Intensive Care Unit, Wuhan No. 1 Hospital, Wuhan, 430022, People’s Republic of China; 2Department of Oncology, Wuhan No.1 Hospital, Wuhan, 430022, People’s Republic of ChinaCorrespondence: Yaling LiDepartment of Intensive Care Unit, Wuhan No.1 Hospital, 215 Zhongshan Road, Wuhan, Hubei Province, People’s Republic of ChinaTel +86 027-85332691Email 2861696710@qq.comPurpose: The lymph node gross target volume (GTV) delineation in patients with non-small cell lung cancer (NSCLC) is crucial for prognosis. This study aimed to develop a predictive model that can be used to differentiate between lymph nodes micrometastasis (LNM) and non-lymph nodes micrometastasis (non-LNM).Patients and Methods: A retrospective study involving 1524 patients diagnosed with NSCLC was collected in the First Hospital of Wuhan between January 1, 2017, and April 1, 2020. Duplicated and useless variables were excluded, and 16 candidate variables were selected for further analysis. The random forest (RF) algorithm and generalized linear (GL) algorithm were used to screen out the variables that greatly affected the LNM prediction, respectively. The area under the curve (AUC) was compared between the RF model and GL model.Results: The RF model revealed that the variables, including pathology, degree of differentiation, maximum short diameter of lymph node, tumor diameter, pulmonary membrane invasion, clustered lymph nodes, and T stage, were more significant for LNM prediction. Multifactorial logistic regression analysis for the GL model indicated that vascular invasion, tumor diameter, degree of differentiation, pulmonary membrane invasion, and maximum standard uptake value (SUVmax) were positively associated with LNM. The AUC for the RF model and GL model was 0.83 (95% CI: 0.75 to 0.90) and 0.64 (95% CI: 0.60 to 0.70), respectively.Conclusion: We successfully established an accurate and optimized RF model that could be used to predict LNM in patients with NSCLC. This model can be used to evaluate the risk of an individual patient experiencing LNM and therefore facilitate the choice of treatment.Keywords: non-small cell lung cancer, lymph nodes micrometastasis, prediction model, random forest, gross target volume, machine learning

In recent years, there has been a progressive trend towards less invasive technologies for detecting metastatic cancer and guiding therapy with the goal of lower morbidity, better outcomes, and superior cosmetic appearance than traditional methods. This mini-review examines three emerging noninvasive hybrid technologies for detecting primary cancer, metastasis and guiding thermal therapy. Real-time thermoacoustic imaging and thermometry potentially provides valuable and critical feedback for guiding focused microwave ablation therapy. Label-free photoacoustic monitoring of cancer cells is a promising clinical diagnostic and theranostic tool for detecting metastatic disease and monitoring the response to therapy. Finally, immunologically targeted gold nanoparticles combined with photoacoustic imaging is able to detect lymph node micrometastasis in mouse models of breast cancer. These emerging techniques have the potential to improve the decision to biopsy, provide more accurate prognosis, and enhance the efficacy of therapy for early and late stage cancers.

Our study aimed to validate the clinicopathological characteristics and prognosis of lung adenocarcinoma (ADC) with a filigree pattern and to further investigate the relationship between the filigree pattern and the classical micropapillary (MP) pattern. We retrospectively reviewed the clinical and pathologic characteristics of 461 Chinese patients with completely resected ADC (stage I, 310; stage II, 44; stage III, 107). The filigree pattern was more likely to be observed in ADC with a higher stage (p = 0.003) and the classical MP pattern (p < 0.001). Patients with filigree-predominant ADC showed poor survival, similar to those with classical MP-predominant ADC. Multivariate analysis confirmed that the presence of the filigree pattern was an independent prognostic factor for recurrence-free survival (hazard ratio (HR), 2.01; 95% confidence interval (CI), 1.50-2.68; p < 0.001) and overall survival (OS; HR, 1.83; 95% CI, 1.34-2.50; p < 0.001). Patients with both classical MP-positive and filigree-positive ADC had the worst survival compared with those with the filigree pattern or classical MP pattern alone. In stage I, ADC with both the filigree and classical MP patterns had a higher incidence of micrometastasis than ADC with the filigree pattern or classical MP pattern alone. Lymph node micrometastasis indicated poor survival in patients with ADC with the filigree pattern or classical MP pattern. Similar clinicopathologic features between patients with the filigree pattern and the classical MP pattern support the inclusion of the filigree pattern in the MP category. Recognition of the filigree pattern could provide helpful prognostic information, especially for stage I ADC.

Sentinel lymph node biopsy is the gold standard for axillary assessment in patients with clinically node negative breast cancer. Further management depends upon the histologic status of the retrieved sentinel nodes. Therefore, authors have been developing and searching for an accurate intraoperative method to detect or exclude metastasis in these nodes. Internationally accepted intraoperative assessment tools include frozen section, imprint cytology and molecular analysis. However, variable results derived from these studies led to a debate about which is the most reliable test. Therefore, we planned our study to assess the sensitivity and specificity of frozen section examination as it is still the most common practice in many centres especially in developing countries including Egypt. All were subjected to sentinel lymph node biopsy using both 1% patent blue dye and radioactive nanocolloid (combination technique). The retrieved sentinel nodes were sent for intraoperative frozen section evaluation which was later confirmed by the permanent paraffin section. The resultant sentinel node identification rate was 93.4%. Our case series analysis involved 458 patients with clinically negative early breast cancer. The study revealed that intraoperative frozen section had a specificity of 100% (0% false positive cases). However, it failed to detect micrometastasis in 7 of these patients (0.9% false negative) producing a 95.6% sensitivity (P value < 0.001). Based on the forementioned results and the previous studies’ reports, we believe that the frozen section examination is a reliable assessment tool in intraoperative axillary staging with a high accuracy rate.

This study aimed to assess the clinical effect of the pathological axillary assessment method in breast cancer without clinical lymph node metastasis. Data of patients with clinically node-negative breast cancer were retrospectively reviewed. The study period was divided into early (January 2000–July 2007) and late (August 2007–December 2014) periods based on the pathological assessment method used (single-sectional and detailed multi-sectional lymph node processing). In the late period, lymph nodes were evaluated at six levels including immunohistochemistry on each 1.5–2 mm interval section. The axillary diagnostic accuracy and role of chemotherapy were assessed. In 1698 patients, 27 isolated tumor cells (ITCs), 39 micrometastases, and 205 macrometastases were noted. The sensitivity for pathological N0 diagnosis was dependent on clinical T stage, Tis (97.8%), T1 (83.0%), T2 (74.2%), T3 (54.5%), and T4 (63.6%). ITCs and micrometastases were detected only in the late period, and 84.7% and 91.6% of cases in the early and late period, respectively, did not have macrometastases. The 5-year disease-free interval (DFI) rates were 95.2% in node-negative cases, 98.4% in ITCs/micrometastases, and 91.4% in macrometastases (P

The ACOSOG Z0011 study, heralded as a "practice changing" trial, suggested that women with T1-2 breast cancer with 1-2 SLN+, undergoing breast conservation therapy, need not be offered further ALND. However, whether these results are applicable to all women in the Indian setting, it remains debatable. A retrospective audit of all cN0 operated from 2013 to 2018 was conducted. We analyzed the percentage of additional LN positive (LN+) in the ALND group and compared it to the ACOZOG Z11 trial. Of the 2350 cN0 with EBC who underwent LAS, 687 (29%) had positive lymph nodes on final histopathology. Five hundred ninety-seven (86.9%) patients had 1-2 LN+, 40 (5.8%) patients had 3 LN+, and 50 (7.3%) had 4 or more nodes positive. Demographic features in the ACOSOG Z11 are different from those in our study, looking at ACOZOG Z11 versus our cohort-median pT 1.7 cm versus 3 cm, 45% micrometastasis versus 99.16% macrometastasis, and 28-30% grade 3 tumors versus 73.7%. In our cohort 31.82% of the 1-2 LN positive had additional LN+ on ALND. Keeping in mind the difference in clinicopathological features between our cohort and that of ACOZOG Z0011 and that 31.82% of women had additional LN+ on ALND, it may not be appropriate to apply the results of the ACOSOG Z0011 trial directly to our general population. Possibly, only a select subset of patients who match the trial population of the ACOSOG Z11 could be offered observation of the axilla and validated nomograms can be used to identify high-risk patients.

Axillary lymph node status and pathological diagnosis of sentinel lymph nodes (SLNs) is an important factor that influences management of postoperative therapy. Recent reports indicate that one-step nucleic acid amplification (OSNA) and hematoxylin and eosin (HE)-stained frozen sections are effective for intraoperative diagnosis of SLNs. In the present study, we report a rapid-immunohistochemical staining (R-IHC) method that enables intraoperative detection of SLN metastases within 16 min using an anti-cytokeratin antibody. With this R-IHC system, we apply a high-voltage, low-frequency AC electric field to lymph node sections while they are incubating with the antibodies. The antibodies are mixed within microdroplets and the opportunity for contact between the antibody and antigen is increased. This greatly reduces the time required for the antigen-antibody reaction. This is the report on SLN diagnosis using R-IHC in patients with breast cancer. We prospectively examined 632 dissected SLNs from 260 breast cancer patients who underwent surgery at our institute between July 2014 and March 2020. The dissected SLNs were sectioned and conventionally stained with HE or immunohistochemically labeled with anti-cytokeratin antibody using R-IHC procedures. Intraoperative R-IHC analyses were completed within 16 min, after which diagnoses were made by two pathologists. The total time required for intraoperative diagnosis was about 20 min. In this study, R-IHC detected four metastatic SLNs that were undetected using conventional HE staining (10/52, 19.2%). Compared with subsequent permanent diagnosis, R-IHC offered 98.0% sensitivity, 100% specificity and 99.8% accuracy while those values for intraoperative HE were 80.4%, 100%, 98.4%, respectively (isolated tumor cells were counted as negative). These findings indicate R-IHC is a clinically applicable technique that enables precise, and quick intraoperative detection of micro- and macrometastases in breast cancer. Moreover, R-IHC is cost-effective method: it’s cost is less than a quarter of OSNA and previous report showed that the concentration of primary antibody could be reduced by more than 90% by using R-IHC because AC mixing activated antigen-antibody reaction. Another benefit is its ability to shorten the time needed for microscopic diagnosis itself. When using R-IHC, pathologists are able to readily find metastatic lesions, even within low-power fields (e.g. 40x). This reduces not only the time needed for intraoperative diagnosis, but also the effort necessary to find unclear lesions like small cancer cells (even though it is macrometastasis), micrometastasis, and artifacts of frozen section. This study was conducted at a single institute. Further investigation in a multi-institutional collaborative prospective study will be needed to confirm the utility of this method. But for now, R-IHC appears to be a cost-effective and clinically applicable method for diagnosis of breast cancer and SLN metastasis. Citation Format: Kaori Terata, Hiroshi Nanjo, Eriko Takahashi, Ryuta Nakamura, Yoichi Akagami, Ayuko Yamaguchi, Misako Yatsuyanagi, Chiaki Kudo, Yoshihiro Minamiya. Utility of rapid- immunohistochemistry using an alternating current electric field for intraoperative diagnosis of sentinel lymph nodes in breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS1-04.

Introduction: Solid papillary carcinoma (SPC) and encapsulated papillary carcinoma (EPC) of the breast are usually considered in situ lesions due to favorable prognosis, despite the variable presence of myoepithelial cells. We aimed to describe clinical-pathologic features including basement membrane (BM) studies in these tumors. Methods: Patients diagnosed with SPC and EPC in 2000–2019 were retrospectively identified. Microscopic slides and clinical history were reviewed. Immunohistochemical stains for BM and myoepithelial markers were performed. Results: Of 23 SPCs and 27 EPCs, there were 5/23 (21.7%) pure SPCs and 9/27 (33.3%) pure EPCs, while 4/23 (17.4%) and 12/27 (44.5%) were associated with ductal carcinoma in situ (DCIS), and 6/23 (26.1%) and 6/27 (22.2%) with invasive carcinoma, respectively; 8/23 (34.8%) SPCs were considered invasive. The median tumor size was 1.7 cm (range 0.1–16). All tumors were positive for hormone receptors and negative for HER2. Myoepithelial cells were absent in 20 tumors (40%) and focally present in 30 (60%). Collagen IV and laminin were negative in most invasive lesions, but they were expressed in 21/21 (100%) and 18/21 (85.7%) of EPCs without invasion, and 16/17 (94.1%) and 10/17 (58.8%) SPCs, including invasive SPCs, respectively. Lymph node involvement was identified in 3/26 (11.5%) patients, including micrometastasis in 1 EPC associated with DCIS, macrometastasis in 1 EPC associated with invasive carcinoma, and isolated tumor cells in 1 invasive SPC. Of 31 patients with outcome data (median follow-up 35 months, range 1–85), 2 (6.5%; 1 SPC, 1 EPC) developed local recurrence, both associated with invasive carcinoma. No distant recurrences or deaths were observed. Conclusions: Our study confirms favorable prognosis of SPCs and EPCs, with 2 local recurrences occurring in the presence of invasion. SPCs are more commonly associated with invasive carcinoma or considered invasive compared to EPCs (60.9 vs. 22.2%). The presence of BM material and lack of lymph node involvement in most cases indicates that the majority of these tumors may represent in situ lesions; however, some may behave as low-grade invasive malignancy with metastatic potential even in the absence of conventional invasion.

Purpose To document a unique case of anorectal squamous cell carcinoma that was metastatic to the microvasculature of the lacrimal gland in a patient with human immunodeficiency virus and to review previously reported cases of metastases to the lacrimal gland. Methods Both a retrospective chart review and comprehensive literature review were performed. The unusual histopathologic pattern of the current case was illustrated with immunohistochemical studies (CD31, D2-40, pancytokeratin, p16, and p63) and in situ hybridization studies for high-risk human papillomavirus types 16 and 18. Results The authors describe the first case of metastatic anorectal squamous cell carcinoma to the lacrimal gland. Only 24 cases of metastatic disease to the lacrimal gland have been reported, the majority from breast carcinomas. The metastasis did not form a macroscopic lesions, instead was composed of microscopic intravascular and intraparenchymal tumor deposits, a subtle phenomena. Immunohistochemistry confirmed the presence of the intravascular neoplastic cells. p16 served as a surrogate marker for human papillomavirus-associated squamous cell carcinoma and was confirmed with in situ hybridization for human papillomavirus 16 and 18. This testing, combined with the clinical history, defined the diagnosis and confirmed human papillomavirus as the tumor driver. Conclusions Metastases to the lacrimal gland remain rare, but clinicians and pathologists alike must be attuned to the possibility of subtle microscopic foci of tumor as a pattern of metastasis in scenarios without a discrete mass-forming lesion, as this may portend a poor prognosis.

Background The breast cancer treatment paradigm has shifted to neoadjuvant treatment. There are many advantages to neoadjuvant treatment, such as tumor downsizing, in vivo tumor biology testing, treating micrometastasis, and achieving complete pathological response (a surrogate marker for overall survival). However, in the post neoadjuvant settings, sentinel lymph node biopsy can be done using a dual staining technique to decrease the false-negative rate (FNR) and increase the detection rate. However, many hospitals are not equipped to use radioisotopes. Here we investigate the detection rate and accuracy of sentinel lymph node biopsy in post neoadjuvant treatment breast cancer, comparing radioisotope, isosulfan blue, and indocyanine green (ICG) approaches. Material and methods This prospective study includes breast cancer patients (T2–4, N1–2) who had received neoadjuvant treatment. Carcinomas were confirmed by tissue pathology. Patients who had previous surgical biopsy or surgery involving the axillary regions, and those with a history of allergy to ICG, isosulfan blue, or radioisotope were excluded from the study. Result The study was done between July 1, 2019 to March 31, 2020. The mean age of participants was 53 years. Fourteen (60.87%) were post-menopause, two (8.7%) were perimenopause, and seven (30.43%) were premenopause. The clinical-stage distribution of the participants was: 2A (8.7%), 2B (34.78%), 3A (43.48%), and 3B (13.04%). The primary tumor size was 4.82 ± 2.73 cm. The lymph node size was 1.8 ± 0.96 cm. The detection rates at the individual level were 95.23% with ICG, 85.71% with isosulfan blue, and 85.71% with a radioisotope. The detection rate increased up to 100% when the ICG and blue dye methods were combined. The FNRs of sentinel lymph node biopsy at the individual level were: 10% using ICG, 30% using isosulfan blue, and 40% using radioisotope. At the lymph node level, the detection rates were 93.22% using ICG, 81.78% using isosulfan blue, and 53.87% using a radioisotope. The FNRs of sentinel lymph node biopsy at the lymph node level were 19.05% with ICG, 21.43% with isosulfan blue, and 18.03% with a radioisotope. However, the FNR was less than 10% when ICG, isosulfan blue, and a radioisotope were combined. Conclusion We can perform sentinel lymph node biopsy by combining blue dye with ICG as an optional modality and achieve a comparable outcome with combine radioisotope in locally advanced breast cancer after neoadjuvant treatment., Highlights • ICG alone has a high detection rate.93.22% • Detection rate will increase to 96.71% when combined with blue dye. • The accuracy of blue dye combined with ICG was statistically significant better than combine with isotope (p = 0.014). • The combined use of blue dye with ICG is appropriate for the detection of sentinel lymph nodes in locally advanced breast cancer patients.

Circulating tumour cells (CTCs), are disseminated tumour cells found in the blood in solid tumour malignancies. Identification of CTCs act as emerging tools in the field of the Liquid Biopsy. Majority of the studies focused on detection and enumeration of CTCs due to technological challenges those results from the rarity of CTCs in the blood. Enumeration of CTCs has already proven their value as prognostic as well as predictive biomarkers for disease prognosis. However, recent advances in technology permitted to study the molecular and functional features of CTCs and these features have the potential to change the diagnostic, prognostic and predictive landscape in oncology. In this review, we summarize the paradigm shift in the field of liquid biopsy-based cancer diagnostics using CTC isolation and detection. We have discussed recent advances in the technologies for molecular characterization of CTCs which have aided a shift from CTC enumeration to an in-depth analysis of the CTC genome, transcriptomes, proteins, epigenomes along with various functional features. Finally, as a prognosticating strategy, the potentials of CTCs as a tool of liquid biopsy to predict micrometastasis, monitor prognosis and how to use them as an additional tool for cancer staging has been discussed.

Introduction The purpose of this study was to clarify the clinicopathological features of patients with false-negative fine needle aspiration cytology (FNAC) and to determine the factors associated with negative FNAC. Methods Patients with negative FNAC from January 2010 to December 2019 were included. The patients with positive sentinel nodes (SN) were divided into two groups: micrometastasis (≤2 mm) group and macrometastasis (>2 mm) group. The clinicopathological characteristics were compared between the two groups using the χ2 test. Results A total of 165 patients with negative FNAC were included; 52 (31.5%) had positive SNs. Of the 52 patients, 13 (25%) had micrometastasis and the remaining 39 (75%) had macrometastasis. Of the 113 patients with negative SNs, none had metastases found in non-SNs. No significant differences were observed in age, cT stage or subtype, and preoperative ultrasound findings between the two groups. Conclusions The false-negative rate of FNAC was high (31.5%). Micrometastatic disease was seen in patients with negative FNAC, and this might be the cause of false-negative FNAC results.

Background The mammary glands are the second most common tumor development site in female dogs. One of the ways of staging such tumors is to evaluate the presence or absence of distant metastasis, including in bone marrow. Such findings in human medicine are associated with poor survival of women with breast tumors. However, in veterinary medicine, this clinical staging is used more for patients with lymphomas and mastocytomas. Studies using bone marrow biopsies as a staging method for mammary tumors are scarce. Objectives The present study was to evaluate mammary lesions and bone marrow in 23 female dogs, searching for disseminated tumor cells or metastatic foci. Results: Grade I carcinoma in mixed tumors was the type most observed (22.4%), and there was no statistical difference in relation to tumor size or presence of metastasis in lymph nodes. In the bone marrow of one female dog with carcinosarcoma (4.35%), there was cytoplasmic marking of a probable disseminated tumor cell of epithelial origin, and immunohistochemical evaluation showed presence of cytokeratin-19 antibodies. None of the female dogs presenting reduced cellularity or medullary fibrosis, confirmed through Masson’s trichrome technique, had cell marking in immunohistochemical analyses. Conclusions Bone marrow evaluation can be used as a staging method for mammary gland tumors in female dogs, since disseminated tumor cells present the potential to become secondary lesions and to disseminate to distant foci, thereby causing tertiary metastases over an indeterminate period of time.

Background and aims: Colorectal cancer (CRC) is known as the fourth leading cause of death across the world. The fate of patients depends on the metastatic spread of cancer cells. Micrometastases are small clusters of cancer cells with no diagnostic evidence during diagnosis and surgery. Therefore, experimental models for micrometastasis are necessary to investigate tumors. We developed a mouse model to evaluate micrometastasis of colon carcinoma cells by systemic injection of tumor cells. Methods: In this study, stably transfected CT26 cells expressing Leishmania major GP63 were intravenously (IV) injected into BALB/c mice for induction of micrometastases. The mice were divided into three groups and the groups were sacrificed on days 3, 7, and 14 of the injection. reverse transcriptase-polymerase chain reaction (RT-PCR) was performed on tissue samples to detect Gp63 gene. Results: Our results showed the successful construction and transfection of pcDNA3 L. major Gp63 into CT26 cells. After IV injection, total cellular RNA was extracted and the Gp63 gene was detected in the liver, lung, and kidney but not in the colon. Conclusion: Due to the significance of micrometastasis and the need to establish simple models for cancer research, an experimental mouse model was developed. CT26 tumor cells stably expressing Gp63 generated a potent system for diagnosis of micrometastatic cells in tissues. Injection into the tail vein is a practical model for cancer research because of the lower fatality rate and no need for anesthesia

Endometrial cancer (EC) is a rare condition in young women. The objective of this study was to evaluate the risk of pelvic lymph node (LN) metastasis in young women with EC who are candidates for conservative management.Using the SEER database, a population-based analysis was conducted to identify women45 years with grade 1, 2, or 3 endometrioid adenocarcinoma stage IA (FIGO 2009) who underwent pelvic lymphadenectomy with at least ten LNs removed. The LN macrometastases rate based on conventional histological diagnosis was analyzed according to tumor grade and myometrial invasion (MI) on final histology.A cohort of 1284 women was analyzed. The LN metastasis rates were: 2/414 (0.5%) grade 1 EC without MI, 5/239 (2.1%) grade 2 or 3 EC without MI, 5/308 (1.6%) grade 1 EC with MI, and 14/323 (4.3%) grade 2 or 3 EC with MI. Tumor size was not correlated with LN metastasis probability.Young patients eligible for conservative management have a low rate of LN macrometastasis, especially in stage IA without MI grade 1 EC. A systematic lymphadenectomy should not be performed in these patients. Prospective study evaluating the sentinel LN mapping in conservative management of EC could be performed to assess the LN micrometastasis rate.

To investigate the significance of lymph node micrometastasis in T1N0 early gastric cancer. Lymph node micrometastasis may be a key mechanism in the recurrent T1N0 EGC patients after surgical treatment. It's unknow whether it is safe to leave the lymph nodes with micrometastasis untreated after ESD. A total of 106 T1N0 EGC patients were enrolled in this study. Immunohistochemical technique with CAM5.2 was employed to detect lymph node micrometastasis, and Immunohistochemical with D2-40 was used to detect the lymphatic vessels. Prognostic significance of lymph node micrometastasis and the relationship of lymph nodes micrometastasis with Clinicopathological features were analyzed. Twenty-two of the 106 T1N0 EGC cases were detected with lymph nodes micrometastasis, with the detection rate of 20.8%. The median survival time of the group with positive lymph nodes micrometastasis was lower than that of the group with negative micrometastasis, 48 vs 60 months. The incidence of lymph nodes micrometastasis in submucosal T1N0 EGC was 23.9%, while no micrometastasis was found in the mucosal T1N0 EGC. Of all the 30 cases according with the expanded ESD indications, six patients were found with lymph nodes micrometastasis. The occurrence of lymph node micrometastasis was common in T1N0 EGC. The cases with positive lymph nodes micrometastasis showed a lower median survival time than those with negative micrometastasis. lymph nodes micrometastasis incidence was higher in the submucosal ECG than in the mucosal ECG. lymph nodes micrometastasis was also found in the cases according to the expanded ESD indications.

The aim of the present study was to investigate the expression of human papillomavirus (HPV) DNA in sentinel lymph nodes (SLN) in patients with early-stage cervical cancer (CC). In addition, the present study compared the positive rate of SLNs metastasis detected by routine pathological examination, and investigated the value of HPV-DNA in the detection of early CC lymph node micrometastasis. Reverse transcription-quantitative PCR (RT-qPCR) was used in order to evaluate the HPV DNA detection in all CC samples [International Federation of Gynecology and Obstetrics (FIGO) stage IA2-IIA2]. The consistency of HPV-DNA was compared between primary lesions and SLNs. The positive rates of HPV-DNA were compared with pathological diagnosis of SLN metastasis, and the association between the positive expression of HPV-DNA in SLNs and the clinical and pathological parameters of patients with cervical cancer were analyzed. A total of 345 sentinel lymph nodes were detected in 100 patients with IA2-IIA2 CC. The positive rates of RT-qPCR and conventional histopathological detection of SLNs metastasis were 31.6% (109/345) and 12.8% (44/345), respectively (P0.05). The detection of HPV-DNA expression in pelvic lymph nodes of early CC may be used to improve the detection rate of micrometastasis, guide the postoperative adjuvant therapy more accurately and improve prognosis. Patients with positive HPV-DNA would require closer surveillance than those with negative HPV-DNA.

Background: We aimed to assess patient satisfaction and aesthetic outcome in breast cancer patients undergoing nipple-sparing mastectomy (NSM) and immediate breast reconstruction. Materials and Methods: The study population comprised 215 patients with histopathologically diagnosed breast cancer. The inclusion criteria were as follows: a diagnosis of breast cancer, a tumor of any size, any stage of nodal metastasis, and a tumor margin >2.0 cm from the margin of the nipple-areola complex. To measure the aesthetic outcome, the Lowery scale was used. After mastectomy, immediate breast reconstruction was performed using the transverse rectus abdominis myocutaneous (TRAM) flap, and by pacing the silicone implant. Results: Most of the patients were aged between 40 and 51 years. Lymphadenopathy was positive in 87 out of 215 subjects; among these 87 subjects, 61 showed macrometastasis and 26 micrometastasis. A lateral incision was performed for mastectomy in all cases, and immediate breast reconstruction was performed using autologous grafts: the latissimus dorsi myocutaneous (TRAM) flap in 83% of cases, and silicone implants in 17% of cases were used for reconstruction. An excellent aesthetic outcome was seen in 70% of the cases, and 22% showed a good outcome. Conclusions: NSM is a very safe and technically feasible procedure that provides a high level of patient satisfaction and an excellent aesthetic outcome.

Introduction/Background* SENTIX is a prospective cohort multicentric international study on sentinel lymph node (SLN) biopsy without pelvic lymph node dissection (PLND) in patients with early-stage cervical cancer. SLN frozen section (FS) and pathological ultrastaging were mandatory by the protocol. Samples from SLN were reviewed centrally for pathological assessment quality control. Only sites experienced in SLN biopsy technique could join the trial. Methodology In total, 47 sites from 18 countries participated in the trial. Patients with FIGO 2009 stages T1A1/LVSI+ – T1B1 ( Result(s)* Altogether 733 patients were registered until Sentix enrolment closure in October 2020, 83 patients were excluded (table 1) and 650 patients was analysed. Patients` characteristics are shown in table 1. Bilateral SLN detection rate reached 95%. FS detected macrometastases (MAC) in 44 cases and micrometastasis (MIC) in 4 cases. SLN ultrastaging found additional 9 cases with MAC, 26 with micrometastases (MIC) and all 19 cases with isolated tumor cells (ITC). Sensitivity of FS was 83.0% for the detection of MAC, 57.8% for pN1 status (MAC or MIC) and 47.1% for any type of SLN involvement (MAC, MIC, ITC). Table 2. Conclusion* High bilateral detection rate of 95% was achieved in Sentix sites experienced in the SLN biopsy technique. Intraoperative pathological assessment of SLN failed to detect majority of MIC (86.7%), all cases with ITC and 42.2% with pN1 (MIC or MAC).

Introduction/Background* Lymph node status is a major prognostic factor in early-stage cervical cancer. According to the International Federation of Gynecology and Obstetrics (FIGO) 2018 classification, the presence of metastatic lymph node involvement, including the presence of macrometastasis (MAC) or micrometastasis (MIC), is classified as stage IIIC. The recommended treatment is a combination of chemoradiation without complete surgery. Assigning initial staging of patients is therefore essential for the therapeutic management. Methodology We performed a secondary analysis of data from two prospective multicenter trials assessing the role of the sentinel node in the surgical management of cervical cancer (SENTICOL 1 and 2 pooled together in the training dataset). The histological risk factors were included in a multivariate logistic regression model in order to determine the most suitable prediction model. An internal validation of the chosen prediction model was then carried out by a cross validation of the ‘leave one out cross validation’ type. The prediction model implemented into an interactive online application of the ’Shinyapp’ type. Finally, an external validation was performed with a retrospective cohort of L’Hotel-Dieu de Quebec in Canada. Result(s)* Three hundred twenty-one patients participating in Senticol 1 and 2 were included in our training analysis. Among these patients, 280 did not present lymph node invasion (87.2%), 13 presented ITC (4%), 11 presented MIC (3.4%) and 17 MAC (5.3%). Tumor size, presence of lymph-vascular space invasion and stromal invasion were included in the prediction model. The Receiver Operating Characteristic (ROC) Curve from this model had an area under the curve (AUC) of 0.79 (95% CI [0.69 – 0.90]). The AUC ROC curve from the cross validation was 0.63. The external validation on the Canadian cohort confirmed a good discrimination of the model with AUC ROC of 0.83. Conclusion* This study is the first study of a prediction score for lymph node involvement in early-stage cervical cancer that includes internal and external validation of a prediction score for lymph node involvement in early-stage cervical cancer. The web application is a simple, practical, and modern method of using this prediction score in clinical management. Link of the CER-CAP: https://thomas-gaillard.shinyapps.io/senticol_n_pred/?_ga=2.9061948.842752796.1621805282-1130361826.1585828032

Lymph Node Dissection (SLND) is standard of care for diagnosing sentinel lymph node (SLN) status in patients with early breast cancer. Study aim was to determine whether the combination of Superparamagnetic iron oxide nanoparticles (SPIO) MRI-lymphography (MRI-LG) and a Magnetic-guided Axillary UltraSound (MagUS) with biopsy can allow for minimally invasive, axillary evaluation to de-escalate surgery. Patients were injected with 2 mL of SPIO and underwent MRI-LG for SN mapping. Thereafter MagUS and core needle biopsy (CNB) were performed. Patients planned for neoadjuvant treatment, the SLN was clipped and SLND was performed after neoadjuvant with the addition of isotope. During surgery, SLNs were controlled for signs of previous biopsy or clip. The primary endpoint was MagUS SLN detection rate, defined as successful SLN detection of at least one SLN of those retrieved in SLND. In 79 patients, 48 underwent upfront surgery, 12 received neoadjuvant and 19 had recurrent cancer. MagUS traced the SLN in all upfront and neoadjuvant cases, detecting all patients with macrometastases (n = 10). MagUS missed only one micrometastasis, outperforming baseline axillary ultrasound AUS (AUC: 0.950 vs. 0.508, p &lt, 0.001) and showing no discordance to SLND (p = 1.000). MagUS provides the niche for minimally invasive axillary mapping that can reduce diagnostic surgery.

Cancer-associated fibroblasts (CAFs) have been shown to enhance squamous cell carcinoma (SCC) growth, but it is unclear whether they promote SCC lung metastasis. We generated CAFs from K15.KrasG12D.Smad4–/– mouse SCCs. RNA expression analyses demonstrated that CAFs had enriched transforming growth factor-beta (TGFβ) signaling compared to normal tissue-associated fibroblasts (NAFs), therefore we assessed how TGFβ-enriched CAFs impact SCC metastasis. We co-injected SCC cells with CAFs to the skin, tail vein, or the lung to mimic sequential steps of lung metastasis. CAFs increased SCC volume only in lung co-transplantations, characterized with increased proliferation and angiogenesis and decreased apoptosis compared to NAF co-transplanted SCCs. These CAF effects were attenuated by a clinically relevant TGFβ receptor inhibitor, suggesting that CAFs facilitated TGFβ-dependent SCC cell seeding and survival in the lung. CAFs also increased tumor volume when co-transplanted to the lung with limiting numbers of SCC cancer stem cells (CSCs). In vitro, CSC sphere formation and invasion were increased either with co-cultured CAFs or with CAF conditioned media (which contains the highest TGFβ1 concentration) and these CAF effects were blocked by TGFβ inhibition. Further, TGFβ activation was higher in primary human oral SCCs with lung metastasis than SCCs without lung metastasis. Similarly, TGFβ activation was detected in the lungs of mice with micrometastasis. Our data suggest that TGFβ-enriched CAFs play a causal role in CSC seeding and expansion in the lung during SCC metastasis, providing a prognostic marker and therapeutic target for SCC lung metastasis.

Sentinel lymph node biopsy is an established practice to avoid axillary clearance, in clinically negative axilla, in breast cancer patients. Sentinel nodes harvested by dual technique, if found negative on intraoperative frozen section, can prevent breast cancer patient from a potentially debilitating complete axillary clearance. Hence, analyzing the institutional accuracy of this technique and comparing it with international standards, becomes important in providing optimal treatment to these patients. A retrospective analysis of all patients who had undergone sentinel lymph node biopsy at our institute from December 2014 to December 2018 was carried out. At our institute, sentinel lymph nodes are identified using dual technique of methylene blue and radiocolloid dye. Intraoperative frozen section of these hot or blue or any enlarged nodes is performed. Patients with positive frozen section undergo complete axillary clearance. All frozen and unfrozen biopsy material is subjected to further paraffin sectioning and immunohistochemistry. False negative rate and factors associated with were analyzed. A total number of 424 patients had undergone intraoperative frozen section for the sentinel node in breast cancer at our institute during the study period. Among these, 307 patients had negative sentinel nodes and 117 had positive sentinel nodes of frozen section. Seventeen patients out of 307 had lymph node metastases in final paraffin report (false negative rate = 12.6%). Two of these were found to have macrometastasis, 13 had micrometastasis and 2 had isolated tumor cells on final immunohistochemistry report. Size of metastases to sentinel lymph node was found to be a statistically significant contributor to higher false negative rate. Sentinel lymph node biopsy using intraoperative frozen section, is a sensitive and specific technique of staging axilla in breast cancer patients. Detection of micrometastasis and isolated tumor cells present a technical challenge and are associated with higher false negative rates.

BackgroundThe validity of lymphadenectomy of the lymph node along the superior mesenteric vein (LN14v) in gastric cancer remains controversial. The study investigated the characteristics and prognosis of gastric cancer with metastasis or micrometastasis to LN14v.MethodsA retrospective study of 626 patients undergoing radical gastrectomy in our center from January 2003 to December 2015 was analyzed. In total, 303 patients had lymphadenectomy of LN14v, and lymph node micrometastasis was evaluated by immunohistochemical staining for cytokeratin nodes CK8/18. A logistic regression model was applied to confirm the predictive factors of micrometastasis. Survival analysis was performed to evaluate the effect of micrometastasis or metastasis on prognosis.ResultsThe metastatic rate of the LN14v lymph node was 15.8%, and the micrometastatic rate was 3.3%. Multivariate analysis showed site, Borrmann classification, postoperative lymph node metastasis (pN), and metastasis in LN6 and LN9 were predictive factors for LN14v micrometastasis or metastasis (P < 0.05). The 5-year survival rate in the positive group (LN14v micrometastasis or metastasis) was 12.4%. The prognosis of patients without LN14v lymph node micrometastasis was better than that of the positive group, whereas the difference between group of LN14v micrometastasis and LN14v metastasis was not obvious. In matched analysis, patients with stage III gastric cancer L/M area, pN2-3, and LN6(+) who underwent lymphadenectomy of LN14v had better survival than those without lymphadenectomy of LN14v.ConclusionLymph node micrometastasis may provide accurate prognostic information for patients with gastric cancer. Moreover, lymphadenectomy of LN14v might improve the survival of patients with stage III gastric cancer of L/M area, pN2-3, and LN6(+).

Background Sentinel lymph node biopsy (SLNB) is the standard approach for the axillary region in early breast cancer patients with clinically negative nodes. The present study investigated patients with false-negative sentinel nodes in intraoperative frozen sections (FNSN) using real-world data. Methods A case–control study with a 1:3 ratio was conducted. FNSN was determined when sentinel nodes (SNs) were negative in frozen sections but positive for metastasis in formalin-fixed paraffin-embedded (FFPE) sections. The control was defined as having no metastasis of SNs in both frozen and FFPE sections. Results A total of 20 FNSN cases and 60 matched controls from 333 SLNB patients were enrolled between April 1, 2005, and November 31, 2009. The demographics and intrinsic subtypes of breast cancer were similar between the FNSN and control groups. The FNSN patients had larger tumor sizes on preoperative mammography (P = 0.033) and more lymphatic tumor emboli on core biopsy (P < 0.001). Four FNSN patients had metastasis in nonrelevant SNs. Another 16 FNSN patients had benign lymphoid hyperplasia of SNs in frozen sections and metastasis in the same SNs from FFPE sections. Micrometastasis was detected in seven of 16 patients, and metastases in nonrelevant SNs were recognized in two patients. All FNSN patients underwent a second operation with axillary lymph node dissection (ALND). After a median follow-up of 143 months, no FNSN patients developed breast cancer recurrence. The disease-free survival, breast cancer-specific survival, and overall survival in FNSN were not inferior to those in controls. Conclusions Patients with a larger tumor size and more lymphatic tumor emboli have a higher incidence of FNSN. However, the outcomes of FNSN patients after completing ALND were noninferior to those without SN metastasis. ALND provides a correct staging for patients with metastasis in nonsentinel axillary lymph nodes.

Periodontal diseases can lead to chronic inflammation affecting the integrity of the tooth supporting tissues. Recently, a striking association has been made between periodontal diseases and primary cancers in the absence of a mechanistic understanding. Here we address the effect of periodontal inflammation (PI) on tumor progression, metastasis, and possible underlining mechanisms. We show that an experimental model of PI in mice can promote lymph node (LN) micrometastasis, as well as head and neck metastasis of 4T1 breast cancer cells, both in early and late stages of cancer progression. The cervical LNs had a greater tumor burden and infiltration of MDSC and M2 macrophages compared with LNs at other sites. Pyroptosis and the resultant IL-1β production were detected in patients with PI, mirrored in mouse models. Anakinra, IL-1 receptor antagonist, limited metastasis, and MDSC recruitment at early stages of tumor progression, but failed to reverse established metastatic tumors. PI and the resulting production of IL-1β was found to promote CCL5, CXCL12, CCL2, and CXCL5 expression. These chemokines recruit MDSC and macrophages, finally enabling the generation of a premetastatic niche in the inflammatory site. These findings support the idea that periodontal inflammation promotes metastasis of breast cancer by recruiting MDSC in part by pyroptosis-induced IL-1β generation and downstream CCL2, CCL5, and CXCL5 signaling in the early steps of metastasis. These studies define the role for IL-1β in the metastatic progression of breast cancer and highlight the need to control PI, a pervasive inflammatory condition in older patients.

The cytology of peritoneal washing fluids for gastric cancer is the most basic method for judging peritoneal micrometastasis. However, the clinical value of this method is not clear at present. A retrospective analysis was performed on 277 patients with pathologically proven and surgically treated gastric cancer. The peritoneal washing fluids were collected after opening the abdomen and before the operation, and were sent to the cytology laboratory for screening of occult cancer cells in the collected washing fluids. The number of cases diagnosed as cancer cells, reactive mesothelial cells, serosal balls, and traumatic mesothelial cells were 42, 18, 27, and 190, respectively. Typical adenocarcinoma cell nests were found in eight of 10 T4b samples, whereas 34 cases of cancer cells in T3 and T4a showed that these cell nests usually contained mesothelial cells, and the three-dimensional stereoscopic sense of the nests was not obvious. In the specific subcellular morphological changes of both reactive mesothelial cells and serosal balls, the changes of both the contour of nuclear membrane and the polarity of cell alignment were present only in stage T3 and T4a. The presence or absence of mesothelial cells in the nests of cancer cells and the changes of the contour of nuclear membrane and of the polarity of cell alignment in reactive mesothelial cells or serosal balls may help us to predict the depth of invasion of cancer cells.

BACKGROUND: Carcinoma in the cervix is the most common malignancy and the fourth most common cause of death in females worldwide. It is the most common malignancy in India, the increasing incidence of cancer is escalating burden over radiation. This is a prospective randomized study comparing NACT followed by definitive chemoradiation versus chemoradiation. MATERIALS AND METHODS: This prospective randomized study analyzed 80 cervical cancer patients who were treated at our center during March 2017 and July 2018. Patients were divided into two arms: one received NACT and definitive CT/T and the other received definitive CT/RT. Statistical analysis was done using SPSS V.20 software. RESULTS: Overall response rate in our study was found to be 96.2%. In the study group, it was 97.5%, whereas in the control group, it was 95%. Majority of patients were in the age group 41–50 years, mainly stage IIb and IIIb. Tumor response in both the arms was similar and statistically significant (Chi(2) = 0.348; p > 0.05). The hematologic toxicities ( p > 0.05) were more in the NACT group than in the CCRT group, while gastrointestinal toxicities were slightly higher in the control (statistically insignificant). CONCLUSION: NACT with taxane/platin followed by definitive CT/RT is as effective as the standard care in the treatment of locally advanced cervical cancer. It has even shown better results (p value > .005) and is also helpful in reducing systemic micrometastasis and bulk of the disease. It can be used as an alternative to the standard care at the places of long waiting time for the definitive treatment, without compromising the outcome.

Background The use of one-step nucleic acid amplification (OSNA) allows for lymph node (LN) metastasis to be detected rapidly and accurately. We conducted a prospective single-centre clinical trial to evaluate OSNA assay in detecting LN metastasis of lung cancer. Patients and methods A total of 705 LNs from 160 patients with clinical stage IA to IVA lung cancer were included in this study. The LNs were divided and submitted to routine histological diagnosis and OSNA assay and the results were compared. We also examined keratin 19 expression of different histological types lung primary tumours. Results When the cut-off value was set to 250 copies/µl, the concordance rate between the two methods was 96.17% and the sensitivity 97.14%. Discordant results were observed in 27 LNs of 21 patients. Most of these discordant results were molecular micrometastasis expressing a very low number of copies with negative histology. Most thoracic tumours were positive for keratin 19. Conclusions Our data show that the OSNA assay might be a useful and sensitive method to diagnose LN metastasis in lung cancer and could be applied to intraoperative decision-making in personalised lung cancer surgery based on LN status and a more accurate staging of patients.

In breast cancer, completion axillary lymph node dissection (cALND) was previously recommended for patients with at least one tumour-affected sentinel lymph node (SLN). Several prospective trials predominantly in patients undergoing breast-conserving surgery showed no benefit and increased arm morbidity with this procedure. We report the influence of these trials on clinical practice of patients undergoing mastectomy. We analysed prospectively collected data from patients with primary invasive breast cancer treated at German breast cancer units between January 2008 and December 2015. Time trends of cALND rates were analysed in patients undergoing mastectomy for T1/2N0M0 breast cancer with one or two tumour-involved SLNs. Multivariable logistic regression was used to determine factors influencing the decision not to perform cALND. Among the entire study cohort of 166,074 patients treated at 179 breast cancer units, 4093 patients (2%) had T1/2N0M0 breast cancer with one or two tumour-involved SLNs and underwent mastectomy. cALND rates decreased from 89.9% in 2010 to 55.5% in 2015 (p

The establishment of novel biomarkers in liquid biopsies of cancer patients has come more into focus in prognostic and diagnostic research efforts. Due to their prognostic relevance disseminated tumor cells or circulating tumor cells are the subject of intensive research and are discussed as early diagnostic indicators for treatment failure and the formation of micrometastases. A potential association of this early-systemic tumor component with poor prognosis of cancer patients could be already demonstrated for various entities including breast, colon, lung, melanoma, ovarian and prostate cancers. Thus, the detection of circulating tumor cells seems to be also applicable for minimal-invasive monitoring of therapy progress in head and neck cancer patients. A major problem of the use in clinical routine is that circulating tumor cells could not be detected by modern imaging techniques. To overcome these limitations highly sensitive detection methods and techniques for their molecular characterization are urgently needed allowing mechanistic understanding and targeting of circulating tumor cells. Especially the medical application of nanotechnology (nanomedical methods) has made valuable contributions to the field. Here, we want to provide a comprehensive overview on (nanomedical) detection methods for circulating tumor cells and discuss their merits, pitfalls and future perspectives especially for head and neck solid squamous cell carcinoma (HNSCC) patients.

Background There is only limited information on serum reference ranges of calcitonin (CT) in infants, children and adolescents. This gap hampers valid diagnostics in patients with multiple endocrine neoplasia type 2 (MEN 2) and planned prophylactic thyroidectomy. In addition, age-dependent reference ranges for CT are necessary to define a cure in medullary thyroid carcinoma (MTC). We asked whether the reference ranges for CT levels were age- and gender-dependent in the serum of a pediatric cohort. Methods A total of 6090 serum samples of 2639 subjects of the LIFE-Child cohort aged between 1 month and 17.9 years were analyzed by the CT electrochemiluminescence immunoassay (ECLIA). Reference intervals were estimated using the LMS method. For clinical validation the serum of 28 patients (61 samples) with MEN 2 and 106 patients (136 samples) with thyroid diseases were analyzed. Results CT levels showed a clear age- and gender-dependence with significantly higher values in boys (p Conclusions This is the largest study to establish novel pediatric reference ranges from the CT values of healthy subjects. It allows a precise laboratory monitoring of CT in pediatric patients with MEN 2. Thyroid diseases did not have a relevant influence on CT levels in our pediatric cohort.

BackgroundMicroinvasive breast cancer is an uncommon pathological entity. Owing to the rarity of this condition, its surgical axillary management and overall prognosis remain controversial.MethodsA database was analysed to identify patients with microinvasive ductal carcinoma in situ (DCIS) who had surgery for invasive breast cancer at the European Institute of Oncology, Milan, between 1998 and 2010. Women who had undergone axillary staging by sentinel lymph node biopsy were included in the study.ResultsOf 257 women with microinvasive breast cancer who underwent sentinel lymph node biopsy (SLNB), 226 (87·9 per cent) had negative sentinel lymph nodes (SLNs) and 31 had metastatic SLNs. Twelve patients had isolated tumour cells (ITCs), 14 had micrometastases and five had macrometastases in sentinel nodes. Axillary lymph node dissection was performed in 16 of the 31 patients with positive SLNs. After a median follow-up of 11 years, only one regional first event was observed in the 15 patients with positive SLNs who did not undergo axillary lymph node dissection. There were no regional first events in the 16 patients with positive SLNs who had axillary dissection.ConclusionGood disease-free and overall survival were found in women with positive SLNs and microinvasive DCIS. This study is in line with studies showing that SLNB in microinvasive DCIS may not be useful, and supports the evidence that less surgery can provide the same level of overall survival with better quality of life.

Background: The macrofollicular variant of papillary thyroid cancer (MFVPTC) is a rare histological variant of papillary thyroid cancer (PTC), with only 71 cases reported through 2014. This study analyzed the clinical, preoperative thyroid ultrasonography (US), and fine needle aspiration cytology (FNAC) features; and therapeutic outcomes of 11 patients with MFVPTC. Methods: The records of 393 patients with histologically diagnosed follicular variant of papillary thyroid carcinoma (FVPTC), including 11 with MFVPTC, were retrospectively reviewed. Preoperative thyroid US findings, clinical presentation, treatment outcomes, and survival rates were analyzed. Result: Mean tumor size was significantly greater in patients with MFVPTC than that in those with FVPTC (4.2 ± 2.1 cm vs. 2.9 ± 1.7 cm; p = 0.016). No patient with MFVPTC had lymph node involvement, but one had a micrometastasis to the lung, which responded well to therapeutic radioiodine. All MFVPTC lesions were isoechoic on US. Eight nodules had calcifications and eight had irregular margins. FNAC showed that these tumors had low cellularity, absence or focal presence of enlarged clear nuclei, and subtle or focal nuclear features of PTC. Cells were, arranged in microfollicular pattern, with abundant colloid background. Multifocal PTCs were detected in the opposite lobe of two patients. All 11 patients with MFVPTC had excellent outcomes. No patient experienced recurrence, and survival rates were high. Conclusions: Malignant US criteria combined with FNAC features have a low preoperative diagnostic rate for MFVPTC. Surgery is recommended for patients with thyroid nodules larger than 4 cm and those with subtle and focal atypical nuclei in FNAC. Keywords: Total thyroidectomy, Thyroglobulin, Radioactive iodide, Cancer-specific mortality

Introduction: Although there are several reports on omentum metastasis, limited studies have evaluated omental micrometastases, particularly isolated microscopic metastases in endometrial cancer (EC). We performed this study to assess the frequency of omental micrometastasis in EC, especially when the omentum is the only site of extrauterine spread. Methods: A retrospective study was conducted to assess cases of EC with an omental sample during primary surgical treatment for EC at the Gynecological Oncology Unit, Uludag University Hospital, Bursa, Turkey, between January 2005 and May 2018. Results: In total, 435 patients fulfilled the inclusion criteria, which comprised a complete surgical staging. The prevalence of omental metastases was 5.3% (n = 23), regardless of the subtype or clinical stage. Omental micrometastasis was detected in four cases (17.4%). In half of these patients, the omentum was the only site of disease outside the uterus, with an estimated 0.46% of isolated omental involvement. The grade of the endometrioid tumor was found to be statistically correlated with omental metastases (p = 0.01). There was a significant correlation between omental metastasis and positive peritoneal cytology, as well as adnexal involvement (p = 0.001 and p = 0.03, respectively). Conclusion: We recommend omentectomy routinely in serous EC. In addition, we suggest selective omentectomy in patients with EC who have concomitant adnexal involvement or grade 3 tumors.

Despite continuous improvements in multimodal therapeutic strategies, esophageal carcinoma maintains a high mortality rate. Metastases are a major life-limiting component; however, very little is known about why some tumors have high metastatic potential and others not. In this study, we investigated thermogenic activity and adhesion strength of primary tumor cells and corresponding metastatic cell lines derived from two patients with metastatic adenocarcinoma of the esophagus. We hypothesized that the increased metastatic potential of the metastatic cell lines correlates with higher thermogenic activity and decreased adhesion strength. Our data show that patient-derived metastatic esophageal tumor cells have a higher thermogenic profile as well as a decreased adhesion strength compared to their corresponding primary tumor cells. Using two paired esophageal carcinoma cell lines of primary tumor and lymph nodes makes the data unique. Both higher specific thermogenesis profile and decreased adhesion strength are associated with a higher metastatic potential. They are in congruence with the clinical patient presentation. Understanding these functional, biophysical properties of patient derived esophageal carcinoma cell lines will enable us to gain further insight into the mechanisms of metastatic potential of primary tumors and metastases. Microcalorimetric evaluation will furthermore allow for rapid assessment of new treatment options for primary tumor and metastases aimed at decreasing the metastatic potential., Cells, 10 (5), ISSN:2073-4409

For residual N1 nodal disease following neoadjuvant chemotherapy (NAC) for patients with breast cancer, the optimal local therapy for axilla is an evolving area. We analyzed the long-term results of these patients according to axillary surgical methods using propensity score matching (PSM) to clarify whether omission of axillary lymph node dissection (ALND) is oncologically safe. This was a single institution retrospective study of patients with ypN1 from Asan Medical Center (AMC). We included 324 patients who had undergone axillary surgery with either sentinel lymph node biopsy (SLNB) only or ALND. The patients received NAC at AMC between 2008 and 2013. General indications for ALND included prominent nodes detected clinically before NAC, evident macrometastasis on multiple nodes during SLNB. Patients who had either micrometastasis or macrometastasis in 1 or 2 node(s) were included. SLNB was performed for patients with good responders to NAC with limited nodal burden. Patients were matched for baseline characteristics. After matching, we included 98 patients in each SLNB only group and ALND group respectively. We compared axillary recurrence-free survival (ARFS), distant metastasis-free survival (DMFS), overall survival (OS), and breast cancer-free survival (BCSS) according to the surgical method. The median follow-up period was 71 months. Univariate and multivariate analyses revealed no statistically significant differences between the two groups for ARFS, DMFS, OS, and BCSS. After the propensity score matching, no significant statistical differences were observed in 5-year ARFS, DMFS, OS, and BCSS between the SLNB only group and ALND group. SLNB might be a possible option for ALND in patients with breast cancer who have limited axillary node metastasis after NAC without compromising survival outcomes.

Objective In this study, we aimed to reveal the prognostic differences between skip and non-skip metastasis mediastinal lymph node (MLN) metastasis. Methods A total of 202 patients (179 males and 23 females; mean age, 59.66 ± 9.89 years; range: 29-84 years) who had ipsilateral single-station MLN metastasis were analyzed in two groups retrospectively between January 2009 and December 2017: "skip ipsilateral MLN metastasis" group (sN2) (n = 55,27.3%) [N1(-), N2(+)], "non-skip ipsilateral MLN metastasis" group (nsN2) (n = 147,72.7%) [N1(+), N2(+)]. Results The mean follow-up was 42.63 ± 34.91 months (range: 2-117 months). Among all patients, and in the sN2 and nsN2 groups, the median overall survival times were 63.5 ± 4.56, 68.8 ± 7, and 59.3 ± 5.35 months, respectively, and the 5-year overall survival rates were 38.2%, 46.3%, and 36.4%. Conclusion Skip metastasis did not take its rightful place in TNM classification; thus, further studies will be performed. To detect micrometastasis, future studies on skip metastasis should examine non-metastatic hilar lymph nodes (LNs) through staining methods so that heterogeneity in patient groups can be avoided, that is, to ensure that only true skip metastasis cases are included. Afterwards, more accurate and elucidative studies on skip metastasis can be achieved to propound its prognostic importance in the group of N2 disease.

Background: This systematic review aimed at comparing performances of ultrasonography (US), magnetic resonance imaging (MRI), and fluorodeoxyglucose positron emission tomography (PET) for axillary staging, with a focus on micro- or micrometastases. Methods: A search for relevant studies published between January 2002 and March 2018 was conducted in MEDLINE database. Study quality was assessed using the QUality Assessment of Diagnostic Accuracy Studies checklist. Sensitivity and specificity were meta-analyzed using a bivariate random effects approach; Results: Across 62 studies (n = 10,374 patients), sensitivity and specificity to detect metastatic ALN were, respectively, 51% (95% CI: 43–59%) and 100% (95% CI: 99–100%) for US, 83% (95% CI: 72–91%) and 85% (95% CI: 72–92%) for MRI, and 49% (95% CI: 39–59%) and 94% (95% CI: 91–96%) for PET. Interestingly, US detects a significant proportion of macrometastases (false negative rate was 0.28 (0.22, 0.34) for more than 2 metastatic ALN and 0.96 (0.86, 0.99) for micrometastases). In contrast, PET tends to detect a significant proportion of micrometastases (true positive rate = 0.41 (0.29, 0.54)). Data are not available for MRI. Conclusions: In comparison with MRI and PET Fluorodeoxyglucose (FDG), US is an effective technique for axillary triage, especially to detect high metastatic burden without upstaging majority of micrometastases.

To investigate the diagnostic value of lung-specific X protein (LUNX) messenger ribonucleic acid (mRNA) expression in peripheral blood of patients with nonsmall cell lung cancer (NSCLC) in micrometastasis.Peripheral blood samples of 112 patients with NSCLC were collected, and the expression of LUNX, cytokeratin 19 (CK19), and carcinoembryonic antigen (CEA) mRNA was measured by reverse transcription-polymerase chain reaction (RT-PCR).The expression of LUNX, CK19, and CEA mRNA was increased in peripheral blood of patients with NSCLC compared with that of patients with benign lung disease (P0.05), and the sensitivity of LUNX mRNA was higher than that of CK19 and CEA mRNA (P0.05). LUNX-positive expression was also associated with lymph node metastasis, tumor-node-metastasis (TNM) staging, and reduced 5-year survival rate of patients in our cohort (P0.05). Further, the 5-year survival improved for those LUNX-positive patients who became LUNX negative following adjuvant chemotherapy compared to those who remain LUNX positive (P0.05). Multivariate analysis showed that lymph node metastasis, TNM stage, and LUNX mRNA expression in peripheral blood were independent prognostic factors.The detection of LUNX expression in peripheral blood of patients with NSCLC by RT-PCR is a highly specific and sensitive detection method for tumor micrometastasis that may be used for molecular diagnosis of tumor micrometastasis. LUNX mRNA expression in peripheral blood is an independent factor affecting prognosis of NSCLC and thus may reliably predict NSCLC prognosis and guide appropriate adjuvant chemotherapy treatment.

The clinical significance of lymph node micrometastasis (LNMM) remains controversial in gastric cancer (GC). In this study, we investigated the prognostic impact of LNMM in patients with GC. A total of 624 patients with pathologically lymph node metastasis-negative (pN0) and N1 status (pN1) who underwent gastrectomy between 2004 and 2018 were enrolled in this retrospective study. The diameter of tumor cell clusters in metastatic lymph nodes was measured in 120 patients with pN1 GC. Patients with lymph node tumors

Introduction The intraoperative frozen section is a recommended method to detect breast cancer metastasis to axillary sentinel lymph nodes (SLNs); however, frozen section is not widely available and requires an experienced staff. Alternatively, touch imprint cytology (TIC) is a simple and cost-effective technique to detect metastasis. Therefore, in this study, we assessed the diagnostic accuracy of TIC for detecting SLN metastasis and compared it with intraoperative frozen section evaluation. Methodology A retrospective study was conducted in the Department of Histopathology, Liaquat National Hospital and Medical College, for a duration of two years. A total of 114 patients undergoing surgery for primary breast cancer were included in the study. All patients had clinically and radiologically negative axillary lymph nodes. SLN sampling was done using radioactive dye and sent for intraoperative consultation. The SLNs were sliced at 4-mm intervals and two TIC slides and three step-levels for frozen section were prepared, and the results were compared with final (paraffin) section histology. Results The sensitivity, specificity, and diagnostic accuracy of TIC was 83.7%, 98.5%, and 92.1%, respectively. Alternatively, the sensitivity, specificity, and diagnostic accuracy of frozen section was 93.9%, 100%, and 97.4%, respectively. The sensitivity of TIC and frozen section for detecting micrometastasis was 14.3% and 57.1%, respectively, with a diagnostic accuracy of 90.3% and 95.8%, respectively. Alternatively, with respect to macrometastasis, the sensitivity and specificity of TIC were 95.2% and 98.5%, respectively, while the sensitivity and specificity of frozen section were 100%. Conclusion TIC is a quick and effective technique for detecting breast cancer metastasis in axillary SLNs. Although frozen section had an overall higher sensitivity than TIC, the sensitivity of TIC for detecting macrometastasis was comparable to the frozen section. Therefore, we conclude that TIC is a good alternative to the frozen section in facilities where the frozen section is not available.

In early-stage cervical cancer, lymph node status is of paramount importance to determine the best therapeutic strategy and is one of the most important prognostic factors of survival. According to main international guidelines, pelvic full lymphadenectomy is recommended for lymph node staging. Sentinel lymph node (SLN) biopsy is an accurate method for the assessment of lymph nodal involvement and has been suggested instead of systematic pelvic lymph node dissection (PLND). The SLN technique requires a learning-curve to be well performed. Combined detection with technetium-99 and blue dye has been widely used but the recent introduction of indocyanine green (ICG) is of growing interest since it could improve SLN detection. SLN biopsy offers a more accurate anatomical staging by finding potential metastatic nodes outside of usual lymphadenectomy areas. SLN biopsy improves the diagnostic value of lymph node staging with ultrastaging and detection of low-volume nodal metastases [isolated tumor cells (ITCs) and micrometastases]. Appropriate selection of patient and minimal training combined with some simple rules may guarantee a low false negative rate. Several studies have shown that SLN mapping in these patients is feasible, with excellent detection rates and sensitivity. Less-radical lymph node dissection decreases the associated morbidity of PLND, especially the risk of lower-limb lymphoedema, which severely affects patient quality of life. Some points are still subject to debate such as the low accuracy of intraoperative SLN status assessment by frozen section and the impact of micrometastasis on prognosis. Although international guidelines consider SLN biopsy as an alternative to PLND, SLN biopsy alone is not the gold-standard yet due to lack of prospective evidence on long-term oncological safety. The 3 ongoing prospective trials SENTIX, PHENIX and SENTICOL III will most probably give an answer to these issues.

The current chapter describes the potential application of flow cytometry in various solid tumours. DNA content analysis and synthetic phase evaluation are often helpful to assess the prognosis of the tumour. The simultaneous use of EpCAM and other epithelial markers in flow cytometry (FCM) may detect micrometastasis of carcinoma in the lymph node. The various oncogenic markers and hormone receptors of the solid tumour can be studied in FCM. A panel of antibodies may detect the exact typing of the malignant round cell tumour by flow cytometry.

Bc-DLFL.1 is a novel spontaneous, high-grade transplantable mouse B-cell lymphoma model for selective serosal propagation. These cells attach to the omentum and mesentery and show dissemination in mesenteric lymph nodes. We aimed to investigate its early stage spread at one day post-intraperitoneal inoculation of lymphoma cells (n = 18 mice), and its advanced stage at seven days post-inoculation with in vivo [18F]FDG-PET and [18F]PET/MRI, and ex vivo by autoradiography and Cherenkov luminescence imaging (CLI). Of the early stage group, nine animals received intraperitoneal injections, and nine received intravenous [18F]FDG injections. The advanced stage group (n = 3) received intravenous FDG injections. In the early stage, using autoradiography we observed a marked accumulation in the mesentery after intraperitoneal FDG injection. Using other imaging methods and autoradiography, following the intravenous injection of FDG no accumulations were detected. At the advanced stage, tracer accumulation was clearly detected in mesenteric lymph nodes and in the peritoneum after intravenous administration using PET. We confirmed the results with immunohistochemistry. Our results in this model highlight the importance of local FDG administration during diagnostic imaging to precisely assess early peritoneal manifestations of other malignancies (colon, stomach, ovary). These findings also support the importance of applying topical therapies, in addition to systemic treatments in peritoneal cancer spread.

Lead-212 is recognized as a promising radionuclide for targeted alpha therapy for tumors. Many studies of 212Pb-labeling of various biomolecules through bifunctional chelators have been conducted. Another approach to exploiting the cytotoxic effect is coupling the radionuclide to a microparticle acting as a carrier vehicle, which could be used for treating disseminated cancers in body cavities. Calcium carbonate may represent a suitable material, as it is biocompatible, biodegradable, and easy to synthesize. In this work, we explored 212Pb-labeling of various CaCO3 microparticles and developed a protocol that can be straightforwardly implemented by clinicians. Vaterite microparticles stabilized by pamidronate were effective as 212Pb carriers; labeling yields of ≥98% were achieved, and 212Pb was strongly retained by the particles in an in vitro stability assessment. Moreover, the amounts of 212Pb reaching the kidneys, liver, spleen, and skeleton of mice following intraperitoneal (i.p.) administration were very low compared to i.p. injection of unbound 212Pb2+, indicating that CaCO3-bound 212Pb exhibited stability when administered intraperitoneally. Therapeutic efficacy was observed in a model of i.p. ovarian cancer for all the tested doses, ranging from 63 to 430 kBq per mouse. Lead-212-labeled CaCO3 microparticles represent a promising candidate for treating intracavitary cancers.