Methylation Profile of Small Breast Cancer Tumors Evaluated by Modified MS-HRM.

The DNA methylation profile of breast cancer differs from that in healthy tissues and can be used as a diagnostic and prognostic biomarker. Aim of this study: To compare the levels of gene methylation in small malignant breast cancer tumors (<2 cm), in healthy tissue, and in fibroadenoma, and to evaluate the effectiveness of the modified Methylation Sensitive-High Resolution Melting (MS-HRM) method for this analysis. Analysis was performed using the modified MS-HRM method. For validation, the methylation levels of five genes were confirmed by pyrosequencing. The main study group included 96 breast cancer samples and the control group included 24 fibroadenoma samples and 24 healthy tissue samples obtained from patients with fibroadenoma. Breast cancer samples were divided into two subgroups (test set and validation set). The methylation of the following 15 genes was studied: MAST1, PRDM14, ZNF177, DNM2, SSH1, AP2M1, CACNA1E, CPEB4, DLGAP2, CCDC181, GCM2, ITPRIPL1, POM121L2, KCNQ1, and TIMP3. Significant differences in the validation set of samples were found for seven genes; the combination of the four genes GCM2, ITPRIPL1, CACNA1E, DLGAP2 (AUC = 0.99) showed the highest diagnostic value based on logistic regression for all breast cancer samples. Our modified MS-HRM method demonstrated that small breast cancer tumors have a specific DNA methylation profile that distinguishes them from healthy tissues and benign proliferative lesions.

Prognostic Factors of Small Non-Functional Pancreatic Neuroendocrine Tumors and the Risk of Lymph Node Metastasis: A Population-Level Study.

Background: Small non-functional neuroendocrine tumors (NF-PNETs) are a heterogeneous subset of tumors with controversy regarding their optimal management. We aimed to analyze the prognostic factors of patients with small NF-PNETs and create a risk score for lymph node metastasis (LNM). Methods: Data of 751 patients with NF-PNETs ≤ 2 cm were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Multivariate survival analysis was performed to analyze the prognostic factors. Logistic regression was used to identify risk factors for LNM. Results: Of the 751 patients, 99 (13.2%) were confirmed to have LNM. In multivariate survival analysis, LNM (hazard ratio [HR], 2.12; 95% CI, 1.04-4.32, p = 0.040) was independently associated with disease-specific survival. Logistic regression identified that tumor location in the head of the pancreas (odds ratio [OR], 4.33; 95% CI, 2.75-6.81; p < 0.001), size ≥ 1.5-2 cm (OR, 1.84; 95% CI, 1.17-2.87; p = 0.009), and grade III-IV (OR, 7.90; 95% CI, 1.79-34.90; p = 0.006) were independent risk factors of LNM. According to the OR value, the risk of LNM was scored as follows: a score of 1 for tumors located in the body/tail of the pancreas and 4 for those located in the head; a score of 1 for tumors <1 cm and 2 for those ≥1.5-2 cm; and a score of 1 for tumors with grade I-II and 8 for those with grade III-IV. Finally, the median score for this cohort was 4, with an interquartile range of 3-6. Therefore, patients were classified as three groups based on the risk score system: a total score of 1-3 for low risk, 4-6 for intermediate risk (OR, 2.98; 95% CI, 1.59-5.60; p = 0.001), and 7-14 for high risk (OR, 8.94; 95% CI, 4.50-17.7; p < 0.001), with an incidence of LNM 5.0%, 13.5%, and 31.8%, respectively (p < 0.001). Conclusion: Surgical resection with regional lymphadenectomy is recommended for small NF-PNETs with malignant potential of LNM. A risk score for LNM based on tumor grade, location, and size may preoperatively predict LNM of small NF-PNETs and guide clinical practice.

Clinical Prognosticators of Metastatic Potential in Patients with Small Pancreatic Neuroendocrine Tumors.

BACKGROUND: While observation of T1(≤2cm) nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs) is an accepted practice, an ill-defined subgroup of patients with T1 tumors develops metastases. This study aimed to identify those patients via clinical factors. METHODS: Patients from the Surveillance, Epidemiology, and End Results (SEER) registry who were diagnosed with NF-PanNET with size ≤2cm between 1998 and 2014 and who underwent primary tumor resection were identified. Binary logistic regression analyses were performed to evaluate factors associated with pathological nodal and systemic metastatic disease. RESULTS: A total of 612 patients with T1 NF-PanNETs were identified. Of those, 72 (11.7%) developed nodal metastasis and 35 (5.7%) distant metastasis (M1). In the multivariable analysis, tumor location in the pancreatic body (OR 1.903, p=0.03) (OR 1.407, p=0.038) or tail (OR 1.258, p=0.04) (OR 1.612, p=0.021); tumor grade III-IV (OR 2.042, p=0.022) (OR 5.379, p≤0.001); and younger age (OR 0.963, p=0.01) (OR 0.919, p=0.009) were associated with nodal metastases and the presence of M1 disease, respectively. CONCLUSION: While the low metastatic potential of ≤2cm NF-PanNET implies watchful waiting to be an appropriate strategy for most patients, the increased risk of metastatic disease in younger patients with high grade (III-IV) body/tail tumors suggests individualized risk stratification to be optimal.

Comparison of prognosis between observation and surgical resection groups with small sporadic non-functional pancreatic neuroendocrine neoplasms without distant metastasis.

BACKGROUND: The treatment of small (≤ 2 cm), sporadic localized non-functional pancreatic neuroendocrine neoplasms (PNENs) is often controversial. This study aimed to investigate the clinical outcomes with observation and surgical resection in small PNENs. METHODS: Seventy-five patients with small localized sporadic non-functional PNENs ≤ 2 cm, who underwent observation or surgical resection, were retrospectively reviewed. Changes in tumor size during follow-up in the observation group were also investigated. RESULTS: The median age of the cohort was 61 (range 35-81) years. The tumor grades were G1, G2, and unknown, in 61 (81.3%), 8 (10.7%), and 6 (8.0%) patients, respectively. The mean follow-up periods in the observation (n = 23) and surgical resection groups (n = 52) were 52.3 (range 6.8-133.3) months and 73.0 (range 9.1-179.9) months, respectively. The median overall survival was not reached. During follow-up, no patient died of PNENs, two died of other diseases, three had lymph node metastases, and one experienced recurrence after surgical resection. There was no significant difference in overall survival between the observation and surgical resection groups (hazard ratio: 0.031, P = 0.417). The mean change in tumor size in the observation group was + 0.30 mm (range - 1.6 to + 3.0 mm). No deaths, tumor progression, lymph node metastases, distant metastases, or recurrence were noted in patients with PNENs ≤ 1 cm (n = 36). CONCLUSIONS: The prognosis of small localized PNENs is good. Observation may be an alternative to surgery in high-risk patients and those with small G1 tumors, particularly those measuring ≤ 1 cm.

Laparoscopic compatible device incorporating inductive proximity sensors for precise detection of gastric and colorectal small tumors.

The accurate localization of small tumors of the digestive tract is of paramount importance in surgical oncology because it dictates the limits of resection and the extent of lymph node dissection. In this view, we have designed and fabricated a highly efficient sensing laparoscopic instrument focused on precise non-invasive extralumenal intraoperative detection of small colorectal or gastric tumors. The equipment is fully adapted for laparoscopic surgery and consists of an inductive proximity sensor encapsulated into a watertight stainless-steel case that is connected to an electronic functional block dimensionally scaled-down by the desired form and size for optimal surgical manipulation. The sensor-case unit and the electronic block are coupled together using a modular system which allows disconnection of the latter and sterilization by autoclavation of the former, followed by swift plugging of the electronic block just before surgery in a sterile-controlled environment. The instrument works in tandem with a modified endoscopic hemostatic clip which is attached endoscopically, before surgery, in the mucosa proximal and distal to the tumor. By scanning the serosal side of the digestive organ during the laparoscopic surgical procedure, the detector senses the modified clip and thus pinpoints to the location of the tumor. Additional engineering of the standard endoscopic hemostatic clips by coating them with various combinations of metallic alloys of Cu and Zn was necessary to improve the detection range and sensitivity without compromising on their functionality. The clips were also covered with nanometric layers of Au to ensure their biocompatibility. The ex-vivo dry-lab experiments showed a satisfactory detection distance which was later confirmed in ex-vivo wet-lab experiments on animal organs and human surgical specimens.

Endocrine sensitivity is decisive for patient outcome in small node-negative breast cancers (BC) (pT1a,b) - results from the Munich Cancer Registry.

PURPOSE: In clinical routine, adjuvant systemic therapy in small node-negative (N0) BC is controversial, in particular in HER2-positive disease. We aimed to evaluate outcome of consecutive patients with small N0 BC in a population-based cancer registry and thus consequently substantiate indications for chemotherapy in those patient subgroups at increased relapse risk or poor survival. METHODS: From 2002 to 2009 (median follow-up 6 years), 9707 primary breast cancer patients with N0 tumors <2 cm (pTis, pT1N0M0) were reported to the Munich Cancer Registry. Patients with pTis tumors (n = 1870) served as internal comparator. Time to progression, observed (OS) and relative survival rates (Kaplan-Meier estimates) are presented. Cox regression analysis was used to assess the influence of tumor size, age, HR-, and HER2-status. RESULTS: 10-year-OS for pTis was 94.0%. In HR-positive tumors it was 91.9% in pT1a, 90.6% in pT1b, and 86.8% in pT1c. In HR-negative tumors, rates were 91.7%, 86.8%, and 86.8%, respectively. In HER2-positive tumors it was 81.2%, 88.1%, and 86.7%, in HER2-negative 93.1%, 90.6%, and 86.0%, respectively. In the multivariate model, age, tumor size, and HR-status showed a significant impact on OS (HRneg. vs. HRpos.: hazard ratio 1.50 (95% CI; 1.12-1.99), while HER2-status was not an independent prognostic factor. CONCLUSION: Prognosis of N0 tumors <1 cm is excellent, especially if they are HR-positive, even in HER2-positive cases. Weighing potential benefits vs. side-effects, there seems to be no need for chemotherapy in tumors <0.5 cm. In pT1b chemotherapy may be considered, if tumors are triple negative or HER2-positive and HR-negative. In pT1c guideline-based adjuvant therapy using all therapeutic options seems to be warranted.

[Small renal cell carcinomas and synchronous metastases]. / Litil nyrnafrumukrabbamein og fjarmeinvorp.

OBJECTIVE: The incidence of renal cell carcinoma (RCC) is rising in part due to small tumors (≤4cm) detected incidentally with abdominal imaging. Survival for small RCCs has been regarded as favorable and guidelines recommend partial rather than total nephrecteomy. We studied the frequency of synchronous metastasis in patients with small RCCs in Iceland. MATERIALS AND METHODS: A retrospective study on 257 patients with RCC ≤4cm out of 1102 RCC patients diagnosed in Iceland 1971-2010. Patients with metastasis were compared to those with localized disease. Hospital charts were reviewed and histology, TNM-stage and disease-specific survival compared between groups. RESULTS: The proportion of small tumors increased from 9% in 1971-1980 to 33% in 2001-2010 (p<0,001) and incidental detection increased from 14% to 39% during the same period. Out of the 257 patients with small RCCs, 25 (10%) had synchronous metastases, most frequently in lungs or bones. Patients with metastases were on average 1.9 years older, their tumors were 0.2 cm larger and more often located in the right kidney, their hemoglobin was lower and nuclear grade and T-stage higher. Histology was similar in both groups. Five-year survival of patients with and without metastases was 7 vs. 94%, respectively (p<0.001). CONCLUSIONS: One out of ten patients with small RCC has synchronous metastases at diagnosis. This is higher than in most previous reports that usually include surgical patients only. Patients with metastases are significantly older, more often symptomatic, their tumor are larger and their prognosis worse. Our results indicate that small RCC is a potentially systemic disease at diagnosis that has to be taken seriously.