Negative Node Status Research Articles

Swedish prospective multicenter trial evaluating sentinel lymph node biopsy after neoadjuvant systemic therapy in clinically node-positive breast cancer

PurposePatients with clinically node-positive breast cancer planned for neoadjuvant systemic therapy (NAST) may draw advantages from the nodal downstaging effect and reduce the extent of axillary surgery with sentinel lymph node biopsy (SLNB) performed after NAST. Since there are concerns about lower sentinel lymph node (SLN) detection and higher false-negative rates (FNR) in this setting, our aim was to define the accuracy of SLNB after NAST.MethodsThis Swedish national multicenter trial prospectively recruited 195 breast cancer patients from ten hospitals with T1–T4d biopsy-proven node-positive disease planned for NAST between October 1, 2010 and December 31, 2015. Clinically node-negative axillary status after NAST was not mandatory. SLNB was always attempted and followed by a completion axillary lymph node dissection (ALND).ResultsThe SLN identification rate was 77.9% (152/195) but improved to 80.7% (138/171) with dual mapping. The median number of SLNs was two (range 1–5). A positive SLNB was found in 52% (79/152), almost 66% (52/79) of whom had additional positive non-sentinel lymph nodes. The overall pathologic nodal response rate was 33.3% (66/195). The overall FNR was 14.1% (13/92) but decreased to 4% (2/50) when only patients with two or more sentinel nodes were analyzed.ConclusionsIn biopsy-proven node-positive breast cancer, SLNB after NAST is feasible even though the identification rate is lower than in clinically node-negative patients. Since the overall FNR is unacceptably high, the omission of ALND should only be considered if two or more SLNs are identified.

Local Therapy Improves Overall Survival in Patients With Newly Diagnosed Metastatic Prostate Cancer.

The role of local therapy, in the form of radiation therapy (RT) or radical prostatectomy(RP), and its association on outcomes is not well established in patients with metastatic prostate cancer. Using the National Cancer Database (NCDB), we evaluated patterns of care and outcomes among patients diagnosed with metastatic prostate cancer from 2004 to 2013 treated with local therapy (RP, intensity-modulated radiation therapy [IMRT], or 2D/3D-conformal radiation therapy [CRT]). The association between local therapy, co-variates, and outcomes was assessed in a multivariable Cox proportional hazards model and Propensity score (PS) matching was performed to balance confounding factors. Survival was estimated using the Kaplan-Meier method. Among the 1,208,180 patients in the NCDB with prostate cancer, 6,051 patients met the inclusion criteria. No local therapy was used in 5,224 patients, while 622 (10.3%), 52 (0.9%), 153 (2.5%) patients received RP, IMRT, and 2D/3D-CRT, respectively. Use of local therapy was associated with younger age (≤70), lower co-morbidity score, lower T-stage, Gleason score <8, node-negative status, private, and Medicare insurance, higher income quartile, and treatment at comprehensive or academic/research programs (P < 0.05). Five-year overall survival for patients receiving local therapy was 45.7% versus 17.1% for those not receiving local therapy (P < 0.01). In multivariate analysis, RP (HR = 0.51; 95%CI, 0.45-0.59, P < 0.01) and IMRT (HR = 0.47; 95%CI, 0.31-0.72, P < 0.01) were independently associated with superior overall survival. After PS-matching, the use of local therapy (RP or IMRT) remained significantly associated with overall survival (HR = 0.35; 95%CI, 0.30-0.41, P < 0.01). The use of RP and IMRT, to treat the primary disease, was associated with improvements in overall survival for patients with metastatic prostate cancer. We have identified patient-specific variations in the use of local therapy that may be tested in subsequent prospective clinical trials to improve patient outcomes in this setting. Prostate 77: 559-572, 2017. © 2017 Wiley Periodicals, Inc.

En blocpancreaticoduodenectomy and right hemicolectomy for locally advanced right-sided colon cancer

AIMTo assess the usefulness of en bloc right hemicolectomy with pancreaticoduodenectomy (RHCPD) for locally advanced right-sided colon cancer (LARCC).METHODSWe retrospectively reviewed the database of Saitama Medical Center, Jichi Medical University, between January 2009 and December 2016. During this time, 299 patients underwent radical right hemicolectomy for right-sided colon cancer. Among them, 5 underwent RHCPD for LARCC with tumor infiltration to adjacent organs. Preoperative computed tomography (CT) was routinely performed to evaluate local tumor infiltration into adjacent organs. During the operation, we evaluated the resectability and the amount of infiltration into the adjacent organs without dissecting the adherent organs from the cancer. When we confirmed that radical resection was feasible and could lead to R0 resection, we performed RHCPD. The clinical data were carefully reviewed, and the demographic variables, intraoperative data, and postoperative parameters were recorded.RESULTSThe median age of the 5 patients who underwent RHCPD for LARCC was 70 years. The tumors were located in the ascending colon (three patients) and transverse colon (two patients). Preoperative CT revealed infiltration of the tumor into the duodenum in all patients, the pancreas in four patients, the superior mesenteric vein (SMV) in two patients, and tumor thrombosis in the SMV in one patient. We performed RHCPD plus SMV resection in three patients. Major postoperative complications occurred in 3 patients (60%) as pancreatic fistula (grade B and grade C, according to International Study Group on Pancreatic Fistula Definition) and delayed gastric empty. None of the patients died during their hospital stay. A histological examination confirmed malignant infiltration into the duodenum and/or pancreas in 4 patients (80%), and no patients showed any malignant infiltration into the SMV. Two patients were histologically confirmed to have tumor thrombosis in the SMV. All of the tumors had clear resection margins (R0). The median follow-up time was 77 mo. During this period, two patients with tumor thrombosis died from liver metastasis. The overall survival rates were 80% at 1 year and 60% at 5 years. All patients with node-negative status (n = 2) survived for more than seven years.CONCLUSIONThis study showed that the long-term survival is possible for patients with LARCC if RHCPD is performed successfully, particularly in those with node-negative status.

LHX6, An Independent Prognostic Factor, Inhibits Lung Adenocarcinoma Progression through Transcriptional Silencing of β-catenin

Introduction: Our previous study identified LIM homeobox domain 6 (LHX6) as a frequently epigenetically silenced tumor-suppressor gene in lung cancer. However, its clinical value has never been evaluated, and the in-depth anti-tumor mechanism remains unclear.Methods: Public database was used for lung cancer, lung adenocarcinoma and lung squamous carcinoma patients and tissue microarray data was used for lung adenocarcinoma patients to study prognostic outcome of LHX6 expression by Kaplan-Meier and Cox-regression analysis. In vitro proliferation, metastasis and in vivo nude mice model were used to evaluate the anti-tumor effect of LHX6 on lung adenocarcinoma cell lines. The mechanisms were explored using western blot, TOP/FOP flash assays and luciferase reporter assays. LHX6 expression and clinical stages data were collected from The Cancer Genome Atlas database (TCGA).Results: Expression of LHX6 was found to be a favorable independent prognostic factor for overall survival (OS) of total lung adenocarcinoma patients (P=0.014) and patients with negative lymph nodes status (P=0.014) but not related the prognostic outcome of lung squamous cell carcinoma patients. The expression status of LHX6 significantly correlated to histological grade (P<0.01), tumor size (P=0.026), lymph node status (P=0.039) and clinical stages (P<0.01) of lung adenocarcinoma patients. Functionally, LHX6 inhibited the proliferation and metastasis of lung adenocarcinoma cells in vitro and in vivo. Furthermore, LHX6 suppressed the Wnt/β-catenin pathway through transcriptionally silencing the expression of β-catenin, and the promoter region (-1161 bp to +27 bp) was crucial for its inhibitory activity.Conclusions: Our data indicate that the expression of LHX6 may serve as a favorable prognostic biomarker for lung adenocarcinoma patients and provide a novel mechanism of LHX6 involving in the tumorigenesis of lung adenocarcinoma.

The Prognostic Value of Tyrosine Kinase SRC Expression in Locally Advanced Rectal Cancer.

The cellular sarcoma gene (SRC) is a proto-oncogene encoding for a tyrosine kinase. SRC expression was determined in locally advanced rectal adenocarcinoma tissue from pretreatment biopsies and resection specimens. The expression level was correlated with clinicopathological parameters to evaluate the predictive and prognostic capacity.For this monocentric analysis 186 patients with locally advanced rectal cancer (median: 63.7 years; 130 men (69.9%), 56 women (30.1%)) were included. Patients with a carcinoma of the upper third of the rectum were treated with primary tumor resection (n=27; 14.5%). All other patients received a preoperative chemoradiotherapy (CRT) with 50.4 Gy and concomitant 5-fluorouracil (5-FU) or 5-FU+oxaliplatin followed by postoperative chemotherapy with 5-FU or 5-FU+oxaliplatin. SRC expression was determined with immunohistochemical staining from pretreatment biopsies (n=152) and residual tumor tissue from the resection specimens (n=163). The results were correlated with clinicopathological parameters and long-term follow-up.The expression of SRC was determined in pretherapeutic biopsies (mean H-Score: 229) and resection specimens (mean H-Score: 254). High SRC expression in pretherapeutic tumor samples significantly correlated with a negative postoperative nodal status (p=0.005). Furthermore an increased protein expression in residual tumor tissue was associated with fewer distant metastases (p=0.04). The overexpression of SRC in pretreatment tumor biopsies showed also a trend for a longer cancer-specific survival (CSS; p=0.05) and fewer local relapses (p=0.06) during long-term follow-up.High SRC expression in rectal cancer seems to be associated with a better long-term outcome. This finding could help in the future to stratify patients for a recurrence risk adapted postoperative treatment.

Perioperative Epirubicin, Oxaliplatin, and Capecitabine Chemotherapy in Locally Advanced Gastric Cancer: Safety and Feasibility in an Interim Survival Analysis.

PurposePerioperative chemotherapy improves survival outcomes in locally advanced (LA) gastric cancer.Materials and MethodsWe retrospectively analyzed patients with LA gastric cancer who were offered perioperative chemotherapy consisting of epirubicin, oxaliplatin, and capecitabine (EOX) from May 2013 to December 2015 at Tata Memorial Hospital in Mumbai.ResultsAmong the 268 consecutive patients in our study, 260 patients (97.0%) completed neoadjuvant chemotherapy, 200 patients (74.6%) underwent D2 lymphadenectomy, and 178 patients (66.4%) completed adjuvant chemotherapy. The median follow-up period was 17 months. For the entire cohort, the median overall survival (OS), 3-year OS rate, median progression-free survival (PFS), and 3-year PFS rate were 37 months, 64.4%, 31 months, and 40%, respectively. PFS and OS were significantly inferior in patients who presented with features of obstruction than in those who did not (P=0.0001). There was no difference in survival with respect to tumor histology (well to moderately differentiated vs. poorly differentiated, signet ring vs. non-signet ring histology) or location (proximal vs. distal). Survival was prolonged in patients with an early pathological T stage and a pathological node-negative status. In a multivariate analysis, postoperative pathological nodal status and gastric outlet obstruction on presentation significantly correlated with survival.ConclusionsEOX chemotherapy with curative resection and D2 lymphadenectomy is a suggested alternative to the existing perioperative regimens. The acceptable postoperative complication rate and relatively high resection, chemotherapy completion, and survival rates obtained in this study require further evaluation and validation in a clinical trial.

DWI for Assessment of Rectal Cancer Nodes After Chemoradiotherapy: Is the Absence of Nodes at DWI Proof of a Negative Nodal Status?

When considering organ preservation in patients with rectal cancer with good tumor response, assessment of a node-negative status after chemoradiation therapy (CRT) is important. DWI is a very sensitive technique to detect nodes. The study aim was to test the hypothesis that the absence of nodes at DWI after CRT is concordant with a ypN0 status. A retrospective study was performed of 90 patients with rectal cancer treated with CRT followed by restaging MRI at 1.5 T, including DWI (highest b value, 1000 s/mm2). Two independent readers counted the number of nodes visible in the mesorectal compartment on DW images obtained after CRT. The number of nodes on DWI (0 vs ≥ 1) was compared with the number of metastatic nodes at histopathology or long-term clinical follow-up (yN0 vs yN-positive status). Seventy-one patients had a yN0 status, and 19 had a yN-positive status. For 10 patients, no nodes were observed at DWI, which was concordant with a yN0 status in 100% of cases. In the other 61 patients with a yN0 status, the median number of nodes detected at DWI was three (range, 1-17 nodes). To differentiate between yN0 and yN-positive status, sensitivity was 100%, specificity was 14%, the positive predictive value was 24%, and the negative predictive value was 100%. Although the absence of nodes at DWI is not a frequent finding, it appears to be a reliable predictor of yN0 status after CRT in patients with rectal cancer. DWI may thus be a helpful adjunct in assessing response after CRT and may help select patients for organ-saving treatment.

External validation of the pathological nodal staging score in upper tract urothelial carcinoma: A population-based study

ObjectivesTo externally validate our previously developed pathological nodal staging model (pNSS) that allows quantification of the likelihood that a patient with pathologic node-negative status has, indeed, no lymph node metastasis (LNM). Patients and methodsWe analyzed data from 2,768 patients treated with radical nephroureterectomy (RNU) and lymph node dissection (LND) using the Surveillance, Epidemiology, and End Results database from 1988 to 2010. We estimated the sensitivity of pathologic nodal staging using a beta-binomial model and developed a new pNSS. Then, we compared these findings with those of the initial cohort. ResultsThe mean and median numbers of lymph node (LN) removed were 5 and 2, respectively (interquartile range = 5) in the validation cohort, though 66.5% of the patients (n = 1814) were pN0. Similar to the development cohort, the probability of missing a LNM decreased as the number of nodes examined increased in the validation cohort. If only a single node was examined, 35% of patients would be misclassified as pN0 while harboring LNM. Even when 5 nodes were examined, 8% would be misclassified. The probability of having a positive node increased with advancing pathological T stage in both the cohorts. Patients with pT0-Ta-Tis-T1 disease in both cohorts would have more than a 95% chance of a correct pathologic nodal staging with 2 examined nodes. However, if a patient has pT3–T4 disease, more than 12 examined LNs are needed to reach 95% accuracy. ConclusionsWe confirmed that the number of examined nodes needed for adequate staging depends on pT category. We externally validated our previous pNSS in a population-based database, which could help in the clinical decision-making regarding adjuvant chemotherapy administration.

LAG-3 confers poor prognosis and its blockade reshapes antitumor response in head and neck squamous cell carcinoma

ABSTRACTImmunotherapy with immune checkpoint molecule-specific monoclonal antibody have obtained encouraging results from preclinical studies and clinical trials, which promoted us to explore whether this kind of immunotherapy could be applicable to head and neck squamous cell carcinoma (HNSCC). Lymphocyte activation gene-3 (LAG-3) is an immune checkpoint control protein that negatively regulates T cells and immune response. Here, using the human tissue samples, we report these findings that LAG-3 is overexpressed on tumor-infiltrating lymphocytes (TILs; p < 0.001) and its overexpression correlates with the high pathological grades, lager tumor size and positive lymph node status in human primary HNSCC. Survival analysis identifies LAG-3 as a prognostic factor independent of tumor size and pathological grades for primary HNSCC patients with negative lymph node status (p = 0.014). Study in immunocompetent genetically defined HNSCC mouse model reports that LAG-3 is upregulated on CD4+ T cells, CD8+ T cells and CD4+Foxp3+ regulatory T cells (Tregs). In vivo study, administration of LAG-3-specific antibody retards tumor growth in a way associated with enhanced systemic antitumor response by potentiating the antitumor response of CD8+ T cells and decreasing the population of immunosuppressive cells. Taken together, our results offer a preclinical proof supporting the immunomodulatory effects of LAG-3 and suggest a potential therapeutic target of immunotherapy for HNSCC.

Trends and variation in the use of nipple-sparing mastectomy for breast cancer in the United States.

For many women, nipple-sparing mastectomy (NSM) provides aesthetic and quality-of-life outcomes superior to skin-sparing mastectomy. Accumulating data suggest that NSM provides similar oncologic outcomes in select breast cancer patients. This study sought to determine national trends in NSM use. Using the National Cancer Data Base, 6254 women with breast cancer who underwent NSM between 2010 and 2013 were identified. NSM rates were determined relative to the number of patients who received a mastectomy with reconstruction (n=114,849). Associations between patient, tumor, and facility characteristics and NSM were assessed using logistic regression. The rate of NSM increased from 2.9 to 8.0% between 2010 and 2013. NSM was most commonly performed in academic (adjusted odds ratio [OR] 1.43, p<0.001) and high-volume (OR 1.59, p<0.001) breast centers. There was up to a 5.8-fold variation in its delivery between geographic census regions (p<0.001). Of 1231 hospitals, only 491 (39.9%) reported performing at least one NSM during the study period. Half of all NSMs were performed by the top 6% (n=30) of NSM-performing centers. NSM was associated with small tumor size (p<0.001), lower tumor grades (p<0.05), and negative nodal status (p<0.001). However, half of NSM patients had at least one tumor characteristic that diverged from current (2016) NCCN recommendations for the procedure. The use of therapeutic NSM is increasing dramatically in the United States, despite recommendations that the procedure be used with caution. As NSM becomes increasingly common, efforts are needed to monitor its long-term oncologic outcomes and to ensure equitable access to it.

Radiation Dose Escalation in Esophageal Cancer Revisited: A Contemporary Analysis of the National Cancer Data Base, 2004 to 2012

To evaluate the effect of radiation dose escalation on overall survival (OS) for patients with nonmetastatic esophageal cancer treated with concurrent radiation and chemotherapy. Patients diagnosed with stage I to III esophageal cancer treated from 2004 to 2012 were identified from the National Cancer Data Base. Patients who received concurrent radiation and chemotherapy with radiation doses of ≥50Gy and did not undergo surgery were included. OS was compared using Cox proportional hazards regression and propensity score matching. A total of 6854 patients were included; 3821 (55.7%) received 50 to 50.4Gy and 3033 (44.3%) received doses >50.4Gy. Univariate analysis revealed no significant difference in OS between patients receiving 50 to 50.4Gy and those receiving >50.4Gy(P=.53). The dose analysis, binned as 50 to 50.4, 51 to 54, 55 to 60, and >60Gy, revealed no appreciable difference in OS within any group compared with 50 to 50.4Gy. Subgroup analyses investigating the effect of dose escalation by histologic type and in the setting of intensity modulated radiation therapy also failed to reveal a benefit. Propensity score matching confirmed the absence of a statistically significant difference in OS among the dose levels. The factors associated with improved OS on multivariable analysis included female sex, lower Charlson-Deyo comorbidity score, private insurance, cervical/upper esophagus location, squamous cell histologic type, lower T stage, and node-negative status (P<.01 for all analyses). In this large national cohort, dose escalation >50.4Gy did not result in improved OS among patients with stage I to III esophageal cancer treated with definitive concurrent radiation and chemotherapy. These data suggest that despite advanced contemporary treatment techniques, OS for patients with esophageal cancer remains unaltered by escalation of radiation dose >50.4Gy, consistent with the results of the INT-0123 trial. Furthermore, these data highlight that many radiation oncologists have not embraced the concept that dose escalation does not improve OS. Although local control, not investigated in the present study, might benefit from dose escalation, novel therapies are needed to improve the OS of patients with esophageal cancer.

Role of histological regression grade after two neoadjuvant approaches with or without radiotherapy in locally advanced gastric cancer.

Background:The degree of histopathological response after neoadjuvant therapy in locally advanced gastric cancer (GC) is a key determinant of patients' long-term outcome. We aimed to assess the pattern of histopathological regression after two neoadjuvant approaches and its impact on survival times.Methods:Regression grade of the primary tumour (Becker criteria) and the degree of nodal response by a 4-point scale (grades A–D) were assessed. Grade A—true negative lymph nodes (LNs); grade B and C—infiltrated LNs with any or little evidence of nodal response; and grade D—complete pathological response in a previously infiltrated LN. A favourable pathological response was defined as Becker Ia–b and grade D.Results:From 2004 to 2014, 80 patients with GC (cT3–4/N+ by CT-scan/EUS) were treated with either preoperative chemotherapy (ChT, n=34) or chemoradiation (CRT, n=46). Patients in the CRT group had a higher likelihood of achieving a Becker Ia–b response (58 vs 32%, P=0.001), a grade D nodal regression (30 vs 6%, P=0.009) and a favourable pathological response (23 vs 3% P=0.019). Patients with a grade D nodal response had a longer 5-year PFS and OS compared with those with a grade B or C response. Patients with a baseline negative LN status had similar outcomes irrespective of the preoperative therapy received (5-year OS; ChT vs CRT, 58 vs 51%, P=0.92).Conclusions:Preoperative chemoradiation increases the likelihood of achieving favourable histopathological features that correlate with a 5-year OS>70% in GC patients.

The Accuracy of Breast MR Imaging for Measuring the Size of a Breast Cancer: Analysis of the Histopathologic Factors

BackgroundThe objective of the study was to compare the accuracy of different magnetic resonance (MR) sequences for measuring tumor size and to evaluate whether the imaging and histopathologic features affect the accuracy of the tumor size estimation on the MR sequence. Patients and MethodsEight hundred women were included. The maximum diameter of the tumor was measured on T2-weighted (T2W) sequences, early-subtracted dynamic contrast-enhanced (DCE) T1-weighted (T1W) sequences, and maximal intensity projection (MIP) reconstructions. Agreement between the MR imaging and pathology-determined size were analyzed. Using the best MR sequence to measure the tumor size, the relationship between the accuracy and the imaging and histopathologic features were evaluated. ResultsTumor measurement showed a good agreement with the pathology-determined size, and with the best results using MIP (k = 0.805) compared with the early-subtracted DCE T1W sequence (k = 0.802) and the T2W sequence (k = 0.779). On MIP, the tumors of patients with minimal or mild background parenchymal enhancement, a mass, invasive ductal carcinoma (IDC), pathology-determined size < 2 cm, positive estrogen receptor, negative HER2, luminal A type, nuclear and histologic grade 1, negative nodal status, negative lymphovascular invasion, and negative extensive intraductal component were significantly more accurately estimated. The independent factors associated with the accuracy of tumor measurement were a mass, IDC, and the pathology-determined size < 2 cm. ConclusionOur study showed that tumor size is most accurately measured on MIP, especially for IDC appearing as a mass on MR imaging and with the pathology-determined size < 2 cm.

Long-term outcomes after multidisciplinary management of T3 laryngeal squamous cell carcinomas: Improved functional outcomes and survival with modern therapeutic approaches.

The purpose of this study was to evaluate the long-term outcomes after initial definitive or adjuvant radiotherapy (RT) for T3 laryngeal cancers. We reviewed 412 patients treated for T3 laryngeal squamous cell cancer from 1985 to 2011. The 10-year overall survival (OS) was 35%; disease-specific-survival (DSS) was 61%; locoregional control was 76%; and freedom from distant metastasis was 83%. Chemotherapy, age, performance status <2, node-negative status, and glottic subsite were associated with improved survival (all p < .03). Larynx preservation with induction and/or concurrent chemoradiotherapy (LP-CRT) had better laryngectomy-free survival than RT alone (LP-RT; hazard ratio [HR] = 0.62; 95% confidence interval [CI] = 0.47-0.81; p = .0005); 10-year laryngectomy-free survival rates of the LP-CRT cohort (37%) were higher than those of the LP-RT cohort (18%). The 5-year DSS and OS rates of the LP-CRT cohort (79% and 67%) were better after total laryngectomy with postoperative RT (TL-PORT; 61% and 50%) and LP-RT (64% and 46%; p < .006 for all). In patients with T3 laryngeal cancers, LP-CRT provides better functional, oncologic, and survival outcomes than historical TL-PORT or LP-RT does. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1739-1751, 2016.

Posttreatment Surveillance in Patients with Prolonged Disease-Free Survival After Resection of Colorectal Liver Metastasis.

IntroductionPosttreatment surveillance protocols most often endure for 5 years after resection of colorectal liver metastasis (CRLM). Most recurrences happen within 3 years after surgical removal of the tumour. This study analysed the need of surveillance for patients with at least 3 years of disease-free survival after potentially curative resection of CRLM.MethodsA single-centre, retrospective analysis of all consecutive patients who underwent treatment for CRLM with curative intent between 2000 and 2011.ResultsIn total, 152 of 545 patients (28 %) remained disease-free for 3 years after successful resection of the CRLM. The estimated recurrence rate after 10 years of follow-up in this group of 152 patients was 27 %. More than half of these patients (55 %) could be treated with curative intent for their recurrences. Multivariable analysis revealed that the nodal status of the primary tumour is of significant prognostic value for developing recurrences after 3 years of disease-free survival. A disease-free interval of less than 12 months between resection of primary tumour and detection of CRLM shows a trend towards significance. Both factors were used to create a risk score, showing that patients with a low-risk profile (node-negative status and a disease-free interval <12 months) have an estimated recurrence rate of 5 % and might not benefit from intensive surveillance beyond 3 years of follow-up without a recurrence.ConclusionsThe currently developed risk score shows that follow-up can be stopped in a specific subgroup 3 years after treatment for their CRLM with curative intent.Electronic supplementary materialThe online version of this article (doi:10.1245/s10434-016-5388-8) contains supplementary material, which is available to authorized users.

Detailed Lymph Node Sectioning of Papillary Thyroid Carcinoma Specimen Increases the Number of pN1a Patients.

Papillary thyroid carcinoma (PTC) is a common endocrine malignancy, frequently presenting with lymph node metastasis at the time of diagnosis. Lymph node staging (N) partly determines treatment, follow-up, and prognosis. Since 2011, our institution has employed a more comprehensive histopathological work-up of lymph nodes in patients with PTC. We sought to retrospectively determine the value of serial lymph node level sectioning in PTCs with negative preoperative lymph node status (pN0) as a method to increase the sensitivity of detecting metastatic disease. We included all patients that underwent thyroidectomy and central neck dissection and subsequent comprehensive lymph node level sectioning due to PTC with an initial pN0 status between the years 2011 and 2015 at our institution. Sixty-seven cases of PTC with a median of 10 metastatic free lymph nodes identified per case were included. After serial lymph node sectioning of the central compartment, 11 cases (16%) revealed lymph node metastasis, six of which (55%) presented with a small primary tumor (<20mm, T1). Of all T1 tumors with initial pN0 status, 18% (T1a) and 9% (T1b) reached a pN1 stage after comprehensive lymph node sectioning. Cases with altered lymph node status had a median of 15 identified lymph nodes as compared to ten in cases that remained negative. We conclude that comprehensive lymph node sectioning increased the sensitivity of detecting metastases in PTC and altered the pathological TNM staging (pTNM) for a significant number of patients. Although of limited prognostic significance, the method should be considered as an adjunct tool when assessing lymph node status of PTC as a part of the routine histological work-up to ensure an accurate cancer staging.

Genetic Polymorphism of SUMO-Specific Cysteine Proteases - SENP1 and SENP2 in Breast Cancer.

SENP proteases take part in post-translational modification of proteins known as sumoylation. They catalyze three distinct processes during sumoylation: processing of SUMO protein, deconjugation of SUMO from the target protein, and chain editing which mentions to the dismantling of SUMO chain. Many proteins that are involved in the basic processes of cells, such as regulation of transcription, DNA repair or cell cycle control, are sumoylated. The aim of these studies was to investigate an association between polymorphic variants (SNPs) of the SENP1 gene (c.1691 + 36C > T, rs12297820) and SENP2 gene (c.902C > A, p.Thr301Lys, rs6762208) and a risk of breast cancer occurrence. We performed a case-control study in 324 breast cancer cases and 335 controls using PCR-RLFP. In the case of the SENP1 gene polymorphism we did not find any association between this polymorphism and breast cancer risk. In the case of SENP2 gene polymorphism we observed higher risk of breast cancer for carriers of the A allele (OR =1.33; 95 % CI 1.04–1.69). Our analysis also showed the genotype C/C (OR =0.67, 95 % CI 0.48–0.93) and the allele C (OR =0.75, 95 % CI 0.59–0.69) of this polymorphism decrease a risk of breast cancer. We also checked the distribution of genotypes and frequency of alleles of the SENP1 and SENP2 genes polymorphisms in groups of patients with different hormone receptor status, patients with positive and negative lymph node status and patients with different tumor grade. Odds ratio analysis showed a higher risk of metastases in women with the genotype C/C (OR =2.07, 95 % CI 1.06–4.05) and allele C (OR =2.10 95 % CI 1.10–4.01) of the c.1691 + 36C > T SENP1 gene polymorphism. Moreover, we observed reduced risk in women with the allele T (OR =0.48, 95 % CI 0.25–0.91) in this polymorphic site. In the case of SENP2 gene polymorphism we observed that the A/A genotype correlated with the lack of estrogen receptor (OR =1.94, 95 % CI 1.04–3.62). Our results suggest that the variability of the SENP1 and SENP2 genes may play a role in breast cancer occurrence. Further studies are needed to clarify their biological functions in breast cancer.

Increased lymph node retrieval decreases adjuvant chemotherapy rate for stage II colon cancer

Objective: Investigation of lymph nodes in colorectal specimens after surgery due to cancer is important for staging the cancer. There has to be an adequate number of lymph nodes to conclude a node-negative status. Our aim was to investigate if change in fixative could give increased lymph node yield, and if this could result in a potential decrease of adjuvant treatment for stage II patients. In addition, we wanted to evaluate if the change in fixative could potentially affect subsequent molecular testing. Material and methods: All resection specimens from one hospital were from 2011 fixed in GEWF while resection specimens from two other hospitals were fixed in conventional buffered formalin. Number of lymph nodes harvested were compared from two periods; 2009/2010 and 2012/2013. In addition, tumors fixed in GEWF and tumors fixed in formalin were tested separately with immunohistochemical staining and molecular testing. Results: There was a significant increase in lymph node retrieval in specimens fixed in GEWF compared to number of lymph nodes found before the implementation of this fixative (p < 0.001). For hospitals using only formalin, the number of nodes did not increase significantly. Number of positive lymph nodes did not increase. Immunohistochemical staining can be a problem with tumors fixed in GEWF, but DNA quality seems not affected by the changes. Conclusions: GEWF enhances lymph node detection in colorectal cancer specimens, leading to fewer patients being falsely defined as high-risk stage II. The loss of stability when staining for MMR-proteins can be overcome by molecular analysis when needed.

Testing chemotherapy efficacy in HER2 negative breast cancer using patient-derived spheroids.

BackgroundTargeted anti-HER2 therapy has greatly improved the prognosis for many breast cancer patients. However, treatment for HER2 negative disease is currently still selected from a multitude of untargeted chemotherapeutic treatment options. A predictive test was developed using patient-derived spheroids to identify the most effective therapy for patients with HER2 negative breast cancer of all stages, for clinically relevant subgroups, as well as individual patients.MethodsTumor samples from 120 HER2 negative patients obtained through biopsy or surgical excision were tested in the breast cancer spheroid model using scaffold-free cell culture. Similarly, spheroids were also generated from established HER2 negative breast cancer cell lines T-47D, MCF7, HCC1143, and HCC1937 to compare treatment efficacy of heterogeneous cell populations from patient tumor tissue with homogeneous cell lines. Spheroids were treated in vitro with guideline-recommended compounds. Treatment mediated impact on cell survival was subsequently quantified using an ATP assay.ResultsDifferences were observed in the metabolic activity of the untreated spheroids, whereby cell lines consistently achieved higher values compared to tissue spheroids (p < 0.001). A higher number of cells per spheroid correlated with a higher basal metabolic activity in tissue-derived spheroids (p < 0.01), while the opposite was observed for cell line spheroids (p < 0.01). Recurrent tumors showed a higher mean vitality (p < 0.01) compared to primary tumors. Except for taxanes, treatment efficacy for most tested compounds differed significantly between breast cancer tissue spheroids and breast cancer cell lines. Overall a high variability in treatment response in vitro was seen in the tissue spheroids regardless of the tested substances. A greater response to anthracycline/docetaxel was observed for hormone receptor negative samples (p < 0.01). A higher response to 5-FU (p < 0.01) and anthracycline (p < 0.05) was seen in high grade tumors. Smaller tumor size and negative lymph node status were both associated with a higher treatment efficacy to anthracycline treatment combined with 5-FU (cT1/2 vs cT3/4, p = 0.035, cN+ vs cN−, p < 0.05).ConclusionsThe tissue spheroid model reflects current guideline treatment recommendations for HER2 negative breast cancer, whereas tested cell lines did not. This model represents a unique diagnostic method to select the most effective therapy out of several equivalent treatment options.

Lymph node micrometastases are associated with disease recurrence and poor survival for early-stage non-small cell lung cancer patients: a meta-analysis

BackgroundWe performed a meta-analysis to clarify whether the molecular detection of tumor cells or micrometastases in the lymph node (LN) indicates a high risk of disease recurrence and poor survival in negative pathologic lymph node status non-small cell lung cancer (NSCLC).MethodsA literature search was performed using relevant keywords. We searched relevant studies from PubMed, Embase, and the Cochrane Library. Direct and indirect meta-estimates were generated using Review Manager software with fixed effects for the study. Study-to-study heterogeneity was summarized using I2 statistics and predictive intervals (PIs).ResultsOur analysis of eight eligible studies revealed that patients with lymph node micrometastases (LNMM) were associated with poor overall survival (OS) (HR, 1.98; 95 % CI, 1.50 to 2.62; p < 0.00001) and disease-free survival (DFS) (HR, 2.34; 95 % CI, 1.67-3.27; p < 0.00001).ConclusionLNMM is associated with an increased risk of disease recurrence and poor survival in patients with negative pathologic node negative NSCLC. Thus, these patients need to be carefully followed up after the initial pulmonary resection.