High Risk Of Distant Metastasis Research Articles

Concordance of Biomarkers and Tumor Location for in-Breast Tumor Recurrences in Early Stage Breast Cancer Patients Treated with Breast Conserving Surgery and Adjuvant RT

Patients with an in-breast tumor recurrence (IBTR) after breast-conserving therapy have a high risk of distant metastasis and disease-related mortality. Identifying clinical parameters that increase risk for recurrence after IBTR remains a challenge. Our purpose is to describe clinical and treatment parameters of primary and IBTRs that may predict decreased disease free survival after IBTR. Patients with stage 0-II breast cancer treated with lumpectomy and adjuvant radiation were identified from institutional databases of patients treated from 2003-2017 at our institution. Overall survival (OS), Disease free survival (DFS), and Local recurrence free survival (LRFS) were estimated using the Kaplan Meier method. We subsequently identified patients who experienced an isolated IBTR. Concordance of hormone receptor status and location of tumor from primary to recurrence was evaluated using chi-squared tests. The effect of clinical and treatment parameters with time interval to the first IBTR was evaluated using ANOVA. We identified 2217 patients who met eligibility criteria. The median follow-up (FU) was 44 months (IQR: 25.7 – 70.9). OS at 5-years was 97.7%, DFS was 96.1% and LRFS was 97.9%. The median time to IBTR was 33.8 months (IQR: 21 – 44). We identified 37 patients with isolated IBTR, 51.4% as DCIS, and 48.6% as invasive disease, of whom 83.3% had an in situ component. Radiotherapy information was available for 30 patients. Median whole-breast dose was 40.5Gy; 23 patients received a boost to the tumor bed, with the median dose with boost of 48Gy. In 80.6% of patients, hormone receptor status at recurrence was concordant with the primary tumor. ER and PR receptor status from primary to IBTR were highly associated (ER: χ2, p = 0.006; PR: χ2, p=0.001). There were no changes in HER2 status from primary to IBTR. There was a high level of concordance between quadrant of tumor from primary to IBTR (62.2% of IBTRs, χ2, p=0.008). Tumor size greater than 1.5 cm and endocrine therapy upfront were associated with longer interval to IBTR (ANOVA p=0.02, p=0.004, respectively). At the time of IBTR, 86.5% of patients underwent salvage surgery (43.2% bilateral mastectomy, 24.3% unilateral mastectomy, and 16.2% local excision), 21.6 % received chemotherapy, and 43.2% received endocrine therapy. DFS after IBTR was 81.1% (median FU = 25.5 months, IQR: 11.6 – 56.4) with 57% local, 14% regional and 29% distant recurrences after IBTR. DFS after IBTR was not associated with histology at initial presentation (p=0.4), concordance of biomarkers (p=0.8), concordance of tumor location (p=0.8), or presence of an in situ component with IBTR (p=0.9). Among patients with early stage breast cancer patients who had BCS treated with adjuvant RT, ER/PR status and quadrant are highly concordant from primary to IBTR. The overall recurrence rate in this modern series was low. There was no correlation between concordance of biomarkers and tumor location and the presence of an in situ component at recurrence with improved DFS after IBTR.

Lymph Node Ratio as a Predictor of Distant Metastases in Major Salivary Gland Carcinomas

To investigate the prognostic value of lymph node ratio (LNR, number of positive lymph nodes[LN]/total number of excised LN) on distant metastases (DM) and overall survival (OS) in patients (pts) with major salivary gland carcinoma (SGC). An REB-approved retrospective review was conducted for SGC patients treated at our institution with curative surgery and neck dissection (>=6 dissected LN)+/−adjuvant treatment in 2000-2015. Patients, treatment and outcomes data were collected from our institutional maintained databases. Staging was reviewed according to the AJCC-UICC 8th edition. High risk pathology was defined with histologic grade and WHO histologic criteria, and included: adenoid cystic carcinoma (ACC), salivary duct carcinoma, SCC, G2/3 adenocarcinoma, G2/3 mucoepidermoid carcinoma (MEC), G2/3 carcinoma ex-pleomorphic adenoma, carcinosarcoma, undifferentiated (small-, large-cell or lymphoepithelial) carcinoma and G3 of other histologic subtypes. Distant control (DC) and OS were analyzed with competing risk and Kaplan-Meier methods respectively. LNR (continuous variable) was subjected to multivariable analysis (MVA) for DM and OS (adjusted for age, gender, primary SGC subsite, pathologic stage, high-risk pathology, lymphovascuar invasion [LVI], perineural invasion [PNI], extranodal extension [ENE] and surgical margin status). The optimal cutpoint of LNR that maximized the difference in outcomes was determined using maximally selected rank statistics. Subgroup analysis was performed for patients with pN+. A total of 204 pts were identified: median age: 56 yr (16-91); median follow-up: 5.2 yr (0.4- 17.6); parotid gland primary tumor location: 168 (82%); high risk pathology: 151 (74%); pT3-4: 132 (65%), pN+: 99 (44%); LVI: 49 (26%); positive microscopic surgical margin: 103 (52%); ENE: 37 (19%). PORT was used in 195 pts (96%); and adjuvant concurrent chemotherapy in 11 (5%). Of 2,725 LNs evaluated, 328 (12%) were pN+. The median number of dissected LN was 23 (6–101). For pN+ pts, the median number of involved LN was 3 (1-65) and median LNR was 14% (1%–100%). High-risk pathology and LVI were associated with high LNR (p<0.001 for both). On MVA LNR was independently correlated with DM (HR:1.18, 95%CI: 1.07-1.30, p<0.001) and OS (HR:1.16; 95%CI: 1.06-1.28, p=0.002) and so did LVI+ (DM: HR:2.54, 95%CI: 1.38-4.70, p=0.003) and OS (HR:2.50; 95%CI: 1.33-4.70, p=0.004), positive margins (DM: HR:2.47, 95%CI: 1.31-4.65, p=0.005) and OS (HR:2.59; 95%CI: 1.35-4.95, p=0.004),. The optimal cut-off point for LNR was 8%; 5-yr DC: 42% vs 88%, p<0.001; 5-yr OS: 44% vs 89%, p<0.001 for LNR ≥8% vs <8%. In a subgroup analysis of patients with pN+, LNR remained predictive for DM (HR:1.24, 95%CI: 1.14-1.35, p<0.001) and OS (HR 1.27, 95%CI: 1.16-1.38, p<0.001). High LNR is associated with a higher risk of DM and lower OS. LNR should be evaluated in future prospective studies for intensified therapy or surveillance schedule in patients with SGC.

Interactions Between ABCB1 Genotype and Preoperative Statin Use Impact Clinical Outcomes Among Breast Cancer Patients.

Multiple clinical trials investigate statins' effects in breast cancer. The ABCB1 genotype appears to influence statin response and toxicity in the cardiovascular setting. This exploratory study aimed to investigate the interplay between preoperative statin use, ABCB1 genotype, and tumor-specific expression of the statin target 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in breast cancer. Preoperative statin use, ABCB1 C3435T genotype, and HMGCR expression in relation to outcome were analyzed in 985 primary breast cancer patients from a population-based prospective cohort in Sweden from 2002 to 2012. Preoperative statin use (n = 80) was not associated with ABCB1 C3435T genotype (n = 576), HMGCR expression (n = 848), or clinical outcomes. ABCB1 C3435T TT-carriers had lower risk of breast cancer events than any C-carriers (adjusted hazard ratio (HRadj) 0.74; 95%CI 0.49, 1.12), but only in non-statin users (Pinteraction = 0.042). Statin users with TT genotype had higher risk of distant metastasis (HRadj 4.37; 95%CI 1.20, 15.91; Pinteraction = 0.009) and shorter overall survival than other patients (HRadj 3.77; 95%CI 1.37, 10.39; Pinteraction = 0.019). In conclusion, there were nominally significant interactions between ABCB1 genotype and preoperative statin use on clinical outcomes, while preoperative statin use was not associated with outcomes. Since this is an exploratory study of the impact of the ABCB1 genotype in relation to statin use and clinical outcomes in the breast cancer setting, the results should be interpreted with caution and warrant replication in an independent cohort, preferably in a randomized setting. Since statin use is common in breast cancer patients, it would be of interest to further elucidate the clinical impact of the ABCB1 genotype in breast cancer.

The interplay of IMRT and transoral surgery in HPV-mediated oropharyngeal cancer: Getting the balance right

Transoral surgery (TOS) and IMRT represent two primary local ablative treatment modalities for oropharyngeal cancer (OPC). The choice of one over the other represents an interplay between the chance of cure vs risk of late sequelae. HPV-mediated (HPV+) OPC patients generally have excellent outcomes, especially in TNM-8 stage I disease. Controversies exist over which treatment has a more favorable toxicity profile and equal efficacy in the management of this population. Non-randomized retrospective data show comparable oncological and functional outcomes between TOS-based vs IMRT-based treatment for this disease. Several de-intensification concepts have been explored in this subset in both primary surgery-based vs primary radiotherapy-based trials. However, no robust mature trial data are available to convincingly guide treatment selection. TOS is often presented as one of the de-intensification options although the majority of series also describe the use of adjuvant treatments which inevitably result in non-negligible toxicities. Patient selection and surgeons’ training are paramount. Understanding tumor biology and the prognostic value of traditional ‘adverse’ features will further guide trial design for refinement of risk tailored approach. In conclusion, comparative data suggests TOS and IMRT are both effective treatment for TNM-8 stage I HPV+ OPC with similar oncological and functional outcomes. TOS as a single modality has potential advantages in mitigating radiation included toxicities. TOS should be avoided in the presence of clinically overt extranodal extension or when negative margins are unlikely to be achieved. TOS is also less ideal for cases with radiological features predicting a high risk of distant metastasis.

Impact of Biochemical Failure After Salvage Radiation Therapy on Prostate Cancer–specific Mortality: Competition Between Age and Time to Biochemical Failure

BackgroundDisease progression following salvage radiotherapy (SRT) for prostate cancer (PC) is common, and the time to biochemical recurrence (BCR) is heterogeneous. ObjectiveTo describe the temporal distribution and clinical impact of BCR following SRT and model outcomes using patient age and time to BCR from SRT. Design, setting, and participantsA retrospective multi-institutional study included 547 consecutive men with lymph node–negative PC receiving SRT from 1985 to 2013. The median follow-up after SRT was 8.4 yr.Intervention All men received SRT with three-dimensional or intensity-modulated RT. Outcome measurements and statistical analysisBCR was defined as a rise in prostate-specific antigen (PSA) ≥0.2ng/ml above the PSA nadir followed by a sequentially equal or higher value. Additional outcomes included distant metastasis (DM), PC-specific mortality (PCSM), and overall mortality (OM). Cox proportional hazards models, a landmark analysis, and comparison of c-indices were used. Cumulative incidence curves were estimated from a Fine and Gray regression model. Results and limitationsThe estimated 10-yr cumulative incidence of BCR was 60%. Of the 274 men experiencing BCR, 149 (54%) had BCR within 18 mo of SRT. BCR ≤18 mo after SRT was associated with a higher risk of DM (hazard ratio [HR] 7.44, 95% confidence interval [CI] 4.91–11.3; p<0.001), PCSM (HR 12.3, 95% CI 5.95–25.2; p<0.001), and OM (HR 2.85, 95% CI 1.94–4.17; p<0.001). We provide a model to estimate the cumulative incidence of DM and PCSM using age and time to BCR. The retrospective nature of our analysis limits our findings. ConclusionsA strikingly large proportion of men experience early BCR following SRT and are at higher risk of DM and PCSM. Novel predictive biomarkers are needed to identify men harboring micrometastatic disease to avoid potentially futile local therapies or allow for intensification of systemic therapies. Patient summaryMany men will develop biochemical recurrence of prostate cancer after salvage radiotherapy. Men with biochemical recurrence within 18 mo of salvage radiotherapy constitute a cohort at higher risk of distant metastasis and prostate cancer–specific mortality.

Chirurgie après chimioradiothérapie des cancers de l’œsophage : faut-il la faire ou pas ?

The treatment of locally advanced esophageal cancer is still evolving. Surgery was considered as the backbone of the therapeutic management for a long time. Nowadays, chemoradiation has taken a major place in the neoadjuvant setting or as an exclusive treatment. Although some patients benefit from esophagectomy after chemoradiotherapy, a large subset of patients has no benefit and morbi-mortality rates are increased with a trimodality strategy. Patients who will have a local failure are at high risk of distant metastases in the follow-up. A third group of patients will have persistent locoregional disease after chemoradiotherapy and may benefit from surgery, but only a minority of patients with locally advanced disease are eligible. The impact of surgery after upfront chemoradiotherapy on survival and the quality of life of patients with locally advanced squamous cell esophageal cancer remain uncertain. An active surveillance strategy after chemoradiation or salvage esophagectomy for a locally residual disease might improve the prognosis of these patients. An optimized bimodality such as chemoradiotherapy delivering at least 50Gy is still standard and salvage surgery for local persistent disease or a local failure must be discussed in the framework of a multidisciplinary group for selected patients only.

RAB37 Hypermethylation Regulates Metastasis and Resistance to Docetaxel-Based Induction Chemotherapy in Nasopharyngeal Carcinoma.

Epigenetic alterations play important roles in metastasis and drug resistance through gene regulation. However, the functional features and molecular mechanisms of epigenetic changes remain largely unclear in nasopharyngeal carcinoma (NPC) metastasis. Gene regulatory network analysis was used to identify metastatic-specific dysregulated genes between normal and NPC tissues and the expression was validated in published Gene-Expression Omnibus data set. The regulatory and functional role of RAB37 downregulation was examined in NPC and was validated in vitro and in vivo, and downstream target of RAB37 was explored. The clinical value of RAB37 methylation was evaluated in NPC metastasis and chemosensitivity. We identified RAB37 as a specific hypermethylated gene that is most commonly downregulated in NPC. Moreover, RAB37 downregulation was attributed to hypermethylation of its promoter and was significantly associated with metastasis- and docetaxel chemoresistance-related features in NPC. Ectopic RAB37 overexpression suppressed NPC cell metastasis and enhanced chemosensitivity to docetaxel. Mechanistically, RAB37 colocalized with TIMP2, regulated TIMP2 secretion, inhibited downstream MMP2 activity, and consequently altered NPC cell metastasis. Furthermore, RAB37 hypermethylation was correlated with poor clinical outcomes in patients with NPC. We developed a prognostic model based on RAB37 methylation and N stage that effectively predicted an increased risk of distant metastasis and a favorable response to docetaxel-containing induction chemotherapy (IC) in NPC patients. This study shows that RAB37 hypermethylation is involved in NPC metastasis and chemoresistance, and that our prognostic model can identify patients who are at a high risk of distant metastasis and might benefit from for docetaxel IC.

Carcinome papillaire thyroïdien variante solide/trabéculaire avec mutation DICER1 chez une enfant de 11 ans

We report the case of an 11-year-old patient diagnosed with a solid variant of papillary thyroid carcinoma. Papillary thyroid carcinoma (PTC) is the most common thyroid cancer, representing 80-90% of all newly diagnosed thyroid cancers. Among the many variants described, solid/trabecular variant of papillary thyroid carcinoma is a rare entity and account for 3% of thyroid cancers. It is more common in children and young adults, and it is seen in higher proportion in post radiation papillary thyroid carcinoma cases. Histologically, solid variant papillary carcinoma is characterized by a predominantly solid, trabecular or insular growth pattern, and the presence of cytological features typical of PTC. Its main differential diagnosis is poorly differentiated thyroid carcinoma. It has a less favorable prognosis than the classical papillary type, with a higher risk of distant metastasis, extrathyroidal extension and lympho-vascular invasion. It is associated with a slightly lower long-term survival in adult cases, but not in children. The management of solid variant PTC includes surgery, associated or not with postoperative radioiodine ablation, according to the aggressiveness criteria. Our patient had a DICER1 somatic mutation. Carriers of germline DICER1 mutations are predisposed to a rare cancer syndrome, the DICER1 syndrome, with a higher risk of numerous tumors and infrequently differentiated thyroid carcinomas.

Caffeic Acid Phenethyl Ester Induces N-myc Downstream Regulated Gene 1 to Inhibit Cell Proliferation and Invasion of Human Nasopharyngeal Cancer Cells.

Caffeic acid phenethyl ester (CAPE), a bioactive component extracted from propolis, is widely studied due to its anti-cancer effect. Nasopharyngeal carcinoma (NPC) is distinct from other head and neck carcinomas and has a high risk of distant metastases. N-myc downstream regulated gene 1 (NDRG1) is demonstrated as a tumor suppressor gene in several cancers. Our result showed that CAPE treatment could repress NPC cell growth, through induction of S phase cell cycle arrest, and invasion. CAPE treatment stimulated NDRG1 expression in NPC cells. NDRG1 knockdown increased NPC cell proliferation and invasion and rendered NPC cells less responsive to CAPE growth-inhibiting effect, indicating CAPE repressed NPC cell growth partly through NDRG1indcution. CAPE treatment increased phosphorylation of ERK, JNK, and p38 in a dose- and time-dependent manner. Pre-treatments by inhibitors of ERK (PD0325901), JNK (SP600125), or p38 (SB201290), respectively, all could partly inhibit the CAPE effect on NDRG1 induction in NPC cells. Further, STAT3 activity was also repressed by CAPE in NPC cells. In summary, CAPE attenuates NPC cell proliferation and invasion by upregulating NDRG1 expression via MAPK pathway and by inhibiting phosphorylation of STAT3. Considering the poor prognosis of NPC patients with metastasis, CAPE could be a promising agent against NPC.

Comparative effectiveness of different treatment strategies for bladder cancer of regional lymph nodes involvement

Objective Patients with bladder cancer with clinical lymph node involvement (cN+ ) are at high risk for distant metastases, but are potentially curable. Such patients are excluded fromneoadjuvant chemotherapy trials and pooled with patients with distant metastases in first-line chemotherapy trials not suited to define the role of combined-modality therapy. To analyze a comparative effectiveness for avoiding invalid evidence. Methods A retrospective study was conducted for 522 patients who underwent chemotherapy and/or cystectomy between January 2003 and January 2013 for cTanyN1-3M0 bladder cancer patients. We used multivariable adjustment for tumor- and patient- characteristics to assess effectiveness. Results Among 522 patients (cN1, 47%; cN2, 43%; cN3, 10%), 342 patients underwent cystectomy and 180 patients were treated with chemotherapy alone. Of the cystectomy patients, 116 patients received preoperative and 96 patients received adjuvant chemotherapy. The crude 5-year OS for chemotherapy alone, cystectomy alone, preoperative chemotherapy followed by cystectomy, and cystectomy followed by adjuvant chemotherapy was 12%(95% CI: 9%~14%), 19%(95% CI: 13%~23%), 32%(95% CI: 26%~37%), 25%(95% CI: 20%~32%), respectively. Compared with cystectomy alone, preoperative chemotherapy was associated with a significant improvement in OS (HR 0.68, 95% CI: 0.54~0.92). Adjuvant chemotherapy was also associated with a significant improvement in survival compared with cystectomy alone. The survival in patients were treated with chemotherapy alone was worse than those were treated with cystectomy alone. Conclusions The patients with cN+ bladder cancer achieves long survival.Combined-modality therapy, with chemotherapy and cystectomy, is associated with the best effect. Key words: Urinary Bladder Neoplasms; Lymph Nodes; Cystectomy

Impact of duration of adjuvant chemotherapy in radically resected patients with T4bN1-3M0/TxN3bM0 gastric cancer.

AIMTo provide evidence regarding the postoperative treatment of patients with T4bN1-3M0/TxN3bM0 gastric cancer, for which guidelines have not been established.METHODSPatients who had undergone curative resection between 1996 and 2014 with a pathological stage of T4bN1-3M0/TxN3bM0 for gastric cancer were retrospectively analyzed; staging was based on the 7th edition of the American Joint Committee on Cancer staging system. The clinicopathological characteristics, administration of adjuvant chemotherapy, and patterns of recurrence were studied. Univariate and multivariate analyses of prognostic factors were conducted. The chemotherapeutic agents mainly included fluorouropyrimidine, platinum and taxanes, used as monotherapy, doublet, or triplet regimens. Patterns of first recurrence were categorized as locoregional recurrence, peritoneal dissemination, or distant metastasis.RESULTSThe 5-year overall survival (OS) of the whole group (n = 176) was 16.8%, and the median OS was 25.7 mo (95%CI: 20.9-30.5). Lymphovascular invasion and a node positive rate (NPR) ≥ 0.8 were associated with a poor prognosis (P = 0.01 and P = 0.048, respectively). One hundred forty-seven (83.5%) of the 176 patients eventually experienced recurrence; the most common pattern of the first recurrence was distant metastasis. The prognosis was best for patients with locoregional recurrence and worst for those with peritoneal dissemination. Twelve (6.8%) of the 176 patients did not receive adjuvant chemotherapy, while 164 (93.2%) patients received adjuvant chemotherapy. Combined chemotherapy, including doublet and triplet regimens, was associated with a better prognosis than monotherapy, with no significant difference in 5-year OS (17.5% vs 0%, P = 0.613). The triplet regimen showed no significant survival benefit compared with the doublet regimen for 5-year OS (18.5% vs 17.4%, P = 0.661). Thirty-nine (22.1%) patients received adjuvant chemotherapy for longer than six months; the median OS in patients who received adjuvant chemotherapy for longer than six months was 40.2 mo (95%CI: 30.6-48.2), significantly longer than the 21.6 mo (95%CI: 19.1-24.0) in patients who received adjuvant chemotherapy for less than six months (P = 0.001).CONCLUSIONPatients with T4bN1-3M0/TxN3bM0 gastric cancer showed a poor prognosis and a high risk of distant metastasis. Adjuvant chemotherapy for longer than six months improved outcomes for them.

The Epithelial-Mesenchymal Transition Pathway in Two Cases with Gastric Metastasis Originating from Breast Carcinoma, One with a Metachronous Primary Gastric Cancer

Metastases to the stomach are extremely rare and the metastatic pathway is not well understood. To present two unusual gastric metastases and a review of the literature regarding the pathway of Epithelial Mesenchymal Transition (EMT) in the metastatic cells. The clinicopathological aspects of the two cases were presented in the light of the most recent patents. Data about patents were obtained from the online databases PubMed, World Intellectual Property Organization (WIPO) and Google patents. In the first case, in a 73-year-old female, total gastrectomy was performed for a Gastric Cancer (GC) that was proved to be, based on the immunohistochemical features (positivity for mammaglobin and estrogen receptor and negativity for E-cadherin, β-catenin, CD44 and maspin), a metastasis from an invasive lobular carcinoma of the breast, that was later confirmed. In the second case, a 67-year-old female with invasive ductal carcinoma of the breast, which benefited from chemotherapy and mastectomy, presented a metachronous gastric adenocarcinoma with collision-type metastatic breast ductal carcinoma. The aggressiveness of the GC cells was induced through the E-cadherin/maspin pathway, while the CD44-related stem-like properties of the tumor cells induced the aggressiveness of ductal carcinoma. In females with breast cancer, a possible metastasis in the stomach should be taken into account. Maspin and VSIG1 are not involved in breast cancer histogenesis. The Wnt/β-catenin signaling is not involved in the lobular carcinoma progression. The CD44/HER2 positivity in ductal carcinoma cells might indicate high risk of distant metastasis and low response to chemotherapy.

Mutations of key driver genes in colorectal cancer progression and metastasis.

The association between mutations of key driver genes and colorectal cancer (CRC) metastasis has been investigated by many studies. However, the results of these studies have been contradictory. Here, we perform a comprehensive analysis to screen key driver genes from the TCGA database and validate the roles of these mutations in CRC metastasis. Using bioinformatics analysis, we identified six key driver genes, namely APC, KRAS, BRAF, PIK3CA, SMAD4 and p53. Through a systematic search, 120 articles published by November 30, 2017, were included, which all showed roles for these gene mutations in CRC metastasis. A meta-analysis showed that KRAS mutations (combined OR 1.18, 95% CI 1.05-1.33) and p53 mutations (combined OR 1.49, 95% CI 1.23-1.80) were associated with CRC metastasis, including lymphatic and distant metastases. Moreover, CRC patients with a KRAS mutation (combined OR 1.29, 95% CI 1.13-1.47), p53 mutation (combined OR 1.35, 95% CI 1.06-1.72) or SMAD4 mutation (combined OR 2.04, 95% CI 1.41-2.95) were at a higher risk of distant metastasis. Subgroup analysis stratified by ethnic populations indicated that the BRAF mutation was related to CRC metastasis (combined OR 1.42, 95% CI 1.18-1.71) and distant metastasis (combined OR 1.51, 95% CI 1.20-1.91) in an Asian population. No significant association was found between mutations of APC or PIK3CA and CRC metastasis. In conclusion, mutations of KRAS, p53, SMAD4 and BRAF play significant roles in CRC metastasis and may be both potential biomarkers of CRC metastasis as well as therapeutic targets.

Cycle number of neoadjuvant chemotherapy might influence survival of patients with T1-4N2-3M0 nasopharyngeal carcinoma.

Stage N2-3 nasopharyngeal carcinoma (NPC) shows a high risk of distant metastasis, which will finally cause death. This study aimed to evaluate the impact of neoadjuvant chemotherapy (NACT) of various cycles before radical radiotherapy on distant metastasis and survival of patients with stage N2-3 diseases. In this study, a total of 1,164 consecutive patients with non-metastatic N2-3 NPC were recruited and prospectively observed. Then 231 patients who received NACT of 4 cycles (NACT=4 group) were matched 1:2:1 to 462 patients treated with NACT of 2 cycles (NACT=2 group) and 231 patients treated without NACT (NACT=0 group), according to age, histological subtype, N stage and NACT regimen. Five candidate variables (sex, T stage, concurrent chemotherapy, intensity-modulated radiation therapy and cycle number of NACT) were analyzed for their association with patients' survival. After matching, the overall survival (OS), disease-free survival (DFS), local-recurrence-free survival (RFS) and distant-metastasis-free survival (MFS) of the NACT=4 group (89.2%, 81.0%, 83.3% and 84.8%, respectively) were better than those of the NACT=2 group (83.3%, 72.5%, 81.2% and 77.9%, respectively) and the NACT=0 group (74.0%, 63.2%, 74.0% and 68.8%, respectively). In multivariate analysis, the cycle number of NACT maintained statistical significance on the OS, DFS, RFS and MFS (all P<0.05). For N2-3 NPC, cycle number of NACT appeared to be an independent factor associated with an improvement of survival.

Prediction of distant metastasis and survival in adenoid cystic carcinoma using quantitative 18F-FDG PET/CT measurements

ObjectivesAdenoid cystic carcinoma (AdCC) in the salivary gland shows a high rate of distant metastasis, which is related to the resulting poor prognosis. We therefore examined the role of pretreatment 18F-FDG PET/CT for prediction of distant metastasis, recurrence/progression, and survival in AdCC. MethodsThis study included 52 patients who underwent pretreatment 18F-FDG PET/CT scanning and subsequent treatments for AdCC. Maximum, mean, and peak standardized uptake value (SUVmax, SUVmean, and SUVpeak), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured on 18F-FDG PET/CT. Univariate and multivariate Cox proportional hazards regression analyses were used to identify associations between the quantitative measurements of 18F-FDG PET, and progression-free survival (PFS), distant metastasis-free survival (DMFS), and disease-specific survival (DSS). ResultsDistant metastases were found in 20 (39%) patients: 6 (12%) at initial diagnosis and 14 (27%) during the median follow-up of 72 months after treatment. Univariate analyses showed that all the 18F-FDG PET parameters of SUVmax, SUVmean, SUVpeak, MTV, and TLG were significantly associated with overall PFS, DMFS, and OS (all P < .05). After controlling for clinicopathological variables, SUVmax remained an independent factor predictive of PFS (P = .001), while MTV and TLG were independent predictors of DMFS (P = .009) and DSS (P = .017). Patients with MTV > 14.8 mL showed a 5.9-fold higher risk of distant metastasis and a 4.2-fold higher risk of disease-specific death than those with a lower MTV. ConclusionsQuantitative measurements using 18F-FDG PET/CT are useful for predicting tumor progression, distant metastasis, and survival in patients with AdCC.

Relationship between positive lymph nodes and distant metastasis after intensity-modulated radiotherapy in patients with nasopharyngeal carcinoma

Objective To explore the relationship between positive cervical lymph nodes and distant metastasis after intensity-modulated radiotherapy (IMRT) in patients with nasopharyngeal carcinoma (NPC). Methods A retrospective analysis was performed on the clinical data of 474 patients who were newly diagnosed with NPC but no distant metastasis and received IMRT from 2010 to 2012. The survival rates were calculated by the Kaplan-Meier method. The log-rank test was used for comparison of survival rates and univariate prognostic analysis. The multivariate analysis was made by the Cox regression model. Results In the 474 patients, 400 had positive cervical lymph nodes and 122 had residual masses in the neck after IMRT. The four-year distant metastasis, overall survival, disease-free survival, local relapse-free survival, and distant metastasis-free survival (DMFS) rates were 13.71%(65/474), 82.9%, 81.4%, 93.5%, and 86.3%, respectively. The univariate and multivariate analyses showed that treatment approach, lymph node metastases in lower neck Ⅳ/Ⅴb/Ⅴc regions, the greatest diameter of the positive cervical lymph nodes, the diameter of residual lymph nodes, and time to lymph node recession were independent prognostic factors for DMFS (all P<0.05). Conclusions Chemoradiotherapy can reduce the distant metastasis rate after IMRT for NPC. The larger the cervical lymph nodes are, the more likely there are residual masses; the larger the residual cervical lymph nodes are, the higher risk of distant metastasis there is. Large cervical lymph nodes (≥6 cm), residual masses larger than 1 cm, and residual masses at 3 months after IMRT are negative prognostic factors for DMFS after IMRT for NPC. Better intervention treatment approaches need to be explored. Key words: Nasopharyngeal neoplasms/intensity-modulated radiotherapy; Distant metastasis; Lymph node

Correlation between resistin gene polymorphism and clinical aspects of lung cancer.

Lung cancer is one of the most common cancers and is associated with a poor survival rate in the Chinese Han population. Analysis of genetic variants could lead to improvements in prognosis following lung cancer treatment. Resistin (RETN) is an important mediator of metabolic diseases and tumor progression. In this study, we explored the effects of RETN single nucleotide polymorphisms (SNPs) on the susceptibility and clinicopathological characteristics of patients with lung cancer. Four RETN SNPs (rs7408174, rs1862513, rs3745367, and rs3219175) were analyzed using TaqMan SNP genotyping in 371 patients with lung cancer and 451 cancer-free controls. The results showed that the RETN SNP rs3219175 with AG or at least 1 A allele was associated with a higher risk of lung cancer than wild-type (GG) carriers. Moreover, the RETN SNP rs3219175 with AG or AG + AA alleles was associated with a higher risk of distant metastasis than that in patients carrying GG alleles. We also used genotype-tissue expression datasets to compare the correlation of the RETN SNP rs3219175 in lung tissue and whole blood. In conclusion, our study demonstrated, for the first time, that RETN polymorphisms were correlated with lung cancer progression in the Chinese Han population.

CRHR2/Ucn2 signaling is a novel regulator of miR-7/YY1/Fas circuitry contributing to reversal of colorectal cancer cell resistance to Fas-mediated apoptosis.

Colorectal cancer (CRC) responds poorly to immuno-mediated cytotoxicity. Underexpression of corticotropin-releasing-hormone-receptor-2 (CRHR2) in CRC, promotes tumor survival, growth and Epithelial to Mesenchymal Transition (EMT), in vitro and in vivo. We explored the role of CRHR2 downregulation in CRC cell resistance to Fas/FasL-mediated apoptosis and the underlying molecular mechanism. CRC cell sensitivity to CH11-induced apoptosis was compared between Urocortin-2 (Ucn2)-stimulated parental and CRHR2-overexpressing CRC cell lines and targets of CRHR2/Ucn2 signaling were identified through in vitro and ex vivo analyses. Induced CRHR2/Ucn2 signaling in SW620 and DLD1 cells increased specifically their sensitivity to CH11-mediated apoptosis, via Fas mRNA and protein upregulation. CRC compared to control tissues had reduced Fas expression that was associated with lost CRHR2 mRNA, poor tumor differentiation and high risk for distant metastasis. YY1 silencing increased Fas promoter activity in SW620 and re-sensitized them to CH11-apoptosis, thus suggesting YY1 as a putative transcriptional repressor of Fas in CRC. An inverse correlation between Fas and YY1 expression was confirmed in CRC tissue arrays, while elevated YY1 mRNA was clinically relevant with advanced CRC grade and higher risk for distant metastasis. CRHR2/Ucn2 signaling downregulated specifically YY1 expression through miR-7 elevation, while miR-7 modulation in miR-7high SW620-CRHR2+ and miR-7low HCT116 cells, had opposite effects on YY1 and Fas expressions and cell sensitivity to CH11-killing. CRHR2/Ucn2 signaling is a negative regulator of CRC cell resistance to Fas/FasL-apoptosis via targeting the miR-7/YY1/Fas circuitry. CRHR2 restoration might prove effective in managing CRC response to immune-mediated apoptotic stimuli.

Factors Associated With a High Risk of Locoregional Failure in Well-Differentiated Thyroid Carcinoma

While adjuvant external beam radiotherapy is a standard for locoregionally advanced squamous carcinomas of the head and neck, its’ utility in locoregionally advanced well-differentiated thyroid cancers is less clear. Current standard of care for well-differentiated thyroid cancer with cervical adenopathy includes total thyroidectomy and neck dissection followed by radioactive iodine. We sought to determine the risk of locoregional failure and potential prognostic factors in this group of patients. After approval by the institutional review board (IRB), records of patients with well-differentiated thyroid cancer with cervical adenopathy between 1998 and 2012 were retrospectively reviewed. Patients with medullary, poorly differentiated, or anaplastic histology, N0-N1a, or distant metastases at presentation, or those who received external beam radiation were excluded. Locoregional control (LRC) was assessed via Kaplan-Meier analysis. Potential predictors were compared via log-rank test. Variables with prognostic potential on univariate analysis were subjected to multivariate analysis with Cox proportional hazards regression. After exclusions, 152 patients remained for analysis. Median follow up of the entire cohort was 38 months (range 0 – 197) for LRC, and 67.5 months for overall survival (range 0-197). The LRC rate for the entire cohort at 3 years was 77.3%. Patients with 1-5 positive lymph nodes (LN) had a significantly higher rate of LRC at 3 years versus patients with ≥6 LN (92.1% vs 65.9%; p=0.001). Similarly, LRC at 3 years was also higher in patients with T0-1 stage patients versus those with T2-4 (97.5% vs 67.9% vs; p<0.001). The presence of extracapsular extension (70.9% vs 84.2%; p=0.026) and histology (papillary 76.8% vs follicular 0%; p=0.036) were also associated with a lower rate of LRC at 3 years. On multivariate analysis, T stage (hazard ratio [HR] = 0.176; 95% confidence interval [CI], 0.053-0.582; p =0.004) and the number of positive lymph nodes (HR = 0.464; 95% [CI], 0.218-0.986; p =0.046) remained significant for LRC at 3 years. Patients with T2-4 N1b tumors with 6 or more nodes had a 3 year rate of LRC of 60%. In addition, those patients with locoregional recurrence were found to have a significantly higher risk of distant metastasis, 1% vs 15.7% at 5 years (p < 0.001). Our findings indicate that both T stage and the number of lymph nodes are the independent prognostic factors for locoregional recurrence for patients with well differentiated thyroid cancer. Despite treatment with RAI after surgical resection, patients with T2-T4 disease and those with ≥ 6 positive lymph nodes are at a high risk of locoregional recurrence. This cohort of patients may benefit from adjuvant radiotherapy, which will need to be tested in a prospective clinical trial.

A Radiomic Prognostic Index Refines Risk Models for Distant Metastasis in HPV-Related Oropharyngeal Cancer

Distant metastasis (DM) is the main cause of treatment failure in human papillomavirus (HPV)-related oropharyngeal cancers (OPC). However, predicting DM remains challenging. We hypothesize that quantitative imaging (i.e. radiomic) features may help identify primary tumor features associated with higher risk of DM. We retrieved radiotherapy planning CT scans for 280 UICC/AJCC 8th ed. stage I-III p16-positive OPC patients treated with definitive radiotherapy or chemoradiotherapy at a single institution between 2005 and 2010. Gross tumor volumes (GTVs) were previously contoured by each treating radiation oncologist. A radiomic prognostic index (RPI) was derived based on four validated prognostic radiomic features from tumor intensity, shape, texture, and wavelet feature groups. RPIs were extracted from each GTV based on published algorithms. We used univariate and multivariate analysis with Cox proportional hazards models to identify predictors of DM. Feature selection for multivariate models was performed using recursive partitioning analysis (RPA) and validated. Receiver-operating characteristic (ROC) curves were used to compare models. Median follow-up was five years. There were a total of 34 DM events. Factors associated with increased risk of DM included UICC/AJCC 8th ed. stage III (T4 or N3) (73/280; p<0.001), large GTV (140/280; p=0.048), and high risk RPI (25/280; p<0.001). High risk RPI remained significant (p<0.001) on multivariate analysis. RPA confirmed RPI as a key predictor segregating p16-positive OPCs into low (n=255) and high (n=25) risks of DM with 3-year distant control rates of 91% (0.88-0.95) and 50% (0.32-0.78) respectively. Area under the ROC curve for the RPI-based DM model was 0.72 (0.62-0.82) compared with 0.65 (0.56-0.74) for the conventional stage-based DM model. In subgroup analyses, the RPI consistently stratified patients for DM risk, particularly for those cohorts with greater risk, such as UICC/AJCC 8th ed. stage III cancers. The four-feature RPI can be used alone or in conjunction with other clinical or treatment characteristics to classify HPV-related OPC patients by DM risk. The RPI may therefore allow for greater precision in selection of patients for systemic therapies for HPV-related OPC.