Development Of Distant Metastases Research Articles

Radical Versus Partial Nephrectomy for cT1 Renal Cell Carcinoma

BackgroundNephron-sparing surgery is the preferred surgical management of cT1 renal masses, but observational and randomized data conflict regarding a survival benefit. ObjectiveTo examine the associations of radical nephrectomy (RN) versus partial nephrectomy (PN) with oncologic and nononcologic outcomes. Design, setting, and participantsA total of 2459 adults were treated with RN or PN between 1990 and 2011 for a unilateral, sporadic, cT1, M0 solid renal mass. InterventionRN or PN. Outcome measurements and statistical analysisAssociations of the type of nephrectomy with oncologic outcomes (local ipsilateral recurrence, distant metastases, and cancer-specific mortality [CSM]) and nononcologic outcomes (other-cause mortality [OCM], all-cause mortality [ACM], ≥10% decrease in estimated glomerular filtration rate [CKD10%], and decrease in estimated glomerular filtration rate to <45ml/min/1.73m2 [CKD<45]) were evaluated using several propensity score (PS) techniques. Results and limitationsAfter PS adjustment using preoperative features, RN was associated with an increased risk of distant metastases, CSM, ACM, CKD10%, and CKD<45, but not with OCM. However, there remained imbalance in pathologic features. We therefore repeated these analyses in the subset of 1609 patients with renal cell carcinoma (RCC). After adjusting for both preoperative and pathologic features, there was no significant difference in the development of distant metastases or CSM. Although RN remained associated with an increased risk of CKD10% (hazard ratio [HR] 2.07–2.21; p<0.001 for each PS technique) and CKD<45 (HR 2.70–2.99; p<0.001 for each PS technique), it was not significantly associated with OCM (HR 1.10–1.17; p=0.08–0.5 for each PS technique) or ACM (HR 1.14–1.15; p=0.2–0.3 for each PS technique, except HR 1.18; p=0.03 by inverse probability weights). Limitations include unmeasured confounding. ConclusionsAlthough RN was associated with an increased risk of chronic kidney disease compared with PN, it was not associated with a statistically significant difference in CSM or ACM among patients with cT1 RCC. Patient summaryThis study suggests that partial nephrectomy is not associated with markedly improved survival compared with radical nephrectomy.

C-X-C Motif Ligand 1 (CXCL1) from melanoma cells down-regulates the invasion of their metastatic melanoma cells.

The surgical resection of a primary melanoma is sometimes followed by the immediate development of distant metastases, suggesting that the primary melanoma might control the metastatic process. We hypothesized that a paracrine factor(s) from primary melanoma cells might regulate the progression of metastasizing melanoma cells. Here we attempted to identify the factor(s) from primary melanoma cells that regulate the invasion ability of metastatic melanoma cells. We used two mouse melanoma cell lines, B16 and B16/BL6, that latter of which is a subline of B16 melanoma and shows high metastatic potential to lung. We investigated the interaction between the parent B16 cells and daughter B16/BL6 cells by invasion assay, cell morphology, cytokine array, RT-PCR, and gelatin-zymography. The conditioned medium (CM) from B16 significantly (p=0.02) inhibited the invasion ability of B16/BL6 cells. The morphology of the B16/BL6 cells was changed from bipolar shape to a multipolar shape following the addition of the CM from B16. The B16 cells produced high levels of C-X-C motif ligand 1 (CXCL1), CXCL10, and M-CSF compared to the B16/BL6 cells. CXCL1 significantly (p=0.01) decreased the invasion ability of B16/BL6 cells, but CXCL10 and M-CSF did not. The invasion-inhibitory activity of the CM from B16 was significantly (p=0.046) suppressed following the addition of a neutralizing anti-CXCL1 antibody. The CM of B16 and CXCL1 increased the E-cadherin mRNA level and decreased MMP2 activity of B16/BL6 cells. These findings suggested that primary melanoma cells might down-regulate the invasion activity of metastatic melanoma cells through CXCL1 signaling.

PO-249 Phylogenetic relationships between paired primary papillary thyroid carcinomas and distant metastasis: intra-tumour molecular heterogeneity and clonal evolution

IntroductionThough the vast majority of Papillary Thyroid carcinomas (PTC) are indolent tumours, around 5%–15% behave aggressively, developing distant metastases (DM), which cause patient´s death. The molecular events underlying metastatic spread are poorly understood. Little it is known about the contribution of intratumor molecular heterogeneity to DM.Material and methodsIn this study, by genotyping 13 cases of matched primary tumours (PrT) and DMs, we sought to determine the prevalence of mutations in genes that have been associated with progression and aggressiveness in thyroid cancer (TERTp, BRAF, NRAS, KRAS, HRAS, PIK3CA). To asses the contribution of intratumor heterogeneity and clonal evolution to DMs, 54 tumour areas, including different areas across space and time within the PrTs and DMs, were characterised. Mutational analysis was done by means of PCR and SSCP or direct sequencing.Results and discussionsTwelve cases (92%) were mutated in at least one of the genes screened [TERTp=9 cases (69%), BRAF=7 cases (54%), KRAS=3 cases (23%), NRAS=3 cases (23%), HRAS=2 cases (15.4%) and PIK3CA=2 cases (15.4%). Among the mutated cases 67% exhibited more than 1 gene activated. Three mutated genes coexisted in 62.5% of the cases bearing several mutations [3 cases (60%) TERTp +RAS + BRAF and 2 cases (40%) TERTp +BRAF+PIK3CA]. Concurrent activation of TERTp +RAS or TERTp +BRAF was seen in 5 cases each combination(62.5%). Parallel activation of BRAF and RAS was found in 4 of the cases (50%) with genetic heterogeneity. In all of the cases in which more than 1 area of DM, across space and time, was analysed, the mutations at TERTp, KRAS and HRAS resulted clonal. ’De novo’ mutations at DM, not present in the PrT, were seen in 3 cases mutated at TERTp, 2 cases mutated at NRAS and 1 case mutated at KRAS. Among the mutated cases, in which more than one area of PrT was analysed, TERTp mutations were clonal in 80% of the cases and BRAF mutations subclonal in 80% of the cases.The activation of RAS within the PrT tended to be a clonal event.ConclusionThe number of mutational events in PTC with DM is strikingly higher than in in PTC without DM. While TERTp and RAS mutations tend to be clonal within the PrT and the DMs, BRAF mutations tend to be subconal. TERTp and RAS mutations may appear the novo at DM. PTC with DM display a much higher rate of genetic heterogeneity (67%). The coexistence of mutations in different genes is in agreement with the hypothesis that tumour progression relies on progressive accumulation of genetic alterations.

Abstract 4011: Deciphering the clonal evolution of recurrent tumor-initiating cells with a CRISPR/Cas9 genome-wide loss-of-function screen in an orthotopic HNSCC surgical model in vivo

Abstract Local recurrence and distant metastasis constitutes a major obstacle in the curative treatment of cancer. The clonal evolution and molecular mechanisms governing these processes remain elusive. We utilized the CRISPR/Cas9 based genome-wide GeCKO library stably transduced in head and neck cancer (HNSCC) cells (FaDu) and orthotopically transplanted into submental area of the floor-of-mouth (FOM) of NMRI nude mice to identify candidate genes which drive molecular processes leading to the development of local recurrences. Primary tumor bulks were resected leaving a minimal residual disease (MRD) consisting of few loco-regionally disseminated tumor cells to form loco-regional recurrences and distant metastasis - the recurrent tumor initiating cells (R-TIC). Primary tumors (PT) developed within the first 14 days with well-defined borders. Following surgical resection of the primary tumors recurrences started to develop approximately 21 days post-surgery. The rate of local recurrences was 2-fold higher in mice which were transplanted with the GeCKO library compared to the parental FaDu line. From mice with local recurrence (LR), also the lymph nodes (LN) and the lung metastases (LM) were collected. Following multiplex low cycling quantitative PCR of the guide RNA sequences (gRNA-seq) by NGS, 270 million reads were extracted enabling a comprehensive evaluation of the GeCKO library representation and specific functional gene knockout (KO) in the PT and matching LR, LN and LM. In line with the proposed R-TIC hypothesis, we found a highly clonal evolution of few dominating “trunk” KO cells governing the locally recurrent, LN and distant metastases. In average, we could detect close to 13K gRNA-seq in PT indicating a polyclonal composition of the tumor bulk prior to surgery. In contrast, all recurrent tumors exhibited a highly clonal composition with &amp;gt;95% of the read counts originating from only 2-4 unique gRNA-seq. This indicates that the clonal expansion which has led to the growth of the recurrent tumor is initiated by few clones carrying loss-of-function mutations in 2-4 genes. Interestingly the abundancy of these clones was very low or below NGS detection limit in the corresponding PT and clones which initiated LR were also found in the corresponding LN and LM of the same mice. 14 loss-of function candidate genes were shared in all mice which developed LR post-surgery underlining their importance in mechanistically promoting the initiation of local recurrences. We provide here evidence for the existence and clonal evolution of an R-TIC population in HNSCC. Novel R-TIC specific molecular targets discovered in this study will facilitate rational design of treatment strategies aiming to prevent the development of loco-regional recurrences and distant metastasis. Citation Format: Ali Nowrouzi, Mahdi Akbarpour, Vincent Roh, Anne Wursthorn, Agnés Hiou-Feige, Maximillian Knoll, Bouchra Tawk, Christian Schwager, Christian Simon, Jürgen Debus, Genrich Tolstonog, Amir Abdollahi. Deciphering the clonal evolution of recurrent tumor-initiating cells with a CRISPR/Cas9 genome-wide loss-of-function screen in an orthotopic HNSCC surgical model in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4011.

PO-419 Use of origanum majorana oil in lung cancer therapy

IntroductionLung cancer is the most common form of cancer with the highest mortality rate in the world accounting for 1.69 million deaths in 2015 (WHO data). Despite the advances in targeted therapies, cure of lung cancer remains elusive and patients die due the development of distant metastasis, resistance to the treatment, and to the cytotoxicity of the drugs used.A large number of the chemotherapeutic drugs used in cancer treatment are either from plant origin or chemically-altered plant products and phytochemicals. It has been shown that extract of Origanum majorana reduced the side effects induced by cyclophosphamide and cisplatin, two established anticancer drug, without altering their cytotoxicity.Material and methodsThe question whether the pharmaceutically available Origanum Majorana ‘100% pure’ essential Oil will be a successful option in lung cancer therapy is a major challenge that we tried to address in this study using two major human lung cancer cells namely A549 and LNM35.Results and discussionsWe demonstrate that Origanum majorana causes a concentration- and time-dependent decrease in the viability of the lung cancer cells (A549 and LNM35) and their related colonies growth in vitro. Similarly, treatment with Origanum majorana significantly decreased the growth of LNM35 and A549 xenografts in chick embryo and in nude mice models in vivo without significant side effects.ConclusionThis study increases our understanding of the potential benefit of using the Origanum Majorana Oil in lung cancer therapy. Based on these results, our next step is the identification and characterisation of Origanum Majorana Oil major constituents that mediate its anti-cancer effects.

Abstract 5394: Initial results from TRANSCAN ERA-NET BREMIR project: MicroRNAs expression profiling for identification of breast cancer patients at high risk to develop distant metastases

Abstract The mortality of breast cancer (BC) is primarily caused by metastatic spread to distant organs, rendering the ability to predict, detect and eliminate metastases one of the most important challenges in patients' management. This study is aimed to evaluate the potential role of several candidate miRNAs as predictive markers of the metastatic processes. The TRANSCAN ERA-NET BREMIR project has been designed to identify miRNA biomarkers able to predict distant metastases development. The correlation of miRNAs expression with distant metastasis free survival is evaluated in a large retrospective cohort (n=302). The best candidate markers will be validated in the independent prospective cohorts which currently include 505 patients. Additionally, miRNA potentialities as circulating biomarkers for treatment monitoring and early metastases detection will be evaluated in plasma samples. The analysis of the retrospective cohort has identified miR-10b-5p, miR-10a-5p, miR-210-3p, miR-30a-5p, miR200a-3p,miR200b-3p,miR200c-3p, miR141-3p, miR-429, miR-155-5p, miR-9-3p and miR-9-5p as crucially involved in BC progression. For miR-9-5p and miR-9-3p we also found a strong inverse correlation with ER and PgR expression, suggesting that they may be directly involved in hormone regulated pathways. To identify novel miRNAs associated with tumour metastases potentials, we also executed a global miRNA profiling on a selected number of breast cancer cases by using the Affymetrix GeneChip® miRNA 4.0. In particular, we analysed 34 BC cases characterized by different outcomes: 17 non metastatic after 10-years follow-up and 17 who developed metastatic disease within 5-years follow-up. As controls, 3 Normal Breast Tissues from reductive mammoplasty, 3 in situ carcinomas and 3 breast cancer cases with synchronous metastases were also evaluated. This analysis identified 8 miRNAs differentially expressed between metastatic and non metastatic cases. The association with study endpoints is currently under evaluation on the entire retrospective cohort. Our hope is that this study will lead to the identification of novel biomarkers allowing a better management of breast cancer patients. Citation Format: Paola Parrella, Raffaela Barbano, Ella Evron, Barbara Pasculli, Orazio Palumbo, Michelina Rendina, Raffaella Stallone, Michela Coco, Andrea Fontana, Tommaso Mazza, Massimiliano Copetti, Vanna Maria Valori, Maria Morritti, Paolo Graziano, Roberto Murgo, Evaristo Maiello, Massimo Carella, Vito Michele Fazio, Manel Esteller. Initial results from TRANSCAN ERA-NET BREMIR project: MicroRNAs expression profiling for identification of breast cancer patients at high risk to develop distant metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5394.

Adenocarcinoma of the oesophagus: neoadjuvant chemoradiation and radical surgery

To retrospectively evaluate long-term treatment results following neoadjuvant chemoradiation (CRT) and radical surgery in patients with advanced adenocarcinoma (AC) of the oesophagus. Between 2005 and 2015, atotal of 102 consecutive patients with amedian age of 64years (range, 44-86years) and AC of the oesophagus were evaluated of whom 84 received afull CRT. Agroup of 51patients was treated with neoadjuvant intent followed by radical surgery. Atotal dose of 50.4 Gy with mostly weekly paclitaxel/fluorouracil chemotherapy was administered. Six to eight weeks following CRT, atransthoracic subtotal oesophageal and proximal gastric resection was performed. Survival curves for overall survival and no evidence of disease (NED) survival (primary endpoints) were calculated according to Kaplan-Meier, and possible prognostic factors were evaluated by the log-rank test as well as by aCox regression analysis. Median follow-up time of the surviving patients was 48months (range, 14-134 months). Overall and NED survival rates for patients of the study group (n = 51) were 40 and 32%, respectively, at 5years. Age (p = 0.04), ypT category (p = 0.1) and the development of distant metastases (p = 0.05) were identified as (marginally) independent prognostic variables with impact on survival. Median survival time for patients of the study group (n = 51) was 45 ± 18months (95%CI 9-81months). Clear resection margins were achieved in 46/51 patients (92%). Regression rates with complete regression rare residual cancer and increased number of residual cells, but predominantly fibrosis were 33, 41, and 10%, respectively. Patterns of failure revealed local with distant recurrence in 2/51 (4%), regional recurrence alone in 2/51 (4%), and distant metastases in 27/51 (53%) patients. Neoadjuvant CRT in patients with AC of the oesophagus followed by thoracoabdominal surgery is alocally very effective concept. Asignificant tumour regression in almost 75% of the patients may stimulate prospective trials on the omission of radical surgery for some elderly patients. Due to ahigh rate of distant metastases further investigations in terms of effective systemic therapy may be warranted.

Association of surgical approach with complication rate, progression-free survival time, and disease-specific survival time in cats with mammary adenocarcinoma: 107 cases (1991-2014).

OBJECTIVE To evaluate potential associations between surgical approach and complication rate, progression-free survival time, and disease-specific survival time in cats with mammary adenocarcinoma. DESIGN Retrospective case series. ANIMALS 107 client-owned cats. PROCEDURES Medical records of cats that underwent surgical excision of mammary adenocarcinoma by means of a unilateral or bilateral (staged or single-session) mastectomy at 9 hospitals between 1991 and 2014 were reviewed. Relevant clinicopathologic data and details of surgical and adjuvant treatments were recorded. Outcome data were obtained, including postoperative complications, progression-free survival time, and disease-specific survival time. RESULTS Complications occurred in 12 of 61 (19.7%) cats treated with unilateral mastectomy, 5 of 14 (35.7%) cats treated with staged bilateral mastectomy, and 13 of 32 (40.6%) cats treated with single-session bilateral mastectomy. Complications were significantly more likely to occur in cats undergoing bilateral versus unilateral mastectomy. Median progression-free survival time was longer for cats treated with bilateral mastectomy (542 days) than for cats treated with unilateral mastectomy (289 days). Significant risk factors for disease progression included unilateral mastectomy, tumor ulceration, lymph node metastasis, and tumors arising in the fourth mammary gland. Significant risk factors for disease-specific death included lymph node metastasis and development of regional or distant metastasis. Among cats that did not develop metastasis, unilateral mastectomy was a significant risk factor for disease-specific death. Treatment with chemotherapy was associated with a significantly decreased risk of disease-specific death. CONCLUSIONS AND CLINICAL RELEVANCE Results supported bilateral mastectomy for the treatment of mammary adenocarcinoma in cats to improve progression-free and disease-specific survival time. Performing bilateral mastectomy in a staged fashion may help to decrease the complication rate.

Budding and tumor—infiltrating lymphocytes — combination of both parameters predicts survival in colorectal cancer and leads to new prognostic subgroups

Tumor budding is an independent prognostic factor in colorectal cancer (CRC) and has recently been well defined by the International Concensus Conference on Tumor Budding (ITBCC). Tumor-infiltrating lymphocytes (TILs) are also an issue in different human cancers and correlate with prognosis in CRC. Here we evaluate the combination of budding and TILs in CRC with regard to prognosis. Hematoxylin and eosin (H&E)-stained slides of 501 CRC patients, diagnosed between 2005 and 2010, were reevaluated for tumor budding according to the ITBCC criteria. Low (n = 331) was compared to intermediate/high budding (n = 170). The percentage of TILs was also assessed, and the following four groups were established: low budding + TILs >5% (n = 162), low budding + TILS ≤5% (n = 169), high budding + TILS >5% (n = 68), high budding + TILs ≤5% (n = 93). The combination of both markers revealed highly significant differences in overall survival (OS) between the four groups (P = .001). The low budding/>5% TILs group showed longest OS, followed by high budding/>5% TILs cases, followed by tumors with low budding/≤5% TILs. OS was worst for the high budding/≤ 5% TILs group. The combined score also correlated with T, N, M, L, Vstaging, development of disease relapse and distant metastasis. Our study shows that - even in the age of molecular pathology - it is still important to pay special attention to tumor morphology for additional information on tumor behavior and prognosis. Combining different morphological parameters of tumor and tumor environment can help to further subdivide CRC into new prognostic groups.

Dynamics of the hazard for distant metastases after ipsilateral breast tumor recurrence according to estrogen receptor status: An analysis of 2851 patients

BackgroundBreast cancer (BC) patients with ipsilateral breast tumor recurrence (IBTR) are at high risk of developing distant metastases (DM). We aimed to evaluate the risk pattern of developing DM, with respect to the occurrence of IBTR, in a large series of patients homogeneously treated by conservative surgery (QUART) with a considerably long follow-up. MethodsPiecewise exponential model was used to investigate DM dynamics conditioning on known prognostic factors and IBTR occurrence as time dependent covariate. The model was extended to account for the timescale induced by IBTR, namely the time elapsed since IBTR to the endpoint. ResultsAmong 2851 BCE patients receiving QUART, 209 were assessable for IBTR. After a median follow-up of 129 months, 588 patients presented DM (CCI = 27.3%) as first event and 92 (CCI = 48.8%) following IBTR. Primary tumor size and nodal status confirmed their prognostic value. The hazard for DM was early and high in Estrogen Receptor (ER) negative BC patients; while it was initially low but increases during follow-up in ER positive cases. Patients experiencing IBTR showed DM dynamic similar to that following primary tumor, with a sudden increased risk within 24 months from surgery, regardless the time elapsed since QUART. ConclusionBC patients experiencing IBTR showed a sudden and sustained risk of DM following surgery. Our findings are consistent with the hypothesis that IBTR occurrence might act as a “time resector” for risk of DM, and provide a rationale for proper surveillance guidelines and systemic therapy for optimizing BC recurrence and appropriate choice of treatment.

Identification of an epigenetic biomarker panel for predicting the development of distant metastases in differentiated thyroid cancer

Identification of an epigenetic biomarker panel for predicting the development of distant metastases in differentiated thyroid cancer

High Expression of Ubiquitin C-terminal Hydrolase L1 Is Associated With Poor Prognosis in Endometrial Cancer Patients.

The ubiquitin C-terminal hydrolase L1 (UCHL1) plays a key role in tumor invasion and metastasis. Ubiquitin C-terminal hydrolase L1 is overexpressed in various cancers and reported to be correlated with a poor prognosis. The objective of this study was to determine the prognostic significance of UCHL1 in endometrial cancer. The expression of UCHL1 in endometrial cancer was assessed using quantitative reverse transcription polymerase chain reaction and immunohistochemistry in 56 and 215 resected tumor specimens, respectively. The 4-year survival rates of the high UCHL1 messenger RNA expression group and high UCHL1 protein expression group were 78% and 71%, respectively, compared with 96% and 95% for the low UCHL1 messenger RNA expression group and low UCHL1 protein expression group, respectively. Kaplan-Meier and log-rank tests indicated a significant correlation between expression of UCHL1 and disease-free survival and overall survival. Moreover, multivariate stepwise Cox proportional hazard regression model analysis showed that UCHL1 was a significant independent marker for predicting a poor disease-free survival and overall survival. In 43 patients with metastatic lesions, immunohistochemical analysis of metastatic lesions revealed that the recurrence rate and mortality rate were 62% and 41%, respectively, in 29 UCHL1-positive patients and 36% and 29%, respectively, in 14 UCHL1-negative patients. The results of this study suggest that high UCHL1 expression is a strong marker of poor prognosis of endometrial cancer. Furthermore, we suggest that UCHL1 may be involved in the development of distant metastasis in endometrial cancer.

Prognostic significance of 1p36 locus deletion in adenoid cystic carcinoma of the salivary glands.

Adenoid cystic carcinoma (AdCC) of the salivary glands is characterized by MYB-NFIB or MYBL1-NFIB fusion, prolonged but relentlessly progressive clinical course with frequent recurrences, and development of distant metastasis resulting in high long-term mortality. Currently, no effective therapy is available for patients with advanced non-resectable and/or metastatic disease. Complicating the clinical management of this patient group is the lack of prognostic markers. The purpose of this study is to investigate the prognostic value of 1p36 loss in patients with AdCC. The presence of 1p36 deletion and gene fusions involving the MYB, NFIB, and MYBL1 genes in a cohort of 93 salivary gland AdCCs was studied using fluorescence in situ hybridization. These results were statistically correlated with clinical data and outcome. Deletion of 1p36 in AdCC was identified in 13 of 85 analyzable cases (15.29%). MYB-NFIB fusion was detected in 57/85 (67.1%), MYBL1-NFIB fusion in 12/85 (14.1%), MYB-X fusion in 4/85 (4.7%), MYBL1-X in 4/85 (4.7%), and NFIB-X in 2/85 (2.4%) of AdCC cases. None of the 1p36-deleted samples showed MYBL1 rearrangement. Statistical analysis demonstrated a significant correlation between 1p36 deletion and advanced tumor stage and solid histology (p = 0.0061 and 0.0007, respectively). Kaplan-Meier survival curves showed statistically significant correlations between 1p36 deletion and decreased overall survival, disease-specific survival, recurrence-free interval, and recurrence-free survival, all of which were maintained in multivariate analysis. We demonstrate that 1p36 deletion can serve as an indicator of unfavorable outcome of patients with salivary gland AdCC.

The importance of the need for better systemic therapy in the definitive treatment of high-risk prostate cancer regardless of whether the initial treatment modality was external beam radiation, I-125 brachytherapy, or radical prostatectomy.

65 Background: While androgen deprivation therapy (ADT) is a common form of systemic therapy for treating high-risk prostate cancer (HRCaP), distant metastases development remains the predominate form of failure. We present a description of the sites of failure after treatment of HRCaP with External Beam Radiation (EBRT), I-125 Brachytherapy (PB), or Radical Prostatectomy (RP). This is accompanied by an analysis of prostate cancer-specific mortality (PCSM) after clinical failure. Methods: The study includes 2186 patients with HRCaP according to NCCN guidelines (684 EBRT, 409 PB, and 1093 RP). The association of PCSM with clinical and pathologic variables was assessed with Fine and Gray regression with non-PCSM mortality treated as a competing event. Results: The median f/u is 52 months. Overall, there were 323 clinical failures (sites of first failures: 287 distant (DM), 34 local (LF), 2 DM + LF). The median time to the diagnosis of DM was 44 months. ADT was used in 93% of EBRT, 53% of PB and 19% of RP patients. Further details regarding the development of DM is shown in Table 1. The type of initial treatment was not associated with PCSM after DM (Table 1). The only factor significantly associated with PCSM was Gleason Score (p = 0.0372). Conclusions: DM is the primary mode of failure after definitive treatment of HRCaP. The type of initial definitive treatment did not affect PCSM after DM. The cure rates of all forms of definitive treatment of HRCaP would benefit from better systemic therapy. [Table: see text]

The relationship between local recurrences and distant metastases in prostate cancer: can 11C-choline PET/CT contribute to understand the link?

Previous studies in prostate cancer (PCa) patients tried to correlate the onset of local recurrence (LR) with the development of distant metastases and formulated, based on theoretical and experimental data, hypotheses linking the two events. We aimed to address this issue with 11C-choline positron emission tomography/computed tomography (PET/CT). This retrospective study included 491 PCa patients previously treated with radical prostatectomy who had undergone 11C-choline PET/CT owing to biochemical failure. Further inclusion criteria were availability of clinical and pathological variables for survival analysis. Statistical significance was taken at P < 0.05. Seventy-two patients (14.7%) had evidence of LR at 11C-choline PET/CT. The frequency of LR increased from 13.8% in the interval 0-4years after prostatectomy, to 23.9% in the 12-16-year interval (P = 0.080). On the contrary, the frequency of lymph node metastases (overall rate in the 0-16years interval after prostatectomy: 26.3%) and of bone metastases (overall rate: 13.8%) decreased significantly over time. Kaplan-Meier curves showed no significant group difference in the rates of lymph node or bone metastases between patients with LR and patients without LR. LR significantly predicted PCa-specific survival at univariate analysis, but the statistical significance was lost at multivariate analysis. We found no differences in the rates of lymph node and bone metastases between patients with and without LR. An inverse time-dependent trend was observed in the frequency of LR on one side and of lymph node and bone metastases on the other side. These findings were discussed in relation to previous theories linking LR to distant metastases and our study design.

Outcomes and toxicities in patients with intermediate-risk prostate cancer treated with brachytherapy alone or brachytherapy and supplemental external beam radiation therapy.

To evaluate the cancer control outcomes and long-term treatment-related morbidity of brachytherapy as well as combination brachytherapy and external beam radiation therapy (EBRT) in patients with intermediate-risk prostate cancer. A retrospective review was conducted in a prospectively collected database of patients with intermediate-risk prostate cancer who were treated either with brachytherapy or brachytherapy and EBRT, with or without androgen deprivation therapy (ADT), in the period 1990-2014. Urinary and erectile dysfunction symptoms were measured using the International Prostate Symptom Score (IPSS), the Mount Sinai erectile function scale and the Sexual Health Inventory for Men (SHIM). Cancer control endpoints included biochemical failure and development of distant metastases. All statistical analyses were carried out using the Statistical Package for Social Science (SPSS). Survival curves were calculated using Kaplan-Meier actuarial methods and compared using log-rank tests. Cox regression multivariate analyses were used to test the effect of multiple variables on treatment outcomes. A total of 902 patients were identified, with a median follow-up of 91 months. Of these, 390 received brachytherapy and 512 received combination therapy with EBRT. In patients with one intermediate-risk factor, the addition of EBRT did not significantly affect freedom from biochemical failure or distant metastases. Among patients with two or three intermediate-risk factors, added EBRT did not improve freedom from biochemical failure. Significant differences in late toxicity between patients treated with brachytherapy vs combination brachytherapy and EBRT were identified including urge incontinence (P < 0.001), haematuria (P < 0.001), dysuria (P < 0.001), and change in quality-of-life IPSS (P = 0.002). These symptoms were reported by patients at any point during treatment follow-up. Analysis of patients who were potent before treatment using actuarial methods showed that patients receiving combination therapy more frequently experienced loss of potency, as measured by the Mount Sinai erectile function scale (P = 0.040). Brachytherapy monotherapy results in equal biochemical and distant control in both patients with one and more than one intermediate-risk features. While no significant benefit was shown, we believe that the addition of EBRT may prevent recurrence in patients with multiple intermediate-risk features and should be considered.

Investigating multi-radiomic models for enhancing prediction power of cervical cancer treatment outcomes

Quantitative image features, also known as radiomic features, have shown potential for predicting treatment outcomes in several body sites. We quantitatively analyzed 18Fluorine–fluorodeoxyglucose (18F-FDG) Positron Emission Tomography (PET) uptake heterogeneity in the Metabolic Tumor Volume (MTV) of eighty cervical cancer patients to investigate the predictive performance of radiomic features for two treatment outcomes: the development of distant metastases (DM) and loco-regional recurrent disease (LRR). We aimed to fit the highest predictive features in multiple logistic regression models (MLRs). To generate such models, we applied backward feature selection method as part of Leave-One-Out Cross Validation (LOOCV) within a training set consisting of 70% of the original patient cohort. The trained MLRs were tested on an independent set consisted of 30% of the original cohort. We evaluated the performance of the final models using the Area under the Receiver Operator Characteristic Curve (AUC). Accordingly, six models demonstrated superior predictive performance for both outcomes (four for DM and two for LRR) when compared to both univariate-radiomic feature models and Standard Uptake Value (SUV) measurements. This demonstrated approach suggests that the ability of the pre-radiochemotherapy PET radiomics to stratify patient risk for DM and LRR could potentially guide management decisions such as adjuvant systemic therapy or radiation dose escalation.

Mouse model of postsurgical primary tumor recurrence and regional lymph node metastasis progression in HPV-related head and neck cancer.

HPV-positive head and neck squamous cell carcinoma (HNSCC) is increasingly frequent. Management is particularly debated in the case of postsurgical high-risk features, that is, positive surgical margins and extracapsular spread (ECS). In this increasingly complex emerging framework of HNSCC treatment, representative preclinical models are needed to support future clinical trials and advances in personalized medicine. Here, we present an immunocompetent mouse model based on the implantation of mouse tonsil epithelial HPV16-E6/E7-expressing cancer cells into the submental region of the floor-of-the-mouth. Primary tumors were found to replicate the patterns of human HNSCC local invasion and lymphatic dissemination. To study disease progression after surgery, tumors were removed likely leaving behind residual disease. Surgical resection of tumors was followed by a high rate of local recurrences (>90%) within the first 2-3 weeks. While only 50% of mice had lymph node metastases (LNM) at time of primary tumor excision, all mice with recurrent tumors showed evidence of LNM. To study the consecutive steps of LNM progression and distant metastasis development, LNs from tumor-bearing mice were transplanted into naïve recipient mice. Using this approach, transplanted LNs were found to recapitulate all stages and relevant histological features of regional metastasis progression, including ECS and metastatic spread to the lungs. Altogether, we have developed an immunocompetent HPV-positive HNSCC mouse model of postsurgical local recurrence and regional and distant metastasis progression suitable for preclinical studies.

A study on the expression of CD44 adhesion molecule in oral squamous cell carcinoma and its correlation with tumor histological grading

Background: The increasing incidence of oral squamous cell carcinoma (OSCC) combined with its poor and unchanged prognosis motivates a need for research into the aspects of tumor biology such as the expression of adhesion molecules. Alterations in the properties of adhesion molecules could play a pivotal role in the development and progression of invasive cancer and distant metastasis. Aim: This study aims to quantify the expression of cluster of differentiation 44 (CD44) in the different grades of OSCC. Materials and Methods: Immunohistochemical staining for CD44 was performed in 10 tissue sections each of normal mucosa, well-differentiated OSCC, moderately differentiated OSCC, and poorly differentiated OSCC. CD44 positivity was analyzed quantitatively in 10 representative fields of each section under 20× magnification. Statistical Analysis Used: Statistical analysis was performed using Statistical Package for Social Sciences software, version 20.0 (SPSS Inc., Chicago, IL, United States). Results: The mean value of the number of positive cells in controls was 745 ± 68.17, in well-differentiated OSCC was 694.2 ± 145.47, in moderately differentiated OSCC was 349 ± 78.40, and in poorly differentiated OSCC was 108.8 ± 34.39. Conclusion: The results of this study suggest an altered expression of CD44 in OSCC with weak immunostaining in poorly differentiated squamous cell carcinoma. Thus, it can be inferred that the loss of cell adhesion, correlated to the decrease of CD44 expression, might be of value in determining the progression of OSCC.

KISS1 tumor suppressor restricts angiogenesis of breast cancer brain metastases and sensitizes them to oncolytic virotherapy in vitro

KISS1 tumor suppressor protein regulates cancer cell invasion via MMP9 metalloproteinase. Downregulation of KISS1 gene expression promotes progression of breast cancer and melanoma, resulting in the development of distant metastases. In the current study, we investigated whether restoration of KISS1 expression in KISS1-deficient human metastatic breast cancer cells holds potential as an advanced anticancer strategy. To this end we engineered an infectivity-enhanced conditionally-replicative human adenovirus type 5 encoding KISS1 as an “arming” transgene in the Ad5 E3 region for an ectopic KISS1 expression in transduced cancer cells. The oncolytic potential of the vector was examined using brain-invading metastatic clones of CN34 and MDA-MB-231 breast cancer cells, which supported high levels of AdKISS1 replication, correlating with a robust CRAd-mediated cytotoxicity. Secretion of cellular factors responsible for tumor angiogenesis, cell-to-cell communication and anti-tumoral immune responses upon KISS1 expression in breast cancer cells was analyzed by a RayBiotech Kiloplex Quantibody array. Overall, our results indicate that KISS1 transgene expression provides an important benefit for CRAd-mediated cytotoxicity in breast cancer cells and holds potential as an anticancer treatment in conjunction with oncolytic virotherapy of breast and other metastatic cancers.