Distant Metastatic Dissemination Research Articles

An Overview of the Role of MicroRNAs on Carcinogenesis: A Focus on Cell Cycle, Angiogenesis and Metastasis.

In recent years, the importance of epigenetic markers in the carcinogenesis of different malignant neoplasms has been demonstrated, also demonstrating their utility for understanding metastatic spread and tumor progression in cancer patients. Among the different biomarkers, microRNAs represent a set of non-coding RNAs that regulate gene expression, having been involved in a wide variety of neoplasia acting in different oncogenic pathways. Both the overexpression and downregulation of microRNAs represent a complex interaction with various genes whose ultimate consequence is increased cell proliferation, tumor invasion and interaction with various driver markers. It should be noted that in current clinical practice, even though the combination of different microRNAs has been shown to be useful by different authors at diagnostic and prognostic levels, there are no diagnostic kits that can be used for the initial approach or to assess recurrences of oncological diseases. Previous works have cited microRNAs as having a critical role in several carcinogenic mechanisms, ranging from cell cycle alterations to angiogenesis and mechanisms of distant metastatic dissemination. Indeed, the overexpression or downregulation of specific microRNAs seem to be tightly involved in the modulation of various components related to these processes. For instance, cyclins and cyclin-dependent kinases, transcription factors, signaling molecules and angiogenic/antiangiogenic products, among others, have been recognized as specific targets of microRNAs in different types of cancer. Therefore, the purpose of this article is to describe the main implications of different microRNAs in cell cycle alterations, metastasis and angiogenesis, trying to summarize their involvement in carcinogenesis.

Skin lesions on a man's face and scalp

An 87-year-old male patient was admitted to our Clinic for diagnostic evaluation and treatment of extensive, confluent erythematous-livid areas that affected almost the entire skin of his face, scalp, and neck Figure (1). The patient also showed left eyelid ectropion and a palpable subcutaneous, painless nodule in the left mandibular region the size of an apple that bled easily. The patient had been treated for undiagnosed erythematous papules on his left cheek 2 years before and reported that his condition had dramatically worsened over the last few weeks. The patient was otherwise healthy and was only being treated for hypertension and hyperlipemia. Multiple computed tomography (CT) scans were performed which showed an extensive disease affecting the skin and subcutaneous tissue of almost the entire face, scalp and neck, with occasional involvement of muscle tissue as well. Numerous secondarily altered lymph nodes of the neck and multiple tumour infiltrates in the liver were also seen. A skin biopsy from the scalp was performed Figure (2). Histopathology showed a tumoral lesion composed of irregular, anastomosing vascular spaces and an increased number of surrounding endothelial cells with hyperchromatic, atypical nuclei. The clinical and pathological features corresponded to a typical presentation of angiosarcoma (AS). The patient had an inoperable disseminated disease and palliative chemotherapy with paclitaxel was initiated. After three cycles of therapy, the patient's general condition worsened, and was admitted to a palliative care facility. cAS is a rare vascular malignant tumour that has a high risk of both local and distant metastatic dissemination despite aggressive therapy. It is classified into primary AS that occurs sporadically, usually in the scalp or face, and secondary AS that is most often related to a history of radiation treatment and chronic lymphedema.1 This malignant tumour resembles a “spreading bruise” that varies from blue to red in colour. The diagnosis of cAS is often delayed due to its subtle initial clinical appearance as it is often mistaken for an ecchymosis or haematoma, especially in elderly patients on anticoagulants. Most patients are asymptomatic although some may present with bleeding, oedema, and/or ulceration. Diagnosis is based on clinical examination and histopathological and immunohistochemical analysis. The extent of the disease may be assessed with magnetic resonance imaging or CT.1, 2 AS represents less than 0.1% of all head and neck malignancies but is associated with the highest rate of lymphatic dissemination among all head and neck soft tissue sarcomas.3, 4 AS shows aggressive behaviour and carries a poor prognosis, thus early diagnosis is crucial. The optimal treatment is surgery followed by wide-field radiotherapy. Clear surgical margins are of paramount importance and correlate with better outcome, but the disease is often so extensive at the time of diagnosis that it is not possible to excise.5, 6 Despite inconsistent data regarding chemotherapy, this is usually employed for patients with metastatic or inoperable disease. Doxorubicin-based regimens are most recommended, but recent use of paclitaxel has shown better efficacy compared with doxorubicin.6, 7 Though involvement of the face and scalp is common in cAS, the extent of disease in our case was striking. AS should be considered in the differential diagnosis of violaceous or ecchymotic lesions on the head or scalp in the elderly. All authors contributed to the manuscript conception, design, and writing. All authors read and approved the final manuscript. The authors have not declared a specific grant from any funding agency in the public, commercial or not-for-profit sectors. The authors declare no conflict of interest. This article did not require the approval of the Ethics committee. The patient in this manuscript has given written informed consent to the publication of his case details. Due to privacy and ethical concerns, neither the data nor the source of the data can be made available.

A Novel CXCR4-Targeted Diphtheria Toxin Nanoparticle Inhibits Invasion and Metastatic Dissemination in a Head and Neck Squamous Cell Carcinoma Mouse Model.

Loco-regional recurrences and metastasis represent the leading causes of death in head and neck squamous cell carcinoma (HNSCC) patients, highlighting the need for novel therapies. Chemokine receptor 4 (CXCR4) has been related to loco-regional and distant recurrence and worse patient prognosis. In this regard, we developed a novel protein nanoparticle, T22-DITOX-H6, aiming to selectively deliver the diphtheria toxin cytotoxic domain to CXCR4+ HNSCC cells. The antimetastatic effect of T22-DITOX-H6 was evaluated in vivo in an orthotopic mouse model. IVIS imaging system was utilized to assess the metastatic dissemination in the mouse model. Immunohistochemistry and histopathological analyses were used to study the CXCR4 expression in the cancer cells, to evaluate the effect of the nanotoxin treatment, and its potential off-target toxicity. In this study, we report that CXCR4+ cancer cells were present in the invasive tumor front in an orthotopic mouse model. Upon repeated T22-DITOX-H6 administration, the number of CXCR4+ cancer cells was significantly reduced. Similarly, nanotoxin treatment effectively blocked regional and distant metastatic dissemination in the absence of systemic toxicity in the metastatic HNSCC mouse model. The repeated administration of T22-DITOX-H6 clearly abrogates tumor invasiveness and metastatic dissemination without inducing any off-target toxicity. Thus, T22-DITOX-H6 holds great promise for the treatment of CXCR4+ HNSCC patients presenting worse prognosis.

Adult Head and Neck Rhabdomyosarcoma: Management, Outcomes, and the Impact of IMRT on Locoregional Control

<h3>Purpose/Objective(s)</h3> Only 9% of adult Rhabdomyosarcomas (RMS) present with primary disease in the head and neck (HNRMS), often as a paranasal mass with proptosis, orbital and skull base invasion, and a prodigious risk of regional node involvement and distant metastatic dissemination to unusual locations in the young adult with the embryonal/alveolar (E/A) subtype. E/A-RMS respond rapidly to chemotherapy and radiotherapy (RT) and management is extrapolated from the pediatric experience where prognosis is better but treatment imperatives differ. We report on adults with HNRMS treated over 3 decades. <h3>Materials/Methods</h3> We reviewed adult patients treated from 1984 – 2017 via chart review and a prospectively maintained database from 1989 onward. RMS were categorized as embryonal/alveolar (E/A) or pleomorphic (P). Standard management was as follows: E/A-RMS were treated with neoadjuvant chemotherapy, definitive chemoradiotherapy (CRT), and then maintenance chemotherapy. Chemotherapy regimens included VAC and VAC/IE, with VC given concurrently with RT. P-RMS were treated with surgery +/- RT. IMRT was adopted from 2005 onward. <h3>Results</h3> Fifty-eight patients met inclusion criteria; median age was 32 years. Seventy-six percent of tumors (n = 45) were parameningeal and 45% (n = 26) were > 5cm. Of 45 patients with M0 disease treated with curative intent, 33 (73%) had E/A-RMS and 12 (27%) had P-RMS. All E/A-RMS patients received definitive RT with either 66 Gy or 70 Gy in 2 Gy per fraction, except 2 who had surgery for diagnostic purposes. Involved nodal regions were treated with radical dose RT and elective nodal RT was routinely delivered. In the IMRT-era, patients with primary disease in the nasopharynx or paranasal sinuses were treated with bilateral neck RT, while patients with well lateralized primary disease were generally treated with ipsilateral neck RT. Pre-IMRT, out of 23 patients with initial M0 E/A-RMS, 12 (52%) had a loco-regional recurrence. Post-IMRT, out of 10 patients with initial MO disease, only 1 (10%) had a local recurrence; this patient achieved a complete clinical response despite a 3-week interruption after 48 Gy due to local toxicity, but experienced an in-field local recurrence 45 months later that resulted in death. Locoregional control was statistically superior in the IMRT era as compared to pre-IMRT (Fisher's exact test, <i>P</i> = 0.049). Overall, distant metastasis was the predominant mode of treatment failure (n = 17/33, 52%). <h3>Conclusion</h3> In our experience, the rate of locoregional control for adult E/A-HNRMS following definitive CRT using IMRT is excellent. As such CRT should be considered the treatment of choice in this population to avoid extensive surgery including craniofacial resection and orbital exenteration, which would be needed for many of these patients but has functional and cosmetic consequence; it would also interrupt ongoing maintenance chemotherapy which has proven survival benefit. In contrast P-RMS is distinct and requires surgery +/- RT.

Radiological evaluation of malignant pleural mesothelioma - defining distant metastatic disease

BackgroundMalignant pleural mesothelioma (MPM) is traditionally characterized by local destructive spread of the pleura and surrounding tissues. Patient outcomes in MPM with distant metastatic dissemination are lacking.MethodsIn this retrospective study, we reviewed a cohort of 164 MPM patients referred to a Phase I trials unit, aiming to describe identified metastatic sites, and correlate with clinical outcomes.Results67% of patients were diagnosed with distant metastatic disease with a high incidence of bone (19%), visceral (14%), contralateral lung (35%) and peritoneal metastases (22%). Peritoneal metastases were more likely in epithelioid versus biphasic/ sarcomatoid MPM (p = 0.015). Overall survival was 23.8 months with no statistical difference in survival between those with distant metastases and those without.ConclusionsThis report highlights the frequency of distant metastases and encourages further radiological investigations in the presence of symptoms. In particular, given the relatively high incidence of bone metastases, bone imaging should be considered in advanced MPM clinical workflow and trial protocols. The presence of distant metastases does not appear to have prognostic implications under existing treatment paradigms. This cohort of MPM patients gives an indication of patterns of metastatic spread that are likely to become prevalent as prognosis improves with emerging treatment paradigms.

Computer navigation-assisted surgery for musculoskeletal tumors: a closer look into the learning curve.

Computer navigation-assisted surgery for musculoskeletal tumors has shown to reduce the risk of intra-lesional margins in resection. Experiences with this method are still limited to smaller case series. We reviewed our first experiences in 24 patients in whom computer navigation-assisted surgery had been performed. In 7 of these patients (6 male and 1 female), this has influenced the surgical treatment plan and navigation was used for both tumor resection and reconstruction. Three of the patients suffered from a chondrosarcoma, 2 from an osteosarcoma, 1 from a fibrosarcoma and 1 from an Ewing's sarcoma. Tumors were localized in the femur (n=2), the tibia (n=1), the sacrum (n=1), the humerus (n=1), the ilium (n=1) and in the gluteal region (n=1). The mean registration error was 0.9mm. No intra-operative complications occurred. Two postoperative complications were observed which required revision surgery. Except for one marginal resection, all tumors were excised with wide margins. One patient suffered from a local recurrence, and one patient died of disease after distant metastatic dissemination. Computer navigation-assisted surgery represents a safe and helpful tool for the resection of musculoskeletal tumors and may influence surgical treatment plans in selected cases to provide more limited resections. Surgeons should be aware of risks considering biomechanical and oncological consequences in doing so. Further investigations and the evaluation of newer techniques (e.g., computed tomography-guided navigation) are needed to assess long-term outcomes of computer navigation assistance in musculoskeletal tumor surgery.

P-cadherin and the journey to cancer metastasis.

P-cadherin is a classical cell-to-cell adhesion molecule with a homeostatic function in several normal tissues. However, its behaviour in the malignant setting is notably dependent on the cellular context. In some tumour models, such as melanoma and oral squamous cell carcinoma, P-cadherin acts as a tumour suppressor, since its absence is associated with a more aggressive cancer cell phenotype; nevertheless, the overexpression of this molecule is linked to significant tumour promoting effects in the breast, ovarian, prostate, endometrial, skin, gastric, pancreas and colon neoplasms. Herein, we review the role of P-cadherin in cancer cell invasion, as well as in loco-regional and distant metastatic dissemination. We focus in P-cadherin signalling pathways that are activated to induce invasion and metastasis, as well as cancer stem cell properties. The signalling network downstream of P-cadherin is notably dependent on the cellular and tissue context and includes the activation of integrin molecules, receptor tyrosine kinases, small molecule GTPases, EMT transcription factors, and crosstalk with other cadherin family members. As new oncogenic molecular pathways mediated by P-cadherin are uncovered, putative therapeutic options can be tested, which will allow for the targeting of invasion or metastatic disease, depending on the tumour model.

Vasculotide reduces endothelial permeability and tumor cell extravasation in the absence of binding to or agonistic activation of Tie2

Angiopoietin-1 (Ang1) activation of Tie2 receptors on endothelial cells (ECs) reduces adhesion by tumor cells (TCs) and limits junctional permeability to TC diapedesis. We hypothesized that systemic therapy with Vasculotide (VT)—a purported Ang1 mimetic, Tie2 agonist—can reduce the extravasation of potentially metastatic circulating TCs by similarly stabilizing the host vasculature. In vitro, VT and Ang1 treatments impeded endothelial hypermeability and the transendothelial migration of MDA-MB-231•LM2-4 (breast), HT29 (colon), or SN12 (renal) cancer cells to varying degrees. In mice, VT treatment inhibited the transit of TCs through the pulmonary endothelium, but not the hepatic or lymphatic endothelium. In the in vivo LM2-4 model, VT monotherapy had no effect on primary tumors, but significantly delayed distant metastatic dissemination to the lungs. In the post-surgical adjuvant treatment setting, VT therapeutically complemented sunitinib therapy, an anti-angiogenic tyrosine kinase inhibitor which limited the local growth of residual disease. Unexpectedly, detailed investigations into the putative mechanism of action of VT revealed no evidence of Tie2 agonism or Tie2 binding; alternative mechanisms have yet to be determined.

Inhibition of VEGF-C Modulates Distal Lymphatic Remodeling and Secondary Metastasis

Tumor-associated lymphatics are postulated to provide a transit route for disseminating metastatic cells. This notion is supported by preclinical findings that inhibition of pro-lymphangiogenic signaling during tumor development reduces cell spread to sentinel lymph nodes (SLNs). However, it is unclear how lymphatics downstream of SLNs contribute to metastatic spread into distal organs, or if modulating distal lymph transport impacts disease progression. Utilizing murine models of metastasis, longitudinal in vivo imaging of lymph transport, and function blocking antibodies against two VEGF family members, we provide evidence that distal lymphatics undergo disease course-dependent up-regulation of lymph transport coincidental with structural remodeling. Inhibition of VEGF-C activity with antibodies against VEGF-C or NRP2 prevented these disease-associated changes. Furthermore, utilizing a novel model of adjuvant treatment, we demonstrate that antagonism of VEGF-C or NRP2 decreases post SLN metastasis. These data support a potential therapeutic strategy for inhibiting distant metastatic dissemination via targeting tumor-associated lymphatic remodeling.

Bone marrow disseminated tumor cells, loco-regional and adjuvant treatment are prognostic factors for loco-regional relapses in early breast cancers.

Abstract Abstract #307 Purpose: To study in early breast cancer (BC) patients (pts) if bone marrow (BM) disseminated tumor cells (DTC) are associated with a specific loco-regional dissemination of cancer cells, according to the radiotherapy fields and to the pattern of loco-regional relapses.&amp;#x2028; Patient and methods: BM aspirates were prospectively screened for cytokeratin positive (CK+) cells at primary treatment in stage I-III BC pts. Local recurrence (LR) was defined as recurrence of the breast or chest wall; Regional recurrence (RR) was defined as lymph node recurrence after loco-regional treatment. Irradiation fields, BM DTC status, clinical and pathological variables of the pts were correlated with loco-regional relapse-free survival (LRRFS).&amp;#x2028; Results: BM DTC were detected in 94 out of 621 pts (15%) and were not associated with the axillary lymph node status and other prognostic factors. After a median follow-up of 56 months, 18 pts (2,9%) experienced loco-regional relapses: 15 LR occurred in the RT fields whereas 2 LR and 1 RR were out. 8 of the 18 relapsing pts (44%) were DTC positive (8 LR in the RT fields). BM DTC detection was the only prognostic factor for LRRFS (p=0.0005, OR=5.2 [2.0-13.1]) in multivariate analysis. In BM DTC positive patients, longer LRRFS were observed in those who were given adjuvant hormonal therapy (p=0.03) and RT on supra-clavicular (SCN) and internal mammary (IMN) nodes (p=0.055) (multivariate analysis).&amp;#x2028; Conclusions: BM DTC strongly influence loco-regional relapse in early BC patients. Our data support the hypothesis of a different lymphatic spread of BM DTC positive BC and of a possible re-seeding of BM DTC to the breast. Survival analyses suggest that BM DTC positive patients take advantage of adjuvant hormone therapy but also of adjuvant SCN and IMN irradiation. This observation could be one explanation of the influence of systemic treatment on locoregional relapse and of radiotherapy on distant metastatic dissemination. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 307.

Prognosis after regional lymph node recurrence in patients with stage I-II breast carcinoma treated with breast conservation therapy.

The authors evaluated the risk factors for regional lymph node recurrence and the prognosis of patients with regional nodal recurrence after breast conservation therapy for Stage I-II breast carcinoma. Between 1977 and 1995, 1293 women with pathologic Stage I and II (T1-2, N0-1) breast carcinoma were treated with breast-conserving therapy including lumpectomy, axillary lymph node dissection, and definitive breast irradiation. A total of 39 women (3%) had any regional lymph node recurrence. The median follow-up was 8.5 years (range, 1.5-24 years). Among 39 patients with a regional lymph node recurrence, 10 women had regional recurrence only, 16 had simultaneous locoregional recurrence, and 13 had simultaneous regional and distant recurrence. Regional recurrence occurred in the axillary lymph nodes only (n = 21; 51%), supraclavicular lymph nodes only (n = 8; 23%), internal mammary lymph nodes only (n = 3; 8%), infraclavicular lymph nodes only (n = 3; 8%), or multiple lymph node sites (n = 4; 10%). The median time to regional lymph node recurrence was 3.1 years (range, 0.2-20.9 years). Overall survival after regional-only disease recurrence was 44%, locoregional disease recurrence was 26%, and regional with distant disease recurrence was 12%. Cause-specific survival rates at 10 years for the 3 groups were 44%, 40%, and 12%, respectively. For patients who presented with simultaneous regional and distant metastases, the median survival period was 1.1 years, compared with 5.2 years for women who developed distant disease subsequent to regional recurrence. Regional lymph node recurrence after breast conservation therapy may be salvaged, but is associated with a high rate of either simultaneous or subsequent distant metastatic dissemination and poor overall prognosis.

The effect of loco-regional control on distant metastatic dissemination in carcinoma of the nasopharynx: An analysis of 1301 patients

Purpose : This study evaluated the effect of loco-regional control on incidence of distant metastases in patients with nasopharyngeal carcinoma. Methods and Materials : Retrospective analysis was performed on 1301 patients with nasopharyngeal carcinoma treated from 1976–1989 in our hospital. The effect of different prognostic indicators on distant metastases free survival (DMFS) was analyzed, including T stage, N stage, sex, and loco-regional control. The significance of locoregional control in distant metastatic dissemination was further studied with period and subgroup analysis. Cox regression was performed to identify the independent prognostic variables. Results : Patients with loco-regional relapse had significantly higher distant metastases rate than patients with loco-regional control (time-adjusted distant metastases rate at 5 years was 40.7% vs. 29.4%, p = 0.0012). By period analysis, the effect of loco-regional control on distant metastases was found to be significant in the first 2 years from diagnosis. Subgroup analysis showed that loco-regional relapse was associated with significantly higher distant metastases rate in patients with T1, N0, and N1 disease ( p = 0.001, 0.001, 0.0226, respectively). The Cox regression model also confirmed loco-regional control as an independent prognostic indicator of distant metastases ( p = 0.0001) besides T stage ( p = 0.0006) and N stage ( p = 0.0001). Conclusion : Loco-regional relapse is a significant risk factor for development of distant metastases. Further effort should be made to improve loco-regional control and to eradicate distant metastases.

The effect of local-regional control on distant metastatic dissemination in carcinoma of the head and neck: Results of an analysis from the RTOG head and neck database

A retrospective analysis of the effect of local control on the development of distant metastases was performed in 2648 patients with carcinoma of the head and neck selected from the RTOG database. The 5-year time-adjusted incidence of distant metastases was 21% for patients who were in local-regional control at 6 months after the start of treatment, compared to 38% for local-regional failure patients ( p < 0.001). The incidence of distant metastases detected between the interval of 6 months to 2.5 years after treatment was significantly increased in patients with tumors of the oral cavity, oropharynx, supraglottic larynx, and glottis who developed local-regional failure within this time period, compared to those who remained locally controlled (19% distant metastases for local-regional failure vs 7% for local-regional control ( p < 0.001)). In contrast, there as no difference in the incidence of distant metastases in patients with carcinoma of the nasopharynx or hypopharynx regardless of the local-regional disease status. A Cox proportional hazards regression analysis demonstrated that local-regional control was the most significant variable affecting the development of distant metastases, followed by tumor site, N-stage, and T-stage. For all tumor sites, except for the hypopharynx and nasopharynx, improvements in local-regional control are likely to improve survival. Tumors of the hypopharynx and nasopharynx have a higher probability of micrometastatic dissemination at the time of initial diagnosis, and until effective methods to treat disseminated disease are developed, the effect of local control on survival will not be readily discerned.

Natural history of human breast cancer: Recent data and clinical implications

This study of the natural history of human breast cancer was based on the analysis of a series of 3000 patients treated by radical mastectomy at a single institution (Institut Gustave Roussy) at a time when adjuvant chemotherapy was not prescribed. The follow-up of the patients ranged from 15 to 30 years; for each patient the tumor size, the number of involved axillary nodes, and the histological grade were prospectively registered. A highly significant correlation was found between tumor size and the probability of distant metastatic dissemination. The distribution of tumor sizes at metastatic spread was log-normal with a median diameter equal to 3.5 cm. The patients were subdivided into 3 groups according to the histological grade. In each subgroup there was a significant correlation between tumor size and the probability of distant spread; the distributions were log-normal and the median size was markedly larger for grade 1 tumors. Moreover the proportion of grade 1 tumors was higher in small tumors than in large ones while the reverse was observed for grade 3 tumors; these data suggest that during their growth tumors progress towards higher grades. One of the chief fundamental characteristics of a tumor seems to be its propensity for axillary node invasion. The orderly pattern of nodal involvement makes it possible to calculate the tumor size at invasion of the first axillary node in each subset of patients. A strong and highly significant correlation exists between the size of the tumor at initiation of distant metastasis and at invasion of the first lymph node. However the capacity for lymphatic spread is, on average, acquired much earlier than the capacity for metastatic spread. With a simple model based on these data it was possible to compute the proportion of patients with occult metastases as a function of tumor size, histological grade, and number of involved axillary nodes. Early invasion of axillary nodes is associated with a rapid growth rate of the primary tumor (or a high S-phase fraction). However each of these variables has an independent prognostic significance; the S-phase fraction appears as one of the strongest prognostic indicators. A model of tumor growth was used to assess the impact of screening procedures on the proportion of patients with distant metastases. The predictions of the model are consistent with the results of the screening programs.(ABSTRACT TRUNCATED AT 400 WORDS)