Superior vena cava syndrome (SVCS) is a relatively common sequela of mediastinal malignancies and may cause significant patient distress. SVCS is a medical emergency if associated with laryngeal or cerebral edema. The etiologies and management of SVCS have evolved over time. Non-malignant SVCS is typically caused by infectious etiologies or by thrombus in the superior vena cava and can be managed with antibiotics or anti-coagulation therapy, respectively. Radiation therapy (RT) has long been a mainstay of treatment of malignant SVCS. Chemotherapy has also been used to manage SVCS. In the past 20 years, percutaneous stenting of the superior vena cava has emerged as a viable option for SVCS symptom palliation. RT and chemotherapy are still the only modalities that can provide curative treatment for underlying malignant etiologies of SVCS. The first experiences with treating SVCS with RT were reported in the 1970’s, and several advances in RT delivery have subsequently occurred. Hypo-fractionated RT has the potential to be a more convenient therapy for patients and may provide equal or superior control of underlying malignancies. RT may be combined with stenting and/or chemotherapy to provide both immediate symptom palliation and long-term disease control. Clinicians should tailor therapy on a case-by-case basis. Multi-disciplinary care will maximize treatment expediency and efficacy.
Experimental and clinical evidence suggests that N‐myc downregulated gene 1 (NDRG1) functions as a suppressor of prostate cancer metastasis. Elucidating pathways that drive survival and invasiveness of NDRG1‐deficient prostate cancer cells can help in designing therapeutics to target metastatic prostate cancer cells. However, the molecular mechanisms that lead NDRG1‐deficient prostate cancer cells to increased invasiveness remain largely unknown. In this study, we demonstrate that NDRG1‐deficient prostate tumors have decreased integrin expression and reduced cell adhesion and motility. Our data indicate that loss of NDRG1 differentially affects Rho GTPases. Specifically, there is a downregulation of active RhoA and Rac1 GTPases with a concomitant upregulation of active Cdc42 in NDRG1‐deficient cells. Live cell imaging using a fluorescent sensor that binds to polymerized actin revealed that NDRG1‐deficient cells have restricted actin dynamics, thereby affecting cell migration. These cellular and molecular characteristics are in sharp contrast to what is expected after loss of a metastasis suppressor. We further demonstrate that NDRG1‐deficient cells have increased resistance to anoikis and increased invasiveness which is independent of its elevated Cdc42 activity. Furthermore, NDRG1 regulates expression and glycosylation of EMMPRIN, a master regulator of matrix metalloproteases. NDRG1 deficiency leads to an increase in EMMPRIN expression with a concomitant increase in matrix metalloproteases and thus invadopodial activity. Using a three‐dimensional invasion assay and an in vivo metastasis assay for human prostate xenografts, we demonstrate that NDRG1‐deficient prostate cancer cells exhibit a collective invasion phenotype and are highly invasive. Thus, our findings provide novel insights suggesting that loss of NDRG1 leads to a decrease in actin‐mediated cellular motility but an increase in cellular invasion, resulting in increased tumor dissemination which positively impacts metastatic outcome.
Extended follow-up demonstrates that despite SRT failure, PCSS remains high in select patients. Early failure (≤1 y after SRT) predicted for significantly worse outcome and may represent a subgroup with more aggressive disease that may be considered for further prospective clinical studies.
A 49-year-old Hispanic male with stage IV non-squamous, non-small-cell lung cancer (NSCLC) on maintenance bevacizumab treatment, presented with progressive paresthesias over the back, abdomen, and chest; left foot numbness; unsteady gait; and mid-back pain. He had been diagnosed with advanced lung cancer 14 months prior, including bulky thoracic adenopathy, brain metastases, and malignant pleural and pericardial effusions. Imaging demonstrated no spinal, dural, or vertebral lesions. He was initially treated with pericardiectomy and whole brain radiation therapy (RT), followed by administration of six cycles carboplatin-paclitaxel plus bevacizumab then 12 cycles of bevacizumab maintenance monotherapy. To evaluate the patient's neurologic symptoms, magnetic resonance imaging (MRI) of the spine was performed, which suggested the presence of intramedullary spinal cord metastases (ISCM) at the T4 level, with associated hemorrhage (Fig. 1A, B). Additional imaging revealed stable disease elsewhere. He was started on systemic steroids, and bevacizumab was discontinued. Neurosurgery was consulted with recommendation against surgical intervention. RT (45 Gray/25 fractions) was delivered to the intramedullary metastases. Back pain resolved, neurologic symptoms improved, and steroids were discontinued. MRI evaluation after RT demonstrated reduction in size of the metastases with resolution of hemorrhage. (Fig. 1C, D). Discussion This could be the first reported case of bevacizumabassociated intramedullary hemorrhage in NSCLC. ISCM is a rare event, reported to affect only 0.1-0.4% of cancer patients and typically associated with poor prognosis. 1 Of these cases, approximately 55% are attributed to lung cancer. 1 Clinical
133 Background: 20% of men with prostate cancer (PCa) are diagnosed with high-risk disease. The optimal therapy for these patients, prostatectomy followed by adjuvant radiation therapy (ART) or definitive radiation with androgen deprivation (DRT), is still unclear. Previous randomized trials failed to accrue; therefore we sought to answer this using an IRB-approved retrospective cohort study. Methods: High-risk PCa was defined using NCCN criteria. Adjuvant radiation was defined as radiotherapy started within 6 months of prostatectomy. Biochemical progression-free survival (BPFS), castrate resistance-free survival (CRFS), distant metastasis-free survival (DMFS), prostate cancer-specific survival (PCSS), and overall survival (OS) were calculated using Kaplan-Meier estimates. Biochemical failure was defined using the AUA definition in the ART group and by the Phoenix definition in the DRT group. Castrate resistance was defined as ≥2 episodes of rising PSA with testosterone <50 ng/ml or rising PSA despite second line anti-androgen. Statistical analysis was performed using log rank and Cox testing. Results: 60 men with high-risk PCa treated between 1992-2011 were included in the ART group and 154 men were included in the DRT group. 58% of men in the ART group received short course of androgen depravation therapy (ADT). Nearly all men received 2 years of ADT in the DRT group. The median follow up for the ART group was 62 months and 55 months for the DRT group. Men in ART group were younger (p<0.0001) and had a lower pre-treatment PSA (p=0.0338). Log rank testing revealed the ART group had worse BPFS (5 year: 57% vs. 71%; p=0.008), but there was no difference in the other endpoints including CRFS (p=0.9693), DMFS (p=0.7345), PCSS (p=0.5481), or OS (p=0.2557). On multivariable analysis ADT use, ADT length, type of treatment, and stage were not predictive of BRFS whereas Gleason score was (p=.0001). Conclusions: This study suggests that for high-risk PCa patients there is no difference between DRT and ART with regards to BPFS, CRFS, DMFS, PCSS, or OS. Therefore, over a short follow-up period, there does not appear to be a difference between these approaches. Prospective trials are required to validate this finding.
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