Long-Term Outcomes Following Fairly Brief Androgen Suppression and Stereotactic Radiation Therapy in High-Risk Prostate Cancer: Update From the FASTR/FASTR-2 Trials.

PURPOSE: There is limited data on the long-term outcomes of ultrahypofractionated radiation therapy in high-risk prostate cancer. The FASTR and FASTR-2 trials were designed to assess the tolerability of stereotactic ablative radiation therapy (SABR) in this context. Herein, the long-term results are reported. METHODS AND MATERIALS: Eligible patients had localized high-risk prostate cancer and were either ≥70 years old, had a score of ≥3 on the Vulnerable Elderly Scale, or declined standard therapy. Nineteen patients from a single institution were enrolled on FASTR between 2011 and 2015. They received 40 Gy to the prostate and 25 Gy to the pelvic lymph nodes in 5 weekly fractions, with 12 months of androgen deprivation therapy (ADT). Thirty patients from the same institution were enrolled on FASTR-2 between 2015 and 2017. They received 35 Gy to the prostate alone in 5 weekly fractions, with 18 months of ADT. Updated toxicity and outcomes were assessed retrospectively. Kaplan-Meier estimates were calculated for biochemical failure-free survival, freedom from distant metastases, prostate cancer-specific survival, and overall survival. RESULTS: Forty-four patients were eligible for analysis, 16 from FASTR and 28 from FASTR-2. Thirty-four patients (77%) were >70 years old. High-risk features included Gleason score ≥8 (n = 20, 46%), T3-T4 disease (n = 12, 27%), and baseline prostate-specific antigen > 20 (n = 22, 50%). Median follow-up was 6.4 years. The 5-year cumulative incidence of late grade ≥3 genitourinary/gastrointestinal toxicity was 32% in FASTR and 11% in FASTR-2. At 5 years, the combined rates of biochemical failure-free survival, freedom from distant metastases, prostate cancer-specific survival, and overall survival were 72%, 90%, 92%, and 83%, respectively. CONCLUSIONS: SABR can be safely delivered in high-risk prostate cancer by optimizing technical delivery, particularly with adherence to strict dose constraints for organs at risk. The clinical outcomes in FASTR and FASTR-2 were largely comparable to more standard fractionation schemes plus ADT, but further modifications may improve disease control. Larger randomized trials are necessary to better understand the efficacy and tolerability of this approach.

Predicting stereotactic radiosurgery outcomes with multi-observer qualitative appearance labelling versus MRI radiomics.

Qualitative observer-based and quantitative radiomics-based analyses of T1w contrast-enhanced magnetic resonance imaging (T1w-CE MRI) have both been shown to predict the outcomes of brain metastasis (BM) stereotactic radiosurgery (SRS). Comparison of these methods and interpretation of radiomics-based machine learning (ML) models remains limited. To address this need, we collected a dataset of n = 123 BMs from 99 patients including 12 clinical features, 107 pre-treatment T1w-CE MRI radiomic features, and BM post-SRS progression scores. A previously published outcome model using SRS dose prescription and five-way BM qualitative appearance scoring was evaluated. We found high qualitative scoring interobserver variability across five observers that negatively impacted the model's risk stratification. Radiomics-based ML models trained to replicate the qualitative scoring did so with high accuracy (bootstrap-corrected AUC = 0.84-0.94), but risk stratification using these replicated qualitative scores remained poor. Radiomics-based ML models trained to directly predict post-SRS progression offered enhanced risk stratification (Kaplan-Meier rank-sum p = 0.0003) compared to using qualitative appearance. The qualitative appearance scoring enabled interpretation of the progression radiomics-based ML model, with necrotic BMs and a subset of heterogeneous BMs predicted as being at high-risk of post-SRS progression, in agreement with current radiobiological understanding. Our study's results show that while radiomics-based SRS outcome models out-perform qualitative appearance analysis, qualitative appearance still provides critical insight into ML model operation.

Identifying clusters of coexisting conditions and outcomes among adults admitted to hospital with community-acquired pneumonia: a multicentre cohort study.

BACKGROUND: Little is known about patterns of coexisting conditions and their influence on clinical care or outcomes in adults admitted to hospital for community-acquired pneumonia (CAP). We sought to evaluate how coexisting conditions cluster in this population to advance understanding of how multimorbidity affects CAP. METHODS: We studied 11 085 adults admitted to hospital with CAP at 7 hospitals in Ontario, Canada. Using cluster analysis, we identified patient subgroups based on clustering of comorbidities in the Charlson Comorbidity Index. We derived and replicated cluster analyses in independent cohorts (derivation sample 2010-2015, replication sample 2015-2017), then combined these into a total cohort for final cluster analyses. We described differences in medications, imaging and outcomes. RESULTS: Patients clustered into 7 subgroups. The low comorbidity subgroup (n = 3052, 27.5%) had no comorbidities. The DM-HF-Pulm subgroup had prevalent diabetes, heart failure and chronic lung disease (n = 1710, 15.4%). One disease category defined each remaining subgroup, as follows: pulmonary (n = 1621, 14.6%), diabetes (n = 1281, 11.6%), heart failure (n = 1370, 12.4%), dementia (n = 1038, 9.4%) and cancer (n = 1013, 9.1%). Corticosteroid use ranged from 11.5% to 64.9% in the dementia and pulmonary subgroups, respectively. Piperacillin-tazobactam use ranged from 9.1% to 28.0% in the pulmonary and cancer subgroups, respectively. The use of thoracic computed tomography ranged from 5.7% to 36.3% in the dementia and cancer subgroups, respectively. Adjusting for patient factors, the risk of in-hospital death was greater in the cancer (adjusted odds ratio [OR] 3.12, 95% confidence interval [CI] 2.44-3.99), dementia (adjusted OR 1.57, 95% CI 1.05-2.35), heart failure (adjusted OR 1.66, 95% CI 1.35-2.03) and DM-HF-Pulm subgroups (adjusted OR 1.35, 95% CI 1.12-1.61), and lower in the diabetes subgroup (adjusted OR 0.67, 95% CI 0.50-0.89), compared with the low comorbidity group. INTERPRETATION: Patients admitted to hospital with CAP cluster into clinically recognizable subgroups based on coexisting conditions. Clinical care and outcomes vary among these subgroups with little evidence to guide decision-making, highlighting opportunities for research to personalize care.

Dual-center validation of using magnetic resonance imaging radiomics to predict stereotactic radiosurgery outcomes.

Background: MRI radiomic features and machine learning have been used to predict brain metastasis (BM) stereotactic radiosurgery (SRS) outcomes. Previous studies used only single-center datasets, representing a significant barrier to clinical translation and further research. This study, therefore, presents the first dual-center validation of these techniques. Methods: SRS datasets were acquired from 2 centers (n = 123 BMs and n = 117 BMs). Each dataset contained 8 clinical features, 107 pretreatment T1w contrast-enhanced MRI radiomic features, and post-SRS BM progression endpoints determined from follow-up MRI. Random decision forest models were used with clinical and/or radiomic features to predict progression. 250 bootstrap repetitions were used for single-center experiments. Results: Training a model with one center's dataset and testing it with the other center's dataset required using a set of features important for outcome prediction at both centers, and achieved area under the receiver operating characteristic curve (AUC) values up to 0.70. A model training methodology developed using the first center's dataset was locked and externally validated with the second center's dataset, achieving a bootstrap-corrected AUC of 0.80. Lastly, models trained on pooled data from both centers offered balanced accuracy across centers with an overall bootstrap-corrected AUC of 0.78. Conclusions: Using the presented validated methodology, radiomic models trained at a single center can be used externally, though they must utilize features important across all centers. These models' accuracies are inferior to those of models trained using each individual center's data. Pooling data across centers shows accurate and balanced performance, though further validation is required.

Does brachytherapy boost improve survival outcomes in Gleason Grade Group 5 patients treated with external beam radiotherapy and androgen deprivation therapy? A systematic review and meta-analysis.

Background: Localized Gleason Grade Group 5 (GG5) prostate cancer has a poor prognosis and is associated with a higher risk of treatment failure, metastases, and death. Treatment intensification with the addition of a brachytherapy (BT) boost to external beam radiation (EBRT) maximizes local control, which may translate into improved survival outcomes. Methods: A systematic review and meta-analysis was performed to compare survival outcomes for Gleason GG5 patients treated with androgen deprivation therapy (ADT) and either EBRT or EBRT + BT. The MEDLINE (PubMed), EMBASE and Cochrane databases were searched to identify relevant studies. Survival probabilities for distant metastasis-free survival (DMFS), prostate cancer-specific survival (PCSS), and overall survival (OS) were extracted and pooled to create a summary survival curve for each treatment modality, which were then compared at fixed points in time. An additional analysis was performed among studies directly comparing EBRT and EBRT + BT using a random-effects model. Results: Eight retrospective studies were selected for inclusion, representing a total of 1393 EBRT patients and 877 EBRT + BT patients. EBRT + BT was associated with higher DMFS starting at 6 years (86.8 % vs 78.8 %; p = 0.018) and extending out to 10 years (81.8 % vs 66.1 %; p < 0.001), with an overall hazard ratio of 0.53 (p = 0.02). There was no difference in PCSS or OS between treatment modalities. Differences in toxicity were not assessed. There was a wide range of heterogeneity between studies. Conclusion: The addition of BT boost is associated with improved long-term DMFS in Gleason GG5 prostate cancer, but its impact on PCSS and OS remains unclear. These results may be confounded by the heterogeneity across study populations with concern for a risk of bias. Therefore, prospective studies are necessary to further elucidate the survival advantage associated with BT boost, which must ultimately be weighed against the toxicity-related implications of this treatment strategy.

Long-term survival in a patient with extensive-stage small cell lung cancer treated with multiple courses of salvage stereotactic radiation after whole brain radiotherapy: A case report.

Intracranial recurrence following initial cranial irradiation for extensive-stage small cell lung cancer (ES-SCLC) can often be a treatment dilemma given the aggressive nature of the disease, the overall poor prognosis and concerns regarding re-treatment toxicity. The present report describes the case of a 62-year-old man diagnosed with ES-SCLC and synchronous brain metastases who initially underwent whole brain radiotherapy, chemotherapy and consolidative thoracic radiotherapy. The patient was found to have a solitary intracranial recurrence at both 3.5 and 6 years after his diagnosis. On both occasions, the patient received salvage stereotactic radiation, 30 Gy in 5 fractions, and continues to remain functionally independent. Overall, the present case demonstrates that with the appropriate patient selection, aggressive local salvage of recurrent intracranial ES-SCLC with stereotactic radiation can yield excellent and durable clinical outcomes.

Small Molecule 20S Proteasome Enhancer Regulates MYC Protein Stability and Exhibits Antitumor Activity in Multiple Myeloma.

Despite the addition of several new agents to the armamentarium for the treatment of multiple myeloma (MM) in the last decade and improvements in outcomes, the refractory and relapsing disease continues to take a great toll, limiting overall survival. Therefore, additional novel approaches are needed to improve outcomes for MM patients. The oncogenic transcription factor MYC drives cell growth, differentiation and tumor development in many cancers. MYC protein levels are tightly regulated by the proteasome and an increase in MYC protein expression is found in more than 70% of all human cancers, including MM. In addition to the ubiquitin-dependent degradation of MYC by the 26S proteasome, MYC levels are also regulated in a ubiquitin-independent manner through the REGγ activation of the 20S proteasome. Here, we demonstrate that a small molecule activator of the 20S proteasome, TCH-165, decreases MYC protein levels, in a manner that parallels REGγ protein-mediated MYC degradation. TCH-165 enhances MYC degradation and reduces cancer cell growth in vitro and in vivo models of multiple myeloma by enhancing apoptotic signaling, as assessed by targeted gene expression analysis of cancer pathways. Furthermore, 20S proteasome enhancement is well tolerated in mice and dogs. These data support the therapeutic potential of small molecule-driven 20S proteasome activation for the treatments of MYC-driven cancers, especially MM.

Using a Mobile App-Based Video Recommender System of Patient Narratives to Prepare Women for Breast Cancer Surgery: Development and Usability Study Informed by Qualitative Data.

BACKGROUND: Women diagnosed with breast cancer are often bombarded with information. Such information overload can lead to misunderstandings and hamper women's capacity for making informed decisions about their care. For women with breast cancer, this uncertainty is particularly severe in the period before surgery. Personalized narratives about others' experiences can help patients better understand the disease course, the quality and type of care to be expected, the clinical decision-making processes, and the strategies for coping. Existing resources and eHealth apps rarely include experiential information, and no tools exist that tailor information for individual preferences and needs-offering the right information at the right time and in the right format. Combining high-quality experiential evidence with novel technical approaches may contribute to patient-centered solutions in this area. OBJECTIVE: This study aims to design and seek preliminary feedback on a mobile app that will improve information access about surgery for patients with breast cancer, by drawing on a qualitative collection of personal narratives from a diverse sample of Canadian women and using video and audio recordings or audio recordings from the Canadian Health Experiences Research Network. METHODS: In a previous study, we conducted in-depth interviews with 35 Canadian women and used video and audio recordings or audio recordings to collect stories about the lived experiences of breast cancer. The participants highlighted the need for more specific information between diagnosis and surgery that was relevant to their personal situations and preferences. They also wanted to learn from other women's experiences. We worked with patients, clinicians, and informatics experts to develop a mobile app that provides access to tailored experiential information relevant to women's personal situations and preferences. We completed focus groups and qualitative interviews, conducted a further analysis of the original qualitative data, designed novel software using artificial intelligence, and sought preliminary feedback from users on a new app via focus groups and a survey. RESULTS: The secondary analysis of the breast cancer narratives revealed key themes and their interconnections relevant to the experience of surgery, including preparation, treatment decisions, aftercare, reconstruction, prostheses, lumpectomy and mastectomy, and complications. These themes informed the development of the structure and content of the app. We developed a recommender system within the app by using content matching (user and speaker profiles and user interests and video content) and collaborative filtering to identify clips marked as relevant by the user and by similar users. A 2-minute animated introductory video for users was developed. Pilot testing revealed generally positive responses regarding the content and value of this type of e-tool. CONCLUSIONS: Developing reliable, evidence-based tools and apps that are based on diverse collections of people's experiences of illness offers a novel approach to help manage the plethora of information that women face after a diagnosis of breast cancer.

Dose-sparing effect of deep inspiration breath hold technique on coronary artery and left ventricle segments in treatment of breast cancer.

BACKGROUND AND PURPOSE: The risk of radiation-induced cardiac injury remains a challenging problem in the treatment of breast cancer. Certain cardiac structures receive higher doses than others, which results in variable frequencies of radiation-induced injuries across these structures. Radiation dose can be reduced using the deep inspiration breath hold (DIBH) technique. We aimed to investigate the dose reductions from DIBH in individual cardiac segments. MATERIALS AND METHODS: A dosimetric analysis was performed on left-sided breast cancer patients who underwent breast-conserving surgery and whole breast irradiation. Radiation doses to the cardiac structures were compared between the DIBH and free-breathing (FB) techniques and the dose reductions with DIBH were correlated to the lung expansion. RESULTS: For the 75 patients included in our study, DIBH effectively reduced doses to the heart, left lung, left anterior descending coronary artery (LAD) and left ventricle (LV), but the degree of dose reductions was variable across different structures. The absolute dose reductions were greatest in the distal LAD (14.4 Gy) and apical LV (12.1 Gy) segments, compared with the other LAD (middle 9.7 Gy, proximal 1.6 Gy) and LV (anterior 5.3 Gy, lateral 2.9 Gy, septal 2.0 Gy, inferior 0.2 Gy) segments. Left lung expansion was significantly correlated with the dose reductions in the LAD (Spearman's rank correlation coefficient, ρ, 0.304) and LV (ρ, 0.420) segments. CONCLUSIONS: Our study demonstrates the dose-sparing effects of DIBH in various cardiac structures, especially the distal LAD and apical LV segments. The large dose reductions seen in the distal LAD and apical LV segments could potentially translate into clinical benefit of reduced cardiac toxicity, as these structures have been previously shown to receive the highest doses and are associated with radiation-induced injury.

Value of routine echocardiography in the management of stroke.

BACKGROUND: Transthoracic echocardiography is routinely performed in patients with stroke or transient ischemic attack (TIA) to help plan secondary stroke management, but recent data evaluating its usefulness in this context are lacking. We sought to evaluate the value of echocardiography for identifying clinically actionable findings for secondary stroke prevention. METHODS: We conducted a multicentre cohort study of patients admitted to hospital with stroke or TIA between 2010 and 2015 at 2 academic hospitals in Toronto, Ontario, Canada. Clinically actionable echocardiographic findings for secondary stroke prevention included cardiac thrombus, patent foramen ovale, atrial myxoma or valvular vegetation. We identified patient characteristics associated with clinically actionable findings using logistic regression. RESULTS: Of the 1862 patients with stroke or TIA we identified, 1272 (68%) had at least 1 echocardiogram. Nearly all echocardiograms were transthoracic; 1097 (86%) were normal, 1 (0.08%) had an atrial myxoma, 2 (0.2%) had a valvular vegetation, 11 (0.9%) had a cardiac thrombus and 66 (5.2%) had a PFO. Patent foramen ovale was less likely among patients older than 60 years (adjusted odds ratio [OR] 0.34, 95% confidence interval [CI] 0.20-0.57), with prior stroke or TIA (adjusted OR 0.31, 95% CI 0.09-0.76) or with dyslipidemia (adjusted OR 0.39, 95% CI 0.15-0.84). Among the 130 patients with cryptogenic stroke who had an echocardiogram (n = 110), a PFO was detected in 19 (17%) on transthoracic echocardiogram. INTERPRETATION: Most patients with stroke or TIA had a normal echocardiogram, with few having clinically actionable findings for secondary stroke prevention. Clinically actionable findings, specifically PFO, were more common in patients with cryptogenic stroke.

SNS01-T modulation of eIF5A inhibits B-cell cancer progression and synergizes with bortezomib and lenalidomide.

The high rates of recurrence and low median survival in many B-cell cancers highlight a need for new targeted therapeutic modalities. In dividing cells, eukaryotic translation initiation factor 5A (eIF5A) is hypusinated and involved in regulation of protein synthesis and proliferation, whereas the non-hypusinated form of eIF5A is a potent inducer of cell death in malignant cells. Here, we demonstrate the potential of modulating eIF5A expression as a novel approach to treating B-cell cancers. SNS01-T is a nonviral polyethylenimine-based nanoparticle, designed to induce apoptosis selectively in B-cell cancers by small interfering RNA-mediated suppression of hypusinated eIF5A and plasmid-based overexpression of a non-hypusinable eIF5A mutant. In this study, we show that SNS01-T is preferentially taken up by malignant B cells, inhibits tumor growth in multiple animal models of B-cell cancers without damaging normal tissues, and synergizes with the current therapies bortezomib and lenalidomide to inhibit tumor progression. The results collectively demonstrate the potential of SNS01-T as a novel therapeutic for treatment of a diverse range of B-cell malignancies.

Modulation of eIF5A expression using SNS01 nanoparticles inhibits NF-κB activity and tumor growth in murine models of multiple myeloma.

Despite recent advances in the first-line treatment of multiple myeloma, almost all patients eventually experience relapse with drug-resistant disease. New therapeutic modalities are needed, and to this end, SNS01, a therapeutic nanoparticle, is being investigated for treatment of multiple myeloma. The antitumoral activity of SNS01 is based upon modulation of eukaryotic translation initiation factor 5A (eIF5A), a highly conserved protein that is involved in many cellular processes including proliferation, apoptosis, differentiation and inflammation. eIF5A is regulated by post-translational hypusine modification, and overexpression of hypusination-resistant mutants of eIF5A induces apoptosis in many types of cancer cells. SNS01 is a polyethylenimine (PEI)-based nanoparticle that contains both a B-cell-specific expression plasmid expressing a non-hypusinable mutant of eIF5A and a small interfering RNA (siRNA) which depletes endogenous hypusinated eIF5A. Reducing hypusine-modified eIF5A levels was found to inhibit phosphorylation and activity of ERK MAPK and nuclear factor-κB (NF-κB), and thus sensitize myeloma cells to apoptosis resulting from transfection of a plasmid expressing eIF5A(K50R). SNS01 exhibited significant antitumoral activity in both KAS-6/1 (95% inhibition; P < 0.05) and RPMI 8226 (59% inhibition; P < 0.05) multiple myeloma xenograft models following systemic administration. These results highlight the potential of using this approach as a new therapeutic strategy for multiple myeloma.

Assessment for frailty is useful for predicting morbidity in elderly patients undergoing colorectal cancer resection whose comorbidities are already optimized.

BACKGROUND: The clinical syndrome of frailty identified through the assessment of weight loss, gait speed, grip strength, physical activity, and physical exhaustion has been used to identify patients with reduced reserves. We hypothesized that frailty is useful in predicting adverse outcomes in optimized elective elderly colorectal surgery patients. METHODS: A prospective study was conducted at 2 centers (Singapore and Japan). All patients over 75 years of age undergoing colorectal resection were assessed for the presence of the syndrome of frailty. All these patients had already had their comorbidities optimized for surgery. The outcome measure was postoperative major complications (defined as Clavien-Dindo type II and above complications). RESULTS: Eighty-three patients were studied from February 2008 to April 2010. The mean age was 81.5 years (range 75-93 years). The mean comorbidity index was 3.37 (range 0-11). Twenty-six (31.3%) patients were an American Society of Anesthesiologists (ASA) score of 3 and above. Chi-square analysis revealed that the odds ratio of postoperative major complications was 4.083 (95% confidence interval, 1.433-11.638) when the patient satisfied the criteria for frailty. Albumin <35, ASA >3, comorbidity index >5, and Physiologic and Operative Severity Score for the enUmeration of Mortality and Morbidity (POSSUM) scores were not predictive of postoperative major complications. CONCLUSIONS: Preliminary findings show that frailty is a potent adjunctive tool of predicting postoperative morbidity. Frailty can be used to identify elderly patients needing further optimization before major surgery.

Development of a resistance-like phenotype to sorafenib by human hepatocellular carcinoma cells is reversible and can be delayed by metronomic UFT chemotherapy.

Acquired resistance to antiangiogenic drugs, such as sorafenib, is a major clinical problem. We studied development of a resistance to sorafenib in new preclinical models of human hepatocellular carcinoma (HCC) along with a strategy to delay such resistance--combination with metronomic chemotherapy. Three different xenograft models were studied using human Hep3B HCC cells, which are highly responsive to sorafenib, namely, orthotopic and subcutaneous transplant in severe combined immunodeficient mice, and an orthotopic transplant in nude mice. The complementary DNA for the ß-subunit of human choriogonadotropin was transfected into HCC cells, and urine levels of the protein were monitored as a surrogate of tumor burden. Extended daily treatments, sometimes interrupted by a break period of 3 to 7 days to allow recovery from toxicity at sorafenib doses of 30 to 60 mg/kg, were maintained until and after evidence of tumor relapse. Initially responsive tumors seemed to develop a resistance-like phenotype after long-term daily treatment (e.g., >42 days) at doses of 30 to 60 mg/kg. Transplantation of cell lines established from progressing tumors into new hosts showed that the resistant phenotype was not propagated. Furthermore, a regimen of daily metronomic uracil + tegafur (UFT, an oral 5-fluorouracil prodrug) chemotherapy with a less toxic regimen of sorafenib (15 mg/kg per day) significantly delayed the onset of resistance (>91 days). In conclusion, development of a resistance-like phenotype to sorafenib is reversible, and metronomic UFT plus sorafenib may be a promising and well-tolerated treatment for increasing efficacy by delaying emergence of such resistance.

Potent preclinical impact of metronomic low-dose oral topotecan combined with the antiangiogenic drug pazopanib for the treatment of ovarian cancer.

Low-dose metronomic chemotherapy has shown promising activity in many preclinical and some phase II clinical studies involving various tumor types. To evaluate further the potential therapeutic impact of metronomic chemotherapy for ovarian cancer, we developed a preclinical model of advanced human ovarian cancer and tested various low-dose metronomic chemotherapy regimens alone or in concurrent combination with an antiangiogenic drug, pazopanib. Clones of the SKOV-3 human ovarian carcinoma cell line expressing a secretable beta-subunit of human choriogonadotropic (beta-hCG) protein and firefly luciferase were generated and evaluated for growth after orthotopic (i.p.) injection into severe combined immunodeficient mice; a highly aggressive clone, SKOV-3-13, was selected for further study. Mice were treated beginning 10 to 14 days after injection of cells when evidence of carcinomatosis-like disease in the peritoneum was established as assessed by imaging analysis. Chemotherapy drugs tested for initial experiments included oral cyclophosphamide, injected irinotecan or paclitaxel alone or in doublet combinations with cyclophosphamide; the results indicated that metronomic cyclophosphamide had no antitumor activity whereas metronomic irinotecan had potent activity. We therefore tested an oral topoisomerase-1 inhibitor, oral topotecan, at optimal biological dose of 1 mg/kg/d. Metronomic oral topotecan showed excellent antitumor activity, the extent of which was significantly enhanced by concurrent pazopanib, which itself had only modest activity, with 100% survival values of the drug combination after six months of continuous therapy. In conclusion, oral topotecan may be an ideal agent to consider for clinical trial assessment of metronomic chemotherapy for ovarian cancer, especially when combined with an antiangiogenic drug targeting the vascular endothelial growth factor pathway, such as pazopanib. Mol Cancer Ther; 9(4); 996-1006. (c)2010 AACR.

Impact of metronomic UFT/cyclophosphamide chemotherapy and antiangiogenic drug assessed in a new preclinical model of locally advanced orthotopic hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is an intrinsically chemotherapy refractory malignancy. Development of effective therapeutic regimens would be facilitated by improved preclinical HCC models. Currently, most models consist of subcutaneous human tumor transplants in immunodeficient mice; however, these do not reproduce the extensive liver disease associated with HCC or metastasize. To address this deficiency, we developed an orthotopic model. Human HCC cells were transfected with the gene encoding secretable beta-subunit human choriogonadotropin (beta-hCG), which was used as a surrogate marker of tumor burden. The HCC cells were implanted into the left liver lobe of severe combined immunodeficient (SCID) mice, after which the efficacy of different therapies was evaluated on established, but liver-confined human Hep3B cell line HCC. Treatments included sorafenib or metronomic chemotherapy using cyclophosphamide (CTX), UFT, an oral 5-fluorouracil prodrug, or doxorubicin either alone or in various combinations, with or without an antiangiogenic agent, DC101, an anti-vascular endothelial growth factor receptor-2 antibody. Sorafenib inhibited tumor growth in a dose-dependent manner but caused severe weight loss in SCID mice, thus necessitating use of DC101 in subsequent experiments. Although less toxicity was observed using either single or doublet metronomic chemotherapy without any added antiangiogenic agent, none, provided survival benefit. In contrast, significantly improved overall survival was observed using various combinations of metronomic chemotherapy regimens such as UFT + CTX with DC101. In conclusion, using this model of liver-confined but advanced HCC suggests that the efficacy of a targeted antiangiogenic drug or metronomic chemotherapy can be mutually enhanced by concurrent combination treatment.

Liver surgery induces an immediate mobilization of progenitor cells in liver cancer patients: A potential role for G-CSF.

BACKGROUND: In preclinical models recruitment of bone-marrow derived (endothelial) progenitor cells (BD(E)PCs) contributes to tumor growth and metastasis formation. Here we investigated whether these (E)PCs and mobilizing cytokines are released after partial hepatectomy or radiofrequency ablation (RFA) for liver tumors. In addition, we tested whether G-CSF could play a role in EPC mobilization in mice and in human volunteers. RESULTS: Patients undergoing partial hepatectomy or RFA showed an instantaneous release of EPCs following laparotomy and mobilization of the liver. Elevated EPC levels were maintained during the entire procedure, but dropped to near-baseline levels 4 h after completion of the procedure. Plasma G-CSF levels showed a 5-10-fold increase after the procedure and low-dose G-CSF administration to mice or healthy volunteers was sufficient to induce an immediate release of EPCs. Surgery also caused an increase in the plasma levels of VEGF, but not SDF-1alpha. METHODS: Before, during and after liver surgery plasma and mononuclear cells were collected from 12 patients undergoing partial hepatectomy or RFA. To explore the role of G-CSF C57Bl/6 mice and 20 human volunteers received G-CSF (0.3, 3 or 300microg). In all individuals, (E)PC numbers were determined by flow cytometry at predefined timepoints shortly after therapy. Plasma levels of G-CSF, VEGF and SDF-1alpha were measured by ELISA. CONCLUSION: Compliant with previous published data concerning VDA and chemotherapy treatment, liver surgery induces an instantaneous release of EPCs, conceivably in response to elevated G-CSF levels. This suggests the value of exploring therapeutic avenues to prevent this process.

Contribution of granulocyte colony-stimulating factor to the acute mobilization of endothelial precursor cells by vascular disrupting agents.

Vascular disrupting agents (VDA) cause acute shutdown of abnormal established tumor vasculature, followed by massive intratumoral hypoxia and necrosis. However, a viable rim of tumor tissue invariably remains from which tumor regrowth rapidly resumes. We have recently shown that an acute systemic mobilization and homing of bone marrow-derived circulating endothelial precursor (CEP) cells could promote tumor regrowth following treatment with either a VDA or certain chemotherapy drugs. The molecular mediators of this systemic reactive host process are unknown. Here, we show that following treatment of mice with OXi-4503, a second-generation potent prodrug derivative of combretastatin-A4 phosphate, rapid increases in circulating plasma vascular endothelial growth factor, stromal derived factor-1 (SDF-1), and granulocyte colony-stimulating factor (G-CSF) levels are detected. With the aim of determining whether G-CSF is involved in VDA-induced CEP mobilization, mutant G-CSF-R(-/-) mice were treated with OXi-4503. We found that as opposed to wild-type controls, G-CSF-R(-/-) mice failed to mobilize CEPs or show induction of SDF-1 plasma levels. Furthermore, Lewis lung carcinomas grown in such mice treated with OXi-4503 showed greater levels of necrosis compared with tumors treated in wild-type mice. Evidence for rapid elevations in circulating plasma G-CSF, vascular endothelial growth factor, and SDF-1 were also observed in patients with VDA (combretastatin-A4 phosphate)-treated cancer. These results highlight the possible effect of drug-induced G-CSF on tumor regrowth following certain cytotoxic drug therapies, in this case using a VDA, and hence G-CSF as a possible therapeutic target.

Glioma tumor stem-like cells promote tumor angiogenesis and vasculogenesis via vascular endothelial growth factor and stromal-derived factor 1.

Cancer stem cells (CSC) are predicted to be critical drivers of tumor progression due to their self-renewal capacity and limitless proliferative potential. An emerging area of research suggests that CSC may also support tumor progression by promoting tumor angiogenesis. To investigate how CSC contribute to tumor vascular development, we used an approach comparing tumor xenografts of the C6 glioma cell line containing either a low or a high fraction of CSC. Compared with CSC-low tumors, CSC-high tumors exhibited increased microvessel density and blood perfusion and induced increased mobilization and tumor recruitment of bone marrow-derived endothelial progenitor cells (EPC). CSC-high C6 cell cultures also induced higher levels of endothelial cell proliferation and tubule organization in vitro compared with CSC-low cultures. CSC-high cultures and tumors expressed increased levels of the proangiogenic factors vascular endothelial growth factor and stromal-derived factor 1, and when signaling by either factor was blocked, all aspects of angiogenesis observed in CSC-high cultures and tumors, including microvessel density, perfusion, EPC mobilization/recruitment, and stimulation of endothelial cell activity, were reduced to levels comparable with those observed in CSC-low cultures/tumors. These results suggest that CSC contribute to tumor angiogenesis by promoting both local endothelial cell activity and systemic angiogenic processes involving bone marrow-derived EPC in a vascular endothelial growth factor-dependent and stromal-derived factor 1-dependent manner.

Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents.

Several hypotheses have been proposed to explain how antiangiogenic drugs enhance the treatment efficacy of cytotoxic chemotherapy, including impairing the ability of chemotherapy-responsive tumors to regrow after therapy. With respect to the latter, we show that certain chemotherapy drugs, e.g., paclitaxel, can rapidly induce proangiogenic bone marrow-derived circulating endothelial progenitor (CEP) mobilization and subsequent tumor homing, whereas others, e.g., gemcitabine, do not. Acute CEP mobilization was mediated, at least in part, by systemic induction of SDF-1alpha and could be prevented by various procedures such as treatment with anti-VEGFR2 blocking antibodies or paclitaxel treatment in CEP-deficient Id mutant mice, both of which resulted in enhanced antitumor effects mediated by paclitaxel, but not by gemcitabine.