Coefficient of Variation in Metastatic Lymph Nodes Determined by 18F-FDG PET/CT in Patients with Advanced NSCLC: Combination with Coefficient of Variation in Primary Tumors.

Purpose The aim of the present study was to test whether the coefficient of variation (CoV) of 18F-FDG PET/CT images of metastatic lymph nodes and primary tumors may predict clinical outcome in patients with advanced non-small cell lung cancer (NSCLC). Materials and Methods Fifty-eight NSCLC patients who had undergone 18F-FDG PET/CT at diagnosis were evaluated. SUVmax, SUVmean, CoV, MTV and TLG were determined in targeted lymph nodes and corresponding primary tumors along with Total MTV (MTVTOT) and Whole-Body TLG (TLGWB) of all malignant lesions. Univariate analysis was performed using Cox proportional hazards regression whereas the Kaplan-Meier method and log-rank tests were used for survival analysis. Results Fifty-eight metastatic lymph nodes were analyzed and average values of SUVmax, SUVmean, CoV, MTV and TLG were 11.89 ± 8.54, 4.85 ± 1.90, 0.37 ± 0.16, 46.16 ± 99.59 mL and 256.84 ± 548.27 g, respectively, whereas in primary tumors they were 11.92 ± 6.21, 5.47 ± 2.34, 0.36 ± 0.14, 48.03 ± 64.45 mL and 285.21 ± 397.95 g, respectively. At univariate analysis, overall survival (OS) was predicted by SUVmax (p = 0.0363), SUVmean (p = 0.0200) and CoV (p = 0.0139) of targeted lymph nodes as well as by CoV of primary tumors (p = 0.0173), MTVTOT (p = 0.0007), TLGWB (p = 0.0129) and stage (p = 0.0122). Using Kaplan-Meier analysis, OS was significantly better in patients with CoV of targeted lymph nodes ≤ 0.29 than those with CoV > 0.29 (p = 0.0147), meanwhile patients with CoV of primary tumors > 0.38 had a better prognosis compared to those with CoV ≤ 0.38 (p = 0.0137). Finally, we combined the CoV values of targeted lymph nodes and primary tumors in all possible arrangements and a statistically significant difference was found among the four survival curves (p = 0.0133). In particular, patients with CoV of targeted lymph nodes ≤ 0.29 and CoV of primary tumors > 0.38 had the best prognosis. Conclusions The CoV of targeted lymph nodes combined with the CoV of primary tumors can predict prognosis of NSCLC patients.

Machine Learning and Texture Analysis of [18F]FDG PET/CT Images for the Prediction of Distant Metastases in Non-Small-Cell Lung Cancer Patients.

The aim of our study was to predict the occurrence of distant metastases in non-small-cell lung cancer (NSCLC) patients using machine learning methods and texture analysis of 18F-labeled 2-deoxy-d-glucose Positron Emission Tomography/Computed Tomography {[18F]FDG PET/CT} images. In this retrospective and single-center study, we evaluated 79 patients with advanced NSCLC who had undergone [18F]FDG PET/CT scan at diagnosis before any therapy. Patients were divided into two independent training (n = 44) and final testing (n = 35) cohorts. Texture features of primary tumors and lymph node metastases were extracted from [18F]FDG PET/CT images using the LIFEx program. Six machine learning methods were applied to the training dataset using the entire panel of features. Dedicated selection methods were used to generate different combinations of five features. The performance of selected machine learning methods applied to the different combinations of features was determined using accuracy, the confusion matrix, receiver operating characteristic (ROC) curves, and area under the curve (AUC). A total of 104 and 78 lesions were analyzed in the training and final testing cohorts, respectively. The support vector machine (SVM) and decision tree methods showed the highest accuracy in the training cohort. Seven combinations of five features were obtained and introduced in the models and subsequently applied to the training and final testing cohorts using the SVM and decision tree. The accuracy and the AUC of the decision tree method were higher than those obtained with the SVM in the final testing cohort. The best combination of features included shape sphericity, gray level run length matrix_run length non-uniformity (GLRLM_RLNU), Total Lesion Glycolysis (TLG), Metabolic Tumor Volume (MTV), and shape compacity. The combination of these features with the decision tree method could predict the occurrence of distant metastases with an accuracy of 74.4% and an AUC of 0.63 in NSCLC patients.

Heterogeneity of Glycolytic Phenotype Determined by 18F-FDG PET/CT Using Coefficient of Variation in Patients with Advanced Non-Small Cell Lung Cancer.

We investigated the role of Coefficient of Variation (CoV), a first-order texture parameter derived from 18F-FDG PET/CT, in the prognosis of Non-Small Cell Lung Cancer (NSCLC) patients. Eighty-four patients with advanced NSCLC who underwent 18F-FDG PET/CT before therapy were retrospectively studied. SUVmax, SUVmean, CoV, total Metabolic Tumor Volume (MTVTOT) and whole-body Total Lesion Glycolysis (TLGWB) were determined by an automated contouring program (SUV threshold at 2.5). We analyzed 194 lesions: primary tumors (n = 84), regional (n = 48) and non-regional (n = 17) lymph nodes and metastases in liver (n = 9), bone (n = 23) and other sites (n = 13); average CoVs were 0.36 ± 0.13, 0.36 ± 0.14, 0.42 ± 0.18, 0.30 ± 0.14, 0.37 ± 0.17, 0.34 ± 0.13, respectively. No significant differences were found between the CoV values among the different lesion categories. Survival analysis included age, gender, histology, stage, MTVTOT, TLGWB and imaging parameters derived from primary tumors. At univariate analysis, CoV (p = 0.0184), MTVTOT (p = 0.0050), TLGWB (p = 0.0108) and stage (p = 0.0041) predicted Overall Survival (OS). At multivariate analysis, age, CoV, MTVTOT and stage were retained in the model (p = 0.0001). Patients with CoV > 0.38 had significantly better OS than those with CoV ≤ 0.38 (p = 0.0143). Patients with MTVTOT ≤ 89.5 mL had higher OS than those with MTVTOT > 89.5 mL (p = 0.0063). Combining CoV and MTVTOT, patients with CoV ≤ 0.38 and MTVTOT > 89.5 mL had the worst prognosis. CoV, by reflecting the heterogeneity of glycolytic phenotype, can predict clinical outcomes in NSCLC patients.

Extraskeletal Ewing's sarcoma of the mediastinum: Case report.

Background: Ewing sarcoma (ES) represents the second most common malignant bone tumor in children and young adults. ES is not a frequent finding in sites different from the skeletal. Common sites of appearance of ES are lower extremities, the pelvis, paravertebral spaces and head and neck. Primary extraskeletal ES located in the anterior mediastinum are very rare. These neoplasms should be discussed in specialized contests with a high volume of patients treated. Here, we present an uncommon mediastinal mass challenging in its characterization and management. Case description: A thirty-year-old woman performed a thoracic CT scan for dyspnea and persistent cough. Imaging showed a solid mass of 14 x 11 cm involving the left thorax with mediastinal deviation to the right side. Patient underwent an en bloc resection of the mass. Initial histological examination was suggestive for B3 thymoma/thymic carcinoma. Patient was then referred to our rare tumor reference center where a histological review excluded the diagnosis of thymic/thymoma neoplasms meanwhile a third revision assessed a diagnosis of ES. Patient refused adjuvant chemotherapy due to her desire of maternity and radiation therapy was not indicated because surgery was performed too many months earlier. A close follow-up was considered. After a few months the patient relapsed and first line chemotherapy was proposed. She reached a complete response at the first evaluation maintained also at the end of the protocol. In order to consolidate the obtained response, high dose chemotherapy followed by autologous stem cell transplantation (HDCT/ASCT) was suggested and the patient agreed. Conclusions: This case underlined that, potentially, ES can arise from any soft tissue site in the body, even in rare sites such as mediastinum. The evaluation of expert centers was critical to establish a correct diagnosis and therapeutic approach in this complex case. Taking into account the time lasting from the diagnosis and the aggressiveness of this kind of neoplasm, frequently relapsing, the patient after a multidisciplinary discussion was a candidate for a multimodal treatment.

Shifting from a Biological-Agnostic Approach to a Molecular-Driven Strategy in Rare Cancers: Ewing Sarcoma Archetype.

Sarcomas of the thoracic cavity are rare entities that predominantly affect children and young adults. They can be very heterogeneous encompassing several different histological entities. Ewing Sarcoma (ES) can potentially arise from every bone, soft tissue, or visceral site in the body. However, it represents an extremely rare finding when it affects the thoracic cavity. It represents the second most frequent type of thoracic sarcoma, after chondrosarcoma. ES arises more frequently in sites that differ from the thoracic cavity, but it displays the same biological features and behavior of extra-thoracic ones. Current management of ES often requires a multidisciplinary treatment approach including surgery, radiotherapy, and systemic therapy, as it can guarantee local and distant disease control, at least transiently, although the long-term outcome remains poor. Unfortunately, due to the paucity of clinical trials purposely designed for this rare malignancy, there are no optimal strategies that can be used for disease recurrence. As a result of its complex biological features, ES might be suitable for emerging biology-based therapeutic strategies. However, a deeper understanding of the molecular mechanisms driving tumor growth and treatment resistance, including those related to oncogenic pathways, epigenetic landscape, and immune microenvironment, is necessary in order to develop new valid therapeutic opportunities. Here, we provide an overview of the most recent therapeutic advances for ES in both the preclinical and clinical settings. We performed a review of the current available literature and of the ongoing clinical trials focusing on new treatment strategies, after failure of conventional multimodal treatments.

Impaired Seroconversion After Severe Acute Respiratory Syndrome Coronavirus 2 mRNA Vaccine in Patients With Thymic Epithelial Tumors.

INTRODUCTION: Thymic epithelial tumors (TETs) are rare malignancies associated with dysregulation of the immune system and humoral- and cell-mediated immunity abnormalities. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine is effective in preventing coronavirus disease 2019 morbidity and mortality. The aim of this study was to evaluate the seroconversion in patients with TET after two doses of mRNA vaccine. METHODS: This is a prospective study in which consecutive patients with TET were enrolled before receiving the first dose of SARS-CoV-2 mRNA vaccine (BNT162b2 by Pfizer-BioNTech). SARS-CoV-2 spike-binding immunoglobulin (Ig)G antibody serologic levels were analyzed at different time points, including before first vaccine dose (T0), 1 month after the second dose (T2), and 3 months after the second dose (T3). RESULTS: Overall, 39 patients were included in the analysis. All patients had negative antibody titer results at T0. There were 19 patients (48.7%) in the follow-up with no residual tumor lesion/s (referred as no evidence of disease), and 20 (51.3%) had evidence of disease (ED) and were receiving systemic treatment. Dysregulations of the immune system were diagnosed in 29 patients (74.4%) with Good syndrome (GS) being the most frequent immune disorder (48.7%). At univariate analysis, lack of seroconversion at T2 was significantly associated with ED (p < 0.001) and with GS (p = 0.043). A significant association with impaired seroconversion was confirmed at multivariate analysis for ED (p = 0.00101) but not for GS (p = 0.625). CONCLUSIONS: Our data revealed that patients with TET with ED had substantially higher probability of impaired seroconversion after SARS-CoV-2 mRNA vaccine as compared with patients with no evidence of disease.

The unusual first sign of presentation of renal cell carcinoma: a rare case report.

Background: Renal cell carcinoma (RCC) usually is characterized by a slow pattern of growth, although with an unpredictable evolution and metastatic potential, favored by its extensive vascularity and related high angioinvasive profile. The most common sites of metastases from kidney cancer are lung, lymph nodes, bone and liver; whereas orbital metastases are very uncommon. In more than 25% of cases, orbital metastases are the first manifestation of a primary tumor of unknown origin. The clinical features of orbital metastases from kidney cancer are non-specific and could divert attention from the real problem. Case Description: In this article, we describe the case of a 72-year-old male patient reporting a painful mass on the right orbit, with exophthalmos and ptosis, as the first and unique signs of a previously undetected advanced RCC. Due to the clinical conditions, the patient underwent palliative radiation therapy delivered to the orbital lesion with the scope to relieve pain; subsequently started systemic therapy with pazopanib at the dose of 800 mg daily. Unfortunately, he did not achieve any benefit from systemic therapy, his conditions progressively worsened, and he finally passed away after four months of treatment due to rapid disease progression. Conclusions: Despite its rarity, differential diagnosis of an orbital lesion should always consider the possibility of metastasis from RCC, performing an appropriate radiological evaluation.

Immunological signature of patients with thymic epithelial tumors and Good syndrome.

Background: Thymic epithelial tumors (TETs) are frequently accompanied by Good Syndrome (GS), a rare immunodeficiency, characterized by hypogammaglobulinemia and peripheral B cell lymphopenia. TETs can be also associated to other immunological disorders, both immunodeficiency and autoimmunity. Methods: In this study, we enrolled TET patients with GS to address differences between patients with or without associated autoimmune diseases (AD). We analyzed the immunophenotype from peripheral blood of these patients focusing on selected immune cell subsets (CD4+T cells, CD8+T cells, T regulatory cells, NK cells, B-cells, monocytes, eosinophils, basophils, neutrophils) and serum levels of cytokines, chemokines and growth factors. Results: We observed higher number of leucocytes, in particular lymphocytes, B lymphopenia and lower number of T regulatory cells in TET patients with associated AD compared to TET patients without AD. In the group of TET patients with AD, we also observed increased serum levels of IL-15, VEGF, IP-10, GM-CSF, IL-6, and MIP-1α. Thus, we identified considerable differences in the lymphocyte profiles of TET patients with and without ADs, in particular a reduction in the numbers of B lymphocytes and T-regulatory cells in the former, as well as differences in the serum levels of various immune modulators. Conclusions: Although the pathogenic mechanisms are still unclear, our results add new knowledge to better understand the disease, suggesting the need of surveilling the immunophenotype of TET patients to ameliorate their clinical management.

The Never-Ending History of Octreotide in Thymic Tumors: A Vintage or A Contemporary Drug?

Thymic epithelial tumors are rare tumors usually presenting as a mass located in the anterior mediastinum and/or with symptoms deriving from associated paraneoplastic syndromes. Unresectable platinum-refractory tumors are often treated with alternative regimens, including chemotherapeutic agents as well as chemo-free regimens. The most popular unconventional therapy is represented by the somatostatin analog octreotide, which can be used alone or with prednisone. The in vivo expression of somatostatin receptors documented by imaging with indium-labeled octreotide or gallium-68 Dotapeptides, the successful use of octreotide and prednisone in a chemo-refractory patient, and, thereafter, the experiences from a case series have enforced the idea that this treatment merits consideration-as proved by its inclusion in the National Comprehensive Cancer Network guidelines. In the present review, we analyze the preclinical basis for the therapeutic use of somatostatin and prednisone in refractory thymic tumors and discuss the available studies looking at future perspectives.

Assessment of Total, PTEN-, and AR-V7+ Circulating Tumor Cell Count by Flow Cytometry in Patients with Metastatic Castration-Resistant Prostate Cancer Receiving Enzalutamide.

INTRODUCTION: Metastatic castration-resistant prostate cancer (mCRPC) is a deadly disease. Enzalutamide is an oral second-generation anti-androgen that is active in mCRPC. Circulating tumor cells (CTC) count correlates with overall survival (OS) in mCRPC, whereas detection of the androgen-receptor splice variant 7 (AR-V7) in CTC predicts poor response to oral second-generation anti-androgens. Also, loss of PTEN (phosphatase and tensin homolog) in CTC is a biomarker of poor prognosis in mCRPC. PATIENTS AND METHODS: In this translational study, we employed flow cytometry to assess total, PTEN-, and AR-V7+ CTC count per 7.5 mL of whole blood in a prospective cohort of patients with mCRPC receiving enzalutamide. RESULTS: CTCs were assessed in a total of 45 men with mCRPC at baseline and at 12 weeks. Overall, CTC, PTEN- CTC, and AR-V7+ CTC detection rate was high, at baseline, with 84.4%, 71.1%, and 51.1% of samples showing at least 1 cell/7.5-mL blood, respectively, and after 3 months, with 93.3%, 64.4%, and 77.7% of samples showing at least 1 cell/7.5-mL blood, respectively. Median radiographic progression-free survival (rPFS) and OS were 6 (95% confidence interval [CI], 5.6-9) and 14.3 (95% CI, 12.8-20.3) months, respectively. Median (interquartile range) total CTC count at baseline was 5 (3; 8), whereas median (interquartile range) PTEN- CTC count was 2 (0; 4) and median (interquartile range) AR-V7+ CTC count was 1 (0; 3). At baseline, ≥ 5 versus < 5 total CTC count was associated with worse rPFS (hazard ratio [HR], 2.35; 95% CI, 1.14-4.84; P= .021) and OS (HR, 3.08; 95% CI, 1.45-6.54; P = .003), whereas ≥ 2 versus < 2 PTEN- CTC count was associated with worse rPFS (HR, 3.96; 95% CI, 1.8-8.72; P= .001) and OS (HR, 2.36; 95% CI, 1.12-5; P= .025). Finally, ≥ 1 versus < 1 AR-V7+ CTC count was also associated with worse rPFS (HR, 5.05; 95% CI, 2.4-10.64; P< .001) and OS (HR, 2.25; 95% CI, 1.1-4.58; P= .026). CONCLUSIONS: Despite multiple limitations, including the small sample size, our preliminary study suggests that assessment of CTC via flow cytometry may provide potentially useful prognostic and predictive information in advanced prostate cancer. Further studies are warranted. Micro-Abstract: In this study, men with metastatic castration-resistant prostate cancer, scheduled to start enzalutamide, were assessed for circulating tumor cell count and molecular characterization (total, PTEN-, and AR-V7+ circulating tumor cell count) by the use of flow cytometry. We found that flow cytometry could be used to enumerate circulating tumor cells, but also to assess molecular biomarkers on their surface.

Outcomes Associated with First-Line anti-PD-1/ PD-L1 agents vs. Sunitinib in Patients with Sarcomatoid Renal Cell Carcinoma: A Systematic Review and Meta-Analysis.

: Immunotherapy based on anti PD-1/PD-L1 inhibitors has proven to be more effective than sunitinib in the first-line setting of advanced renal cell carcinoma (RCC). RCC patients with sarcomatoid histology (sRCC) have a poor prognosis and limited therapeutic options. We performed a systematic review and a meta-analysis of randomized-controlled trials (RCTs) of first-line anti PD-1/PDL-1 agents vs. sunitinib, presenting efficacy data in the sub-group of sRCC patients. The systematic research was conducted on Google Scholar, Cochrane Library, PubMed and Embase and updated until 31th January, 2020. Abstracts from ESMO and ASCO (2010-2019) were also reviewed. Full texts and abstracts reporting about RCTs testing first-line anti-PD-1/ PD-L1 agents vs. sunitinib in RCC were included if sRCC sub-group analyses of either PFS (progression-free survival), OS (overall survival) or radiological response rate were available. Pooled data from 3814 RCC patients in the ITT (intention-to-treat) population and from 512 sRCC patients were included in the quantitative synthesis. In the sRCC sub-group vs. the ITT population, pooled estimates of the PFS-HRs were 0.57 (95%: 0.45-0.74) vs. 0.79 (95% CI: 0.70-0.89), respectively, with a statistically meaningful interaction favoring the sRCC sub-group (pooled ratio of the PFS-HRs = 0.64; 95% CI: 0.50-0.82; p < 0.001). Pooled estimates of the difference in CR-R (complete response-rate) achieved with anti-PD-1/PDL-1 agents vs. sunitinib were + 0.10 (95% CI: 0.04-0.16) vs. + 0.04 (95% CI: 0.00-0.07) in the sRCC vs. the non-sRCC sub groups, with a statistically meaningful difference of + 0.06 (95% CI: 0.02-0.10; p = 0.007) favoring the sRCC sub-group. Sarcomatoid histology may be associated with improved efficacy of anti PD-1/PDL-1 agents vs. sunitinib in terms of PFS and CR-R.

Effect of Psychiatric Comorbidities on In-Hospital Outcomes and Cost for Cervical Spondylotic Myelopathy.

OBJECTIVE: The present study examined the differences in outcomes of cervical spinal surgery for patients with and without a major psychiatric comorbidity using the Healthcare Cost and Utilization Project National Inpatient Sample database. METHODS: Data were queried from the Healthcare Cost and Utilization Project National Inpatient Sample database from 2013 to 2014 for hospitalizations with a major psychiatric comorbidity and a diagnosis of cervical spondylotic myelopathy treated by an appropriate surgical procedure. The included psychiatric comorbidities were schizophrenia, episodic mood disorders (bipolar I and II disorders), delusional disorders, and psychoses not otherwise specified. Univariate and multivariate regression analyses were performed to determine the differences in outcomes between patients with and without a major psychiatric comorbidity. RESULTS: A total of 18,335 hospitalizations met the inclusion criteria, of which 648 (3.5%) included a major psychiatric comorbidity. Multivariate regression analysis demonstrated that psychiatric comorbidity was an independent predictor of non-home discharge (odds ratio [OR], 1.81; 95% confidence interval [CI], 1.43-2.30; P < 0.0001) and a longer hospital stay (+0.52 day; 95% CI, 0.43-0.61; P < 0.0001) but was not an independent predictor of overall complications (OR, 0.79; 95% CI, 0.58-1.07; P = 0.13) or total hospital charges ($1992; 95% CI, -$917-$4902; P = 0.18). CONCLUSIONS: Psychiatric comorbidity was associated with an increased risk of non-home discharge and a longer length of stay for patients undergoing surgical intervention for cervical myelopathy. However, we did not find an associated increased risk of in-hospital mortality, complications, or total hospital charges. Psychiatric comorbidity should not be weighed against patients who require surgical treatment for cervical spondylotic myelopathy, and special attention should be given to postoperative care and discharge planning for this unique patient population.

Combined Inhibition of Both p110α and p110ß Isoforms of Phosphatidylinositol 3-Kinase Is Required for Sustained Therapeutic Effect in PTEN-Deficient, ER+ Breast Cancer.

Purpose: Determine the roles of the PI3K isoforms p110α and p110ß in PTEN-deficient, estrogen receptor α (ER)-positive breast cancer, and the therapeutic potential of isoform-selective inhibitors.Experimental Design: Anti-estrogen-sensitive and -resistant PTEN-deficient, ER+ human breast cancer cell lines, and mice bearing anti-estrogen-resistant xenografts were treated with the anti-estrogen fulvestrant, the p110α inhibitor BYL719, the p110ß inhibitor GSK2636771, or combinations. Temporal response to growth factor receptor-initiated signaling, growth, apoptosis, predictive biomarkers, and tumor volumes were measured.Results: p110ß primed cells for response to growth factor stimulation. Although p110ß inhibition suppressed cell and tumor growth, dual targeting of p110α/ß enhanced apoptosis and provided sustained tumor response. The growth of anti-estrogen-sensitive cells was inhibited by fulvestrant, but fulvestrant inconsistently provided additional therapeutic effects beyond PI3K inhibition alone. Treatment-induced decreases in phosphorylation of AKT and Rb were predictive of therapeutic response. Short-term drug treatment induced tumor cell apoptosis and proliferative arrest to induce tumor regression, whereas long-term treatment only suppressed proliferation to provide durable regression.Conclusions: p110ß is the dominant PI3K isoform in PTEN-deficient, ER+ breast cancer cells. Upon p110ß inhibition, p110α did not induce significant reactivation of AKT, but combined targeting of p110α/ß most effectively induced apoptosis in vitro and in vivo and provided durable tumor regression. Because apoptosis and tumor regression occurred early but not late in the treatment course, and proliferative arrest was maintained throughout treatment, p110α/ß inhibitors may be considered short-term cytotoxic agents and long-term cytostatic agents. Clin Cancer Res; 23(11); 2795-805. ©2016 AACR.

The Influence of Prednisone on the Efficacy of Cabazitaxel in Men with Metastatic Castration-Resistant Prostate Cancer.

Background: Cabazitaxel is a second-generation taxane that is approved for use with concomitant low dose daily prednisone in metastatic castration resistant prostate cancer (mCRPC) after docetaxel failure. Since the role of daily corticosteroids in improving cabazitaxel efficacy or ameliorating its safety profile has not been adequately investigated so far, we compared outcomes of patients receiving cabazitaxel with or without daily corticosteroids in a retrospective single-Institution cohort of mCRPC patients. Patients and methods: Medical records of deceased patients with documented mCRPC treated with cabazitaxel following prior docetaxel between January, 2011 and January, 2017 were reviewed at the single participating center. Patients who were receiving daily doses of systemic corticosteroids other than low dose daily prednisone or prednisolone (<= 10 mg a day) were excluded. The primary end point of this analysis was overall survival (OS). Secondary end-points were exposure to cabazitaxel as well as incidence of grade 3-4 adverse events. Univariable and multivariable Cox proportional hazards regression was used to evaluate prednisone use and other variables as potentially prognostic for overall survival. Results: Overall, among 91 patients, 57 patients received cabazitaxel concurrently with low dose prednisone and 34 patients did not receive concurrent prednisone. The median overall survival of the population was 9.8 months (interquartile range, 9 to 14). Patients receiving prednisone had an overall survival of 9 months (interquartile range, 8 to 12) vs.14 months (interquartile range, 9.4 to 16.7) for patients not treated with prednisone. Approximately 45% of patients had a >30% PSA decline at 12 weeks. Prednisone use was not significantly prognostic for overall survival or PSA decline ≥30% rates on regression analyses. Importantly, a >30% PSA decline at 12, but not at 3, 6, 9 weeks, was prognostic for improved survival at multivariate analysis Conclusions: The data presented here support the hypothesis that omitting daily corticosteroids in cabazitaxel-treated patients has no negative impact on either survival or safety profile. In the large prospective trial CABACARE, cabazitaxel-treated patients will be randomized to receive or not receive daily prednisone. The CABACARE (EudraCT n. 2016-003646-81) study is currently ongoing at University Federico II of Naples and at other multiple participating centers in Italy.

New Monocyclic, Bicyclic, and Tricyclic Ethynylcyanodienones as Activators of the Keap1/Nrf2/ARE Pathway and Inhibitors of Inducible Nitric Oxide Synthase.

A monocyclic compound 3 (3-ethynyl-3-methyl-6-oxocyclohexa-1,4-dienecarbonitrile) is a highly reactive Michael acceptor leading to reversible adducts with nucleophiles, which displays equal or greater potency than the pentacyclic triterpenoid CDDO in inflammation and carcinogenesis related assays. Recently, reversible covalent drugs, which bind with protein targets but not permanently, have been gaining attention because of their unique features. To explore such reversible covalent drugs, we have synthesized monocyclic, bicyclic, and tricyclic compounds containing 3 as an electrophilic fragment and evaluated them as activators of the Keap1/Nrf2/ARE pathway and inhibitors of iNOS. Notably, these compounds maintain the unique features of the chemical reactivity and biological potency of 3. Among them, a monocyclic compound 5 is the most potent in these assays while a tricyclic compound 14 displays a more robust and specific activation profile compared to 5. In conclusion, we demonstrate that 3 is a useful electrophilic fragment for exploring reversible covalent drugs.