Vinflunine in Metastatic Urothelial Carcinoma of the Bladder in Progression after a Platinum-Containing Regimen.

BACKGROUND: Vinflunine is a microtubule inhibitor of the vinca alkaloid class approved for the treatment of urothelial bladder carcinoma after a platinum-containing regimen. METHODS: To evaluate the effectiveness of vinflunine, we enrolled 80 subjects with a histologically confirmed diagnosis of metastatic urothelial bladder carcinoma that had previously undergone chemotherapy with a platinum-containing regimen and had measurable lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST). The patients (n = 80) received vinflunine (Javlor®) every 3 weeks at 320 mg/m2 via 20-min intravenous infusion. The endpoints were progression-free survival (PFS), objective response rate, overall survival (OS), and tolerability. The cumulative survival of the patients was analyzed using the Kaplan-Meier method. RESULTS: In this retrospective study, vinflunine treatment was well tolerated and resulted in a good level of disease control (complete response + partial response + stable disease >50%), with a manageable toxicity profile. The median PFS and OS were 3.2 and 6.8 months, respectively. A significant correlation between pain and PFS was also noted. The major hematologic adverse event was neutropenia, observed in 47% of the patients. The most common nonhematologic adverse events were constipation in 48% of the patients and fatigue in 26%. DISCUSSION: In this real-word non-randomized clinical trial setting, the data showed that vinflunine is an efficacious and safe therapeutic option for second-line treatment of patients with metastatic urothelial carcinoma of the bladder after a platinum-containing regimen.

The Clinical Efficacy of Radium-223 for Bone Metastasis in Patients with Castration-Resistant Prostate Cancer: An Italian Clinical Experience.

BACKGROUND/AIM: Prostate cancer frequently causes bone metastases and skeletal events that impair quality of life (QoL) and survival. The alpha emitter radium-223 is a new drug that improves treatment in men with castration-resistant prostate cancer (CRPC) and bone metastases. Our aim was to evaluate the effectiveness of radium-223. SUBJECTS AND METHODS: In this retrospective study we enrolled 48 subjects. Pain reduction, alkaline phosphatase (ALP), time to first symptomatic skeletal event, and QoL were the variables we evaluated. RESULTS: Radium-223 was well tolerated, with a manageable toxicity profile and a modest objective response rate. A considerable difference in serum ALP levels before and after treatment was observed, with a significant correlation between pain relief and QoL, which showed a value of R2 to 0.44 with a slope of 1.50 (p = 0.0021). CONCLUSIONS: Radium-223 showed a clinical benefit, with a reduction in pain symptoms in 58% of patients. Radium-223 was shown to be an effective and well-tolerated therapeutic option in patients with metastatic CRPC progressing after docetaxel plus prednisone treatment.

Efficacy and Safety of the Oral Multikinase Regorafenib in Metastatic Colorectal Cancer.

BACKGROUND/AIM: A clinical trial demonstrated that treatment with oral multikinase regorafenib improved overall survival (OS), progression-free survival (PFS), and disease control [García-Alfonso et al.: J Clin Transl Oncol 2016;18:1072-1081; Bertocchi et al.: J Chemother 2017;29:102-105]. In this study, we aimed to evaluate its effectiveness in Italian patients with hormone-refractory metastatic castration-resistant prostate cancer (mCRPC) progressing after chemotherapy with docetaxel plus prednisone. MATERIALS AND METHODS: 60 patients were enrolled. OS has been assessed as the primary endpoint while PFS, quality of life, safety, and response rate represented secondary endpoints. RESULTS: A modest tolerability was observed in our group showing a manageable toxicity profile and a modest objective response rate. It was associated with stable disease. A significant correlation between quality of life and OS was also noticed. CONCLUSIONS: Regorafenib has been proven to be an effective and well-tolerated therapeutic option in patients with mCRPC progressing after docetaxel plus prednisone treatment.

The Role of Couples' Attachment Styles in Patients' Adjustment to Cancer.

OBJECTIVE: This study aimed to understand how psychological variables and attachment styles can contribute to improve effective and functional adjustment to the disease and promote better psychological well-being. METHODS: A total of 176 participants (88 couples) took part in this research. One member of each couple attended surgery centers at the Oncology Department of the University Hospital of Palermo. Each participant had filled in 5 questionnaires assessing the variables couple relationships, quality of life, anxiety, depression, and psychosocial adjustment to illness. RESULTS: Significant correlations were found among the observed variables. Levels of anxiety and the attachment styles of couples influence adjustment to tumor disease and negatively affect the quality of conjugal relationships. Moreover, the results highlighted the correlation between levels of anxiety and depression in patients and in their respective partners. Finally, we found a correlation between the level of psychological distress of the patient and the level of marital satisfaction perceived by the partner: the latter is lower in couples where the oncological patient has high levels of distress. CONCLUSIONS: The results suggest that psychological variables and attachment styles of cancer patients and their partners may be important factors affecting adjustment in multiple domains.

Cabazitaxel in Metastatic Castration-Resistant Prostate Cancer Patients Progressing after Docetaxel: A Prospective Single-Center Study.

PURPOSE: The present study aims to evaluate the efficacy of cabazitaxel in combination with prednisone treatment in Italian patients affected by hormone-refractory metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel plus prednisone. METHODS: Thirty patients with mCRPC were enrolled between June 2013 and January 2016 (the last follow-up was in January 2016). Cabazitaxel was used according to the summary of product characteristics and administered at a dose of 25 mg/m2 every 3 weeks plus oral prednisone at a dose of 5-mg tablets twice a day continuously. The reduction in serum prostate-specific antigen (PSA) was the primary endpoint while reducing pain, safety, progression-free survival, response rate and overall survival (OS) were secondary endpoints. RESULTS: Cabazitaxel was well tolerated, showing a manageable toxicity profile, associated with a modest objective response rate and a good reduction in PSA levels. Only 12 patients (40%) had a partial response, 10 patients (33%) showed stabilization of disease and 8 (27%) experienced disease progression. The median OS was 14.8 months (95% CI: 11.6-19.8). The linear regression analysis revealed that PSA response was an important predictor of OS, showing a positive correlation with OS (ß = 0.377, p < 0.01). CONCLUSIONS: Three-week treatment with cabazitaxel was found to be valid and was a well-tolerated treatment option for patients with mCRPC after a first-line docetaxel treatment.

Treatment with abiraterone in metastatic castration-resistant prostate cancer patients progressing after docetaxel: a retrospective study.

The aim of this study was to evaluate abiraterone's efficacy in Italian patients affected with metastatic prostate cancer progressing after treatment with docetaxel. We conducted a retrospective analysis of 60 patients. Prostate-specific antigen (PSA) reduction in serum was the primary endpoint for evaluating the efficacy of abiraterone in combination with prednisone treatment, whereas reduced pain, safety, progression-free survival, response rate, and overall survival (OS) were secondary endpoints. A significant correlation was noticed between PSA response and OS. Further, the Index Bravais-Pearson (r) correlation allowed us to observe a significant negative interdependence between PSA response and reduction in pain of 0.57 (95% confidence interval: -0.30 to 0.80) (P=0.005). Meanwhile, regression analysis revealed that PSA levels are predictive of OS. There was a positive correlation with OS, which showed a value of R to 0.50 with a slope of 1.44 (P=0.0021). Abiraterone is a well-tolerated and effective treatment modality for patients affected with metastatic castration-resistant prostate cancer. The drug has a better tolerability profile, gives significant pain relief, and increases the survival rate.

Ubiquitin E3 ligase Nedd4-1 acts as a downstream target of PI3K/PTEN-mTORC1 signaling to promote neurite growth.

Protein ubiquitination is a core regulatory determinant of neural development. Previous studies have indicated that the Nedd4-family E3 ubiquitin ligases Nedd4-1 and Nedd4-2 may ubiquitinate phosphatase and tensin homolog (PTEN) and thereby regulate axonal growth in neurons. Using conditional knockout mice, we show here that Nedd4-1 and Nedd4-2 are indeed required for axonal growth in murine central nervous system neurons. However, in contrast to previously published data, we demonstrate that PTEN is not a substrate of Nedd4-1 and Nedd4-2, and that aberrant PTEN ubiquitination is not involved in the impaired axon growth upon deletion of Nedd4-1 and Nedd4-2. Rather, PTEN limits Nedd4-1 protein levels by modulating the activity of mTORC1, a protein complex that controls protein synthesis and cell growth. Our data demonstrate that Nedd4-family E3 ligases promote axonal growth and branching in the developing mammalian brain, where PTEN is not a relevant substrate. Instead, PTEN controls neurite growth by regulating Nedd4-1 expression.

Relationship between anxiety level and radiological investigation. Comparison among different diagnostic imaging exams in a prospective single-center study.

OBJECTIVE: Every patient could feel anxious when he waits in a radiological department to undergo diagnostic exams. The aim of our study is to evaluate the impact of the radiological exams on patient anxiety. MATERIALS AND METHODS: We evaluated 343 patients (mean age 54.83 years) who underwent different types of diagnostic exams in the Department of Diagnostic Imaging at our Hospital from April 2013 to August 2014. We administered to patients the State and Trait Anxiety Inventory Test, which detected with high sensitivity both state anxiety and trait anxiety. A team of clinical psychologists and radiologists evaluated the scores obtained. RESULTS: 83 out of 343 patients were excluded because refused to file the questionnaire. 31 % of the patients were submitted to MR, 18 % to breast imaging, 10 % to X-ray, 22 % Computer Tomography and 19 % to ultrasound, as previously described. 41 % of patients were submitted to the examination because of an oncologic disease, while 59 % because of non-oncological disease. Therefore, it was found that high levels of anxiety were present in most (about 91 %) of the patients and the scores varied according to the imaging examination and to the examination's reason: anxiety level was higher in non-oncological patients (54 %) and in patients waiting to undergo to MRI exams (29 %). CONCLUSION: Our data suggest that the diagnostic exams are stressful events for the patient, also in non-oncological patients. So, it is important to adequate the radiological staff to receive the patient, to inform him and perform exams with emotive involvement with a targeted education. Also, further studies are needed to evaluate the anxiety level and the quality of the images, because the anxiety can result in a somatic disorder with hyperactivity of the autonomic nervous system which may affect the patient's physical examination, causing problems in the evaluation of radiological images making to non-cooperative patient. MRI imaging is the examination that more of all led to an anxious state of patients but the main stressor is not related to the type of diagnostic examination, but to the uncertainty of the diagnosis, therapy and prognosis.

One year in review 2015: systemic lupus erythematosus.

Systemic lupus erythematosus is a multiorgan autoimmune disease with a highly variable clinical course, typically involving women in childbearing age. At present, many aspects of its pathogenesis still remain unclear. Moreover, although a significant increase of patient survival has been observed in the last decades, morbidity and mortality remain high. Finally, SLE impacts negatively on the health-related quality-of-life of patients. Therefore, multiple aspects of SLE still remain challenging and it continues to be the object of both clinical and translational clinical research. Herewith, we provide a critical digest of the recent literature on this topic.

Well-being among Italian medical oncologists: an exploratory study.

BACKGROUND: Recently, attention has been focused on physicians' stress and quality-of-life improvement. Due to their relationship with patients, oncologists in particular are overloaded physically, emotionally and psychologically. Previous studies showed that training of communication skills improves the satisfaction and well-being of physicians and patients. AIMS: Our research investigates the relationship between work stress and engagement and personal well-being in physicians working in Italian hospitals. MATERIALS AND METHODS: 176 physicians were included. Doctors filled out self-report questionnaires to evaluate work stress and coping strategies, personal well-being, work engagement and two purpose-built scales to measure the degree of perceived organizational support and the level of specific training of social and relational skills. Descriptive statistics were used to analyze data, as well as correlation analysis (Pearson's r), hierarchical regression analysis (enter step) and analysis of variance (one-way ANOVA). RESULT: Positive and significant correlations were found between variables. Moreover, physicians who obtained higher levels of specific training on social and relational skills reported lower levels of stress. Oncologists experienced greater stress than other physicians in terms of maladaptive coping and lack of additional training. CONCLUSIONS: The study suggests that physicians' well-being is mediated by professional aspects, such as social skills in relationships with patients.

Population Health Strategies to Support Hospital and Intensive Care Unit Resiliency During the COVID-19 Pandemic: The Italian Experience.

Italy was one of the countries most affected by the number of people infected and dead during the first COVID-19 wave. The authors describe the rapid rollout of a population health clinical and organizational response in preparedness and capabilities to support the first wave of the COVID-19 pandemic in the Italian province of Modena. The authors review the processes, the challenges faced, and describe how excess demand for hospital services was successfully mitigated and thus overwhelming the healthcare services avoided the collapse of the local health care system. An analysis of bed occupancy in the region predicted during the first weeks of the epidemic. The SEIR model estimated the number of infected people under different containment measures. Community resources were mobilized to reduce provincial hospitals' burden of care. A population health approach, based on a radical reorganization of the workflow and emergency patient management, was implemented. The bed saturation of the Modena Healthcare Agency was measured by an ad hoc, newly implemented intensive care unit (ICU) bed occupancy and COVID-19 centralized governance dashboard. ICU bed occupancy increased by 114%, avoiding saturation of the Modena Healthcare Agency system. The Emilia-Romagna region achieved a higher rate of ICU bed availability at 2.15 ICU beds per 10,000 inhabitants as compared with community 1 ICU bed availability prior to the pandemic. Rapid and radical local reorganization of regional efforts helped inform the successful development and implementation of strategic choices within the hospital and the community to prevent the saturation of key facilities.

Inhibition of the mTOR pathway and reprogramming of protein synthesis by MDM4 reduce ovarian cancer metastatic properties.

Epithelial ovarian cancer (EOC) is a highly heterogeneous disease with a high death rate mainly due to the metastatic spread. The expression of MDM4, a well-known p53-inhibitor, is positively associated with chemotherapy response and overall survival (OS) in EOC. However, the basis of this association remains elusive. We show that in vivo MDM4 reduces intraperitoneal dissemination of EOC cells, independently of p53 and an immune-competent background. By 2D and 3D assays, MDM4 impairs the early steps of the metastatic process. A 3D-bioprinting system, ad hoc developed by co-culturing EOC spheroids and endothelial cells, showed reduced dissemination and intravasation into vessel-like structures of MDM4-expressing cells. Consistent with these data, high MDM4 levels protect mice from ovarian cancer-related death and, importantly, correlate with increased 15 y OS probability in large data set analysis of 1656 patients. Proteomic analysis of EOC 3D-spheroids revealed decreased protein synthesis and mTOR signaling, upon MDM4 expression. Accordingly, MDM4 does not further inhibit cell migration when its activity towards mTOR is blocked by genetic or pharmacological approaches. Importantly, high levels of MDM4 reduced the efficacy of mTOR inhibitors in constraining cell migration. Overall, these data demonstrate that MDM4 impairs EOC metastatic process by inhibiting mTOR activity and suggest the usefulness of MDM4 assessment for the tailored application of mTOR-targeted therapy.

Quality of Life in Patients With Severe Skin Reactions in Course of First-Generation Epidermal Growth Factor Receptor Inhibitors Monoclonal Antibodies (Our Experience With Cetuximab).

BACKGROUND: Metastatic colorectal cancer (mCRC) with wild type expression of RAS and RAF genes can be treated with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, such as cetuximab, in combination with chemotherapy. Skin toxicity represents the most serious and frequent side effect in these patients. Skin manifestations occur in approximately 80% of patients. In this study, we investigated the consequences on body image and quality of life (QoL) of patients with severe skin toxicity. METHODS: One hundred patients were enrolled with mCRC. All patients signed informed consent and completed questionnaires to assess QoL and body discomfort. Toxicity was assessed on Common Terminology Criteria for Adverse Events (CTCAEs). RESULTS: The greatest impact on QoL was represented by difficulties in managing skin rash-related side effects. Data showed a significant impact in psychological sphere and social relationships. CONCLUSIONS: Skin side effects, particularly rash, influence QoL and social relationships, compromising therapeutic compliance.

The Emerging Challenge of Pain in Systemic Sclerosis: Similarity to the Pain Experience Reported by Sjogren's Syndrome Patients.

In order to evaluate the importance of pain in systemic sclerosis (SSc), the characteristics of pain reported by patients with SSc were analyzed and compared with the characteristics of pain reported by patients with primary Sjogren's syndrome (pSS). Pain was reported by 56 patients (80%) in a group of 70 patients with SSc and by 25 patients (78%) in a group of 32 patients with pSS. Pain severity was assessed by the Pain Rating Index (PRI) and the Present Pain Intensity (PPI) of the McGill Pain Questionnaire (MPQ) and by values obtained by a visual analog scale (VAS) indicating the intensity of pain felt in the moment of the examination and the intensity of pain felt in the week preceding the moment of the examination. No significant difference was detected in the comparison of mean values of pain indices between patients with SSc and patients with pSS and in the comparison among subgroups of patients with SSc. The data indicate that pain is a frequent and important cause of suffering in SSc as in other chronic diseases. The association of different methods may be especially useful to obtain a careful evaluation of pain in clinical research.

TAS-102 in metastatic colorectal cancer (mCRC): efficacy, tolerability, and quality of life in heavily pretreated elderly patients: a real-life study.

BACKGROUND: TAS-102 is an oral monotherapy, combining trifluridine and tipiracil hydrochloride, indicated for the treatment of pretreated metastatic colorectal cancer (mCRC). The aim of this real-life study is to evaluate the efficacy and safety of TAS-102 in heavily pretreated elderly patients with mCRC whose disease has progressed with standard therapies. METHODS: In this retrospective observational study, we enrolled 50 elderly patients >70 years of age (median age 78 years) with a diagnosis of mCRC who were previously treated or were not considered candidates for treatment with other available therapies. Patients aged >70 years with advanced colorectal cancer and with an ECOG performance status of grade 0 (n=18) or grade 1 (n=32) were included. Overall survival and progression-free survival were the primary endpoints, whereas objective response rate, tolerability, and quality of life were the secondary endpoints. RESULTS: Treatment with TAS-102 appeared to be well tolerated and side effects were generally mild, achieving disease control and a benefit on quality of life. The median overall survival was 6.7 (95% CI 5.7-11.3) and the median progression-free survival was 2.1 months (95% CI 1.2-3.2), estimated using the Kaplan-Meier method. CONCLUSION: TAS-102 represents a manageable and effective therapeutic opportunity and appeared to be well tolerated with generally mild side effects in elderly patients with mCRC who were heavily pretreated with standard therapies.

Nab-paclitaxel in pretreated metastatic breast cancer: evaluation of activity, safety, and quality of life.

OBJECTIVE: Metastatic breast cancer (MBC) is an incurable disease; the treatment of this disease prolongs survival, improving the quality of life (QoL) with a balance between efficacy and toxicity of the treatment. In recent years, treatment with nab-paclitaxel has improved the already known antitumor activity of conventional paclitaxel, in terms of increased efficacy and better tolerability. The aim of this study was to evaluate nab-paclitaxel in Italian patients with MBC. METHODS: We conducted a retrospective analysis of 90 patients with histologically confirmed diagnosis of MBC. To evaluate the efficacy of nab-paclitaxel, overall survival (OS), progression-free survival (PFS), and overall response rate were the primary endpoints, whereas carbohydrate antigen 15.3 (Ca15.3) reduction, QoL, and tolerability were secondary endpoints. RESULTS: The median OS was 10.4 months, the median PFS was 6.8 months. A considerable difference Ca15.3 before and after treatment was observed. Descriptive and regression analyses were done to examine the associations between Ca15.3 response and OS, demonstrating good correlation, revealing that Ca15.3 reduction is an important predictor of OS. CONCLUSION: Nab-paclitaxel is an effective and well-tolerated treatment of patients affected by MBC. The drug showed an improved tolerability profile. With all the limitations of the observational nature of our results, nab-paclitaxel has proven to be an effective and safe therapeutic option in patients with MBC.

Estrogens Counteract Platinum-Chemosensitivity by Modifying the Subcellular Localization of MDM4.

Estrogen activity towards cancer-related pathways can impact therapeutic intervention. Recent omics data suggest possible crosstalk between estrogens/gender and MDM4, a key regulator of p53. Since MDM4 can either promote cell transformation or enhance DNA damage-sensitivity, we analysed in vivo impact of estrogens on both MDM4 activities. In Mdm4 transgenic mouse, Mdm4 accelerates the formation of fibrosarcoma and increases tumor sensitivity to cisplatin as well, thus confirming in vivo Mdm4 dual mode of action. Noteworthy, Mdm4 enhances chemo- and radio-sensitivity in male but not in female animals, whereas its tumor-promoting activity is not affected by mouse gender. Combination therapy of transgenic females with cisplatin and fulvestrant, a selective estrogen receptor degrader, was able to recover tumor cisplatin-sensitivity, demonstrating the relevance of estrogens in the observed sexual dimorphism. Molecularly, estrogen receptor-α alters intracellular localization of MDM4 by increasing its nuclear fraction correlated to decreased cell death, in a p53-independent manner. Importantly, MDM4 nuclear localization and intra-tumor estrogen availability correlate with decreased platinum-sensitivity and apoptosis and predicts poor disease-free survival in high-grade serous ovarian carcinoma. These data demonstrate estrogen ability to modulate chemo-sensitivity of MDM4-expressing tumors and to impinge on intracellular trafficking. They support potential usefulness of combination therapy involving anti-estrogenic drugs.

Progression-free survival as a surrogate endpoint of overall survival in patients with metastatic colorectal cancer.

BACKGROUND: In many clinical trials designed to assess the efficacy of anticancer treatments, overall survival (OS) is often used as a primary endpoint despite its several points of weakness. METHODS: This study evaluated the role of progression-free survival (PFS) in the first three lines of treatment as a potential surrogate endpoint of OS in patients with metastatic colorectal cancer (MCRC). One hundred and twenty patients with MCRC were enrolled in this study. The median PFS of the first-, second-, and third-lines of treatment and the OS were evaluated. The correlation between the time to progression and the OS was analyzed. The median PFS of the three lines of treatment were 8.5, 5, and 3 months, respectively. RESULTS: The median OS was 32.4 months. A modest correlation was found between the PFS to the first-line treatment with Folfox-avastin and OS. Similar data were obtained with the second-line treatment. However, no correlation was found between the PFS and OS during the third-line treatment. The regression analysis revealed that PFS is predictive of OS. CONCLUSION: In brief, the PFS of the first- and second-lines of treatment could be a good candidate as a surrogate endpoint of OS in patients with MCRC.

Clinical efficacy of nab-paclitaxel in patients with metastatic pancreatic cancer.

PURPOSE: Pancreatic carcinoma is the neoplasia with the major mortality, and main standard treatments in this cancer increase survival but do not lead to complete recovery of the patient. The aim of this study was to evaluate the efficacy of Abraxane® (nab-paclitaxel) in Italian patients with metastatic pancreatic cancer (MPC). PATIENTS AND METHODS: We conducted a retrospective analysis of 80 patients. Overall survival (OS) was the primary end point for evaluating the efficacy of nab-paclitaxel in combination with gemcitabine treatment, while carbohydrate antigen 19-9 (CA 19-9) reduction, safety, progression-free survival (PFS), overall response rate and reduction in pain were secondary end points. RESULTS: The median OS was 8 months, and the median PFS was 5 months. A considerable difference in CA 19-9 before and after treatment was observed. Descriptive and correlation analyses were done to examine the relationship between CA 19-9 response and OS. Linear regression analysis between OS and CA 19-9 response revealed that CA 19-9 is an important predictor of OS, showing a positive correlation. CONCLUSION: Nab-paclitaxel is a well-tolerated and effective treatment for patients affected by MPC. The drug showed an improved tolerability profile, significant pain relief and an increase in survival rate.

The Clinical Efficacy of Enzalutamide in Metastatic Prostate Cancer: Prospective Single-center Study.

BACKGROUND/AIM: To evaluate the effectiveness of enzalutamide in Italian patients with hormone-refractory metastatic castration-resistant prostate cancer, progressing after chemotherapy with docetaxel plus prednisone. PATIENTS AND METHODS: A total of 60 patients were enrolled. Reduction in serum prostate-specific antigen (PSA) was assessed as the primary endpoint, while reduction in pain, safety, progression-free survival and overall survival represented secondary endpoints. RESULTS: Enzalutamide was well tolerated, with a manageable toxicity profile and a modest objective response rate. A considerable difference in serum levels of PSA before and after treatment was observed. A significant correlation between PSA response and overall survival was also noted. The regression analysis revealed PSA level to be predictive of overall survival. CONCLUSION: Enzalutamide was shown to be an effective and well-tolerated therapeutic option in patients with metastatic castration-resistant prostate cancer progressing after docetaxel plus prednisone treatment.