PET scanning evaluation of response to imatinib mesylate therapy in gastrointestinal stromal tumor (GIST) patients

Background: Unresectable or metastatic gastrointestinal stromal tumors (GISTs) exhibit a dynamic clinical course, with no evidence of benefit from any standard cytotoxic chemotherapy and an inevitably fatal outcome. With the introduction of Imatinib, an oral drug able to inhibit the KIT receptor tyrosine kinase, new questions arise regarding our ability to monitor treatment response with conventional methods and optimally manage such patients on treatment with new agents. Materials and methods: Herein we report two cases of patients with a history of GIST in treatment with Imatinib. Results: After 4 weeks from treatment start, CT scan evaluation demonstrated a massive increase in the size of metastatic lesions, but a confirmatory PET excluded, in both patients, the presence of any metabolic activity in the previously known metastatic sites. Imatinib therapy was continued with subjective clinical benefit for 12 further months before a PET scan-confirmed disease progression had occurred in one patient and is still ongoing after 15 months in the other. Conclusion: These cases open the obvious question of whether conventional imaging techniques are adequate to assess the response to Imatinib treatment in GIST patients

Impact of gefitinib ('Iressa') treatment on the quality of life of patients with advanced non-small-cell lung cancer

Purpose: Patients with advanced non-small-cell lung cancer (NSCLC) have a short life expectancy; therefore, in addition to increasing their survival, improving their quality of life (QoL) is also an important treatment goal. Methods: We evaluated the QoL of patients with advanced NSCLC who were unfit to receive chemotherapy, failed to respond or progress following prior chemotherapy, who received subsequent treatment with gefitinib ('Iressa') on a compassionate use basis, using a standard QoL questionnaire, (EORTC) QLQ-C30 and the related lung cancer-specific module QLQ-LC13. Results: Analysis of the functional scales showed a trend towards improvement for role, emotional and cognitive scales, while a substantial stability was seen for general QoL scale. Analysis of the symptoms scales of QLQ-C30, showed a trend towards improvement for fatigue, dyspnoea, insomnia, and constipation, after one month of therapy. Fifty-six of the 57 patients were considered evaluable for response. One patient evidenced a partial response (patient is still on response), 29 patients had stable disease for a median duration of 5 months (range 4-7 months), and 26 patients progressed. Conclusions: After treatment with Gefitinib, we observed maintenance of QoL in a group of patients with poor prognosis that would be expected to have a worsening QoL. Furthermore important symptoms like dyspnoea fatigue and pain in other parts, that usually afflict patients with NSCLC, showed a trend toward improvement after only one month of therapy

Sequential chemotherapy in nonsmall-cell lung cancer: cisplatin and gemcitabine followed by docetaxel

Background: Improving results in nonsmall-cell lung cancer (NSCLC) will require the development of new drugs and strategies to combine available agents. On the basis of data indicating the activity of docetaxel as second-line therapy, a Phase II study was conducted to evaluate the efficacy and toxicity of the sequential combination of chemotherapy consisting of cisplatin (P) and gemcitabine (G) followed by docetaxel (DOC) in patients with advanced NSCLC. Methods: Patients with 1997 TNM stage IIIB (pleural effusion)/stage IV NSCLC, performance status (PS) of 0-1, and normal organ function were eligible. Therapy consisted of P at 75 mg/m(2) on Day 1 and G 1200 mg/m(2) on Days 1 and 8 every 3 weeks for 3 cycles followed, in nonprogressive patients, by DOC 30 mg/m(2) every week for 6 consecutive weeks every 8 weeks for 2 cycles. Results: Fifty-two eligible patients were enrolled (M/F, 39/13; stage IIIB/IV, 8/44; PS 0, 73%, PS 1, 27%; median age, 58 years; range, 36-73). The overall response rate was 36.5% (95% confidence interval [CI]: 23-49). The median overall survival was 11 months (95% CI: 9-13); the median progression-free survival was 6 months (95% CI: 5-7); and the 1- and 2-year survivals were 48% and 25%, respectively. One- and 2-year progression-free survivals were 12% and 8%, respectively. Both phases of the treatment protocol were well tolerated. Conclusions: P/G followed by weekly DOC is well tolerated and active as first-line therapy for NSCLC patients and provides a feasible chemotherapeutic option in this clinical setting

Phase II trial of neoadjuvant pemetrexed plus cisplatin followed by surgery and radiation in the treatment of pleural mesothelioma

BACKGROUND: Malignant pleural mesothelioma is an aggressive tumor that has a poor prognosis and is resistant to unimodal approaches. Multimodal treatment has provided encouraging results. METHODS: Phase II, open-label study of the combination of chemotherapy (pemetrexed 500 mg/m(2)+cisplatin 75 mg/m(2) IV every 21 days × 3 cycles), followed by surgery (en-bloc extrapleural pneumonectomy, 3–8 weeks after chemotherapy) and hemithoracic radiation (total radiation beam 54 Gy, received 4–8 weeks post-surgery). The primary endpoint was event-free survival, defined as the time from enrollment to time of first observation of disease progression, death due to any cause, or early treatment discontinuation. RESULTS: Fifty-four treatment-naïve patients with T1-3 N0-2 malignant pleural mesothelioma were enrolled, 52 (96.3%) completed chemotherapy, 45 (83.3%) underwent surgery, 22 (40.7%) completed the whole treatment including 90-day post-radiation follow-up. The median event-free survival was 6.9 months (95%CI: 5.0-10.5), median overall survival was 15.5 months (95%CI 11.0-NA) while median time-to-tumor response was 4.8 months (95%CI: 2.5-8.0). Eighteen (33.3%) and 13 (24.1%) patients were still event-free after 1 and 2 years, respectively. The most common treatment-emergent adverse events were nausea (63.0%), anemia (51.9%) and hypertension (42.6%). Following two cardiopulmonary radiation-related deaths the protocol was amended (21 [38.9%] patients were already enrolled in the study): the total radiation beam was reduced from 54 Gy to 50.4 Gy and a more accurate selection of patients was recommended. CONCLUSIONS: The combination of pemetrexed plus cisplatin followed by surgery and hemithoracic radiation is feasible and has a manageable toxicity profile in carefully selected patients. It may be worthy of further investigation. TRIAL REGISTRATION: Clinicaltrial.com registrationID #NCT00087698

A 17-Gene Expression Signature for Early Identification of Poor Prognosis in Clear Cell Renal Cell Carcinoma

: The Identification of reliable Biomarkers able to predict the outcome after nephrectomy of patients with clear cell renal cell carcinoma (ccRCC) is an unmet need. The gene expression analysis in tumor tissues represents a promising tool for better stratification of ccRCC subtypes and patients' evaluation. Methods: In our study we retrospectively analyzed using Next-Generation expression analysis (NanoString), the expression of a gene panel in tumor tissue from 46 consecutive patients treated with nephrectomy for non-metastatic ccRCC at two Italian Oncological Centres. Significant differences in expression levels of selected genes was sought. Additionally, we performed a univariate and a multivariate analysis on overall survival according to Cox regression model. Results: A 17-gene expression signature of patients with a recurrence-free survival (RFS) < 1 year (unfavorable genomic signature (UGS)) and of patients with a RFS > 5 years (favorable genomic signature (FGS)) was identified and resulted in being significantly correlated with overall survival of the patients included in this analysis (HR 51.37, p < 0.0001). Conclusions: The identified Genomic Signatures may serve as potential biomarkers for prognosis prediction of non-metastatic RCC and could drive both follow-up and treatment personalization in RCC management

Influence of Antisynthetase Antibodies Specificities on Antisynthetase Syndrome Clinical Spectrum TimeCourse

Introduction: Increased cardiovascular (CV) morbidity and mortality is observed in inflammatory joint diseases (IJDs) such as rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. However, the management of CV disease in these conditions is far from being well established.Areas covered: This review summarizes the main epidemiologic, pathophysiological, and clinical risk factors of CV disease associated with IJDs. Less common aspects on early diagnosis and risk stratification of the CV disease in these conditions are also discussed. In Europe, the most commonly used risk algorithm in patients with IJDs is the modified SCORE index based on the revised recommendations proposed by the EULAR task force in 2017.Expert opinion: Early identification of IJD patients at high risk of CV disease is essential. It should include the use of complementary noninvasive imaging techniques. A multidisciplinary approach aimed to improve heart-healthy habits, including strict control of classic CV risk factors is crucial. Adequate management of the underlying IJD is also of main importance since the reduction of disease activity decreases the risk of CV events. Non-steroidal anti-inflammatory drugs may have a lesser harmful effect in IJD than in the general population, due to their anti-inflammatory effects along with other potential beneficial effects.This research was partially funded by FOREUM—Foundation for Research in Rheumatolog

Racial differences in systemic sclerosis disease presentation: a European Scleroderma Trials and Research group study

Objectives. Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations.Methods. SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses.Results. The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P < 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P < 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P < 0.001) diffuse skin involvement than had WP.AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P < 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P < 0.001; OR(BP) = 2.4, P < 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P < 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P < 0.001].Conclusion. Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality

Heterogeneity of PD-L1 expression and relationship with biology of NSCLC

Immunotherapy with monoclonal antibodies against programmed cell death (PD-1), such as nivolumab and pembrolizumab, has significantly improved the survival of patients with metastatic non-small cell lung cancer (NSCLC). In order to determine the subset of patients that can benefit most from these therapies, biomarkers such as programmed death ligand-1 (PD-L1) have been proposed. However, the predictive and prognostic role of the use of PD-L1 is controversial. Anti-PD-L1 immunohistochemistry may not represent the actual status of the tumour because of individual variability and tumour heterogeneity. Additionally, there may be analytical variability due to the use of different assays and antibodies to detect PD-L1. Moreover PD-L1 expression is also regulated by oncogenic drivers in NSCLC, such as epidermal growth factor receptor (EGFR), echinoderm microtubule-associated protein-like 4 (EML4) fusion with anaplastic lymphoma kinase (ALK), and Kirsten rat sarcoma viral oncogene homolog (KRAS). Preclinical studies have shown the potential role of targeted therapy in immune escape mechanisms in NSCLC cells. This review summarizes current literature data on the heterogeneity of PD-L1 expression and the relationship with such factors and with clinicopathological features of NSCLC

Molecular basis of drug resistance and insights for new treatment approaches in mCRPC

Inhibiting androgen receptor (AR) signaling with androgen deprivation therapy (ADT) represents the mainstay of therapy for advanced and metastatic prostate cancer. However, about 20-60% of patients receiving first-line treatment for prostate cancer will relapse, evolving in a more aggressive and lethal form of the disease, the castrationresistant prostate cancer (CRPC), despite the use of ADT. Multiple approved systemic therapies able to prolong survival of patients with metastatic CRPC (mCRPC) exist, but almost invariably, patients treated with these drugs develop primary or acquired resistance. Multiple factors are involved in CRPC treatment resistance and elucidating the mechanisms of action of these factors is a key question and an active area of research. Due to such a complex scenario, treatment personalization is necessary to improve treatment effectiveness and reduce relapse rates in CRPC. In this review, current evidence about the major mechanisms of resistance to the available prostate cancer treatments were examined by introducing insights on new and future therapeutic approaches