Clinical relevance of circulating tumor DNA in ovarian cancer: current issues and future opportunities.

Ovarian cancer (OC) is the most lethal gynecologic malignancy worldwide. Due to the lack of effective screening and early detection strategies, many patients with OC are diagnosed with advanced disease, where treatment is rarely curative. Moreover, OC is characterized by high intratumor heterogeneity, which represents a major barrier to the development of effective treatments. Conventional tumor biopsy and blood-based biomarkers, such as cancer antigen 125 (CA125), have different limitations. Liquid biopsy has recently emerged as an attractive and promising area of investigation in oncology, due to its minimally invasive, safe, comprehensive, and real-time dynamic nature. Preliminary evidence suggests a potential role of liquid biopsy to refine OC management, by improving screening, early diagnosis, assessment of response to treatment, detection, and profiling of drug resistance. The current knowledge and the potential clinical value of liquid biopsy in OC is discussed in this review to provide an overview of the clinical settings in which its use might support and improve diagnosis and treatment.

Prognostic and Predictive Role of SPOP Mutations in Prostate Cancer: A Systematic Review and Meta-analysis.

CONTEXT: Mutations in the speckle-type POZ (SPOP) gene are frequently identified in prostate cancer (PC); yet, prognostic implications for affected patients remain unclear. Limited consensus exists regarding tailored treatments for SPOP-mutant (SPOPmut) PC. OBJECTIVE: To elucidate the prognostic and predictive significance of SPOP mutations across distinct PC stages and treatments. EVIDENCE ACQUISITION: A systematic literature search of PubMed, Embase, and Scopus was conducted up to January 29, 2024. The meta-analysis included studies comparing survival outcomes between SPOPmut and SPOP wild-type (SPOPwt) PC. EVIDENCE SYNTHESIS: From 669 records, 26 studies (including five abstracts) were analyzed. A meta-analysis of metastasis-free survival in localized (hazard ratio [HR]: 0.72, 95% confidence interval [CI]: 0.59-0.88; p < 0.01) and overall survival (OS) in metastatic PC (HR: 0.64, 95% CI: 0.53-0.76; p < 0.01) showed a favorable prognosis for patients with SPOPmut PC. In metastatic settings, SPOP mutations correlated with improved progression-free survival (PFS) and OS in patients undergoing androgen deprivation therapy ± androgen receptor signaling inhibitor (HR: 0.51, 95% CI: 0.35-0.76, p < 0.01, and HR: 0.60, 95% CI:0.46-0.79, p < 0.01, respectively). In metastatic castration-resistant PC, only abiraterone provided improved PFS and OS to patients with SPOP mutations compared with patients with SPOPwt, but data were limited. SPOP mutations did not correlate with improved PFS (p = 0.80) or OS (p = 0.27) for docetaxel. CONCLUSIONS: Patients with SPOPmut PC seem to exhibit superior oncological outcomes compared with patients with SPOPwt. Tailored risk stratification and treatment approaches should be explored in such patients. PATIENT SUMMARY: Speckle-type POZ (SPOP) mutations could be a favorable prognostic factor in patients with prostate cancer (PC) and may also predict better progression-free and overall survival than treatment with hormonal agents. Therefore, less intensified treatments omitting chemotherapy for patients with SPOP-mutant PC should be explored in clinical trials.

Preexisting evidence and outcome of phase III trials in gastrointestinal oncology: a systematic review.

BACKGROUND: A minority of phase III trials in gastrointestinal oncology are positive. We assessed the association between their outcome and the level and characteristics of preexisting evidence. METHODS: EMBASE, PubMed, and proceedings from international meetings were searched for phase III gastrointestinal cancer trials (gastroesophageal, hepatocellular, biliary tract, pancreatic, small bowel, colorectal, anal, stromal, and neuroendocrine) between January 2000 and June 2020. Trials investigating anticancer drugs for advanced disease, with superiority design and standard treatments as control were eligible. The highest level of preexisting evidence was retrieved from the main study report. RESULTS: A total of 193 phase III trials were included, and 69 (35.8%) met their primary endpoint. Positivity rates were as follows: gastroesophageal 37%, colorectal 48%, pancreatic 17.1%, hepatocellular 20%, neuroendocrine 75%, and both biliary tract and GIST 60%. No information about preexisting evidence was found for 44 trials (22.8%). For the remaining 149, preexisting evidence consisted of phase II studies in 123 cases (82.6%) and phase I studies in 26 cases (17.4%). The probability of success was 34.1%, 35.8%, and 35.7%, respectively (P = .934). No parameter from prior studies predicted the outcome of phase III trials except ß < .2 (P = .048). A numerically increased success rate was observed for phase III trials preceded by positive phase II studies (41.9% vs 18.5%, P = .2). CONCLUSIONS: There does not appear to be an association between level of prior evidence and success of phase III gastrointestinal cancer trials. These data, along with the high phase III failure rate, highlight the need to improve the drug development process in this setting.

Fibromatosis mimicking relapse of a neuroendocrine tumor at 68Ga-DOTATOC positron-emission tomography/computed tomography.

Mesenteric fibromatosis (desmoid tumor) is a locally aggressive fibroblastic lesion, characterized by a high recurrence rate that makes treatment challenging. Currently, there is no evidence-based treatment approach. We report the case of a female patient with a history of neuroendocrine tumor, who underwent 68Ga-DOTATOC positron-emission tomography/computed tomography (PET/CT), showing increased focal abdominal uptake suggestive of disease relapse. Histological examination revealed typical findings of fibromatosis. These findings indicate the expression of staining for somatostatin receptors (SSTRs) on fibromatosis cell surface and suggest to include fibromatosis among the potential causes of false-positive results at 68Ga PET/CT. Moreover, SSTRs expressed in desmoid tumors could be further investigated as a therapeutic target.

Circulating DNA in the neoadjuvant setting of early stage colon cancer.

BACKGROUND: While circulating tumour (ct)DNA is an indicator of minimal residual disease and negative prognostic factor in stage II-III colon cancer, no study has ever analysed the value of this biomarker in colon cancer patients treated with neoadjuvant chemotherapy. We sought to fill this gap by using prospectively collected plasma samples from 80 stage III colon cancer patients, receiving one cycle of neoadjuvant FOLFOX followed by surgery +/- adjuvant FOLFOX in the PePiTA trial. MATERIAL AND METHODS: Samples were collected at baseline, 2 weeks and surgery. NPY and WIF1 were selected as universal methylation markers for ctDNA, and analysed with ddPCR technology. ROC curves were applied for cut-off points, and outcome measures included 5-year disease-free survival (DFS) and 6-year overall survival (OS). RESULTS: After a median follow-up of 52.5 months, baseline circulating-free (cf) DNA was an independent prognostic factor for DFS (HR 3.35, 95% CI: 1.15-9.77, p = .03), and a trend towards a similar association was observed for relative cfDNA changes between baseline and surgery (HR 2.57, 95% CI: 0.94-7.05, p = .07). Among 60 ctDNA assessable patients, 25 (42%) had detectable ctDNA at baseline. While detection of ctDNA at any pre-operative timepoint was not associated with outcome, patients with ctDNA increase (change of the worst trending methylation marker ≥11%, or mean ctDNA change of NPY and WIF1 ≥ 0%) between baseline and surgery showed a trend towards worse 5-year DFS (HR 3.66, 95% CI: 0.81-16.44, p = .09). CONCLUSION: This is the first study of ctDNA in the neoadjuvant setting of early-stage colon cancer. Results are hypothesis-generating and should be confirmed in larger series.

Prognostic significance of laterality in lung neuroendocrine tumors.

PURPOSE: Well-differentiated lung neuroendocrine tumors (Lu-NET) are classified as typical (TC) and atypical (AC) carcinoids, based on mitotic counts and necrosis. However, prognostic factors, other than tumor node metastasis (TNM) stage and the histopathological diagnosis, are still lacking. The current study is aimed to identify potential prognostic factors to better stratify lung NET, thus, improving patients' treatment strategy and follow-up. METHODS: A multicentric retrospective study, including 300 Lung NET, all surgically removed, from Italian and Spanish Institutions. RESULTS: Median age 61 years (13-86), 37.7% were males, 25.0% were AC, 42.0% were located in the lung left parenchyma, 80.3% presented a TNM stage I-II. Mitotic count was ≥2 per 10 high-power field (HPF) in 24.7%, necrosis in 13.0%. Median overall survival (OS) was 46.1 months (0.6-323), median progression-free survival (PFS) was 36.0 months (0.3-323). Female sex correlated with a more indolent disease (T1; N0; lower Ki67; lower mitotic count and the absence of necrosis). Left-sided primary tumors were associated with higher mitotic count and necrosis. At Cox-multivariate regression model, age, left-sided tumors, nodal (N) positive status and the diagnosis of AC resulted independent negative prognostic factors for PFS and OS. CONCLUSIONS: This study highlights that laterality is an independent prognostic factors in Lu-NETs, with left tumors being less frequent but showing a worse prognosis than right ones. A wider spectrum of clinical and pathological prognostic factors, including TNM stage, age and laterality is suggested. These parameters could help clinicians to personalize the management of Lu-NET.

Serotoninergic brain dysfunction in neuroendocrine tumor patients: A scoping review.

INTRODUCTION: Neuroendocrine tumors (NETs) are rare and malignant neoplasms characterized by their potential to produce metabolically active substances with the capacity to bring about clinical syndromes. The clinical expression of serotonin-producing NETs is known as carcinoid syndrome (CS). The synthesis of serotonin in the brain is dependent on tryptophan availability. At the central level, serotonin is indispensable for mood, anxiety, and sleep regulation. In CS patients, around 60% of all tryptophan is reported to be consumed by tumor cells for the peripheral synthesis of serotonin, increasing the risk of a central deficiency and thus psychiatric disorders. MATERIALS AND METHODS: This manuscript reviews the existing literature about psychiatric disorders associated with NETs and addresses the safety of psychiatric drugs in these patients. A systematic search of the biomedical literature was performed using the following databases: PubMed, Embase, CINAHL (EBSCO), PsycInfo (OVID), and Cochrane CENTRAL (Wiley). The database search included articles published between January 1965 and February 2021. Relevant information were charted using a calibrated charting-form. RESULTS: Twenty-two articles were included in the present review. The overall population size of the studies came to 3319 patients. All patients presented a confirmed diagnosis of NET. The information about the presence of CS was confirmed in 351 cases. The psychiatric symptoms reported included mood disturbances (including, depression and anxiety), psychoses, impulse control disorders and sleeping alterations. We also evaluated the presence of cognitive impairments in NET patients. Finally, we summarize the available data regarding the safety of psychiatric drugs in this setting. CONCLUSIONS: Psychiatric disorders among NET patients are poorly recognized, and therefore have received very little research attention. As a result, no standardized algorithm is presently available. Our findings support detailed psychiatric evaluation in NET patients, especially in those presenting CS and symptoms suggestive of psychiatric involvement. Not only do cognitive impairment and psychiatry symptoms negatively impact health-related quality of life in cancer patients, they can also reduce survival rates.

Luteinized thecoma (thecomatosis) with sclerosing peritonitis: a systematic review of the literature of the last 25 years.

INTRODUCTION: Luteinized thecoma (thecomatosis) with sclerosing peritonitis (LTSP) is a very uncommon syndrome, characterized by the presence of single or bilateral ovarian thecomas and peritoneal fibrotic lesions. The disease occurs in young women and it can lead to peritoneal fibrosis and bowel obstruction. The pathogenesis of this syndrome remains still largely unknown. Surgery represents the cornerstone of treatment, but resection alone does not always allow a complete disease control. Attempts at medical treatments have been reported in recent years, but a real standard therapy has not yet been defined. AREAS COVERED: We performed a systematic review of literature, collecting all the papers that reported cases of LTSP, since its first description in 1994. We found that, in these 25 years, less than 50 cases have been described in literature. EXPERT OPINION: Along with the established role of surgery, adjuvant treatment with hormonal agents, in particular in estrogen receptor expression, seems to be a promising approach. However, more efforts must be carried out to describe treatment and outcome of new cases, improving knowledge about this rare condition.

Prognostic Value of the Pace of Tumor Progression as Assessed by Serial 18F-FDG PET/CT Scan and Liquid Biopsy in Refractory Colorectal Cancer: The CORIOLAN Trial.

INTRODUCTION: Decision making in refractory colorectal cancer (rCRC) is challenging, with limited data available to predict patient outcome. We conducted a study to assess the pace of cancer progression as a potential prognostic and decision tool. METHODS: CORIOLAN was a prospective, single-center, single-arm trial recruiting refractory CRC patients with an ECOG performance status of ≤1 and an estimated life expectancy of ≥12 weeks. 18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scan and blood sample collection were carried out at baseline and after 2 weeks with no cancer treatment given between these timepoints. The primary objective was to evaluate the association between pace of cancer progression as defined by changes of the whole-body metabolically active tumor volume (WB-MATV) and overall survival (OS). Exploratory objectives included evaluation of the prognostic value of circulating cell-free DNA (cfDNA), circulating tumor cells (CTCs) and carcinoembryonic antigen (CEA). RESULTS: 47 eligible patients who had received a median number of 5 (range 2-8) prior treatments were enrolled. At the time of analysis, 45 deaths had occurred, with 26% of patients dying within 12 weeks. The median OS was 6.3 months (range 0.4-14.3). The median relative delta between WB-MATV at baseline and 2 weeks was +21%. Changes of WB-MATV, however, failed to predict OS (hazard ratio (HR) 1.3, p = 0.383). Similarly, no association was observed between changes of any of the circulating biomarkers investigated and prognosis. By contrast, high WB-MATV (4.2 versus 9.4 months; HR 3.1, p = 0.003), high CEA (4.4 versus 7.0 months; HR 1.9, p = 0.053), high cfDNA (4.7 versus 7.0 months; HR 2.2, p = 0.015) and high CTC count (3.3 versus 7.5 months; HR 6.5, p < 0.001) at baseline were associated with worse OS. CONCLUSIONS: In this study, approximately 1 out of 4 refractory CRC patients who were judged to have a life expectancy >12 weeks actually died within 12 weeks. Baseline assessment of WB-MATV, cfDNA, CTCs and CEA, but not early change evaluation of the same, may help to refine patient prognostication and guide management decisions.

Feasibility and clinical impact of routine molecular testing of gastrointestinal cancers at a tertiary centre with a multi-gene, tumor-agnostic, next generation sequencing panel.

BACKGROUND: High-throughput sequencing technologies are increasingly used in research but limited data are available on the feasibility and value of these when routinely adopted in clinical practice. MATERIAL AND METHODS: We analyzed all consecutive cancer patients for whom genomic testing by a 48-gene next-generation sequencing (NGS) panel (Truseq Amplicon Cancer Panel, Illumina) was requested as part of standard care in one of the largest Belgian cancer networks between 2014 and 2019. Feasibility of NGS was assessed in all study patients, while the impact of NGS on the decision making was analyzed in the group of gastrointestinal cancer patients. RESULTS: Tumor samples from 1064 patients with varying tumor types were tested, the number of NGS requests increasing over time (p < .0001). Success rate and median turnaround time were 91.4% and 12.5 days, respectively, both significantly decreasing over time (p ≤ .0002). Non-surgical sampling procedure (OR 7.97, p < .0001), tissue from metastatic site (OR 2.35, p = .0006) and more recent year of testing (OR 1.79, p = .0258) were independently associated with NGS failure. Excluding well-known actionable or clinically relevant mutations which are recommended by international guidelines and commonly tested by targeted sequencing, 57/279 (20.4%) assessable gastrointestinal cancer patients were found to have tumors harboring at least one actionable altered gene according to the OncoKB database. NGS results, however, had a direct impact on management decisions by the treating physician in only 3 cases (1.1%). CONCLUSIONS: Our findings confirm that NGS is feasible in the clinical setting with acceptably low failure rates and rapid turnaround time. In gastrointestinal cancers, however, NGS-based multiple-gene testing adds very little to standard targeted sequencing, and in routine practice the clinical impact of NGS panels including genes which are not routinely recommended by international guidelines remains limited.

Neuroendocrine breast carcinoma: a rare but challenging entity.

Breast carcinoma with neuroendocrine differentiation, also known as neuroendocrine breast carcinoma (NEBC), includes a heterogeneous group of rare tumors, which account for 2-5% of all invasive breast carcinomas. Because of their low incidence, most of the current limited knowledge of these tumors derives from anecdotal case reports or small retrospective series. The diagnosis of NEBC is based on the presence of morphological features similar to gastrointestinal and lung NETs and neuroendocrine markers. NEBCs are usually hormone receptors positive and HER2 negative, but despite this luminal phenotype, most recent studies suggested that NEBC could be associated with worse prognosis compared to invasive breast cancer without neuroendocrine differentiation. Due to its rarity and lack of randomized data, there is little evidence to guide the choice of treatment, so NEBC is currently treated as any invasive breast carcinoma not-otherwise specified. Recently, attempts to molecularly characterize NEBC have been made, in order to provide new targets for a more personalized treatment of this uncommon entity.

MOMENTUM: A Phase I Trial Investigating 2 Schedules of Capecitabine With Aflibercept in Patients With Gastrointestinal and Breast Cancer.

BACKGROUND: Although data from preclinical and clinical studies provide a strong rationale for combining capecitabine with anti-angiogenic agents, clinical development of this fluoropyrimidine in combination with aflibercept has lagged behind other treatments. We conducted a nonrandomized, noncomparative, 2-arm, phase I trial to address this unmet need. PATIENTS AND METHODS: Patients with chemorefractory gastrointestinal and breast cancer were sequentially recruited into a continuous (Arm A, starting dose 1100 mg/m2/day) or intermittent (Arm B, 2 weeks on/1 week off, starting dose 1700 mg/m2/day) capecitabine dosing arm. Aflibercept was administered at a flat dose of 6 mg/kg every 3 weeks in both arms. A classical 3 + 3, dose-escalation design was used. The primary objective was to establish the maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended dose for phase II trials. RESULTS: Thirty-eight eligible patients were recruited of whom 33 were assessable for DLTs (15 in arm A and 18 in arm B). Fourteen had colorectal cancer, 8 gastric cancer, and 11 breast cancer. DLTs included grade 2 hand-foot syndrome, grade 2 anorexia considered unacceptable by the patient, and grade 3 hypertension. The recommended dose for phase II trials for capecitabine was established at 1300 mg/m2/day in Arm A and 2500 mg/m2/day in Arm B with treatment-related grade ≥ 3 adverse events occurring in 47% and 50% of patients, respectively. Among 26 assessable patients, the objective response rate was 15.4% in Arm A and 7.7% in Arm B. CONCLUSION: Combining capecitabine with aflibercept is feasible and associated with a manageable safety profile and some anti-tumor activity in patients with chemorefractory gastrointestinal and breast cancer.

Ocular metastases from neuroendocrine tumors: A literature review.

Background Neuroendocrine tumors (NETs) include malignancies with different origins, clinical presentations and prognosis. Synchronous or metachronous ocular metastases from NET are extremely rare. The diagnostic algorithm and the management of this entity has not been established. The aim of our study was to characterize this subgroup. Methods We performed an electronic search in PubMed Library databases for articles about ocular metastases from NET published from 1966 to August 2019. Results We identified 21 manuscripts with a total of 64 cases. The primary origin of the tumor was lung in 28 (43.7%) cases, ileum in 14, unknown in 8, colon in 3, rectum, esophagus, thymus, testicle and liver in 1 case each, and not reported in 6. The histopathological confirmation of NET metastasis was available in 25 cases (39%). The most common sites of intraocular lesions was the uvea in 30 (46.8%) cases, followed by the orbit in 27. Most of the patients (n = 44, 68.7%) presented eye symptoms. Locoregional interventions were performed in 40 patients (62.5%): 15 cases underwent surgery, 19 had external beam radiotherapy, 5 had brachytherapy, and 1 patient received laser photocoagulation. These treatments ensured the local control in 28 of the 40 (70%) cases treated with a locoregional approach. Conclusions Ocular metastases from NETs are exceptionally rare, and originate more frequently from foregut primary tumors (lung, esophageal, and thymic NETs). The most common ocular site of secondary lesions is the uvea, likely due to its high vascularization. Locoregional approaches appear to be effective in terms of local disease control.

Quality of life assessment and reporting in colorectal cancer: A systematic review of phase III trials published between 2012 and 2018.

BACKGROUND: In this study, our aim was to describe quality of life (QoL) prevalence and heterogeneity in QoL reporting in colorectal cancer phase III trials. METHODS: We included all phase III trials evaluating anticancer drugs in colorectal cancer patients published between 2012 and 2018 by 11 major journals. RESULTS: Out of the 67 publications identified, in 41 (61.2 %) QoL was not listed among endpoints. Out of 26 primary publications of trials including QoL among endpoints, QoL results were not reported in 10 (38.5 %). Overall, no QoL data were available in 51/67 (76.1 %) primary publications. In particular, in the metastatic setting, QoL data were not available in 12/18 (66.7 %) trials with primary endpoint overall survival, and in 20/29 (69.0 %) trials with other primary endpoints. CONCLUSIONS: QoL was absent in a high proportion of recently published phase III trials in colorectal cancer, even in trials of second or further lines, where attention to QoL should be particularly high.

Quality of life analysis in lung cancer: A systematic review of phase III trials published between 2012 and 2018.

OBJECTIVES: We previously reported that quality of life (QoL) is not included among trial endpoints and QoL results are underreported in a significant proportion of phase III oncology trials. Here we describe QoL adoption, reporting and methodology of QoL analysis in lung cancer trials. MATERIALS AND METHODS: We selected all primary publications of lung cancer phase III trials assessing anticancer drugs published between 2012 and 2018 by 11 major journals. RESULTS: 122 publications were included. In 39 (32.0%) publications, QoL was not listed among endpoints: in 10/17 (58.8%) early stage/locally advanced NSCLC, in 15/54 (27.8%) first-line of advanced NSCLC; in 10/41 (24.4%) second and further lines of advanced NSCLC, in 4/10 (40.0%) SCLC. Proportion of trials not including QoL was similar over time: 32.9% publications in 2012-2015 vs. 30.6% in 2016-2018. Out of 83 trials including QoL among endpoints, QoL results were absent in 36 primary publications (43.4%). Proportion of trials without QoL results in primary publication increased over time (30.6% 2012-2015 vs. 61.8% 2016-2018, p = 0.005). Overall, QoL data were not available in 75/122 (61.5%) primary publications, due to the absent endpoint or unpublished results. QoL data were lacking in 48/68 (70.6%) publications of trials with overall survival as primary endpoint, 27/54 (50.0%) with other primary endpoints and 28/54 (51.9%) publications with a positive result. For trials including QoL among endpoints but lacking QoL results in primary publication, probability of secondary publication was 6.3%, 30.1% and 49.8% after 1, 2 and 3 years respectively, without evidence of improvement comparing 2012-2015 vs. 2016-2018. CONCLUSION: QoL is not assessed or published in many phase III lung cancer trials, a setting where QoL value should be highly considered, due to high symptom burden and generally limited life expectancy. Timely inclusion of results in primary publications is worsening in recent years.

Quality-of-Life Assessment and Reporting in Prostate Cancer: Systematic Review of Phase 3 Trials Testing Anticancer Drugs Published Between 2012 and 2018.

Quality of life (QoL) is not included among the end points in many studies, and QoL results are underreported in many phase 3 oncology trials. We performed a systematic review to describe QoL prevalence and heterogeneity in QoL reporting in recently published prostate cancer phase 3 trials. A PubMed search was performed to identify primary publications of randomized phase 3 trials testing anticancer drugs in prostate cancer, issued between 2012 and 2018. We analyzed QoL inclusion among end points, presence of QoL results, and methodology of QoL analysis. Seventy-two publications were identified (15 early-stage, 20 advanced hormone-sensitive, and 37 castration-resistant prostate cancer [CRPC]). QoL was not listed among study end points in 23 studies (31.9%) (40.0% early stage, 40.0% advanced hormone sensitive, and 24.3% CRPC). QoL results were absent in 15 (30.6%) of 49 primary publications of trials that included QoL among end points. Overall, as a result of absent end point or unpublished results, QoL data were lacking in 38 (52.8%) primary publications (53.3% early stage, 55.0% in advanced hormone sensitive, and 51.4% in CRPC). The most commonly used QoL tools were Functional Assessment of Cancer Therapy-Prostate (FACT-P) (21, 53.8%) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) (14, 35.9%); most common methods of analysis were mean changes or mean scores (28, 71.8%), time to deterioration (14, 35.9%), and proportion of patients with response (10, 25.6%). In conclusion, QoL data are lacking in a not negligible proportion of recently published phase 3 trials in prostate cancer, although the presence of QoL results is better in positive trials, especially in CRPC. The methodology of QoL analysis is heterogeneous for type of instruments, analysis, and presentation of results.

Capecitabine plus temozolomide in well- or moderately-differentiated primary atypical neuroendocrine tumours - single-centre experience of two cases.

INTRODUCTION: Neuroendocrine neoplasms (NENs) are a rare and heterogeneous group of tumours, with a variety of primary origins and variable aggressiveness. NENs with an atypical primary origin, such as breast and retroperitoneal NENs, are extremely rare. As a consequence, an established diagnostic and therapeutic strategy in this particular subgroup is lacking. The combination of capecitabine and temozolomide, called CAPTEM regimen, has produced promising response rates in patients with grade 1 or 2 neuroendocrine tumours of multiple origins. CASE PRESENTATION: The first is a case of a 68-year-old woman with a metastatic primary breast neuroendocrine tumour, treated with cisplatin plus etoposide as first line, followed by CAV scheme (cyclophosphamide, doxorubicin, and vincristine), and subsequently treated, in third line with the CAPTEM regimen, obtaining radiological response and good tolerance. The second is the case of a 66-year-old woman affected by a metastatic primitive retroperitoneal NET G2. The patient progressed after a somatostatin analogue-based first line, whereas the CAPTEM regimen led to a partial and durable response with a favourable safety profile. CONCLUSIONS: CAPTEM chemotherapy has been shown to be an active and safe therapeutic option in advanced, metastatic G1/2 atypical primary NENs.

Unplanned Extubations in Intensive Care Unit: evidences for risk factors. A literature review.

BACKGROUND AND AIM: Unplanned extubations (UE) are getting more and more relevant in Critical Care, becoming a quality and care safeness outcome. This happens because after an UE the patient can face some complications concerning the airway management, respiratory and hemodynamic problems, lengthen in the hospital stay and in the mechanical ventilation time.  The aim of this review is identify and classify the factors that could increase UE risk. METHODOLOGY: A systematic review of scientific articles was performed consulting the databases PubMed, Cinahl, Medline, EBSCOhost and Google Scholar. Articles from 2006 to 2011 were included. Pediatric Care settings were excluded. RESULTS: 21 articles were selected. From the results emerged that risk factors associated to the patient are widely controversial. Yet restlessness, a low level of sedation and a high level of consciousness seem to be highly related to UE. Organizational risk factors, as workload, nurse:patient ratio, and the use of interdisciplinary protocols seem to play an important role in UE. CONCLUSION: According the current literature, the research on UE still has to handle a wide uncertainty. There is the need for more studies developing conclusive evidences on the role of different risk factors. Anyway, literature highlights the importance of the nurse and of the healthcare system organization in reducing UE incidence.