Immuno markers in newly diagnosed glioblastoma patients underwent Stupp protocol after neurosurgery: a retrospective series.

PURPOSE: The aims of our retrospective study investigated the role of immune system in glioblastoma (GBM), which is the most aggressive primary brain tumor in adults characterized by a poor prognosis. The recurrence rate remains high, probably due to "immune-desert" tumor microenvironment (TME) making GBM hidden from the anti-tumoral immune clearance. Considering this, we aimed to create a panel of prognostic markers from blood and tumor tissue correlating with overall survival (OS) and progression-free survival (PFS). METHODS: Firstly, we analyzed the inflammatory markers NLR and PLR as the ratio of the absolute neutrophil count and absolute platelet count by the absolute lymphocyte count respectively, collected at different time points in the peripheral blood of 95 patients. Furthermore, in 31 patients of the same cohort, we analyzed the formalin-fixed paraffin embedded samples to further compare the impact of circulating and inflammatory markers within the TME. RESULTS: Patients aged < 60 years and with methylated MGMT showed better OS. While, pre-chemotherapy Systemic Inflammatory Index (SII) < 480 was related to a better OS and PFS, we observed that only CD68+macrophage and CD66b+neutrophils expressed in vascular/perivascular area (V) showed a statistically significant prognostic role in median OS and PFS. CONCLUSIONS: Thus, we underscored a role of SII as predictive value of response to STUPP protocol. Regarding the TME-related markers, we suggested to take into consideration for future studies with new immunotherapy combinations, each component relating to expression of immune infiltrating subsets.

Radiotherapy and palliative care outpatient clinic: a new healthcare integrated model in Italy.

BACKGROUND: On the basis of substantial evidence demonstrate that palliative care combined with standard care improves patient, caregiver, and society outcomes, we have developed a new healthcare model called radiotherapy and palliative care (RaP) outpatient clinic were a radiation oncologist and a palliative care physician make a joint evaluation of advanced cancer patients. METHODS: We performed a monocentric observational cohort study on advanced cancer patients referred for evaluation at the RaP outpatient clinic. Measures of quality of care were carried out. RESULTS: Between April 2016 and April 2018, 287 joint evaluations were performed and 260 patients were evaluated. The primary tumor was lung in 31.9% of cases. One hundred fifty (52.3%) evaluations resulted in an indication for palliative radiotherapy treatment. In 57.6% of cases was used a single dose fraction of radiotherapy (8 Gy). All the irradiated cohort completed the palliative radiotherapy treatment. An 8% of irradiated patients received the palliative radiotherapy treatment in the last 30 days of life. A total of 80% of RaP patients received palliative care assistance until the end of life. CONCLUSION: At the first descriptive analysis, the radiotherapy and palliative care model seem to respond to the need of multidisciplinary approach in order to obtain an improvement on quality of care for advanced cancer patients.

3-T magnetic resonance-guided high-intensity focused ultrasound (3 T-MR-HIFU) for the treatment of pain from bone metastases of solid tumors.

INTRODUCTION: Bone metastases (BM) are still the main cause of morbidity and mortality in cancer patients, not only because of their complications, defined as skeletal-related events (SREs), but also because of the negative impact bone pain has on quality of life (QoL) and survival, especially when opioid analgesics and locoregional treatments fail. MATERIALS AND METHODS: A single-center prospective study was carried out on 12 patients with symptomatic BM treated with MRI-guided focused ultrasound (MR-HIFU). The primary endpoint was the effectiveness of MR-HIFU in reducing current and breakthrough cancer pain (BTCP) scores. The main secondary aims were the evaluation of circulating markers at different time-points and their relation to pain and procedure efficacy. Other secondary objectives included temporal evolution of pain response, evaluation of QoL, and side effects of the treatment. Descriptive statistics were used to evaluate primary and secondary endpoints. Questionnaires on pain and QoL completed at baseline and at 30 days were compared using appropriate statistical tests with exploratory intent. RESULTS: MR-HIFU was successfully completed in all 12 patients enrolled between September 2015 and December 2018. On day 30, 6 (50.0%) patients showed a complete response of current pain and 6 a partial response, while 5 (41.7%) obtained a complete BTCP response. A partial response of BM evaluated by MD Anderson criteria was obtained in 9 (81.8%) patients. Only one patient progressed in the target lesion after MR-HIFU. No treatment-related adverse events were recorded. Bone turnover markers CTX/RANK-L (P) do not demonstrate any significant change with the pain or BM response. CONCLUSION: In our patients, targeted therapy of painful BM with MRI-guided focused ultrasound ablation was safe and showed encouraging early-onset and functional results.

A Remote Monitoring System to Optimize the Home Management of Oral Anticancer Therapies (ONCO-TreC): Prospective Training-Validation Trial.

BACKGROUND: A platform designed to support the home management of oral anticancer treatments and provide a secure web-based patient-health care professional communication modality, ONCO-TreC, was tested in 3 cancer centers in Italy. OBJECTIVE: The overall aims of the trial are to customize the platform; assess the system's ability to facilitate the shared management of oral anticancer therapies by patients and health professionals; and evaluate system usability and acceptability by patients, caregivers, and health care professionals. METHODS: Patients aged ≥18 years who were candidates for oral anticancer treatment as monotherapy with an Eastern Cooperative Oncology Group performance status score of 0 to 1 and a sufficient level of familiarity with mobile devices were eligible. ONCO-TreC consisted of a mobile app for patients and a web-based dashboard for health care professionals. Adherence to treatment (pill count) and toxicities reported by patients through the app were compared with those reported by physicians in medical records. Usability and acceptability were evaluated using questionnaires. RESULTS: A total of 40 patients were enrolled, 38 (95%) of whom were evaluable for adherence to treatment. The ability of the system to measure adherence to treatment was high, with a concordance of 97.3% (95% CI 86.1%-99.9%) between the investigator and system pill count. Only 60% (3/5) of grade 3, 54% (13/24) of grade 2, and 19% (7/36) of grade 1 adverse events reported by physicians in the case report forms were also reported in the app directly by patients. In total, 94% (33/35) of patients had ≥1 app launch each week, and the median number of daily accesses per patient was 2. Approximately 71% (27/38) and 68% (26/38) of patients used the app for messages and vital sign entering, respectively, at least once during the study period. CONCLUSIONS: ONCO-TreC is an important tool for measuring and monitoring adherence to oral anticancer drugs. System usability and acceptability were very high, whereas its reliability in registering toxicity could be improved. TRIAL REGISTRATION: ClinicalTrials.gov NCT02921724; https://www.clinicaltrials.gov/ct2/show/NCT02921724.

Circulating androgen receptor gene amplification and resistance to 177Lu-PSMA-617 in metastatic castration-resistant prostate cancer: results of a Phase 2 trial.

BACKGROUND: In a Phase 2 clinical trial, we aimed to determine the lutetium-177 [177Lu]-PSMA-617 activity and the clinical utility of levels of plasma androgen receptor (AR) gene in patients with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC). METHODS: We determined AR copy number in pretreatment plasma samples. We used logistic regression to estimate the odds ratio (OR) and 95% confidence intervals (95% CIs) in order to evaluate the independent relevance of AR status and to evaluate patients with early progressive disease (PD) defined as treatment interruption occurring within 4 months after the start of 177Lu-PSMA-617. RESULTS: Twelve of the 15 (80%) with AR gene gain and 5 of the 25 (20%) patients with no gain of AR had early PD (p = 0.0002). The OR for patients without PSA response having AR gain was 3.69 (95% CI 0.83-16.36, p = 0.085). The OR for patients with early PD having AR gain was 16.00, (95% CI 3.23-79.27, p = 0.0007). Overall, median PFS and OS were 7.5 and 12.4 months, respectively. AR-gained had a significant shorter OS compared to AR-normal patients (7.4 vs 19.1 months, p = 0.020). No treatment interruptions due to adverse effects were reported. DISCUSSION: Plasma AR status helped to indicate mCRPC with early resistance to 177Lu-PSMA-617. TRIAL REGISTRATION: NCT03454750.

Prospective Observational Study Comparing Calcium and Sodium Levofolinate in Combination with 5-Fluorouracil in the FOLFIRI Regimen.

LESSONS LEARNED: The use of sodium levofolinate (Na-Lev) is safe in combination with continuous infusion 5-fluorouracil in patients with gastrointestinal tumors treated with the FOLFIRI regimen. A comparison with calcium levofolinate (Ca-Lev) showed a similar toxicity profile. The advantages of Na-Lev over Ca-Lev might be the faster drug preparation and the shorter time of drug administration. BACKGROUND: The objectives of this study were to compare the safety profiles of sodium levofolinate (Na-Lev) and calcium levofolinate (Ca-Lev) in combination with 5-fluorouracil (5-FU) in the FOLFIRI regimen and to measure the organizational impact of the introduction of Na-Lev on drug production and administration. METHODS: The study opened in November 2015 and closed in August 2019. Patients with gastrointestinal cancers who were candidates for treatment with the FOLFIRI regimen were included in this nonrandomized study. Age ≥18 years, life expectancy >3 months, adequate bone marrow reserve, adequate hepatic and renal function, and an ECOG performance status of 0-2 were required. Patients in the Ca-Lev arm received a 2-hour infusion of Ca-Lev followed by 5-FU, whereas those in the Na-Lev arm received Na-Lev and 5-FU administered in a single 48-hour pump. RESULTS: Sixty patients were enrolled, 30 in each arm. Patient characteristics were balanced. Grade (G)1-2 adverse events occurred in 18 (60.0%) and 19 (63.4%) patients of Na-Lev and Ca-Lev cohorts, respectively, whereas G3-4 adverse events occurred in 12 (40.0%) and 11 (36.6%) patients, respectively. The use of Na-Lev enabled us to save approximately 13 minutes for drug preparation and 2 hours for treatment administration, per patient per cycle. CONCLUSION: Na-Lev showed a reassuring toxicity profile and a favorable impact on drug preparation and administration.

Temozolomide Alone or Combined with Capecitabine for the Treatment of Metastatic Neuroendocrine Neoplasia: A "Real-World" Data Analysis.

BACKGROUND: Neuroendocrine neoplasias (NENs) are a rare group of tumors with different prognosis and response to therapy. Their heterogeneity is dependent on the site of origin, morphology, and Ki67. Temozolomide (TEM) appears to be active in metastatic NENs (mNENs) but there is limited evidence about its efficacy in gastrointestinal NENs. We analyzed "real-world" data on the use of TEM alone or in association with capecitabine (CAPTEM) in patients with mNENs. PATIENTS AND METHODS: One hundred consecutive patients with advanced NENs treated with TEM or CAPTEM between 2009 and 2019 were included. A pretreatment tumor growth rate (TGR0) was calculated. Overall survival (OS), progression-free survival (PFS), tolerance, objective response rate (ORR), and disease control rate (DCR) were analyzed. A propensity score analysis and inverse probability of treatment weights for Cox regression models were used. RESULTS: TEM-based therapy was administered to 95 patients (26.3% CAPTEM and 83.7% TEM) with a median age of 59 years (range 26-85) years. ECOG performance status was 0-2. Carcinoid syndrome was reported in 12 (12.6%) patients. Twenty (21.1%) patients with grade (G) 3 neuroendocrine carcinoma (NEC) and 9 (9.4%) with G3 neuroendocrine tumors (NETs) were included in the analysis. Median PFS of the entire group was 10.4 months (95% confidence interval [CI]: 6.0-11.5). In multivariate analysis, a higher risk of progression was observed for NEC G3 patients (hazard ratio [HR] 2.70, 95% CI: 1.25-5.84) and for a TGR ≥19.55 (HR: 2.53, 95% CI: 1.45-4.40). Median OS was 23.4 months (95% CI: 17.0-29.0) and was similar in both treatment groups (23.9 vs. 20.5 months for TEM and CAPTEM, respectively, p = 0.585). In multivariate analysis, TGR ≥19.55 was associated with a higher risk of death (HR: 2.18, 95% CI: 1.16-4.11) than TGR <19.55, as was NEC G3 (HR: 2.42, 95% CI: 1.04-5.59) with respect to NETs. No differences in terms of mPFS or mOS were seen in relation to the primary site of disease. In the 86 patients evaluable for response, ORR was 44.1% and the DCR was 70.9%. Mild adverse events (grade I-II) included anemia, neutropenia, and headache. Rare cases of G 3 neutropenia and thrombocytopenia were recorded. CONCLUSIONS: TEM-based regimens are associated with a high DCR and a relatively tolerable toxicity profile in NENs of pancreatic, intestinal, and lung origin. Further investigation of these specific NETs is warranted in prospective clinical trials.

The challenge of sustainability in healthcare systems: cost of radiotherapy in the last month of life in an Italian cancer center.

PURPOSE: Cost evaluation is becoming mandatory to support healthcare sustainability and optimize the decision-making process. This topic is a challenge, especially for complex and rapidly evolving treatment modalities such as radiotherapy (RT). The aim of the present study was to investigate the cost of RT in the last month of life of patients in an Italian cancer center. METHODS: This was a retrospective study on a cancer population (N= 160) who underwent RT or only an RT planning simulation in an end of life (EOL) setting. The cost of RT procedures performed on patients was collected according to treatment status, care setting, and RT technique used. Costs were valued according to the sum of reimbursements relating to all procedures performed and assessed from the perspective of the National Health System. RESULTS: The total cost of RT in the last month of life was €244,774, with an average cost per patient of €1530. Around 7.7% and 30.3% of the total cost was associated with patients who never started RT or who discontinued RT, respectively, while the remaining 62.0% referred to patients who completed treatment. Costs associated with outpatient and inpatient settings represented 54.3% and 38.6% of the total cost, respectively. The higher average cost per patient for the never-started and discontinued groups was correlated with patients who had a poor ECOG Performance Status. CONCLUSION: Improved prognostic accuracy and a better integration between radiotherapy and palliative care units could be a key to a better use of resources and to a reduction in the cost of EOL RT.

MicroRNA-16 Restores Sensitivity to Tyrosine Kinase Inhibitors and Outperforms MEK Inhibitors in KRAS-Mutated Non-Small Cell Lung Cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. Chemotherapy, the treatment of choice in non-operable cases, achieves a dismal success rate, raising the need for new therapeutic options. In about 25% of NSCLC, the activating mutations of the KRAS oncogene define a subclass that cannot benefit from tyrosine kinase inhibitors (TKIs). The tumor suppressor miR-16 is downregulated in many human cancers, including NSCLC. The main objectives of this study were to evaluate miR-16 treatment to restore the TKI sensitivity and compare its efficacy to MEK inhibitors in KRAS-mutated NSCLC. METHODS: We performed in vitro and in vivo studies to investigate whether miR-16 could be exploited to overcome TKI resistance in KRAS-mutated NSCLC. We had three goals: first, to identify the KRAS downstream effectors targeted by mir-16, second, to study the effects of miR-16 restoration on TKI resistance in KRAS-mutated NSCLC both in vitro and in vivo, and finally, to compare miR-16 and the MEK inhibitor selumetinib in reducing KRAS-mutated NSCLC growth in vitro and in vivo. RESULTS: We demonstrated that miR-16 directly targets the three KRAS downstream effectors MAPK3, MAP2K1, and CRAF in NSCLC, restoring the sensitivity to erlotinib in KRAS-mutated NSCLC both in vitro and in vivo. We also provided evidence that the miR-16-erlotinib regimen is more effective than the selumetinib-erlotinib combination in KRAS-mutated NSCLC. CONCLUSIONS: Our findings support the biological preclinical rationale for using miR-16 in combination with erlotinib in the treatment of NSCLC with KRAS-activating mutations.

Insulin-like growth factor-1 receptor (IGF-1R) expression on circulating tumor cells (CTCs) and metastatic breast cancer outcome: results from the TransMYME trial.

PURPOSE: To evaluate the prognostic value of IGF-1R expression on circulating tumor cells (CTCs) in a prospective randomized clinical trial comparing chemotherapy plus metformin with chemotherapy alone in metastatic breast cancer (MBC) patients. METHODS: CTCs were collected at baseline and at the end of chemotherapy. An automated sample preparation and analysis system (CellSearch) were customized for detecting IGF-1R expression. The prognostic role of CTC count and IGF-1R was assessed for PFS and OS by univariate and multivariate analyses. RESULTS: Seventy-two out of 126 randomized patients were evaluated: 57% had ≥ 1 IGF-1R positive CTC and 37.5% ≥ 4 IGF-1R negative cells; 42% had CTC count ≥ 5/7.5 ml. At univariate analysis, the number of IGF-1R negative CTCs was strongly associated with risk of progression and death: HR 1.93 (P = 0.013) and 3.65 (P = 0.001), respectively; no association was detected between number of IGF-1R positive CTCs and PFS or OS (P = 0.322 and P = 0.840). The prognostic role of CTC count was confirmed: HR 1.69, P = 0.042 for PFS and HR 2.80 for OS, P = 0.002. By multivariate analysis, the prognostic role of the number of IGF-1R negative CTCs was maintained, while no residual prognostic role of CTC count or number of IGF-1R positive cells was found. CONCLUSION: Loss of IGF-1R in CTCs is associated with a significantly worse outcome in MBC patients. This finding supports further evaluation for the role of IGF-1R on CTCs to improve patient stratification and to implement new targeted strategies. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov (NCT01885013); European Clinical Trials Database (EudraCT No.2009-014,662-26).

Dosimetry and safety of 177Lu PSMA-617 along with polyglutamate parotid gland protector: preliminary results in metastatic castration-resistant prostate cancer patients.

PURPOSE: Radioligand therapy (RLT) with 177Lu-PSMA-617 is a promising option for patients with metastatic castration-resistant prostate cancer (mCRPC). The present study was designed to define the safety and initial response to a minimal effective injected activity/cycle of 177Lu-PSMA-617 in mCRPC patients. New protective agents for salivary glands and kidney were co-administered and dosimetry was carried out. PATIENTS AND METHODS: A prospective single-arm, open label phase II study on mCRPC was activated at our institute in April 2017. Patients with histologically confirmed advanced mCRPC previously treated with standard life-prolonging agents were enrolled. Folic polyglutamate tablets were orally administered as parotid gland protectors and 500 mL of a 10% mannitol solution was intravenously infused to reduce kidney uptake before the injection of 3.7-5.5 GBq of 177Lu-PSMA-617 repeated four times at interval of 8 weeks. The adsorbed dose calculation was performed with MIRD formalism (OLINDA/EXM software). The Bryant and Day design was used to estimate the sample size taking account of both activity and toxicity. RESULTS: Forty-three eligible patients were evaluated for toxicity and initial response. Dosimetry was carried out in 13 patients. Two (4.8%) patients had G3 and 8 (19.5%) had G2 hematological toxicity. Only 3 (6.9%) patients had mild G1 salivary gland toxicity and 8 (19.5%) had G1 renal toxicity. A decrease of ≥ 30% in prostate-specific antigen (PSA) was achieved after the first cycle in 17 (40.5%) patients, of whom 13 had a PSA decline of >50% after the second cycle. The median adsorbed doses were 0.65 mGy/MBq (range 0.33-2.63) for parotid glands, 0.42 mGy/MBq (0.14-0.81) for kidneys, 0.036 mGy/MBq (0.023-0.067) for red marrow, and 0.038 mGy/MBq (0.018-0.135) for the whole body. CONCLUSION: In advanced, heavily pre-treated mCRPC patients, 3.7 GBq/cycle of 177Lu-PSMA-617 was safe and produced early biochemical and imaging responses at PSMA whole-body scan post injection. Dosimetry of salivary glands suggests that the co-administration of polyglutamate tablets may reduce salivary gland uptake. CLINICAL TRIAL REGISTRATION: EU Clinical Trials Register No.: 2016-002732-32; NCT03454750. Collection and assembly of data: April 2017 and February 2019.

Ten-year experience of the multidisciplinary Osteoncology Center.

PURPOSE: Bone metastases (BMs) are responsible for high morbidity in patients. A multidisciplinary approach involving a team of specialists offers an effective therapeutic strategy based on disease characteristics, medical history, and performance status. We evaluated the impact of our 10-year multidisciplinary experience on the management of patients with BM. METHODS: We retrospectively analyzed 2194 medical reports of 1628 patients referred to our Osteoncology Center from 2005 to 2015. Cases were discussed weekly by a multidisciplinary team. RESULTS: Eight hundred thirty-eight (38.2%) of the 2194 visits were requested because of a risk of complications from BM. Antiblastic treatment and bone-targeted therapy were modified in 709 (66.3%) and 309 (31%) of cases, respectively. Radiotherapy was scheduled in 220 (20%) of the 1099 patients for whom information was recorded. Patients completed the Brief Pain Inventory (BPI) during their first visit, 1296 (59.1%) reporting pain (median intensity 4), and 537 (41.4%) experiencing a level that interfered substantially with daily activities. New ortheses and/or antalgic therapy was prescribed accordingly. After 7 days, 208 (16%) patients were re-evaluated and a new BPI administered. A significant improvement in the worst (p < 0.0001) and current pain (p = 0.03) was seen, together with a favorable impact on daily activities (p = 0.02). Two thousand fifty-one patients completed an anonymous questionnaire on the quality of the service, the majority (69.4%) expressing high satisfaction. CONCLUSIONS: Our 10-year osteoncology experience confirms the importance of a multidisciplinary approach to optimize BM management. Further evaluations are needed in relation to quality of life, outcome, and costs.

68Ga-PSMA PET/CT in patients with recurrent prostate cancer after radical treatment: prospective results in 314 patients.

PURPOSE: We studied the usefulness of 68Ga-prostate-specific membrane antigen (PSMA) PET/CT for detecting relapse in a prospective series of patients with biochemical recurrence (BCR) of prostate cancer (PCa) after radical treatment. METHODS: Patients with BCR of PCa after radical surgery and/or radiotherapy with or without androgen-deprivation therapy were included in the study. 68Ga-PSMA PET/CT scans performed from the top of the head to the mid-thigh 60 min after intravenous injection of 150 ± 50 MBq of 68Ga-PSMA were interpreted by two nuclear medicine physicians. The results were correlated with prostate-specific antigen (PSA) levels at the time of the scan (PSApet), PSA doubling time, Gleason score, tumour stage, postsurgery tumour residue, time from primary therapy to BCR, and patient age. When available, 68Ga-PSMA PET/CT scans were compared with negative 18F-choline PET/CT scans routinely performed up to 1 month previously. RESULTS: From November 2015 to October 2017, 314 PCa patients with BCR were evaluated. Their median age was 70 years (range 44-92 years) and their median PSApet was 0.83 ng/ml (range 0.003-80.0 ng/ml). 68Ga-PSMA PET/CT was positive (one or more suspected PCa lesions detected) in 197 patients (62.7%). Lesions limited to the pelvis, i.e. the prostate/prostate bed and/or pelvic lymph nodes (LNs), were detected in 117 patients (59.4%). At least one distant lesion (LNs, bone, other organs, separately or combined with local lesions) was detected in 80 patients (40.6%). PSApet was higher in PET-positive than in PET-negative patients (P < 0.0001). Of 88 patients negative on choline PET/CT scans, 59 (67%) were positive on 68Ga-PSMA PET/CT. CONCLUSION: We confirmed the value of 68Ga-PSMA PET/CT in restaging PCa patients with BCR, highlighting its superior performance and safety compared with choline PET/CT. Higher PSApet was associated with a higher relapse detection rate.

The challenge of sustainability in healthcare systems: frequency and cost of diagnostic procedures in end-of-life cancer patients.

BACKGROUND: Literature data on the overuse and misuse of diagnostic procedures leading to end-of-life aggressiveness are scarce due to the limited amount of estimated economic waste. This study investigated the potential overuse of diagnostic procedures in a population of end-of-life patients. METHODS: This is a retrospective study on consecutive advanced patients admitted into two Italian hospices. Frequency and relative costs of X-ray imaging, CT scans, MRI, and interventional procedures prescribed in the 3 months before admission were collected in patient electronic charts and/or in administrative databases. We conducted a deeper analysis of 83 cancer patients with a diagnosis of at least 1 year before admission to compare the number of examinations performed at two distant time periods. RESULTS: Out of 541 patients, 463 (85.6%) had at least one radiological exam in the 3 months before last admission. The mean radiological exam number was 3.9 ± 3.2 with a relative mean cost of 278.60 ± 270.20 € per patient with a statistically significant (p < 0.001) rise near death. In the 86-patient group, a higher number of procedures was performed in the last 3 months of life than in the first quarter of the year preceding last admission (38.43 ± 28.62 vs. 27.95 ± 23.21, p < 0.001) with a consequent increase in cost. CONCLUSIONS: Patients nearing death are subjected to a high level of "diagnostic aggressiveness." Further studies on the integration of palliative care into the healthcare pathway could impact the appropriateness of interventions, quality of care, and, ultimately, estimated costs.

Chemotherapy and palliative care near end-of life: examining the appropriateness at a cancer institute for colorectal cancer patients.

BACKGROUND: Appropriate cessation of chemotherapy and timely referral of patients to hospice services are crucial for the quality of care near death. We investigated the quality of care in our Cancer Institute in very advanced metastatic colorectal cancer patients treated in real life. PATIENTS AND METHODS: We performed a retrospective analysis of electronic medical data of patients with metastatic colorectal cancer who were candidates for chemotherapy during the study period (1 January 2007-30 June 2014) and died before 31 December 2014. Quality-of-cancer-care indicators were calculated for the overuse of chemotherapy and referral to hospice. Predictive factors of chemotherapy discontinuation and hospice referral in end-of life care were investigated using parametric and nonparametric methods. RESULTS: Of the 365 patients who died before 31 December 2014, 26 (7.1%) received chemotherapy in the last 14 days of life and 36 (9.8%) started a new chemotherapy regimen in the last 30 days of life. Factors associated with the overuse of chemotherapy were being < 70 years of age for both indicators and not having received advanced chemotherapy treatments for the former indicator. The majority of patients (74.7%) had access to hospice services, of whom only a small percentage (7.2%) accessed them very near to death. CONCLUSIONS: According to the criteria used, our Institute provides a good quality of cancer care for dying colorectal cancer patients, measured by the use of chemotherapy and referral to hospice in their last days of life.

Prolonged Pemetrexed Infusion Plus Gemcitabine in Refractory Metastatic Colorectal Cancer: Preclinical Rationale and Phase II Study Results.

LESSONS LEARNED: Difficulties in translating in vitro results into clinical practice are inevitable.Further efforts to verify the efficacy of alternative schedules of pemetrexed in solid tumors are encouraged. BACKGROUND: We investigated the cytotoxic activity of pemetrexed in combination with several drugs (gemcitabine, carboplatin, vinorelbine, and mitomycin C) using different exposure schedules in three colon cancer cell lines. The best results were obtained with the following schedule: a prolonged pemetrexed exposure followed by a 48-hour wash-out and then gemcitabine. This combination was then advanced to a phase II clinical trial. METHODS: Patients with metastatic colorectal cancer in progression after standard treatment were included in the study. Adequate bone marrow reserve, normal hepatic and renal function, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were required. Treatment consisted of an 8-hour intravenous infusion of pemetrexed 150 mg/m2 on day 1 and a 30-minute intravenous infusion of gemcitabine 1,000 mg/m2 on day 3 of each cycle, repeated every 14 days. RESULTS: Fourteen patients were enrolled onto the study (first step). No objective responses were seen, and evidence of stable disease was observed in only one of the 12 evaluable patients. The most important grade 3-4 side effects were hematological toxicity (neutropenia 64.2%, thrombocytopenia 71.4%, anemia 28.7%), fatigue (50.0%), and stomatitis (21.5%). Median overall survival and time to progression were 5.8 months (95% confidence interval [CI]: 3.9-7.1) and 2.1 months (95% CI: 1.7-2.8), respectively. CONCLUSION: The experimental pemetrexed-gemcitabine combination proved to be inactive and moderately toxic.

Androgen and oestrogen receptors as potential prognostic markers for patients with ductal carcinoma in situ treated with surgery and radiotherapy.

Ductal carcinoma in situ (DCIS) is a heterogeneous disease that has been investigated less extensively than invasive breast cancer. Women with DCIS are mainly treated with conservative surgery almost exclusively followed by radiotherapy. However, as radiation treatment is not always effective, the search for biomarkers capable of identifying DCIS lesions that could progress to invasive cancer is ongoing. Although conventional biomarkers have been thoroughly studied in invasive tumours, little is known about the role played by androgen receptor (AR), widely expressed in DCIS. A series of 42 DCIS patients treated with quadrantectomy and radiotherapy were followed for a period of up to 95 months. Of these, 11 had recurrent DCIS or progressed to invasive cancer. All tumours were analysed for clinical pathological features. Conventional biomarkers and androgen receptor expression were determined by immunohistochemistry. Our results showed that AR was higher in tumours of relapsed patients than non-relapsed patients (P value: 0.0005). Conversely, oestrogen receptor (ER) was higher, albeit not significantly, in non-relapsed patients than in relapsed patients. AR/ER ratio was considerably different in the two subgroups (P value: 0.0033). Area under the curve (AUC) values were 0.85 for AR and 0.80 for the AR/ER ratio. These preliminary results highlight the potentially important role of both AR and the AR/ER ratio as prognostic markers in DCIS.

Recombinant granulocyte colony-stimulating factor (rG-CSF) in the management of neutropenia induced by anthracyclines and ifosfamide in patients with soft tissue sarcomas (NEUSAR).

PURPOSE: Anthracycline and ifosfamide-based chemotherapy represents a widely used regimen both in early and advanced settings in soft tissue sarcoma (STS). Prophylaxis with granulocyte colony-stimulating factor (G-CSF) reduces the severity of chemotherapy-induced neutropenia. The aim of this study was to assess the efficacy and safety of biosimilar G-CSF in these patients. METHODS: Between 2003 and 2013, 67 patients with soft tissue tumors under epirubicin and ifosfamide (EI) treatment receiving biosimilar filgrastim (Zarzio®), originator filgrastim (Granulokine®, Neupogen®), and lenograstim (only originator Myelostim®) as primary prophylaxis for a total of 260 cycles of therapy were retrospectively analyzed. Baseline patient characteristics were summarized in a propensity score (PS). RESULTS: The incidence of febrile neutropenia (FN) was 44.0 % in biosimilar filgrastim, 40.0 % in originator filgrastim, and 45.5 % in the lenograstim groups (p = 0.935). All grade and G4 neutropenia were similar in the three groups with the same safety profile. The use of biosimilar filgrastim achieved cost savings of €225.25 over originator filgrastim and €262.00 over lenograstim. CONCLUSION: Biosimilar G-CSF was effective in preventing FN and in reducing the need for hospitalization in STS patients undergoing EI treatment. It also proved comparable to its reference products from both a clinical and cost-effective standpoint.

Methylation pattern analysis in prostate cancer tissue: identification of biomarkers using an MS-MLPA approach.

BACKGROUND: Epigenetic silencing mediated by CpG island methylation is a common feature of many cancers. Characterizing aberrant DNA methylation changes associated with prostate carcinogenesis could potentially identify a tumour-specific methylation pattern, facilitating the early diagnosis of prostate cancer. The objective of the study was to assess the methylation status of 40 tumour suppressor genes in prostate cancer and healthy prostatic tissues. METHODS: We used methylation specific-multiplex ligation probe amplification (MS-MLPA) assay in two independent case series (training and validation set). The training set comprised samples of prostate cancer tissue (n = 40), healthy prostatic tissue adjacent to the tumor (n = 26), and healthy non prostatic tissue (n = 23), for a total of 89 DNA samples; the validation set was composed of 40 prostate cancer tissue samples and their adjacent healthy prostatic tissue, for a total of 80 DNA samples. Methylation specific-polymerase chain reaction (MSP) was used to confirm the results obtained in the validation set. RESULTS: We identified five highly methylated genes in prostate cancer: GSTP1, RARB, RASSF1, SCGB3A1, CCND2 (P < 0.0001), with an area under the ROC curve varying between 0.89 (95 % CI 0.82-0.97) and 0.95 (95 % CI 0.90-1.00). Diagnostic accuracy ranged from 80 % (95 % CI 70-88) to 90 % (95 % CI 81-96). Moreover, a concordance rate ranging from 83 % (95 % CI 72-90) to 89 % (95 % CI 80-95) was observed between MS-MLPA and MSP. CONCLUSIONS: Our preliminary results highlighted that hypermethylation of GSTP1, RARB, RASSF1, SCGB3A1 and CCND2 was highly tumour-specific in prostate cancer tissue.

Defining the cutoff value of MGMT gene promoter methylation and its predictive capacity in glioblastoma.

Despite advances in the treatment of glioblastoma (GBM), median survival is 12-15 months. O6-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation status is acknowledged as a predictive marker for temozolomide (TMZ) treatment. When MGMT promoter values fall into a "methylated" range, a better response to chemotherapy is expected. However, a cutoff that discriminates between "methylated" and "unmethylated" status has yet to be defined. We aimed to identify the best cutoff value and to find out whether variability in methylation profiles influences the predictive capacity of MGMT promoter methylation. Data from 105 GBM patients treated between 2008 and 2013 were analyzed. MGMT promoter methylation status was determined by analyzing 10 CpG islands by pyrosequencing. Patients were treated with radiotherapy followed by TMZ. MGMT promoter methylation status was classified into unmethylated 0-9 %, methylated 10-29 % and methylated 30-100 %. Statistical analysis showed that an assumed methylation cutoff of 9 % led to an overestimation of responders. All patients in the 10-29 % methylation group relapsed before the 18-month evaluation. Patients with a methylation status ≥30 % showed a median overall survival of 25.2 months compared to 15.2 months in all other patients, confirming this value as the best methylation cutoff. Despite wide variability among individual profiles, single CpG island analysis did not reveal any correlation between single CpG island methylation values and relapse or death. Specific CpG island methylation status did not influence the predictive value of MGMT. The predictive role of MGMT promoter methylation was maintained only with a cutoff value ≥30 %.