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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.

Background: Tumor growth and development is determined by the mutual interaction between the cancer cells themselves and the microenvironment. It contains various elements, including immune cells. Of all, mast cells have one of the most controversial roles. The aim of the present study was to evaluate the expression of mast cell tryptase in the luminal and non-luminal subtypes of breast cancer and establish a possible link between infiltration with MCs and expression of hormone receptors. Material and methods: The experimental study included 80 cases of breast carcinomas that were analyzed immunohistochemically in order to establish the molecular profile and the expression of tryptase, a specific marker of mast cells. The data were processed using the SPSS program. Pearson’s coefficient (r) and the other values were considered statistically significant in case of p≤0.05. Results: Both intratumoral mast cells (MCit) and peritumoral mast cells (MCpt) correlated with the expression of hormone receptors for estrogen (ER) and progesterone (PR). Thus, the following relations were established: MCit and ER (r=0.343, p=0.002), MCpt and ER (r=0.394, p=0.000295) and MCpt and PR (r=0.386, p=0.000409). Statistically significant correlations between HER2 expression and mast cells content have not been established. Conclusions: Mast cells invasion, peri- and intratumoral, is strongly influenced by the expression of hormone receptors. The luminal subtypes of breast cancer are characterized by a higher density of mast cells.

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). 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. 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. Plasma AR status helped to indicate mCRPC with early resistance to 177Lu-PSMA-617. NCT03454750.

Introduction. Juvenile idiopathic arthritis (JIA) is a persistent type of arthritis with no defined cause that starts before the age of 16 years and lasts for at least 6 weeks. The objective of the study was to determine the clinical and laboratory efficacy of tocilizumab treatment in patients with systemic and polyarticular seropositive forms of JIA. Material and methods. The study took place in the Division of Rheumatology, Public Healthcare Institution – Mother and Child Institute, Chisinau, Republic of Moldova. The parents of the patients signed the written consent to participate in the study. The study was approved by the Ethics Committee of the institute. The inclusion criteria for enrolling the patients who underwent the biological treatment were both the systemic and polyarticular JIA forms (seronegative or positive) and active sacroiliitis. The exclusion criteria were the patients with active infections, tuberculosis, sepsis, malignancies, and immunodeficiency disorders. This study included 20 children with JIA, in whom tocilizumab was administered every two weeks. The number of painful joints, the number of swollen joints, and the global evaluation of the disease by the doctor (GEDD) and by the patient (GEDP), as well as via the Childhood Health Assessment Questionnaire (CHAQ), were determined. Furthermore, paraclinical tests, that included complete blood count and C-reactive protein (CRP), were determined. Results. Children treated with tocilizumab exhibited a decreased number of painful and swollen joints, as well as the GEDD, GEDP, and CHAQ scores. Moreover, a decrease of the erythrocyte sedimentation rate (ESR) and CRP was observed. Conclusions. Children with JIA treated with tocilizumab showed a considerable clinical improvement and the paraclinical indices revealed a lower active inflammatory response.

Lessons Learned 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 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.

A cytokine storm, autoimmune features and dysfunctions of myeloid cells significantly contribute to severe coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Genetic background of the host seems to be partly responsible for severe phenotype and genes related to innate immune response seem critical host determinants. The C9orf72 gene has a role in vesicular trafficking, autophagy regulation and lysosome functions, is highly expressed in myeloid cells and is involved in immune functions, regulating the lysosomal degradation of mediators of innate immunity. A large non-coding hexanucleotide repeat expansion (HRE) in this gene is the main genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), both characterized by neuroinflammation and high systemic levels of proinflammatory cytokines, while HREs of intermediate length, although rare, are more frequent in autoimmune disorders. C9orf72 full mutation results in haploinsufficiency and intermediate HREs seem to modulate gene expression as well and impair autophagy. Herein, we sought to explore whether intermediate HREs in C9orf72 may be a risk factor for severe COVID-19. Although we found intermediate HREs in only a small portion of 240 patients with severe COVID-19 pneumonia, the magnitude of risk for requiring non-invasive or mechanical ventilation conferred by harboring intermediate repeats &gt, 10 units in at least one C9orf72 allele was more than twice respect to having shorter expansions, when adjusted for age (odds ratio (OR) 2.36, 95% confidence interval (CI) 1.04–5.37, p = 0.040). The association between intermediate repeats &gt, 10 units and more severe clinical outcome (p = 0.025) was also validated in an independent cohort of 201 SARS-CoV-2 infected patients. These data suggest that C9orf72 HREs &gt, 10 units may influence the pathogenic process driving more severe COVID-19 phenotypes.

Although there is still no standard treatment for recurrent glioblastoma multiforme (rGBM), re-irradiation could be a therapeutic option. We retrospectively evaluated the efficacy and safety of re-irradiation using helical TomoTherapy (HT) with a simultaneous integrated boost (SIB) technique in patients with rGBM. 24 patients with rGBM underwent HT-SIB. A total dose of 20 Gy was prescribed to the Flair (fluid-attenuated inversion recovery) planning tumor volume (PTV) and 25 Gy to the PTV-boost (T1 MRI contrast enhanced area) in 5 daily fractions to the isodose of 67% (maximum dose within the PTV-boost was 37.5 Gy). Toxicity was evaluated by converting the 3D-dose distribution to the equivalent dose in 2 Gy fractions on a voxel-by-voxel basis. Median follow-up after re-irradiation was 27.8 months (range 1.6–88.5 months). Median progression-free survival (PFS) was 4 months (95% CI 2.0–7.9 months), while 6-month PFS was 41.7% (95% CI 22.2–60.1 months). Median overall survival following re-irradiation was 10.7 months (95% CI 7.4–16.1 months). There were no cases of re-operation due to early or late toxicity. Our preliminary results suggest that helical TomoTherapy with the proposed SIB technique is a safe and feasible treatment option for patients with rGBM, including those large disease volumes, reducing toxicity.

The introduction of targeted therapies for the treatment of BRAF-mutated metastatic melanoma was associated with different cutaneous adverse events (AEs).To describe the type, frequency and severity of cutaneous AEs related to vemurafenib; to understand the association between AEs and vemurafenib efficacy in terms of median overall survival (OS) and median progression-free survival (PFS); to identify molecular characteristics of long-term responders.This observational, retrospective, monocentric study included all consecutive patients with unresectable stage III or stage IV melanoma and BRAF V600E mutation that started treatment with vemurafenib between May 2012 and May 2014.62 patients with a median age of 56 years (range 26-82) were enrolled and received vemurafenib for a median period of 7.9 months (range 0.8-63.7). Among them, 45 patients presented at least one skin AE, 12 reduced the dosage due to cutaneous toxicity, and only one firstly reduced and after stopped the therapy. No specific molecular biomarkers were detected in long-term survivors.Among long-term survivors, skin AEs seem to be less frequent and less severe. Results on multivariable analysis revealed that the presence of at least one G2 toxicity is a protective factor considering PFS, but not in terms of OS.

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. 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. 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. 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. EU Clinical Trials Register No.: 2016-002732-32; NCT03454750. Collection and assembly of data: April 2017 and February 2019.

Background: To validate a nodal regression system for gastric cancer and to verify its impact on prognosis. Methods: This is an ancillary study which included 47 patients of the GASTRODOC trial. The dedicated pathologists of each Institute were invited to revise all the lymph nodes included in the surgical specimens in order to classify the regression according to the grading system proposed by Tsekrekos et al. The association of the nodal regression system and the clinico-pathological characteristics and prognosis were investigated. Results: According to the classification of Tsekrekos et al., there were 19 (40.4%) patients with grade a, 14 (29.8%) with grade b and 14 (29.8%) with grade c nodal regression. This regression system showed significant statistical associations with pathological N status (p < 0.001), residual tumor classification (p = 0.003) and Becker regression system (p = 0.011). At multivariable analysis only Tsekrekos’ grading regression system was significantly associated with the PFS (HR 10.1, 95% CI 1.3–75.5; p = 0.025). Conclusions: The analyzed nodal regression system is significantly associated with Becker's regression system and it has a strong correlation with prognosis.

IntroductionBone metastases (BMs) are a negative prognostic factor in patients with non-small cell lung cancer (NSCLC). Although immune-checkpoint inhibitors (ICIs) have dramatically changed the therapeutic landscape of NSCLC, little information is available on BMs from NSCLC treated with ICIs alone or in association with bone-targeted therapy (BTT) such as zoledronate or denosumab.MethodsFrom 2014 to 2020, 111 of the 142 patients with BMs secondary to NSCLC extrapolated from the prospective multicenter Italian BM Database were eligible for analysis. Information on blood count, comorbidities, and toxicity was retrospectively collected. The neutrophil-to-lymphocyte ratio (NLR) pre- and post-treatment was calculated. Survival was analyzed using the Kaplan–Meier method, with statistical significance of survival differences assessed using the log-rank test.ResultsMedian age was 66 (range, 42–84) years. Performance status (PS) Eastern Cooperative Oncology Group (ECOG) was 0–1 in 79/111 patients. The majority of patients (89.2%) had adenocarcinoma histology. At a median follow-up of 47.4 months, median progression-free (mPFS) and overall survival (mOS) was 4.9 (95%CI, 2.8–10.0) and 11.9 (95%CI, 8.2–14.4) months, respectively. Forty-six (43.4%) patients with BM NSCLC underwent first- or further-line therapy with ICIs: 28 (60.8%) received nivolumab, 9 (19.6%) pembrolizumab, and 9 (19.6%) atezolizumab. Of the 46 patients treated with ICIs, 30 (65.2%) underwent BTT: 24 (80.0%) with zoledronate and 6 (20.0%) with denosumab. The ICI-alone group had an mOS of 15.8 months [95%CI, 8.2–not evaluable (NE)] vs. 21.8 months (95%CI, 14.5–not evaluable) for the ICI plus BTT group and 7.5 (95%CI, 6.1–10.9) months for the group receiving other treatments (p < 0.001). NLR ≤5 had a positive impact on OS.ConclusionBTT appears to have a synergistic effect when used in combination with ICIs, improving patient survival.

BackgroundCurrently, no data are available on the burden of morbidity and mortality in people with HIV-1 (PWH) harboring a 4-class drug-resistant (4DR) virus (nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase strand transfer inhibitors). The study aimed to assess the incidence of clinical events and death in this population.MethodsThis was a cohort study on PWH from the PRESTIGIO Registry with a documented 4DR virus. Burden of disease was defined as the occurrence of any new event including an AIDS-defining event (ADE) or non-AIDS-defining event (NADE) or death from any cause after 4DR evidence (baseline). Cox regression models evaluated factors associated with the risk of new clinical events/death.ResultsAmong 148 PWH followed for a median (interquartile range) of 47 (32–84) months after 4DR evidence, 38 PWH had 62 new events or died from any cause (incidence rate, 9.12/100 person-years of follow-up; 95% CI = 6.85–11.39): 12 deaths (6 AIDS-related and 6 non-AIDS-related), 18 ADEs, 32 NADEs; 20 of the 38 NADEs (45%) of the incident clinical events were malignancies. The 4-year cumulative incidence of death was 6% (95% CI, 3%–13%), and that of ≥1 event or death was 22% (95% CI, 16%–31%). A higher risk of new clinical events/death was more likely in PWH with previous clinical events (adjusted hazard ratio [aHR], 2.67; 95% CI, 1.07–6.67) and marginally associated with lower baseline CD4+/CD8+ ratio (aHR, 0.82; 95% CI, 0.65–1.02).ConclusionsPWH harboring 4DR have a high burden of disease with a worrying incidence of malignancies, strongly advising for close prevention and monitoring interventions as well as access to innovative therapeutic strategies, especially in people with a history of clinical events and low CD4+/CD8+ ratio.

Background Acute flaccid paralysis (AFP) surveillance has been adopted globally as a key strategy for monitoring the progress of the polio eradication initiative. Hereby, to evaluate the completeness of the ascertainment of AFP cases in Italy, a hospital-discharges based search was carried out. Methods AFP cases occurring between 2007 and 2016 among children under 15 years of age were searched in the Italian Hospital Discharge Records (HDR) database using specific ICD-9-CM diagnostic codes. AFP cases identified between 2015 and 2016 were then compared with those notified to the National Surveillance System (NSS). Results Over a 10-year period, 4163 hospital discharges with diagnosis of AFP were reported in Italy. Among these, 956 (23.0%) were acute infective polyneuritis, 1803 (43.3%) myopathy, and 1408 (33.8%) encephalitis, myelitis and encephalomyelitis. During the study period, a decreasing trend was observed for all diagnoses and overall the annual incidence rate (IR) declined from 5.5 to 4.5 per 100,000 children. Comparing NSS with HDR data in 2015–2016, we found a remarkable underreporting, being AFP cases from NSS only 14% of those recorded in HDR. In particular, the acute infective polyneuritis cases reported to NSS accounted for 42.6% of those detected in HDR, while only 0.9% of myopathy cases and 13.1% of encephalitis/myelitis/encephalomyelitis cases have been notified to NSS. The highest AFP IRs per 100,000 children calculated on HDR data were identified in Liguria (17.4), Sicily (5.7), and Veneto (5.1) Regions; regarding the AFP notified to the NSS, 11 out of 21 Regions failed to reach the number of expected cases (based on 1/100,000 rate), and the highest discrepancies were observed in the Northern Regions. Overall, the national AFP rate was equal to 0.6, therefore did not reach the target value. Conclusions AFP surveillance data are the final measure of a country’s progress towards polio eradication. The historical data obtained by the HDR have been useful to assess the completeness of the notification data and to identify the Regions with a low AFP ascertainment rate in order to improve the national surveillance system.

Objective: Older patients with cancer value functional outcomes as much as survival, but surgical studies lack functional recovery (FR) data. The value of a standardized frailty assessment has been confirmed, yet it's infrequently utilized due to time restrictions into everyday practice. The multicenter GOSAFE study was designed to (1) evaluate the trajectory of patients' quality of life (QoL) after cancer surgery (2) assess baseline frailty indicators in unselected patients (3) clarify the most relevant tools in predicting FR and clinical outcomes. This is a report of the study design and baseline patient evaluations. Materials & Methods: GOSAFE prospectively collected a baseline multidimensional evaluation before major elective surgery in patients (≥70 years) from 26 international units. Short−/mid−/long-term surgical outcomes were recorded with QoL and FR data. Results: 1003 patients were enrolled in a 26-month span. Complete baseline data were available for 977(97.4%). Median age was 78 years (range 70–94); 52.8% males. 968(99%) lived at home, 51.6% without caregiver. 54.4% had ≥ 3 medications, 5.9% none. Patients were dependent (ADL < 5) in 7.9% of the cases. Frailty was either detected by G8 ≤ 14(68.4%), fTRST ≥ 2(37.4%), TUG > 20 s (5.2%) or ASAIII-IV (48.8%). Major comorbidities (CACI > 6) were detected in 36%; 20.9% of patients had cognitive impairment according to Mini-Cog. Conclusion: The GOSAFE showed that frailty is frequent in older patients undergoing cancer surgery. QoL and FR, for the first time, are going to be primary outcomes of a real-life observational study. The crucial role of frailty assessment is going to be addressed in the ability to predict postoperative outcomes and to correlate with QoL and FR.

Background Adult SOT recipients with COVID‐19 have higher mortality rates when compared to general population. There is paucity of data on outcomes in pediatric SOT recipients. Methods This is a cross‐sectional study investigating the prevalence of COVID‐19 infection and outcomes in pediatric SOT (heart, liver, and kidney) recipients. We extracted demographic and clinical characteristics and COVID‐19 testing (PCR or [Ab] test) results from medical records. Clinical characteristics were compared between patients who were positive for COVID‐19 (PCR or Ab) and those who did not, using Mann‐Whitney, Student's t test, or chi‐square test. p value

Currently, there are over 1.9 million confirmed cases of coronavirus disease 2019 (COVID-19) globally with over 590,000 cases in the United States.1 The number of COVID-19–positive children in the United States is unknown. A report summarizing 72,314 COVID-19 cases from the Chinese Center for Disease Control and Prevention noted 416 COVID-19–positive children younger than 10.2 An observational study at Wuhan Children's Hospital noted 31 COVID-19–positive children younger than 1 year with the youngest confirmed case in a 1-day-old.3 Cases were largely characterized by upper respiratory tract infection or pneumonia, fever, cough, and pharyngeal erythema.3 Concomitant neurologic problems have been reported among COVID-19–positive adult patients.4

Rationale: RNA helicase DDX5 is downregulated during hepatitis B virus (HBV) replication, and poor prognosis HBV-related hepatocellular carcinoma (HCC). The aim of this study is to determine the mechanism and significance of DDX5 downregulation for HBV-driven HCC, and identify biologics to prevent DDX5 downregulation. Methods: Molecular approaches including immunoblotting, qRT-PCR, luciferase transfections, hepatosphere assays, Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq), and RNA-seq were used with cellular models of HBV replication, HBV infection, and HBV-related liver tumors, as well as bioinformatic analyses of liver cancer cells from two independent cohorts. Results: We demonstrate that HBV infection induces expression of the proto-oncogenic miR17~92 and miR106b~25 clusters which target the downregulation of DDX5. Increased expression of these miRNAs is also detected in HBV-driven HCCs exhibiting reduced DDX5 mRNA. Stable DDX5 knockdown (DDX5KD) in HBV replicating hepatocytes increased viral replication, and resulted in hepatosphere formation, drug resistance, Wnt activation, and pluripotency gene expression. ATAC-seq of DDX5KD compared to DDX5 wild-type (WT) cells identified accessible chromatin regions enriched in regulation of Wnt signaling genes. RNA-seq analysis comparing WT versus DDX5KD cells identified enhanced expression of multiple genes involved in Wnt pathway. Additionally, expression of Disheveled, DVL1, a key regulator of Wnt pathway activation, was significantly higher in liver cancer cells with low DDX5 expression, from two independent cohorts. Importantly, inhibitors (antagomirs) to miR17~92 and miR106b~25 restored DDX5 levels, reduced DVL1 expression, and suppressed both Wnt activation and viral replication. Conclusion : DDX5 is a negative regulator of Wnt signaling and hepatocyte reprogramming in HCCs. Restoration of DDX5 levels by miR17~92 / miR106b~25 antagomirs in HBV-infected patients can be explored as both antitumor and antiviral strategy.

Mitochondrial impairment is reported in HIV-infected children receiving antiretroviral therapy (ART), as well as those naive to ART. Whether mitochondrial function recovers with early initiation of ART and sustained viral suppression on long-term ART is unclear. In this study, we evaluate mitochondrial markers in well-suppressed perinatally HIV-infected children initiated on ART early in life. We selected a cross-sectional sample of 120 HIV-infected children with viral load

Background To evaluate the appropriateness of chemotherapy use at the Oncology Department of the Bugando Medical Centre of Mwanza, Tanzania. Methods The study was an observational prevalence‐based study designed to evaluate a single‐chemotherapy cycle during a defined time period for a cross‐section of patients at varying stages of their clinical history. The sample included 103 consecutive subjects who were treated during January‐March 2017 and had at least one previous cycle. Chemotherapy treatment omissions, cycle delays, and dose reductions and their causes were recorded using a standard form that included demographic, anthropometric, and clinical items. The data were analyzed descriptively. Results There were 59 males (57.3%) and 44 females (42.7%). Ninety‐four patients were aged ≥18 years. Considering cancer type/site, there were 23 distinct groups of patients. The recorded number of drugs in the chemotherapy regimens varied between one and five. The median cycle number was three (range: 2‐11). Sixty‐eight (66.0%) patients were treated in a standard fashion. For the remaining, cycle delay and dose reduction were the most common cause for nonstandard treatment. Hematologic toxicity was responsible for the greater part of cycle delays, whereas dose reductions were accounted for by a larger spectrum of causes. Overall, toxicity explained 21/35 (60.0%) patients receiving nonstandard treatment. The distribution of toxic events was skewed toward grade 1 and grade 2. Conclusions The observed level of appropriateness of chemotherapy was encouraging. The proportion of patients experiencing severe toxic effects was lower than expected., The study aims to evaluate the appropriateness of chemotherapy use at the Oncology Department of the Bugando Medical Centre of Mwanza, Tanzania. The study was an observational prevalence‐based study designed to evaluate a single‐chemotherapy cycle during a defined time period for a cross‐section of patients at varying stages of their clinical history. The observed level of appropriateness of chemotherapy was encouraging. The proportion of patients experiencing severe toxic effects was lower than expected.

Background: Due to its high incidence, evaluating performance of care delivered to breast cancer patients is a crucial issue. The multidisciplinary panel E.Pic.A. (Economic Appropriateness of an Integrated Care Pathway) defined a set of key performance indicators (KPIs) to evaluate economic waste in breast cancer healthcare interventions. Methods: The E.Pic.A. panel identified the principal KPIs that are crucial within the breast cancer care pathway to evaluate the performance of care. KPIs were defined taking into account their reliability, validity, usability and feasibility of measurement through the linkage between multiple routine healthcare data sources. Results: Seven KPIs were identified: three on instrumental diagnostics, two on surgery and two on treatment. The three KPIs regarding instrumental diagnostics are aimed at assessing the inappropriateness of diagnostic tests performed before and after the index surgery. The two KPIs regarding surgery measure the inappropriateness of possible repeated interventions considering the time elapsed from the index surgery. The two KPIs regarding oncologic therapy measure the inappropriateness about the administration time of adjuvant therapy and radiotherapy considering the time elapsed from the index surgery. Conclusion: E.Pic.A methodology could help to evaluate economic waste in healthcare interventions with the objective of redirecting resources to interventions with greater value. (HTA & Market Access)

BackgroundThe presence of hypoxic cells in high-grade glioma (HGG) is one of major reasons for failure of local tumour control with radiotherapy (RT). The use of hyperbaric oxygen therapy (HBO) could help to overcome the problem of oxygen deficiency in poorly oxygenated regions of the tumour. We propose an innovative approach to improve the efficacy of hypofractionated stereotactic radiotherapy (HSRT) after HBO (HBO-RT) for the treatment of recurrent HGG (rHGG) and herein report the results of an ad interim analysis.MethodsWe enrolled a preliminary cohort of 9 adult patients (aged >18 years) with a diagnosis of rHGG. HSRT was administered in daily 5-Gy fractions for 3-5 consecutive days a week. Each fraction was delivered up to maximum of 60 minutes after HBO.ResultsMedian follow-up from re-irradiation was 11.6 months (range: 3.2-11.6 months). The disease control rate (DCR) 3 months after HBO-RT was 55.5% (5 patients). Median progression-free survival (mPFS) for all patients was 5.2 months (95%CI: 1.34-NE), while 3-month and 6-month PFS was 55.5% (95%CI: 20.4-80.4) and 27.7% (95%CI: 4.4-59.1), respectively. Median overall survival (mOS) of HBO-RT was 10.7 months (95% CI: 7.7-NE). No acute or late neurologic toxicity >grade (G)2 was observed in 88.88% of patients. One patient developed G3 radionecrosis.ConclusionsHSRT delivered after HBO appears to be effective for the treatment of rHGG, it could represent an alternative, with low toxicity, to systemic therapies for patients who cannot or refuse to undergo such treatments.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier NCT 03411408.

Bone metastases (BM) are still the main cause of morbidity in cancer patients because of skeletal-related events (SREs) that reduce quality of life. They have also led to increased social and healthcare costs. At present, data available on BM are insufficient. This was a multicentre prospective observational study of patients with BM from breast cancer (BC) with at least 6 months’ follow-up. Information on patients at the first diagnosis of BM, including demographics and characteristics of the primary tumor and BM. Data were periodically updated by participating centres and reviewed by the coordinator centre. From October 2014 to July 2019, 618 patients with BM from solid tumors were enrolled and 220 were eligible for the present study. Median age was 62 years (range 26–86). Median follow-up was 34 months (range 6–149). At the time of enrolment, 109 (50%) had only BM (BOM) and 109 (50%) had concomitant visceral lesions and BM (BVM). Median time-to-first BM was 47 months (range 0–312) in BOM and 78.6 months in BVM patients. Disease-free interval differed on the basis of BC molecular subtype and stage. Ninety-eight BM patients had at least on SRE. Zoledronate was used in 69.1% of cases and denosumab in 28.3%. First-line treatment was hormone-based (50.7%), chemotherapy-based (38.7%) or chemotherapy- + hormone therapy-based (9.7%). Median progression-free and overall survival were 15.1 months (95% CI 12.6–18.4) and 66.8 months (95% CI 52.1–79.2), respectively. Our prospective study could substantially help to better understand the natural history of BM from BC.

Cisplatin-pemetrexed is a frequently adopted first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) ineligible for biological therapy, notwithstanding its limited efficacy. In the present study, the RAL cell line, an epidermal growth factor receptor (EGFR)-wild-type, p53- and KRAS-mutated model of NSCLC, was used to investigate novel biomarkers of resistance to this treatment. Cells were analyzed 96 h (96 h-post wo) and 21 days (21 days-post wo) after the combined treatment washout. Following an initial moderate sensitivity to the treatment, the cell growth proliferative capability had fully recovered. Gene expression analysis of the resistant surviving cells revealed a significant upregulation of CDKN1A expression in the cells at 96-h post-wo and, although to a lesser extent, in the cells at 21 days-post wo, accompanied by an enrichment of acetylated histone H3 in its promoter region. CDKN1A was also upregulated at the protein level, being mainly detected in the cytoplasm of the cells at 96 h-post wo. A marked increase in the number of apoptotic cells, together with a significant G1 phase block, were observed at 96-h post wo in the cells in which CDKN1A was knocked down, suggesting its involvement in the modulation of the response of RAL cells to the drug combination. On the whole, these data suggest that CDKN1A plays a role in the response to the cisplatin-pemetrexed combination in advanced KRAS-mutated NSCLC, thus suggesting that it may be used as a promising predictive marker.

Objectives NEAT001/ANRS143 demonstrated non-inferiority of once-daily darunavir/ritonavir (800/100 mg) + twice-daily raltegravir (400 mg) versus darunavir/ritonavir + tenofovir disoproxil fumarate/emtricitabine (245/200 mg once daily) in treatment-naive patients. We investigated the population pharmacokinetics of darunavir, ritonavir, tenofovir and emtricitabine and relationships with demographics, genetic polymorphisms and virological failure. Methods Non-linear mixed-effects models (NONMEM v. 7.3) were applied to determine pharmacokinetic parameters and assess demographic covariates and relationships with SNPs (SLCO3A1, SLCO1B1, NR1I2, NR1I3, CYP3A5*3, CYP3A4*22, ABCC2, ABCC10, ABCG2 and SCL47A1). The relationship between model-predicted darunavir AUC0–24 and C24 with time to virological failure was evaluated by Cox regression. Results Of 805 enrolled, 716, 720, 347 and 361 were included in the darunavir, ritonavir, tenofovir and emtricitabine models, respectively (11% female, 83% Caucasian). No significant effect of patient demographics or SNPs was observed for darunavir or tenofovir apparent oral clearance (CL/F); coadministration of raltegravir did not influence darunavir or ritonavir CL/F. Ritonavir CL/F decreased by 23% in NR1I2 63396C>T carriers and emtricitabine CL/F was linearly associated with creatinine clearance (P Conclusions Darunavir concentrations were unaltered in the presence of raltegravir and not associated with virological failure. Polymorphisms investigated had little impact on study-drug pharmacokinetics. Darunavir/ritonavir + raltegravir may be an appropriate option for patients experiencing NRTI-associated toxicity.

Simple Summary An evaluation process and adequate referrals are an important part of a distress screening program but insufficient consideration is given to referrals and uptake of available supportive services. Identifying the reasons for accepting or refusing help is needed to implement a screening-for-distress policy in a clinical cancer setting, as confirmed in the present study. It is vital to reach and motivate the highest possible number of patients to be referred to psycho-oncology services when needed. A multidisciplinary approach could help to raise awareness of the benefit of screening for distress, the implementation of which would improve uptake. Abstract Introduction: Little consideration is given to the referral and uptake of available supportive services after distress screening. However, identifying the reasons for accepting or refusing help is mandatory for implementing a screening policy. The present study explored the practical usefulness of and potential barriers to the application of distress management. Methods: 406 cancer patients were consecutively selected and asked to complete the Distress Thermometer (DT) and Problem Check List (PL). All patients with a DT score ≥6 were invited for a post-DT telephone interview with a trained psychologist. Results: The 112 patients who refused to take part were more often older, retired, at a more advanced stage of illness, and with no previous experience of psychological intervention with respect to those who accepted. Of the 78 patients with a score ≥6 who were referred to the Psycho-Oncology Service, 65.4% accepted the telephone interview. Twenty-two patients rejected the initial invitation immediately for various reasons including logistic difficulties, physical problems, and feeling embarrassed about opening up to a psychologist. Conclusions: Our study confirms that screening per sé is insufficient to deal with the problem of distress and that more emphasis should be placed on implementing referral and treatment.

To evaluate the clinical value of 68Ga-PSMA PET/CT negativity in patients with biochemical recurrent prostate cancer (BCR). One hundred three BCR patients (median age, 70 years; median PSA, 0.47 ng/mL) with negative 68Ga-PSMA PET/CT, followed up for at least 1 year, were retrospectively identified in a database of 1003 consecutive patients undergoing 68Ga-PSMA PET/CT for BCR. Clinical recurrence (CR) was determined or excluded on follow-up imaging selected as per clinical practice. Clinical recurrence-free survival (CRFS) was computed from the date of negative 68Ga-PSMA PET/CT to the date of evident disease; frequencies of CRFS were described as per ISUP patient subset (subset 1: ISUP grades 1 and 2; subset 2: ISUP grade 3; subset 3: ISUP grades 4 and 5) and other conventional variables. In 57 patients out of 103 (55.3%), CR was detected in the prostatic fossa (45.6%), nodes (38.6%), and bone (15.8%). The median CRFS was 15.4 months (range, 12.1–20.5), with a CRFS at 12 months in 61.4% of cases (range, 50.9–70.4) whereas the 24-month CRFS was 34.8% (range, 24–45.8). ISUP subset 1 benefited from significantly longer CRFS compared to subset 2 and subset 3 (median CRFS, 20.5 months, 12.6 months, and 12.1 months, respectively). ISUP subset 3 had significantly poorer 24-month CRFS (9.3%) compared to subset 1 (47.8%) and subset 2 (33.5%). At the univariate and multivariate analyses, the ISUP subset was the only significant risk factor for clinical relapse; ISUP subset 3 and subset 2 patients held a higher risk of CR compared to subset 1 patients (HR of 2.75 [1.35–5.57] for subset 3 versus subset 1; HR of 2.08 [1.11–3.88] for subset 2 versus subset 1). 68Ga-PSMA PET/CT negativity in early BCR patients (PSA

BACKGROUND HCT leaves patients in a relative state of immune deficiency both during their initial transplant admission and for several years following discharge. NTM are generally harmless colonizers of the outside environment, but for immunocompromised patients, they can cause significant disease due to a paucity of T-cell defense. While routine prophylaxis against NTM is recommended for patients with low CD4 counts in certain clinical settings (eg, AIDS), this is not yet established for HCT patients despite their higher risk. METHODS Here we build upon our prior work to determine risk factors for NTM in pediatric HCT patients by comparing NTM patient characteristics to matched HCT controls. RESULTS We followed 272 patients across a 13-year time period, with 11 cases of NTM. Patients with NTM had a significantly lower CD4 count at Day 365 than matched HCT controls (105.5 ± 97.0 cells/µl vs. 856.2 ± 446.1 cells/µl, respectively; p = .001). No other potential risk factors (eg, CMV, GvHD, disease type) were found to be statistically significant, including use of T-cell depleting agents. This is consistent with an average diagnosis of NTM at Day +323 (ie, outside immediate post-transplant period). All-cause mortality was similar between NTM and control HCT groups, with an NTM attributable mortality of

Importance Descriptions of the coronavirus disease 2019 (COVID-19) experience in pediatrics will help inform clinical practices and infection prevention and control for pediatric facilities. Objective To describe the epidemiology, clinical, and laboratory features of patients with COVID-19 hospitalized at a children’s hospital and to compare these parameters between patients hospitalized with and without severe disease. Design, Setting, and Participants This retrospective review of electronic medical records from a tertiary care academically affiliated children’s hospital in New York City, New York, included hospitalized children and adolescents (≤21 years) who were tested based on suspicion for COVID-19 between March 1 to April 15, 2020, and had positive results for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Exposures Detection of SARS-CoV-2 from a nasopharyngeal specimen using a reverse transcription–polymerase chain reaction assay. Main Outcomes and Measures Severe disease as defined by the requirement for mechanical ventilation. Results Among 50 patients, 27 (54%) were boys and 25 (50%) were Hispanic. The median days from onset of symptoms to admission was 2 days (interquartile range, 1-5 days). Most patients (40 [80%]) had fever or respiratory symptoms (32 [64%]), but 3 patients (6%) with only gastrointestinal tract presentations were identified. Obesity (11 [22%]) was the most prevalent comorbidity. Respiratory support was required for 16 patients (32%), including 9 patients (18%) who required mechanical ventilation. One patient (2%) died. None of 14 infants and 1 of 8 immunocompromised patients had severe disease. Obesity was significantly associated with mechanical ventilation in children 2 years or older (6 of 9 [67%] vs 5 of 25 [20%];P = .03). Lymphopenia was commonly observed at admission (36 [72%]) but did not differ significantly between those with and without severe disease. Those with severe disease had significantly higher C-reactive protein (median, 8.978 mg/dL [to convert to milligrams per liter, multiply by 10] vs 0.64 mg/dL) and procalcitonin levels (median, 0.31 ng/mL vs 0.17 ng/mL) at admission (P Conclusions and Relevance In this case series study of children and adolescents hospitalized with COVID-19, the disease had diverse manifestations. Infants and immunocompromised patients were not at increased risk of severe disease. Obesity was significantly associated with disease severity. Elevated inflammatory markers were seen in those with severe disease.

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 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.

Background A link between HBV and PLK1 was clearly evidenced in HBV-driven carcinogenesis, and we have also recently shown that PLK1 is a proviral factor in the early phases of HBV infection. Moreover, we have shown that BI-2536, a small molecule PLK1 inhibitor, was very efficient at inhibiting HBV DNA neosynthesis, notably by affecting nucleocapsid assembly as a result of the modulation of HBc phosphorylation. Yet, as small molecule kinase inhibitors often feature poor selectivity, a more specific and safer strategy to target PLK1 would be needed for a potential development against chronic HBV infections. Methods Here, we analysed using both freshly isolated primary human hepatocytes and differentiated HepaRG, the anti-HBV properties of an LNP-encapsulated PLK1-targeting siRNA. Standard assays were used to monitor the effect of LNP siPLK1, or controls (LNP siHBV and LNP siNon-targeting), on HBV replication and cell viability. Results A dose as low as 100 ng/ml of LNP-siPLK1 resulted in a >75% decrease in secreted HBV DNA (viral particles), which was comparable to that obtained with LNP siHBV or 10 μM of tenofovir (TFV), without affecting cell viability. Interestingly, and in contrast to that obtained with TFV, a strong inhibition of viral RNA and HBe/HBsAg secretions was also observed under LNP siPLK1 treatment. This correlated with a significant intracellular decrease of vRNA accumulation, which was independent of any change in cccDNA levels, thus suggesting a transcriptional or post-transcriptional modulation. Such an effect was not obtained with a biochemical approach of PLK1 inhibition, suggesting an enzymatic-independent role of PLK1. Conclusions This study emphasizes that a specific PLK1 inhibition could help in achieving an improved HBsAg loss in CHB patients, likely in combination with other HBsAg-targeting strategies.

Multiple sclerosis (MS) is a chronic autoimmune disease of the CNS that is characterized by demyelination, axonal loss, gliosis, and inflammation. The murine model of MS is the experimental autoimmune encephalopathy (EAE) induced by immunization of mice with myelin oligodendrocyte glycoprotein (MOG)35–55. Ig-like transcript 3 (ILT3) is an inhibitory cell surface receptor expressed by tolerogenic human dendritic cells. In this study, we show that the recombinant human ILT3.Fc protein binds to murine immune cells and inhibits the release of proinflammatory cytokines that cause the neuroinflammatory process that result in paralysis. Administration of ILT3.Fc prevents the rapid evolution of the disease in C57BL/6 mice and is associated with a profound reduction of proliferation of MOG35–55–specific Th1 and Th17 cells. Inhibition of IFN-γ and IL-17A in mice treated with ILT3.Fc is associated with delayed time of onset of the disease and its evolution to a peak clinical score. Neuropathological analysis shows a reduction in inflammatory infiltrates and demyelinated areas in the brains and spinal cords of treated mice. These results indicate that inhibition of Th1 and Th17 development provides effective suppression of EAE and suggests the feasibility of a clinical approach based on the use of ILT3.Fc for treatment of MS. Furthermore, our results open the way to further studies on the effect of the human ILT3.Fc protein in murine experimental models of autoimmunity and cancer.

Introduction: In a gastric cancer (GC) setting, phase II and III studies refer to an ideal patient population and only describe a specific category of patients. Older patients or those in poorer clinical condition are generally excluded from clinical trials. We aimed to evaluate therapeutic approaches to GC in a real-world setting at our institute (Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori [IRST] IRCCS) over a 10-year period. Methods: A total of 621 consecutive patients with GC diagnosed between January 2000 and December 2009 were considered retrospectively. Among these, 573 with available information on stage of disease were included in the analysis. Demographic and clinical data were collected from paper or electronic medical records. Results: During the study period, 343 (59.8%) patients were diagnosed with GC stage 0 to IIIC (M0): of these, 118 patients had a relapse of disease. A total of 230 patients (40.2%) presented with metastatic disease at diagnosis. Older age was associated with less frequent administration of adjuvant chemotherapy (odds ratio [OR], 0.87; 95% confidence interval [CI], 0.83–0.91); interaction between age and period (OR, 1.02; 95% CI, 1.01–1.03) and stage of disease at diagnosis (OR, 7.95; 95% CI, 3.71–17.1) were positively associated with administration of adjuvant chemotherapy. Older age (OR, 0.87; 95% CI, 0.84–0.90) and presence of comorbidity (OR, 0.46; 95% CI, 0.26–0.83) were associated with less frequent administration of palliative chemotherapy, whereas from 2000–2004 to 2005–2009, patients were more frequently treated with palliative chemotherapy overall (OR, 3.70; 95% CI, 2.01–6.81). Conclusions: Our results confirm that resection is the standard surgical approach to GC, and that chemotherapy is not widely used in adjuvant and metastatic settings. Older age and comorbidities are associated with nontreatment.

The incidence of neuroendocrine neoplasia (NEN) is higher in individuals ≥70 years of age (elderly) who are underrepresented in clinical trials because of comorbidities and low performance status. We retrospectively analyzed the outcome of elderly patients with metastatic NEN (mNEN). Comorbidities were summarized by Charlson Comorbidity Index (CCI), Kaplan–Meier method was applied to estimate overall survival (OS) and Cox’s proportional hazard model was used to assess the impact of known prognostic factors. We retrieved data on 145 mNEN patients aged ≥70 years seen at our center from June 2007 to March 2016. Fifty-six (38.6%) were aged ≥75 years. ECOG PS was 0 in 45.7% of cases and CCI was 0 in 41.0% and 1 in 37.4%. A total of 75.4% of patients had grade (G)1/G2 NEN and 24.6%, G3. Octreoscan/Gallium PET/CT and FDG-PET/CT were positive in 94.2% and 70.3% of cases, respectively. Median follow-up was 72.3 (53.2–85.1) months. Seventy-nine patients received first-line somatostatin analogs (SSA), 23 peptide receptor radionuclide therapy (PRRT) and 36 chemotherapy (CHT). Seven did not undergo first-line therapy and 102 received more than one line. Median overall survival (mOS) was 5.1 years (95% CI: 3.4–6.6). No differences in mOS were seen according to CCI. First-line PRRT patients had a mOS of 6.5 years (95% CI: 3.3–not reached (NR)), SSA 5.7 years (95% CI: 4.2–7) and CHT 5.9 years (95% CI: 0.4–NR). mOS in CHT-treated G3 patients was 1.5 years (1.0–2.5). ECOG PS and FDG PET/CT were identified as independent prognostic factors. Results suggest that the above treatments positively impacted OS in elderly mNEN patients, including those aged ≥75 years.

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

Preliminary studies suggest that capecitabine may be safe and effective in HCC patients. The aim of this study was to retrospectively evaluate the safety and efficacy of metronomic capecitabine as second-line treatment. This multicentric study retrospectively analyzed data of HCC patients unresponsive or intolerant to sorafenib treatment with metronomic capecitabine or best supportive care (BSC).Median progression free survival was 3.1 months in patients treated with capecitabine (95%CI: 2.7–3.5). Median overall survival was 12.0 months (95% CI: 10.7–15.8) in patients receiving capecitabine, while 9.0 months (95% CI: 6.5–13.9) in patients receiving BSC. The result of univariate unweighted Cox regression model shows a 46% reduction in death risk for patients on capecitabine (95%CI: 0.357–0.829; p =0.005) compared to patients receiving BSC alone. After weighting for potential confounders, death risk remained essentially unaltered (45%; 95%CI: 0.354–0.883; p = 0.013). Metronomic capecitabine seems a safe second-line treatment for HCC patients in terms of management of adverse events, showing a potential anti-tumour activity which needs further evaluation in phase III studies.

Docetaxel associated with oxaliplatin and 5-fluorouracil (FLOT) has been reported as the best perioperative treatment for gastric cancer. However, there is still some debate about the most appropriate number and timing of chemotherapy cycles. In this randomized multicenter phase II study, patients with resectable gastric cancer were staged through laparoscopy and peritoneal lavage cytology, and randomly assigned (1:1) to either four cycles of neoadjuvant chemotherapy (arm A) or two preoperative + two postoperative cycles of docetaxel, oxaliplatin, and capecitabine (DOC) chemotherapy (arm B). The primary endpoint was to assess the percentage of patients receiving all the planned preoperative or perioperative chemotherapeutic cycles. Ninety-one patients were enrolled between September 2010 and August 2016. The treatment was well tolerated in both arms. Thirty-three (71.7%) and 24 (53.3%) patients completed the planned cycles in arms A and B, respectively (p = 0.066), reporting an odds ratio for early interruption of treatment of 0.45 (95% confidence interval (CI): 0.18&ndash, 1.07). Resection was curative in 39 (88.6%) arm A patients and 35 (83.3%) arm B patients. Five-year progression-free survival (PFS) was 51.2% (95% CI: 34.2&ndash, 65.8) in arm A and 40.3% (95% CI: 28.9&ndash, 55.2) in arm B (p = 0.300). Five-year survival was 58.5% (95% CI: 41.3&ndash, 72.2) and 53.9% (95% CI: 35.5&ndash, 69.3) (p = 0.883) in arms A and B, respectively. The planned treatment was more frequently completed and was more active, albeit not significantly, in the neoadjuvant arm than in the perioperative group.

Purpose: To investigate the efficacy of metformin (M) plus chemotherapy versus chemotherapy alone in metastatic breast cancer (MBC). Methods: Non-diabetic women with HER2-negative MBC were randomized to receive non-pegylated liposomal doxorubicin (NPLD) 60 mg/m2 + cyclophosphamide (C) 600 mg/m2 × 8 cycles Q21 days plus M 2000 mg/day (arm A) versus NPLD/C (arm B). The primary endpoint was progression-free survival (PFS). Results: One-hundred-twenty-two patients were evaluable for PFS. At a median follow-up of 39.6 months (interquartile range [IQR] 24.6-50.7 months), 112 PFS events and 71 deaths have been registered. Median PFS was 9.4 months (95% CI 7.8-10.4) in arm A and 9.9 (95% CI 7.4-11.5) in arm B (P = 0.651). In patients with HOMA index

Introduction: Osteoporosis represents one of the most frequent comorbidity among HIV patients. The current standard method for osteoporosis diagnosis is dual-energy X-ray absorptiometry. Calcaneal quantitative ultrasound can provide information about bone quality. The aims of this study are to compare these two methods and to evaluate their ability to screen for vertebral fracture. Methods: This cross-sectional study was conducted in HIV patients attending the Clinic of Infectious and Tropical Diseases of Brescia during 2014 and who underwent lumbar/femoral dual-energy X-ray absorptiometry, vertebral fracture assessment and calcaneal quantitative ultrasound. The assessment of osteoporosis diagnostic accuracy was performed for calcaneal quantitative ultrasound and for vertebral fracture comparing them with dual-energy X-ray absorptiometry. Results: We enrolled 73 patients and almost 48% of them had osteoporosis with at least one of the method used. Vertebral fracture were present in 27.4%. Among patients with normal bone measurements, we found vertebral fracture in proportion between 10% and 30%. If we used calcaneal quantitative ultrasound method and/or X-ray as screening, the percentages of possible savable dual-energy X-ray absorptiometry ranged from 12% to 89% and misclassification rates ranged from 0 to 24.6%. A combined strategy, calcaneal quantitative ultrasound and X-Ray, identified 67% of patients with low risk of osteoporosis, but 16.4% of patients were misclassified. Conclusions: We observed that patients with osteoporosis determined by calcaneal quantitative ultrasound and/or dual-energy X-ray absorptiometry have higher probability to undergo vertebral fracture, but neither of them can be used for predicting vertebral fracture. Use of calcaneal quantitative ultrasound for screening is a reasonable alternative of dual-energy X-ray absorptiometry since our study confirm that none strategy is clearly superior, but both screen tools must be always completed with X-ray. Keywords: Osteoporosis, HIV, Calcaneal ultrasound

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.

Introduction Pulmonary carcinoids (PCs) are classed according to the World Health Organization 2004 classification as typical or atypical carcinoids. Owing to their rarity, no dedicated clinical trials with somatostatin analogs (SSAs) have been carried out on primary PCs. Patients and Methods From January 2007 to December 2015, 30 patients with metastatic PCs underwent first-line SSA treatment (20 with octreotide long-acting repeatable 30 mg and 10 with lanreotide 120 mg every 28 days). Eight (23.3%) patients had typical carcinoids and 23 (76.7%) had atypical carcinoids. Results The median age was 65.5 years (range, 47-82 years). All patients (23 males and 7 females) were Gallium-68-DOTA-TOC-positron emission tomography/computed tomography (PET/CT)-positive (29 patients) or octreoscan-positive (1 patient). Of the 20 patients who performed fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 FDG-PET/CT), 14 (70.0%) were positive and 6 negative (30.0%). The median treatment duration was 10 months (range, 2-59 months). One patient achieved a partial response (3.3%), and 26 (86.6%) showed stable disease. One patient interrupted SSA treatment owing to symptomatic cholelithiasis. Five-year survival was 53.0% (95% confidence interval [CI], 15.0%-80.0%). The median progression-free survival (mPFS) was 11.1 months (95% CI, 7.0-15.0 months). Negative 18 FDG-PET/CT patients had an mPFS of 15.2 months (95% CI, 7.6 months to not reached) compared with 7.0 months (95% CI, 4.0-10.1 months) for 18 FDG-PET/CT-positive patients. No differences in mPFS were found in relation to TTF1-value, histologic subtype, and presence of extrahepatic metastases. Conclusion SSAs showed antitumor activity in terms of disease control rate and PFS and proved safe, even in patients with poor Eastern Cooperative Oncology Group status. 18 FDG-PET/CT would appear to be a prognostic factor.

Blood stream infections (BSI) caused by enteric organisms are associated with a particularly high mortality rate in allogeneic hematopoietic cell transplantation (alloHCT) recipients. We conducted a retrospective multicenter study aiming to analyze the risk factors associated with antibiotic resistance and impact of BSI on transplantation-related mortality (TRM) in children after alloHCT. During the study period from 2004 to 2014, 395 children (mean age, 9.4 years) with at least 1 BSI were included. The incidences of resistant gram-negative rods were 20.7% to piperacillin-tazobactam, 10.9% to cefepime, 21% to ceftazidime, 11.4% to levofloxacin, and 8.16% to meropenem. Thirty-eight percent of Enterococcus spp. isolates were resistant to vancomycin. More than 1 episode of BSI was associated with significant increase in the risk of resistance to piperacillin-tazobactam, cefepime, and vancomycin. On multivariate analysis of risk factors for TRM, achievement of neutrophil engraftment by day 30 was associated with lower TRM (P = .002). However, infection with an antibiotic-resistant organism was not associated with TRM. Development of enteric bacterial BSI after the onset of acute gastrointestinal graft-versus-host disease (GVHD) was the strongest predictor of TRM (hazard ratio, 4.786; 95% confidence interval, 2.833 to 8.087; P .001). In patients with acute gastrointestinal GVHD who subsequently developed enteric bacterial BSI, the incidence of 1-year TRM was 33.4% (SE = 7%), compared with 15.3% (SE = 2%) for those without acute gastrointestinal GVHD (P = .004). Primary prevention of a first episode of BSI is arguably the most important intervention to decrease antibiotic resistance. It is also imperative that we develop strategies to maintain gastrointestinal health, especially in patients with gastrointestinal GVHD, in an effort to prevent subsequent enteric bacterial BSI and improve survival.

// Roberta Maltoni 1 , Valentina Casadio 2, * , Sara Ravaioli 2, * , Flavia Foca 3 , Maria Maddalena Tumedei 2 , Samanta Salvi 2 , Filippo Martignano 2 , Daniele Calistri 2 , Andrea Rocca 1 , Alessio Schirone 1 , Dino Amadori 1 , Sara Bravaccini 2 1 Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy 2 Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy 3 Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy * These authors contributed equally to this work Correspondence to: Sara Bravaccini, email: sara.bravaccini@irst.emr.it Keywords: CF-DNA, HER2, PI3KCA, prognosis, breast cancer subtypes Received: August 20, 2016 Accepted: January 23, 2017 Published: February 06, 2017 ABSTRACT As conventional biomarkers for defining breast cancer (BC) subtypes are not always capable of predicting prognosis, search for new biomarkers which can be easily detected by liquid biopsy is ongoing. It has long been known that cell-free DNA (CF-DNA) could be a promising diagnostic and prognostic marker in different tumor types, although its prognostic value in BC is yet to be confirmed. This retrospective study evaluated the prognostic role of CF-DNA quantity and integrity of HER2 , MYC , BCAS1 and PI3KCA , which are frequently altered in BC. We collected 79 serum samples before surgery from women at first diagnosis of BC at Forli Hospital (Italy) from 2002 to 2010. Twenty-one relapsed and 58 non-relapsed patients were matched by subtype and age. Blood samples were also collected from 10 healthy donors. All samples were analyzed by Real Time PCR for CF-DNA quantity and integrity of all oncogenes. Except for MYC , BC patients showed significantly higher median values of CF-DNA quantity (ng) than healthy controls, who had higher integrity and lower apoptotic index. A difference nearing statistical significance was observed for HER2 short CF-DNA ( p = 0.078, AUC value: 0.6305). HER2 short CF-DNA showed an odds ratio of 1.39 for disease recurrence with p = 0.056 (95% CI 0.991-1.973). Our study suggests that CF-DNA detected as liquid biopsy could have great potential in clinical practice once demonstration of its clinical validity and utility has been provided by prospective studies with robust assays.

Supplemental material, Supplementary_Table_1 for Retrospective analysis of gastric cancer management in a real-world setting: a single-institution experience by Manlio Monti, Ilaria Massa, Flavia Foca, Paolo Morgagni, Massimo Framarini, Alessandro Passardi, Fabio Falcini and Giovanni Luca Frassineti in Tumori Journal