The Italian Association of Radiotherapy and Oncology Recommendation for Breast Tumor Recurrence: Grades of Recommendation, Assessment, Development and Evaluation Criteria.

Salvage mastectomy is currently considered the standard of care for ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery (BCS) and postoperative radiotherapy (RT). Alternative treatment options for these patients, such as a second BCS followed by repeated RT, have been suggested. The panel of the Italian Association of Radiotherapy and Clinical Oncology developed clinical recommendations for second BCS followed by re-irradiation over mastectomy alone for women with IBTR using the Grades of Recommendation, Assessment, Development, and Evaluation methodology and the evidence to decision framework. The following outcomes were identified by the panel: locoregional control, metastasis-free survival, overall survival, and cancer-specific survival; acute and late toxicity, specific late toxicity, second locoregional tumor, and death related to treatment. An Embase and PubMed literature search was performed by two independent authors. Five retrospective observational studies were eligible for inclusion in the present analysis. According to the reports in the literature and our analysis, the advantages of second quadrantectomy and re-irradiation (re-QUART) outweigh its side effects, with overall good rates of survival and adequate toxicity without increasing costs. Given the very low level of evidence, the panel stated that a second BCS plus re-irradiation can be considered as an alternative to salvage mastectomy for selected patients with IBTR.

Management of kidney cancer patients: 2018 guidelines of the Italian Medical Oncology Association (AIOM).

In the past two decades, the treatment landscape for patients with metastatic renal cell carcinoma has significantly changed thanks to the approval of several targeted molecular therapies (VEGF and mTOR inhibitors) and recently immune-checkpoint inhibitors. The Italian Association of Medical Oncology (AIOM) Renal Cell Cancer (RCC) Guidelines Panel has developed clinical guidelines to provide evidence-based information and recommendations to oncologists, urologists and all professionals involved in the management of patients with renal cell cancer.

Biweekly combination of trastuzumab, docetaxel and gemcitabine for HER2-positive metastatic breast cancer: results of a Phase II GOIM study.

AIMS: Clinical activity of chemotherapy plus trastuzumab in HER2 overexpressing advanced breast cancer has been documented. We report the activity and safety results of biweekly combination of trastuzumab, docetaxel and gemcitabine as first-line therapy in HER2-positive advanced breast cancer. PATIENTS & METHODS: Patients were biweekly treated with trastuzumab (4 mg/kg), gemcitabine (1000 mg/m(2)) and docetaxel (50 mg/m(2)). The primary end point was overall response rate, secondary time to progression, clinical benefit rate (partial response plus complete response plus stable disease for ≥ 24 weeks) and tolerability. RESULTS: A total of 65 patients with HER2-positive advanced breast cancer have been enrolled. In total, 47 patients responded (73%; 95% CI, 60-84), 11 achieved complete response (17%; 95% CI: 8.9-28.7), 36 achieved partial response (56%; 95% CI: 43-68.6). The clinical benefit rate was 87.5% (95% CI: 77-94). Three patients (4.7%) experienced progressive disease. The median time to progression was 14.2 months (95% CI: 10.6-17.8), the median overall survival was 39.3 months and the 36-month survival rate was 55.5% (95% CI: 58-73). The worst toxicities were grade 3 neutropenia (12%), thrombocytopenia (6%) and diarrhea (6%). No cardiac toxicity was reported. CONCLUSION: As first-line therapy, this combination allowed the delivery of polychemotherapy in association to targeted therapy, with clinical activity and mild toxicity. The promising results should be further explored in Phase III randomized clinical trials.

Evidence-based guidelines for the treatment of lower urinary tract symptoms related to uncomplicated benign prostatic hyperplasia in Italy: updated summary from AURO.it.

BACKGROUND: The first Italian national guidelines were developed by the Italian Association of Urologists and published in 2007. Since then, a number of new drugs or classes of drugs have emerged for the treatment of lower urinary tract symptoms (LUTS) related to benign prostatic hyperplasia (BPH), new data have emerged on medical therapy (monotherapies and combination therapies), new surgical techniques have come into practice, and our understanding of disease pathogenesis has increased. Consequently, a new update of the guidelines has become necessary. METHODS: A structured literature review was conducted to identify relevant papers published between 1 August 2006 and 12 December 2010. Publications before or after this timeframe were considered only if they were recognised as important milestones in the field or if the literature search did not identify publications within this timeframe. The quality of evidence and strength of recommendations were determined according to the Grading of Recommendations Assessment, Development and Evaluation framework. MAIN FINDINGS: Decisions on therapeutic intervention should be based on the impact of symptoms on quality of life (QoL) rather than the severity of symptoms (International Prostate Symptom Score (IPSS) score). A threshold for intervention was therefore based on the IPSS Q8, with intervention recommended for patients with a score of at least 4. Several differences in clinical recommendations have emerged. For example, combination therapy with a 5α-reductase inhibitor plus α blocker is now the recommended option for the treatment of patients at risk of BPH progression. Other differences include the warning of potential worsening of cognitive disturbances with use of anticholinergics in older patients, the distinction between Serenoa repens preparations (according to the method of extraction), and the clearly defined threshold of prostate size for performing open surgery (>80 g). While the recommendations included in these guidelines are evidence based, clinical decisions should also be informed by patients' clinical and physical circumstances, as well as patients' preferences and actions. CONCLUSIONS: These guidelines are intended to assist physicians and patients in the decision-making process regarding the management of LUTS/BPH, and support the process of continuous improvement of the quality of care and services to patients.

Induction pemetrexed and cisplatin followed by maintenance pemetrexed versus carboplatin plus paclitaxel plus bevacizumab followed by maintenance bevacizumab: a quality of life-oriented randomized phase III study in patients with advanced non-squamous non-small-cell lung cancer (ERACLE).

In advanced non-small-cell lung cancer (NSCLC), substantial similarities in terms of treatment efficacy and survival have emerged over the years between the different systemic chemotherapy regimens used. More recently, other topics such as histotype, maintenance therapy and quality of life have been explored to ameliorate this plateau. We present the treatment rationale and study design of the ERACLE (induction pEmetrexed and cisplatin followed by maintenance pemetRexed versus cArboplatin-paCLitaxel and bEvacizumab followed by maintenance bevacizumab) trial. Patients enrolled in the ERACLE trial are randomized between combination treatment arms: (A) cisplatin 75 mg/m(2) day 1 and pemetrexed 500 mg/m(2) day 1, every 3 weeks for six cycles followed (in responders or with stable disease) by pemetrexed 500 mg/m(2) day 1, every 3 weeks until progression; and (B) carboplatin AUC 6 day 1, plus paclitaxel 200 mg/m(2) day 1 and plus bevacizumab 15 mg/kg, every 3 weeks for six cycles followed (in responders or patients with stable disease) by bevacizumab 15 mg/kg every 3 weeks until progression. The primary objective of the study is to evaluate the difference in terms of quality of life between treatment arms. together with co-primary endpoints represented by the EuroQoL group (EQ-5D) questionnaire total score and the EQ-5D visual analog scale. Secondary endpoints are the evaluation of treatment activity and exploratory evaluation of treatment efficacy.

Evidence-based guidelines for the management of lower urinary tract symptoms related to uncomplicated benign prostatic hyperplasia in Italy: updated summary.

BACKGROUND AND SCOPE: Despite the high prevalence and huge socio-economic impact of benign prostatic hyperplasia (BPH) in Italy, no national guidelines have been produced so far. This is a summary of the first Italian guidelines on the diagnosis and treatment of lower urinary tract symptoms (LUTS) related to uncomplicated BPH, prepared by a multidisciplinary panel under the auspices of the Italian Association of Urologists and introduced in Italy in 2003. An update compiled by the authors is also included. METHODS: Relevant papers published from 1998 to 2003 (updated to 2006) were identified through a structured literature review and the quality of evidence presented therein was graded according to the Centre for the Evaluation of Effectiveness in Health Administration (CeVEAS) system. Recommendations were based on evidence from the literature, but also on feedback from practitioners and specialists. MAIN FINDINGS/RECOMMENDATIONS: Given the prevalence of BPH, all men aged > or = 50 years of age should be asked about LUTS and informed about disease characteristics and therapeutic options, while sexual function should always be assessed in patients with severe and long-standing LUTS. Initial assessment should include medical history (including drug and co-morbidity history), digital rectal examination, urinalysis, International Prostate Symptom Score-Quality of Life (IPSS-QoL) and a voiding diary, while prostate-specific antigen (PSA) and measurement of prostate volume by suprapubic ultrasonography are indicated in fully informed patients with a life expectancy of > or = 10 years in whom BPH progression could influence treatment choices. QoL considerations should dictate whether to start active treatment. When QoL is not affected by LUTS, watchful waiting is indicated if symptoms are mild, acceptable if they are moderate. When QoL is affected, medical therapy with alpha1-blockers or 5alpha-reductase inhibitors (the latter indicated in patients with increased prostate volume) is appropriate. Combined therapy with alpha1-blockers + 5alpha-reductase inhibitors should only be considered in patients at high risk for progression (prostate volume > 40 mL or PSA > 4 ng/mL), since the incremental cost of combination therapy vs. monotherapy with alpha1-blockers or finasteride is prohibitive. Selection of the type of surgery should be based on the surgeon's experience, the presence of co-morbid conditions and the size of the prostate. Open prostatectomy and transurethral resection of the prostate (TURP) are recommended in patients with acute or chronic retention of urine, and acceptable in obstructed patients with moderate/severe symptoms and worsened QoL. Transurethral incision of the prostate (TUIP) is acceptable when prostate volume is < or = 30 mL. Holmium laser enucleation of the prostate (HoLEP) may be proposed to motivated patients where expert surgeons are available. Transurethral microwave thermotherapy (TUMT) or transurethral needle ablation (TUNA) may be proposed to motivated patients who prefer to avoid surgery and/or do not respond to medical treatment. The possible effects of medical or surgical treatments on sexual function should always be discussed. CONCLUSIONS: These guidelines are intended to provide a framework for health professionals involved in BPH management in order to facilitate decision-making in all areas and at all levels of healthcare.

Randomized phase III trial of neoadjuvant chemotherapy in head and neck cancer: 10-year follow-up.

In 1986, we initiated a multicenter, randomized trial to compare induction chemotherapy with cisplatin and 5-fluorouracil followed by locoregional treatment (surgery and radiotherapy or radiotherapy alone) with locoregional treatment alone in patients with head and neck squamous cell carcinoma. Here we report the long-term results of the trial. A total of 237 patients with nonmetastatic stage III or IV head and neck carcinoma were randomly assigned to receive four cycles of neoadjuvant chemotherapy followed by locoregional treatment (group A) or locoregional treatment alone (group B). Among all patients, overall survival at 5 and 10 years was 23% (95% confidence interval [CI] = 15.3% to 30.9%) and 19% (95% CI = 11.6% to 26.4%), respectively, for those in group A and 16% (95% CI = 9.6% to 23.4%) and 9% (95% CI = 3.5% to 14.7%), respectively, for those in group B (P = .13). Among operable patients, we observed no difference between group A and group B in overall survival at 5 and 10 years (group A, 31% [95% CI = 14.9% to 47.3%] and 22.7% [95% CI = 7.1% to 38.3%], respectively; group B, 43.3% [95% CI = 25.6% to 61.0%] and 14.2% [95% CI = 0.1% to 28.3%], respectively; P = .73). Among inoperable patients, overall survival at 5 and 10 years was 21% (95% CI = 12.3% to 30.1%) and 16% (95% CI = 7.7% to 23.9%), respectively, for group A and 8% (95% CI = 1.5% to 12.3%) and 6% (95% CI = 0.1% to 9.1%), respectively, for group B (log-rank P = .04). Four cycles of neoadjuvant chemotherapy is a promising approach for treating patients with inoperable advanced head and neck cancer but not for treating patients with operable disease.

The impact of progenitor enrichment, serum, and cytokines on the ex vivo expansion of mobilized peripheral blood stem cells: a controlled trial.

The aim of this study was to verify, and possibly improve, culture conditions to expand human mobilized peripheral blood stem cells (PBSCs). We investigated the role of three parameters: A) the culture medium (serum-free versus serum-dependent); B) the initial cell population (Ficoll-separated mononucleated cells versus CD34(+)-selected cells), and C) the low concentration of recombinant cytokines, flt3 ligand, and thrombopoietin in association with a basic cocktail of stem cell factor, interleukin (IL)-6, IL-3, GM-CSF, and erythropoietin. Eighteen leukapheresis samples were monitored in static culture for 15 days. The expansion potential was assessed at day 10 and 15 by total nuclear cells, colony-forming-units (CFUs) (burst-forming units-erythroid [BFU-E], colony-forming units-granulocyte-macrophage [CFU-GM], and colony-forming units-granulocyte-erythroid-macrophage-megakaryocyte [CFU-GEMM]), and flow cytometry immunophenotyping (CD34(+)/CD38(-), CD38(+), CD33(+), CD41(+), GlyA(+) progenitor cells). The results, evaluated by multivariate analysis of variance, emphasize that some variables affected the outcome of stem and progenitor cell expansion. CD34(+) enrichment increased expansion of total nuclear cells, number of CD38(+) and CD33(+) late precursors, and number of the CFU-GM compartment. Interestingly, however, quantitative expansion of GlyA(+) and the early progenitor cells (CD34(+)/CD38(-), CFU-GEMM, BFU-E) are favored by the use of unselected mononucleated cells. Regarding the role of serum, no significant difference was observed except for expansion of total nuclear cells, CFU-GM, and BFU-E. Cytokine combinations, in particular the use of flt3 ligand, stimulated expansion of almost all the cellular subsets, reaching a statistical significance for total nuclear cells and CFU-GM. Our study indicates that progenitor and late precursor multilineage cell compartments of mobilized PBSCs may be significantly expanded in short-term cultures by well-defined experimental conditions. Furthermore, these data might be useful when evaluating ex vivo expansion of hematopoietic cells for clinical purposes.

Delayed high-dose intravesical epirubicin therapy of superficial bladder cancer. A way to reduce the side effects and increase the efficacy--a phase 2 trial.

INTRODUCTION: Intravesical epirubicin is a widely used agent for the treatment of superficial bladder cancer. A direct relationship between dose and activity has been reported: unfortunately the dose increase also increased the frequency and the intensity of treatment-related side effects. MATERIALS AND METHODS: A phase 2 trial was designed to evaluate the toxicity and the activity of a delayed (biweekly) high-dose (80 mg) epirubicin therapy of superficial bladder cancer. Thirty patients with intermediate risk superficial bladder cancer (stage mTa, G2) have been treated with transurethral resection and epirubicin intravesical therapy: the patients were given 80 mg epirubicin in 50 ml sterile saline every 2 weeks for 6 times (delayed regimen). The follow-up ranged from 3 to 26 months. Eleven of 30 (37%) patients experienced a local adverse reaction to intravesical epirubicin requiring specific medication (grade > or = 2 according to NCI-CTC v.2.0, 1999). No systemic toxicity related to the treatment was observed. RESULTS: Out of the 29 evaluable patients, 22 (76%) were free of disease after the induction course, 6 (21%) had superficial bladder cancer recurrences and 1 (3%) experienced tumor progression. CONCLUSION: A delayed (biweekly instillation) high-dose (80 mg) intravesical epirubicin regimen was acceptable in terms of side effects and showed a worthwhile therapeutical impact in patients with intermediate risk superficial bladder cancer.

Human fibroblasts from normal and malignant breast tissue grown in vitro show a distinct senescence profile and telomerase activity.

The telomerase activity and the senescence profile of cultured breast fibroblasts from normal human interstitial and malignant stromal tissue were studied in comparison with their proliferation and differentiation pattern. Fibroblasts were grown either in the presence or absence of a conditioned medium (CM) obtained from cultures of the oestrogen receptor-positive breast cancer MCF-7 cell line. At different passages (from the 2nd up to the 48th), fibroblasts were examined for the telomerase activity by the Telomerase Repeats Amplification Protocol (TRAP) assay, for proliferation profile by Ki-67 antigen expression, and the myofibroblast or smooth muscle cell-like differentiation pattern by immunofluorescence with monoclonal antibodies specific for smooth muscle markers. Serial passages of fibroblasts from normal or tumour breast reveal that the relationship between the levels of telomerase activity and phenotypic/proliferation profile changes with cell subcultivation in a different manner in the two cell populations. The fibroblasts from normal tissue completed 12 passages in a CM-independent way prior to senescence whereas fibroblasts from tumour stroma senescence were attained after 48 passages. These cells showed a marked decrease of telomerase activity, growth rate and smooth muscle alpha-actin expressing myofibroblasts after the 32nd passage. CM treatment of this fibroblast population induces a decline in the myofibroblast content, which precedes the changes in telomerase activity. Passaged fibroblasts from normal breast tissue can be converted to myofibroblasts upon CM treatment whereas those from tumour stroma were CM-insensitive. Taken together our data suggest that a heterogeneous fibroblast population with different life span is activated/recruited in the breast interstitium and poses the problem of a unique activation/recruitment of fibroblasts in neoplastic conditions.