Breast cancer electron intraoperative radiotherapy: assessment of preoperative selection factors from a retrospective analysis of 758 patients and review of literature.

PURPOSE: To report our experience with full-dose 21 Gy IORT in early breast cancer patients after breast-conserving surgery to define most important selection factors. METHODS: Seven hundred and fifty eight patients, subjected to conserving surgery and IORT, were retrospectively analyzed evaluating most important clinical outcomes. RESULTS: Median follow up was 5.2 years. Results from Cox analyses defined 2 groups of patients, "suitable" (age > 50 years, non lobular histology, tumour size ≤ 2 cm, pN0 or pNmic, ki67 ≤ 20%, non triple negative receptor status and G1-G2) and "unsuitable" for IORT, with a higher rate of breast related events moving from "suitable" to "unsuitable" group. The 5 year rate of IBR is 1.8% in suitable group with significant differences versus unsuitable (1.8 vs. 11.6%, p < 0.005). Same differences between two groups were evidenced in true local relapse (0.6 vs. 6.9%, p < 0.005) and in new ipsilateral BC (1.1 vs. 4.7%, p < 0.015). CONCLUSIONS: In our current practice we consider the following preoperative factors to select patients suitable for IORT: age > 50 years, absence of lobular histology, tumor size ≤ 2 cm, pN0 or pNmic, according to APBI consensus statement, including also ki67 ≤ 20%, non triple negative receptor status and G1-G2.

Effects of chronic administration of ß-blockers on airway responsiveness in a murine model of heart failure.

Lung function abnormalities, both at rest and during exercise, are frequently observed in patients with chronic heart failure (HF), also in absence of respiratory disease. It has been documented that, in HF, chronic adrenergic stimulation down-regulates ß-adrenoceptors (ß-ARs) and modifies airway relaxant responses. This study was designed to investigate in an animal model of HF whether a treatment with a ß-AR blocker, metoprolol, could modify the altered airway hyperresponsiveness. In rats, randomly assigned to 3 experimental groups sham-operated rats (SH), rats with HF induced by left anterior descending coronaric occlusion (HF n = 10), and rats treated with metoprolol 100 mg/kg/die (MET = 10), HF was evaluated after 10 weeks and resulted in increases in plasma norepinephrine and epinephrine and left ventricular end diastolic pressure. ß2-ARs and G-protein-ßAR2-kinase (GRK2) mRNA levels were determined by real time reverse transcriptase PCR. Carbachol-precontracted isolated tracheal rings were used to functionally assess airway smooth muscle relaxation. In pulmonary tissues, ß2-AR mRNA level was significantly decreased in HF groups (-48.73 ± 5.18%, P < 0.01); in the same groups the GRK2 mRNA-levels were significantly enhanced (+222.50 ± 6.13%, P < 0.001); in lung deriving from MET groups the levels of mRNA were significantly increased (+339.86 ± 11.26%, P < 0.001), while the GRK2 mRNA-levels unchanged (-59.02 ± 3.97%, P < 0.001), when compared to SH groups. Relaxation of tracheal strips in response to salbutamol was significantly reduced in HF groups; in tracheal rings, deriving from MET groups, the relaxant effects of salbutamol were significantly enhanced (SH, Emax: 34.87 ± 2.98%, pD2: 7.45 ± 0.27; HF, Emax: 34.87 ± 2.98%, pD2: 7.45 ± 0.27; MET, Emax: 85.43 ± 6.80%, pD2: 6.95 ± 0.59, P < 0.001). In HF, the down-regulation of pulmonary ß-ARs results in a significant attenuation of airway relaxation. These effects have been reversed by a treatment with metoprolol, suggesting a potential role of ß-AR blockers in the treatment of patients suffering from HF and chronic obstructive airway diseases.

Skip pattern approach toward the early access of innovative anticancer drugs.

BACKGROUND: With the rapid development of innovative anticancer treatments, the optimization of tools able to accelerate the access of new drugs to the market by the regulatory authority is a major issue. The aim of the project was to propose a reliable methodological pathway for the assessment of clinical value of new therapeutic innovative options, to objectively identify drugs which deserve early access (EA) priority for solid and possibly in other cancer scenarios, such as the hematological ones. MATERIALS AND METHODS: After a comprehensive review of the European Public Assessment Report of 21 drugs, to which innovation had previously been attributed by the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA), an expert panel formulated an algorithm for the balanced use of three parameters: Unmet Medical Need (UMN) according to AIFA criteria, Added Benefit (AB) according to the European Society for Medical Oncology's Magnitude of Clinical Benefit Scale (ESMO-MCBS) criteria and Quality of Evidence (QE) assessed by the Grades of Recommendation Assessment, Development and Evaluation (GRADE) method. By sequentially combining the above indicators, a final priority status (i.e. EA or not) was obtained using the skip pattern approach (SPA). RESULTS: By applying the SPA to the non-curative setting in solid cancers, the EA status was obtained by 5 out of 14 investigated drugs (36%); by enhancing the role of some categories of the UMN, additional 4 drugs, for a total of 9 (64%), reached the EA status: 2 and 3 drugs were excluded for not achieving an adequate score according to AB and QE criteria, respectively. For hematology cancer, only the UMN criteria were found to be adequate. CONCLUSIONS: The use of this model may represent a reliable tool for assessment available to the various stakeholders involved in the EA process and may help regulatory agencies in a more comprehensive and objective definition of new treatments' value in these contexts. Its generalizability in other national contexts needs further evaluation.

Outcome in patients with diffuse large B-cell lymphoma who relapse after autologous stem cell transplantation and receive active therapy. A retrospective analysis of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Autologous hematopoietic stem cell transplantation (auto-HSCT) is the standard of care for patients with diffuse large B-cell lymphoma (DLBCL) who relapse/progress after first line chemoimmunotherapy. Long-term outcome of those who relapse after transplant is poor. We present the results of a retrospective study of 256 adult patients reported to the EBMT registry with DLBCL who relapsed after auto-HSCT performed between 2003 and 2013, and who received active salvage strategies. One hundred and fifty-four (60%) were male; median age was 53 years. Median time to relapse was 7 months, 65% relapsed during the first year. Overall response rate after salvage therapy was 46%. Median follow-up after first salvage therapy was 40 months (IQR 23-63 months). Overall survival (OS) at 3 years was 27% (95% CI 22-33). OS at 3 years of patients relapsing longer than 1 year after auto-HSCT was 41% (95% CI 31-53) compared with 20% (95% CI 14-24) in those who relapsed in less than 1 year. Eighty-two patients (32%) had a second HSCT, an allogeneic HSCT (allo-HSCT) in 69 cases, at a median time of 6.5 months after relapse. OS at 3 years after allo-HSCT was 36% (95% CI 25-51). In conclusion, the prognosis of patients with DLBCL that relapse after auto-HSCT is dismal. Patients who relapse in less than 1 year remain an unmet need, and should be considered for CAR T cell therapy or clinical trials. Patients who relapse after 1 year can be rescued with salvage therapies and a second HSCT. These results provide a benchmark to compare data of new prospective studies.

Autologous bone marrow transplantation for acute myeloid leukaemia in children using total body irradiation and melphalan as conditioning regimen.

We conducted a phase II study on 19 children with AML in first (10 patients) or second (nine patients) complete remission (CR) treated with ABMT, evaluating the combination of total body irradiation (TBI, 12 Gy in six divided fractions) and high-dose melphalan (140 mg/m2 in single dose) in an attempt to improve antitumour efficacy of conditioning regimen. All patients received cryopreserved and in vitro purged (mafosfamide at a dose of 100 micrograms/ml) bone marrow. The median time from first CR to ABMT was 5 months compared with a median time of 3 months for patients in second remission. One of the 19 patients, transplanted in second CR, died of transplant-related complication 10 days after transplant and another second CR patient relapsed on day +28, before engraftment. Three further patients in second CR relapsed at 6, 6 and 18 months after marrow transplant, respectively, and this determined a relapse rate of 43% in children given ABMT in second CR and 0% for patients transplanted in first remission (P < 0.05). Seventy-two per cent of all patients are projected to be alive and disease-free at 6 years, whereas the event-free survival of patients in first and in second CR is 100 and 44%, respectively (P < 0.05). Although the number of patients does not allow us to draw any firm conclusion, our results are encouraging and suggest that the association of TBI and high-dose melphalan appears to be safe and valuable.

The effect of very-low-dose warfarin on markers of hypercoagulation in metastatic breast cancer: results from a randomized trial.

Malignancy is a risk factor for thromboembolism and anti-cancer chemotherapy can increase this risk. Prophylaxis of thrombosis with very-low-dose warfarin given concurrently with chemotherapy has a significantly reduced rate of thromboembolism in a randomized trial in women with stage IV breast cancer. In a group of 32 patients randomized in one center (16 subjects on warfarin and 16 on placebo), we have prospectively studied the plasma levels of: 1. Markers of 'in vivo' clotting activation (thrombin-antithrombin complex [TAT], prothrombin fragment 1+2 [F1+2] and D-dimer), 2. Factor VII (FVII), and 3. Natural anticoagulants (protein C [PC] and antithrombin [AT]). The aims of this study were: 1. to examine whether laboratory tests predicted those patients who developed thrombosis, and 2. to evaluate the effect of very-low-dose warfarin on hemostatic variables. The patients' hemostatic parameters were evaluated before entry into the study and after starting chemotherapy +/- prophylaxis, before each course for nine courses. Before-treatment results were compared to those of a sex and age-matched non-cancer control group. There was a significant elevation of plasma levels of TAT (p <0.001), F1+2 (p <0.001), D-dimer (p <0.0001) and FVIIa (p <0.05), as well as an increase of FVII proteolysis (p <0.05), whereas plasma PC and AT concentrations were not different from controls. After starting chemotherapy, markers of clotting activation were progressively lower in the group receiving warfarin prophylaxis compared to the group on placebo. Differences between the groups became statistically significant (p <0.01) after the 4th course of chemotherapy. Deep vein thrombosis occurred in two patients in the placebo arm. The results of this study indicate that before therapy, an hypercoagulable state is present in stage IV breast cancer, and after starting chemotherapy, abnormalities of hypercoagulation markers persist, however they are reduced by very-low-dose-warfarin. None of the laboratory variables could predict thrombosis in the single patient.

Survival and quality of life after intensive care.

OBJECTIVE: To determine survival and changes in quality of life (QOL) after hospital discharge in patients who had stayed in an intensive care unit (ICU). DESIGN: Prospective study by direct interviews during ICU stay and 6 months after hospital discharge. SETTING: Surgical-medical ICU. PATIENTS AND METHODS: We interviewed cooperative, adult patients admitted consecutively to the ICU for more than 24 h, living near the hospital, who gave informed consent. The following QOL domains were investigated: residence, physical activity, social life, perceived QOL, oral communication and functional limitation. RESULTS: One-year survival was 82.4% (predicted 84%). Mortality was 36.3% after urgent neoplastic surgery, 19.4% for medical admissions and 4.9% after non-neoplastic surgery. Of 160 patients studied, eight cases, older and already deteriorated at the first interview, could not respond to the perceived QOL item after ICU discharge. In the other 152 patients, physical activity was reduced in 31% (usually slightly), social life had worsened in 32% and functional limitation increased in 30%. The perceived QOL did not change. CONCLUSIONS: After hospital discharge, the survival of ICU-admitted patients is comparable to that of the general population and not related to ICU treatments. Most patients maintain their physical activity and social status at the preadmission level. Any worsening, if present, is slight and does not influence perceived QOL.

Quality of life before intensive care admission: agreement between patient and relative assessment.

OBJECTIVE: To assess the agreement between patients and relatives concerning the formers' quality of life (QOL) before intensive care unit (ICU) admission. DESIGN: Prospective study involving direct interviews of patients and relatives during ICU stay. SETTING: Two four-bed surgical-medical ICUs in a 960-bed teaching hospital. PATIENTS AND METHODS: A hundred seventy-two adult, co-operative patients consecutively admitted to ICU for more than 24 h, and their relatives were interviewed. The instruments used were two questionnaires suitable for ICU patients: QOL-IT and QOL-SP. Interobserver reproducibility was investigated in 36 patients. RESULTS: Interobserver reproducibility was nearly perfect (weighted Kappa 0.99 for QOL-IT and QOL-SP). Considering global scores, weighted Kappa was 0.78 for QOL-IT and 0.82 for QOL-SP, with the mean difference between patients and relatives lower than 0.3 for both scores but with limits of agreement wider than 4. Among the items, concordance was excellent in the areas of physical activity and social life for both questionnaires. Gender, living together with the patient and the degree of relationship of relatives did not influence the agreement. CONCLUSIONS: The relatives give global scores for both instruments which can be regarded as acceptable substitutes for those given by patients. However, the wide limits of agreement should make investigators cautious in analysing together scores generated by patients and by relatives. The emotional dimension seems to be assessed less accurately by relatives than the physical one.

Validation of two quality of life questionnaires suitable for intensive care patients.

OBJECTIVE: To validate two instruments measuring quality of life (QOL) suitable for patients admitted to the intensive care unit (ICU): QOL-IT and QOL-SP. DESIGN: Prospective study using patient interviews. SETTING: Two four-bed surgical-medical ICUs in a 960-bed teaching hospital. PATIENTS AND METHODS: One hundred seventy-two adult, co-operative patients consecutively admitted to ICU for more than 24 h were interviewed. One year after hospital discharge, 84 survivors were interviewed again. Inter-observer reproducibility was investigated in 36 patients. To validate the instruments, the QOL-IT and QOL-SP scores reported by patients were considered according to the functional limitation evaluated by the interviewer. Moreover, the theoretical prediction that patients with chronic diseases should have a worse QOL before ICU admission than patients with only acute illness was tested. QOL-IT and QOL-SP scores given 1 year after hospital discharge were compared with those recorded at the first interview. RESULTS: Inter-observer reproducibility was excellent. The possible range of QOL-IT is 0-20 and that of QOL-SP 0-29. According to the functional limitation (absent, mild or severe), the median QOL-IT score increased from 3 to 6 to 13 and QOL-SP from 2 to 6 to 12 (p< 0.0001). The patients with chronic diseases gave scores significantly higher than the patients with only acute illness (median QOL-IT 8 versus 3, p< 0.013; QOL-SP 8 versus 4, p< 0.004). The median QOL-IT score changed from 3 to 4 one year after hospital discharge, a difference which is statistically (p< 0.001), but not clinically, significant. The median QOL-SP score was 3 and did not change. CONCLUSIONS: QOL-IT and QOL-SP are instruments able to discriminate between different health states.

Validation of severity scoring systems SAPS II and APACHE II in a single-center population.

OBJECTIVE: To validate two severity scoring systems, the Simplified Acute Physiology Score (SAPS II) and Acute Physiology and Chronic Health Evaluation (APACHE II), in a single-center ICU population. DESIGN AND SETTING: Prospective data collection in a two four-bed multidisciplinary ICUs of a teaching hospital. PATIENTS AND METHODS: Data were collected in ICU over 4 years on 1,721 consecutively admitted patients (aged 18 years or older, no transferrals, ICU stay at least 24 h) regarding SAPS II, APACHE II, predicted hospital mortality, and survival upon hospital discharge. RESULTS: At the predicted risk of 0.5, sensitivity was 39.4 % for SAPS II and 31.6 % for APACHE II, specificity 95.6 % and 97.2 %, and correct classification rate 85.6 % and 85.5 %, respectively. The area under the ROC curve was higher than 0.8 for both models. The goodness-of-fit statistic showed no significant difference between observed and predicted hospital mortality (H = 7.62 for SAPS II, H = 3.87 for APACHE II; and C = 9.32 and C = 5.05, respectively). Observed hospital mortality of patients with risk of death higher than 60 % was overpredicted by SAPS II and underpredicted by APACHE II. The observed hospital mortality was significantly higher than that predicted by the models in medical patients and in those admitted from the ward. CONCLUSIONS: This study validates both SAPS II and APACHE II scores in an ICU population comprised mainly of surgical patients. The type of ICU admission and the location in the hospital before ICU admission influence the predictive ability of the models.

Plasma dopamine concentration and effects of low dopamine doses on urinary output after major vascular surgery.

To evaluate plasma dopamine concentration and the effects of low doses infusion on urinary output after abdominal vascular surgery in patients with renal function impairment we performed a prospective clinical study. Twenty hemodynamically stable patients (mean age 66.6 years), with serum creatinine concentration < 2 mg %, who undergoing general anesthesia for major vascular surgery participated. A low dose of dopamine (3 micrograms/kg/min) was administrated to patients with postoperative protracted urinary output < 0.5 ml/kg/hr for at least eight hours. Plasmatic determinations were taken at T0 (no dopamine administration), when urinary output began to increase, or if not, after two hours (T1), at eight (T2), and 24 (T3) hours after the beginning of infusion. After 24 hours the dopamine infusion was stopped and the patient's plasmatic level was measured four hours later (T4). Dopamine plasma concentrations were measured using high-performance liquid chromatography. Plasma dopamine concentration increased in all patients and reached a steady state at T2 (T2 = 76.41 +/- 16.84 ng/ml). Dopamine induced a concentration-dependent increase in urinary output (T0 = 0.45 +/- 0.14; T1 = 1.49 +/- 1.11; T2 = 2.34 +/- 1.44; T3 = 1.57 +/- 0.57; T4 = 0.85 +/- 0.7 ml/kg/hr). Three patients did not have an enhanced urinary output after dopamine infusion; they did have a prolonged clamping time and operation time (162 +/- 24 and 570 +/ 30 min, respectively). We conclude that low dose dopamine induces a dose-dependent increase of urinary output. This phenomenon also has been found in patients when their plasma concentration had not yet reached the steady-state. Lack of responsiveness to dopamine suggests a renal function impairment probably due to the prolonged aortic clamping time.

Analgesia, sedation, and memory of intensive care.

PURPOSE: The purpose of this article was to investigate the relationship between analgesia, sedation, and memory of intensive care. PATIENTS AND METHODS: One hundred fifty-two adult, cooperative intensive care unit (ICU) patients were interviewed 6 months after hospital discharge about their memory of intensive care. The patient was considered to be cooperative when he/she was aware of self and environment at the interview. The patients were grouped as follows: A (45 patients) substantially no sedation, B (85) morphine, and C (22) morphine and other sedatives. RESULTS: The patients having no memory of intensive care were 38%, 34%, and 23% respectively, in the three groups. They were less ill, according to SAPS II (P <.05), and had a shorter ICU stay (P <.01). Group C patients were more seriously ill according to SAPS II, duration of mechanical ventilation, and length of stay in ICU and in hospital (P <.001). The incidence of factual, sensation, and emotional memories was not different among the three groups. Females reported at least one emotional memory more frequently than males (odds ratio 4.17; 95% CI 10.97-1.59). CONCLUSIONS: The patients receiving sedatives in the ICU are not comparable with those receiving only opiates or nothing, due to the different clinical condition. The lack of memory of intensive care is present in one third of patients and is influenced more by length of stay in ICU than by the sedation received. Sedation does not influence the incidence of factual, sensation, and emotional memories of ICU admitted patients. Females have higher incidences of emotional memories than males.

Multicenter trial comparing tramadol and morphine for pain after abdominal surgery.

Seventy patients (40 male, 30 female), mean (SD) age 60.8 +/- 13.7 years were treated with parenteral morphine (10 mg/1 ml ampul) or tramadol (100 mg/2 ml ampul) to verify their analgesic effects in pain following abdominal surgery. The multicenter trial followed an open, controlled experimental design between patients, randomized within the centers. The drugs were given by intramuscular injection, as requested by patients, starting in the postoperative period when pain was more than 70 mm, assessed on a visual analog scale. Patients were allowed up to six ampuls of tramadol or morphine in the 24-h trial but in the first 4 h, if they asked for supplementary analgesic, only diclofenac (75 mg in a 3-ml ampul) was allowed. Both test drugs gave rapid and constant pain relief. After the first dose, pain intensity was reduced 36.2% with tramadol, and 51% with morphine; the pain-free interval was similar for both treatments. The quality of sleep and the number of hours of sleep the night after surgery were similar for both groups. Tramadol was tolerated better, giving rise to no untoward reactions; with morphine there was one case of mild respiratory depression. In abdominal surgery, therefore, tramadol given by intramuscular injection has postoperative analgesic activity similar to morphine, but is better tolerated.

Cyclophosphamide, epirubicin, etoposide, cis platinum (CEVP) in combination with radiotherapy: evaluation of a protocol adopted for 6 years in 148 cases of small cell lung cancer.

The present study was carried out with the purpose of assessing and evaluating the responsiveness of small cell lung cancer (SCLC) to combined treatment (i.e., chemotherapy and radiotherapy). This approach was applied to all patients observed in our Institution during the last 6 years with the exclusion of patients more than 65 years old, with Karnofsky performance status less than 60, and with concomitant non-neoplastic diseases. One hundred and forty-eight patients were selected and treated with a combination chemotherapy regimen including cyclophosphamide, etoposide, epirubicin and cisplatinum. For patients with limited disease, treatment consisted of 3 cycles of chemotherapy (induction), followed by radiation therapy and then by another 3 cycles of chemotherapy (consolidation). For those with extensive disease, treatment consisted only of 6 consecutive cycles of chemotherapy. Results, besides showing the good activity and tolerability of the chemotherapeutic regimen employed (which induced 80% overall response), indicated that some prognostic factors such as the number of metastatic sites, brain and liver involvement and performance status are essential in determining the outcome of response and, particularly, of survival. In addition, the efficacy and tolerability of the combination chemotherapy-radiotherapy were confirmed, as was the evidence of a synergistic pharmacologic effect between cis-platinum and etoposide.

[Surgical treatment of post-traumatic mobile costal flaps]. / Il trattamento chirurgico dei lembi costali mobili post-traumatici.

Twelve cases of surgical management of post-traumatic mobile costal flap are reported. An account is given of the indications for surgery and the various types of costal immobilisation suitable for the anatomical features of the flap. The technique is described in detail and the results are discussed.

Bendamustine in combination with ofatumumab in relapsed or refractory chronic lymphocytic leukemia: a GIMEMA Multicenter Phase II Trial.

We conducted a phase II, noncomparative, open-label, multicenter GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) study (CLL0809) to assess the efficacy and safety of bendamustine in combination with ofatumumab (BendOfa) in relapsed/refractory chronic lymphocytic leukemia (CLL). Forty-seven patients from 14 centers were evaluated. Therapy consisted of bendamustine (70 mg/m(2)) for 2 consecutive days every 28 days, and ofatumumab 300 mg on day 1 and 1000 mg on day 8 during the first cycle, and 1000 mg on day 1 subsequently. Treatment was administered up to six cycles. The overall response rate (ORR), as per intention-to-treat analysis, was 72.3% (95% confidence of interval (CI), 57-84%), with 17% complete responses. After a median follow-up of 24.2 months, the overall survival was 83.6% (95% CI, 73.0-95.7%) and the progression-free survival (PFS) was 49.6% (95% CI, 35.9-68.6%). The median PFS was 23.6 months. Univariate and multivariate analyses were used to identify clinical and biological characteristics associated with ORR and PFS. Myelosuppression was the most common toxicity; grade ≥3 neutropenia was observed in 61.7% of patients; however, grade ≥3 infections occurred in 6% of patients. BendOfa is feasible and effective in relapsed/refractory CLL patients, including patients with high-risk clinical and biological features.