Phase II study of eribulin in combination with gemcitabine for the treatment of patients with locally advanced or metastatic triple negative breast cancer (ERIGE trial). Clinical and pharmacogenetic results on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC).

BACKGROUND: The combination of a microtubule inhibitor (eribulin) with a nucleoside analog (gemcitabine) may synergistically induce tumor cell death, particularly in triple negative breast cancer (TNBC) characterized by high cell proliferation, aggressive behavior, and chemo-resistance. PATIENTS AND METHODS: This is an open-label, multicenter phase II study evaluating the combination of eribulin (0.88 mg/m2) plus gemcitabine (1000 mg/m2) on days 1 and 8 of a 21-day cycle as either first- or second-line treatment of locally advanced or metastatic TNBC. The primary endpoint was the objective response for evaluable patients. A prospective, molecular correlative study was carried out to assess the role of germinal BRCA pathogenic variants and single nucleotide polymorphisms (SNPs) in predicting efficacy and toxicity of the combination regimen. RESULTS: From July 2013 to September 2016, 83 evaluable patients were enrolled. They received a median number of six cycles of treatment. An overall response rate (ORR) of 37.3% (31 patients) was observed, with a complete response rate of 2.4% and a partial response rate of 34.9%; the clinical benefit rate was 48.8%. With a median follow-up of 28.8 months, the median response duration was 6.6 months, the median progression-free survival (PFS) was 5.1 months, and the median overall survival (OS) was 14.5 months. The most common grade 3-4 adverse events were aminotransferase elevation (in 25% of the patients) and neutropenia (in 23.8%). Women with BRCA1/2 pathogenic variants were associated with worse ORR, PFS, and OS than BRCA1/2 wild-type carriers. CYP3A4 and FGD4 SNPs were associated with increased risk of liver toxicity. Three different SNPs in CDA∗2, RRM1, and CYP2C8 genes were significantly associated with poorer OS. CONCLUSIONS: The combination of eribulin and gemcitabine showed promising activity and a moderate toxicity profile in metastatic TNBC. BRCA status and pharmacogenetics tests may help identify patients with high probability of response with negligible toxicity. EUDRACT NUMBER: 2012-003505-10.

Clinical results of proton therapy reirradiation for recurrent nasopharyngeal carcinoma.

Background and purpose: Recurrent nasopharyngeal carcinoma (NPC) has limited curative treatment options. Reirradiation is the only potential definitive treatment in advanced stages at a cost of substantial severe and often life-threatening toxicity. Proton therapy (PT) reduces irradiated volume compared with X-ray radiotherapy and could be advantageous in terms of safety and efficacy in a population of heavily pretreated patients. We report the retrospective results of PT reirradiation in recurrent NPC patients treated at our Institution Methods: All recurrent NPC patients treated since the beginning of clinical activity entered the present analysis. Clinical target volume consisted of Gross Tumor volume plus a patient-specific margin depending on disease behavior, tumor location, proximity of organs at risk, previous radiation dose. No elective nodal irradiation was performed. Active scanning technique with the use of Single Field Optimization (SFO) or Multifield Optimization (MFO) was adopted. Cumulative X-ray -PT doses were calculated for all patients using a dose accumulation tool since 2016. Treatment toxicity was retrospectively collected. Results: Between February 2015, and October 2018, 17 recurrent NPC patients were treated. Median follow-up (FUP) was 10 months (range 2-41). Median PT reirradiation dose was 60 Gy RBE (range 30.6-66). The majority of patients (53%) underwent concomitant chemotherapy. Acute toxicity was low with no ≥ G3 adverse events. Late events ≥ G3 occurred in 23.5% of patients. Most frequent late toxicity was hearing impairment (17,6%). G2 soft tissue necrosis occurred in two patients. Fatal bleeding of uncertain cause (either tumor recurrence or G5 carotid blowout) occurred in one patient. Kaplan-Meier 18 months Overall Survival (OS) and Local control (LC) rates were 54.4% and 66.6%, respectively. Conclusions: Our initial results with the use of modern PT for reirradiation of recurrent NPC patients are encouraging. Favorable LC and OS rates were obtained at the cost of acceptable severe late toxicity.

A randomized, phase 2 study of cetuximab plus cisplatin with or without paclitaxel for the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: B490 (EudraCT# 2011-002564-24) is a randomized, phase 2b, noninferiority study investigating the efficacy and safety of first-line cetuximab plus cisplatin with/without paclitaxel (CetCis versus CetCisPac) in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). PATIENTS AND METHODS: Eligible patients had confirmed R/M SCCHN (oral cavity/oropharynx/larynx/hypopharynx/paranasal sinus) and no prior therapy for R/M disease. Cetuximab was administered on day 1 (2-h infusion, 400 mg/m2), then weekly (1-h infusions, 250 mg/m2). Cisplatin was given as a 1-h infusion (CetCis arm: 100 mg/m2; CetCisPac arm: 75 mg/m2) on day 1 of each cycle for a maximum of six cycles. Paclitaxel was administered as a 3-h infusion (175 mg/m2) on day 1 of each cycle. After six cycles, maintenance cetuximab was administered until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). We assumed a noninferiority margin of 1.40 as compatible with efficacy. RESULTS: A total of 201 patients were randomized 1 : 1 to each regimen; 191 were assessable. PFS with CetCis (median, 6 months) was noninferior to PFS with CetCisPac (median, 7 months) [HR for CetCis versus CetCisPac 0.99; 95% CI: 0.72-1.36, P = 0.906; margin of noninferiority (90% CI of 1.4) not reached]. Median overall survival was 13 versus 11 months (HR = 0.77; 95% CI: 0.53-1.11, P = 0.117). The overall response rates were 41.8% versus 51.7%, respectively (OR = 0.69; 95% CI: 0.38-1.20, P = 0.181). Grade ≥3 adverse event rates were 76% and 73% for CetCis versus CetCisPac, respectively, while grade 4 toxicities were lower in the two-drug versus three-drug arm (14% versus 33%, P = 0.015). No toxic death or sepsis were reported and cardiac events were negligible (1%). CONCLUSION: The two-drug CetCis regimen proved to be noninferior in PFS to a three-drug combination with CetCisPac. The median OS of both regimens is comparable with that observed in EXTREME, while the life-threatening toxicity rate appeared reduced. CLINICAL TRIAL NUMBER: EudraCT# 2011-002564-24.

Effects of high-intensity interval vs. continuous moderate exercise on intraocular pressure.

Our purpose was to compare the acute effects of high-intensity interval training (HIT) vs. continuous moderate exercise (CME) on intraocular pressure (IOP) in healthy subjects. Fifteen young men (age=22.1±6 years) underwent 30 min of HIT (2 min of walking at 50% of reserve heart rate (HR) alternated with 1 min of running at 80% of reserve HR) and CME sessions (30 min of jogging/running at 60% of reserve HR) in random order (2-5 days between sessions). IOP was measured before (baseline), immediately after (post--exercise), 5 min after (Rec5) and 10 min after (Rec10) each exercise session. IOP was reduced post-exercise and remained reduced at Rec5 during both HIT and CME session, with no significant difference between interventions (~16% between 23%). However, IOP remained reduced at Rec10 only after HIT intervention (~19%), whereas IOP at Rec10 returned to levels similar to the observed at baseline during CME intervention. In summary, both HIT and CME equally reduced IOP immediately and 5 min after exercise session. However, only HIT was able to remain IOP reduced 10 min after exercise. These results suggest that HIT may be more effective than CME for reducing IOP in young healthy men.

Renal toxicity and osteonecrosis of the jaw in cancer patients treated with bisphosphonates: a long-term retrospective analysis.

BACKGROUND: Bisphosphonates (BPs) are the mainstay of bone-directed therapy for bone metastases from multiple myelomas and a wide range of solid tumours, but some patients experience renal toxicity or osteonecrosis of the jaw (ONJ). PATIENTS AND METHODS: We reviewed data relating to 398 patients treated with intravenous BP for bone metastases, checking their serum creatinine levels throughout the treatment period in order to assess renal function, and seeking any signs and symptoms of ONJ recorded in their medical records. We also analysed other risk factors for renal toxicity and ONJ in patients who developed them. RESULTS: The median treatment period was 14 months (range 1-119); 108 patients received BP for more than 1 year, and 112 for more than 2 years. Sixteen patients (4%) developed renal toxicity after a median of 24 months of BP treatment, eight of them had been treated for more than 2 years. Ten patients (2.5%) were diagnosed as having ONJ after a median of 39 months on BP, only three of them had been treated for less than 2 years. Two patients experienced both ONJ and renal toxicity. CONCLUSIONS: The low incidence of ONJ and renal toxicity indicates the safety of BP. However, prevention and early detection are still the "first-line therapy" for decreasing their occurrence further.

Bioelectrical impedance phase angle in constitutionally lean females, ballet dancers and patients with anorexia nervosa.

BACKGROUND/OBJECTIVE: Several articles have described body composition in anorexia nervosa, whereas little is known about this issue in underweight ballet dancers and constitutionally lean females. The main aim of this study was to assess whether phase angle (a bioimpedance variable related to body cell mass) differs according to the type of underweight in female adolescents and young women. SUBJECTS/METHODS: Skinfold thicknesses and bioimpedance analysis (whole body and limbs) were evaluated in three groups of underweight patients (30 patients with anorexia nervosa, 10 constitutionally lean individuals and 15 classical dancers) and 30 normal weight controls. RESULTS: There were no differences between the three groups of underweight patients with respect to anthropometric and bioelectrical impedance analysis (BIA) variables with the exception of phase angle. The latter was significantly higher in dancers, lower in anorectic patients and not different in constitutionally lean patients, as compared with controls. CONCLUSIONS: Phase angle (assessed by single-frequency BIA) appears to discriminate between different forms of underweight, being an effective marker of qualitative changes in body composition.

Body composition changes in patients with anorexia nervosa after complete weight recovery.

OBJECTIVE: To assess body composition changes occurring in female anorectic patients after complete weight recovery. DESIGN: Longitudinal study. SUBJECTS: : Ten female patients with anorexia nervosa (age at baseline: 19.7+/-5.8 y) were studied both when undernourished (body mass index, BMI 14.8+/-1.3 kg/ m(2)) and after the achievement of a BMI >18.5 kg/m(2). The control group comprised 18 well-nourished women (age 20.1+/-4.4 y; BMI 19.0-23.0 kg/ m(2)). INTERVENTIONS: Fat mass and fat-free mass were determined by dual-energy X-ray absorptiometry. Skinfold thicknesses and circumferences were also measured. Arm muscle area and arm fat area were calculated by standard formulas. RESULTS: The undernourished patients had lower fat-free mass, fat mass, skinfold thicknesses and circumferences. After refeeding, fat mass represented 25-71% (mean 56%) of the mass regained, this percentage being directly related to the extent of weight gain. The increases in skinfolds and circumferences depended upon the site considered and were correlated to a various extent with those in weight or BMI. Skinfolds at biceps and abdominal sites and the waist-to-hip ratio remained significantly higher, whereas arm muscle circumference was significantly lower, in the refed group than in the control one. CONCLUSION: The percentage of fat in the weight regained by refed female anorectic patients was directly related to the extent of body mass increase. Refed anorectic patients appear to preferentially regain fat in the abdominal and triceps regions. Abnormalities in skinfolds (at biceps and abdominal sites), arm muscle area and waist-to-hip ratio still persist in refed anorectic patients in comparison to control healthy controls.

Changes in bioimpedance analysis after stable refeeding of undernourished anorexic patients.

OBJECTIVE: To evaluate bioimpedance analysis (BIA) parameters in patients with anorexia nervosa when undernourished and then after stable refeeding. DESIGN: Follow-up study. SUBJECTS: Thirteen patients with anorexia nervosa who were studied when undernourished (body weight (Wt): 36.9+/-5.6kg, body mass index (BMI): 14.8+/-1.8kg/m2) and after stable refeeding (Wt: 52.9+/-7.1kg, BMI: 21.2+/-2.3 kg/m2) compared to 25 well-nourished control women (Wt: 53.7+/-4.9 kg, BMI: 21.1+/-1.3 kg/m2). MEASUREMENTS: Impedance and phase angle were determined for the whole body (13 patients) and separately for arms and legs (10 patients). RESULTS: Bioimpedance index (height2/impedance) and phase angle were lower in the undernourished group. Whole-body impedance declined (median, min-max) by 45, 1-151 Ohm after refeeding; the variations of bioimpedance index (BI-Index) were weakly correlated (P < 0.10) with BMI changes. Limb phase angles increased with refeeding, but only changes in whole-body phase angle were correlated (P < 0.025) with the corresponding variations of Wt or BMI. CONCLUSION: Whole-body phase angle increased after weight recovery of anorexic patients, suggesting the occurence of modifications in the extracellular-to-intracellular water ratio. These changes were proportional to the increase in BMI and Wt.

The prediction of total body water from bioelectrical impedance in patients with anorexia nervosa.

Total body water (TBW) was measured by deuterium oxide (D2O) dilution and predicted from bioelectrical impedance (Z) in nineteen anorexic and twenty-seven control women. The equation of Kushner et al. (1992) based on the impedance index (ZI = height2/Z) gave biases of 0.9 (SD 2.5) and 0.8 (SD 2.5) litres in controls and patients respectively (NS, ANOVA). The ZI-based equation of Deurenberg et al. (1993) gave biases of 1.5 (SD 2.4) litres (NS) and 3.0 (SD 2.1) litres (P < 0.001) in controls and patients respectively. Despite the fact that weight was the most powerful predictor of TBW on the study sample (n 46, r2 0.90, P < 0.0001, SE of the estimate 1.6 litres, CV 5.7%), the formulas of Segal et al. (1991) and Kushner et al. (1992) based on the association of weight and ZI gave an inaccurate prediction of TBW in both control and anorexic subjects, with a bias ranging from -3.2 (SD 2.4) to 2.9 (SD 2.1) litres (P < or = 0.001). Population-specific formulas based on ZI (n 46) gave a more accurate prediction of TBW by bioelectrical impedance analysis on the study subjects, with biases of -0.1 (SD 1.8) and 0.5 (SD 1.7) litres in controls and patients respectively (NS). However, the individual bias was sometimes high. It is concluded that bioelectrical impedance analysis can be used to predict TBW in anorexic women at a population level, but the predictions are less good than those based on body weight alone.

[Evaluation of body composition in anorexia nervosa]. / Valutazione della composizione corporea nell'anoressia nervosa.

Bioimpedance analysis (BI) of body composition has been carried out in 116 women: 22 patients with anorexia nervosa (AN) and IMC between 16 and 18.5 kg/m2 (MPE-I: weight 45.3+/-3.1 kg; BMI 17.0+/-0.7 kg/m2); 39 AN patients with BMI< 16 kg/m2 (MPE-II: weight 37.2+/-3.8 kg; BMI 14.5+/-1.0 kg/ m2; 55 healthy women (control= CTR: weight 60.5+/-9.0 kg; BMI 22.8+/-3.1 kg/m2). BI was determined for the whole body and for body segments (arms, legs and trunk): phase angle (AF) of 50 kHz and impedance (Z) of 100, 50 and 5 kHz. Body water was estimated from Z to 50 kHz according to Kushner et al. (AJCN 1993). AF and Z100/Z5 (multifrequency BI) were considered as related to the ratio between extracellular water and intracellular water. Total body water was significantly different between the three groups: 26.5+/-2.9 L in the MPE-II group, 23.6+/-2.9 L in the MPE-I group; 30.3+/-3.7 L in the CTR women. In comparison with the CTR group whole-body AF and leg-AF was lower (p<0.01) in the MPE-II patients while both the MPE groups differed from the CTR group with respect to arm-AF. Multifrequency BI showed differences (p<0.01) between all the groups for the whole-body and segmental measures. Significant correlations for AF and Z100/Z5 vs BMI and % BF were apparent only in the MPE-II group. In conclusion, in the AN the marked modifications of BI parameters indicated a relative increase of extracellular water and were related to BMI and % BF in the very undernourished patients.

Familial and environmental influences on body composition and body fat distribution in childhood in southern Italy.

The aim of this paper was to evaluate the factors affecting body fat excess and distribution in prepubertal age. A cross-sectional survey was carried out on children attending the 4th grade of a primary school in Naples. Eighty-eight per cent of the total sample was examined: 52 girls, 58 boys; mean age = 9.6 yrs (s.e. +/- 0.10). Each child underwent a medical examination, anthropometric measurements and bio-impedance analysis of body composition. The parents were asked to fill in a questionnaire that included demographic data, family history, parent's weight and height, child's perinatal history and his or her involvement in sports activities. Data were analyzed by multiple linear regression. The results showed a direct correlation between parental BMI and children's anthropometric measurements: the children's BMI correlated with the fathers' (P = 0.02) and mothers' BMI (P = 0.027); the children's waist/hip ratio correlated with the fathers' BMI (P = 0.07); the children's subscapular skinfolds correlated with the father's (P = 0.07) and mothers' BMI (P = 0.02); the children's triceps skinfolds correlated with the fathers' BMI (P = 0.004). Among congenital factors, sex was shown to be correlated with the children's waist/hip ratio (P = 0.05) with a lower ratio in the female, indicating a sex influence on body fat distribution even in prepubertal age. The children's BMI correlated with their waist/hip ratio (P = 0.001). Children's systolic blood pressure showed a positive correlation with triceps (P = 0.04) and subscapular (P = 0.05) skinfolds thickness % FAT-PLI (P = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

[Determinants of body fat in prepubertal age]. / Determinanti della massa corporea lipidica in età prepuberale.

In order to evaluate the factors affecting body fat excess and distribution, we have studied children attending the 4th grade of a primary school randomly selected in Naples. 52 girls, 58 boys; mean age = 9.6 years (SE +/- 0.1) were examined. Among the familial factors assessed, a correlation between parental BMI and child's anthropometry was found. Among congenital factors, sex correlates with the children's waist/hip ratio ("t" = -2.07; p = 0.05). Moreover the girl's percent body fat was higher. These two findings suggest the expression of sexual characters in prepubertal age. Systolic blood pressure showed a positive correlation with children's percent body fat ("t" = 2.43; p = 0.016) and subscapular skinfold thickness ("t" = 1.19; p = 0.05), suggesting an influence of these factors on blood pressure level since this age. No correlation was found between children's BMI and weight at birth, family history of diabetes, hypertension or hyperlipidemia. Among environmental factors, only the mothers weight gain during pregnancy ("t" = -2.21; p = 0.03) and breast feeding ("t" = -2.07; p = 0.05) correlated with the children's BMI. The correlation between children's BMI and waist/hip ratio ("t" = 4.64; p = 0.0001), was not confirmed in children who exercise, suggesting a beneficial action of physical activity on body fat distribution. The identification in different populations of factors associated with childhood obesity is important for prevention planning.

Benzodiazepine antagonism by aminophylline.

A double-blind, randomised study was performed to investigate whether aminophylline could reverse the sedative effect of benzodiazepine and if it could shorten the observation time necessary after benzodiazepine sedation. Forty patients undergoing minor abdominal, urogenital or lower extremity surgery were given benzodiazepine to maintain a state of deep sedation after spinal or epidural analgesia was achieved. Postoperatively, the patients received either aminophylline, 110 mg, or physiological saline intravenously. The aminophylline-treated patients showed a significantly more rapid reversal of sedation, but after 30 min there was no difference between the two groups. It is concluded that aminophylline antagonizes the sedative effect of benzodiazepine, but in routine benzodiazepine sedation, aminophylline will not shorten the necessary observation period after sedation.