Metronomic chemotherapy (mCHT) in metastatic triple-negative breast cancer (TNBC) patients: results of the VICTOR-6 study.

PURPOSE: Triple-negative breast cancer (TNBC) represents a subtype of breast cancer which lacks the expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2): TNBC accounts for approximately 20% of newly diagnosed breast cancers and is associated with younger age at diagnosis, greater recurrence risk and shorter survival time. Therapeutic options are very scarce. Aim of the present analysis is to provide further insights into the clinical activity of metronomic chemotherapy (mCHT), in a real-life setting. METHODS: We used data included in the VICTOR-6 study for the present analysis. VICTOR-6 is an Italian multicentre retrospective cohort study, which collected data of metastatic breast cancer (MBC) patients who have received mCHT between 2011 and 2016. Amongst the 584 patients included in the study, 97 were triple negative. In 40.2% of the TNBC patients, mCHT was the first chemotherapy treatment, whereas 32.9% had received 2 or more lines of treatment for the metastatic disease. 45.4% out of 97 TNBC patients received a vinorelbine (VRL)-based regimen, which resulted in the most used type of mCHT, followed by cyclophosphamide (CTX)-based regimens (30.9%) and capecitabine (CAPE)-based combinations (22.7%). RESULTS: Overall response rate (ORR) and disease control rate (DCR) were 17.5% and 64.9%, respectively. Median progression free survival (PFS) and overall survival (OS) were 6.0 months (95% CI: 4.9-7.2) and 12.1 months (95% CI: 9.6-16.7). Median PFS was 6.9 months for CAPE-based regimens (95% CI: 5.0-18.4), 6.1 months (95% CI: 4.0-8.9) for CTX-based and 5.3 months (95% CI: 4.1-9.5) for VRL-based ones. Median OS was 18.2 months (95% CI: 9.1-NE) for CAPE-based regimens and 11.8 months for VRL- (95% CI: 9.3-16.7 and CTX-based ones (95%CI: 8.7-52.8). Tumour response, PFS and OS decreased proportionally in later lines. CONCLUSION: This analysis represents the largest series of TNBC patients treated with mCHT in a real-life setting and provides further insights into the advantages of using this strategy even in this poor prognosis subpopulation.

Dihydropyrimidine dehydrogenase pharmacogenetics for predicting fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% of the administered dose of fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients' risk of fluoropyrimidine-related severe toxicity. METHODS: The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg's False Discovery Rate (FDR) procedure was used. RESULTS: FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR<0.0001), *2A rs3918290 A allele carriers (FDR<0.0001), and rs2297595 GG genotype carriers (FDR=0.0014). Neutropenia was the most common FAEs (28.5%). *6 rs1801160 (FDR<0.0001), and *2A rs3918290 (FDR=0.0004) variant alleles were significantly associated with time to neutropenia. CONCLUSIONS: This study adds evidence on the role of DPYD pharmacogenetics for safety of patients undergoing fluoropyrimidine-based chemotherapy.

Metronomic chemotherapy with oral vinorelbine (mVNR) and capecitabine (mCAPE) in advanced HER2-negative breast cancer patients: is it a way to optimize disease control? Final results of the VICTOR-2 study.

PURPOSE: The VICTOR-1 study demonstrated that the all-oral metronomic combination of vinorelbine and capecitabine is highly active and well tolerated in hormone receptor-positive/HER2-negative patients. The VICTOR-2 study was designed to confirm these results. METHODS: Patients received mVNR 40 mg three times a week and mCAPE 500 mg three times a day, continuously. The primary endpoint was the clinical benefit rate (CBR); secondary endpoints were toxicity, objective response rate (ORR), and progression-free survival (PFS). RESULTS: Eighty patients were evaluable for the primary efficacy analysis. Median age was 65.3 years; most patients had HR-positive tumors (65 %). The CBR was 45.7 % (95 % CI 28.8-63.4) and 51.1 % (95 % CI 35.8-66.3) in first- and ≥ second-line therapy, respectively. The ORR was 35.5 % in first-line (95 % CI 19.2-54.6) and 25.6 % in ≥second-line (95 % CI 13.5-41.2). The median duration of response was 11.3 and 6.4 months and PFS rates at 1 year were 24.3 and 22.2 %, respectively. In triple-negative breast cancer patients (N = 28, 35 %) a lower, but clinically relevant CBR (35.7, 95 % CI 18.6-55.9) was observed. The main toxicities per cycle were non-febrile neutropenia (1.1 %), hand-foot syndrome (1.0 %), nausea and vomiting (1.0 %), leucopenia (0.8 %), fatigue (0.7 %), and diarrhea (0.4 %). CONCLUSION: The VICTOR-2 study confirms the clinical activity of mVNR and mCAPE in HER2-negative breast cancer patients, suggesting that the easy schedule of administration, which requires monthly blood tests and limits patients' dependence on hospitals, and the low cost of the drugs are valuable elements, even for countries with limited access to innovative or expensive drugs.

Final results of the real-life observational VICTOR-6 study on metronomic chemotherapy in elderly metastatic breast cancer (MBC) patients.

Nowadays, treatment of metastatic breast cancer (MBC) has been enriched with novel therapeutical strategies. Metronomic chemotherapy (mCHT) is a continuous and frequent administration of chemotherapy at a lower dose and so whit less toxicity. Thus, this strategy could be attractive for elderly MBC patients. Aim of this analysis is to provide insights into mCHT's activity in a real-life setting of elderly MBC patients. Data of patients ≥ 75 years old included in VICTOR-6 study were analyzed. VICTOR-6 is a multicentre, Italian, retrospective study, which collected data on mCHT in MBC patients treated between 2011 and 2016. A total of 112 patients were included. At the beginning of mCHT, median age was 81 years (75-98) and in 33% of the patients mCHT was the first line choice. Overall Response Rate (ORR) and Disease Control Rate (DCR) were 27.9% and 79.3%, respectively. Median PFS ranged between 7.6 and 9.1 months, OS between 14.1 and 18.5 months. The most relevant toxicity was the hematological one (24.1%); severe toxicity (grade 3-4) ranged from 0.9% for skin toxicity up to 8% for hematologic one. This is a large study about mCHT in elderly MBC patients, providing insights to be further investigated in this subgroup of frail patients.

Metronomic chemotherapy for advanced breast cancer patients in the real world practice: Final results of the VICTOR-6 study.

Metronomic chemotherapy (mCHT) refers to the minimum biologically effective dose of a chemotherapy agent given as a continuous dosing regimen, with no prolonged drug-free breaks, that leads to antitumor activity. Aim of the present study is to describe the use of mCHT in a retrospective cohort of metastatic breast cancer (MBC) patients in order to collect data regarding the different types and regimens of drugs employed, their efficacy and safety. Between January 2011 and December 2016, data of 584 metastatic breast cancer patients treated with mCHT were collected. The use of VRL-based regimens increased during the time of observation (2011: 16.8% - 2016: 29.8%), as well as CTX-based ones (2011: 17.1% - 2016: 25.6%), whereas CAPE-based and MTX-based regimens remained stable. In the 1st-line setting, the highest ORR and DCR were observed for VRL-based regimens (single agent: 44% and 88%; combination: 36.7% and 82.4%, respectively). Assuming VRL-single agent as the referee treatment (median PFS: 7.2 months, 95% CI: 5.3-10.3), the longest median PFS were observed in VRL-combination regimens (9.5, 95%CI 88.8-11.3, HR = 0.72) and in CAPE-single agent (10.7, 95%CI 8.3-15.8, HR = 0.70). The VICTOR-6 study provides new data coming from the real-life setting, by adding new information regarding the use of mCHT as an option of treatment for MBC patients.

Metronomic Chemotherapy in Triple-Negative Metastatic Breast Cancer: The Future Is Now?

Triple-negative breast cancer (TNBC) shows a very bad prognosis, even in early stages of disease. Metronomic chemotherapy refers to the minimum biologically effective dose of a chemotherapy agent given as a continuous dosing regimen with no prolonged drug-free breaks that leads to antitumor activity. In the present article, we review preclinical and clinical data of metronomic administration of chemotherapy agents with or without biological agents in TNBC cell lines and patients, contextually reporting data from the VICTOR-2 study in the subgroup of patients with TNBC, in order to stimulate new ideas for the design of clinical trials in this subset of patients.

Local mu and delta opioid receptors regulate amphetamine-induced behavior and neuropeptide mRNA in the striatum.

The purpose of this study was to investigate the role that mu and delta opioid receptor blockade has upon stimulant-induced behavior and neuropeptide gene expression in the striatum. Acute administration of amphetamine (2.5 mg/kg i.p.) caused an increase in behavioral activity and preprodynorphin, substance P, and preproenkephalin mRNA expression. Intrastriatal infusion of the mu opioid antagonist, H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP), or the delta opioid antagonist, H-Tyr-Tic[CH(2)NH]-Phe-Phe-OH (TIPPpsi), significantly decreased amphetamine-induced vertical activity. However, only CTAP reduced amphetamine-induced distance traveled. Quantitative in situ hybridization histochemistry revealed that CTAP blocked amphetamine-induced preprodynorphin and substance P mRNA. However, preproenkephalin mRNA levels in the dorsal striatum were increased to the same extent by CTAP, amphetamine, or a combination of the two drugs. In contrast, TIPPpsi significantly decreased amphetamine-induced mRNA expression of all three neuropeptides. These data indicate that both mu and delta receptor subtypes differentially regulate amphetamine-induced behavior and neuropeptide gene expression in the rat striatum.

Experimental aluminum pathology in rabbits: effects of hydrophilic and lipophilic compounds.

Aluminum lactate [Al(lact)3] (hydrophilic, hydrolytically unstable) and aluminum acetylacetonate [Al(acae)3] (lipophilic, hydrolytically stable) were tested as potential toxicants to rabbits upon IV administration both as aqueous solutions and as liposome suspensions. Both chemicals behaved as cardiotoxic agents when administered as aqueous solutions, but Al(acae)3 was at least two orders of magnitude more active than Al(lact)3. Al(acae)3, but not Al(lact)3, caused myocardial infarcts resembling those in humans (with contraction bands) at doses as low as 0.24 mg/kg body weight, as well as a prominent acanthocytosis. Al(lact)3, when administered as a liposome suspension, was about 300 times more toxic than in aqueous solution, although cardiac damage was not infarctual in character. Both chemical and physical speciation of aluminum(III) thus play an essential role in determining the toxicity of the metal.

Deposition of aluminum in brain tissues of rats exposed to inhalation of aluminum acetylacetonate.

The present paper reports data concerning aluminum accumulation and compartmentation in the central nervous system from rats exposed by inhalation to aluminum acetylacetonate [Al(acac)3] for two weeks. The complex Al(aca)3 was chosen for being neutral, hydrolytically stable and lipophilic. After animals treatment, Al(III) was identified fluorimetrically by using morin (3,5,7',2',4'-pentahydroxyflavone) that gives a specific green-yellow fluorescence when complexed to the metal. Al(III) was observed to be accumulated in the brain cortex, hippocampus, enthorinal area, olfactory bulb as well as in the Purkinje cells of cerebellum, and in the white matter.

Pharmacokinetics and tumor concentration of intraarterial and intravenous cisplatin in patients with head and neck squamous cancer.

Tumor-tissue platinum levels and major pharmacokinetic parameters were determined in 11 patients with head and neck squamous cancer (HNSC) who were given cisplatin (50 mg/m2 daily x 2 days) and 5-fluorouracil (5-FU; 1000 mg/m2, continuous infusion x 5 days) either i.a. or i.v. The plasma peak platinum concentrations (cmax) and the areas under the curve for total platinum concentration versus time (AUC) during i.a. infusions were lower than the i.v. cmax (mean, 1.92 +/- 0.28 and 4.08 +/- 2.80 mg/l, for i.a. and i.v. infusions, respectively) and AUC values (mean, 22.55 +/- 4.96 and 40.66 +/- 10.71 mg h-1 l-1 for i.a. and i.v. treatment, respectively), suggesting a first-passage extraction of the drug by the tumor mass during i.a. infusion. However, no statistically significant difference was found in platinum tumor concentrations after i.a. administration versus i.v. infusion. The lack of a difference in tumor platinum concentrations between the i.a. and the i.v. administration routes might be explained either by a relatively high blood supply to the tumor area, enabling efflux of the surplus free platinum from the tissue, or by the delay between drug infusion and biopsy. After three cycles of i.a. treatment good tumor remission was obtained with minimal local toxicity. Larger clinical studies testing the advantages of the i.a. administration route over i.v. infusion appear to be necessary.

Aluminum(III) influences the permeability of the blood-brain barrier to [14C]sucrose in rats.

To determine the influence of the metal coordination sphere on the permeability of the blood-brain barrier (BBB), rats were injected intraperitoneally with aluminum lactate (Al(lact)3), aluminum acetylacetonate (Al(acac)3), aluminum maltolate (Al(malt)3) at pH 7.5, or with physiological saline. Two h after each treatment, [14C]sucrose physiological saline solution was injected in animals, and the radioactivity was measured in 5 brain regions (cerebral cortex, mesencephalon, diencephalon, medulla-pons, cerebellum). Radioactivity was significantly elevated in brains from animals treated with Al(malt)3 (hydrolytically stable and hydrophilic), and with Al(acac)3 (hydrolytically stable and lipophilic) but not with Al(lact)3. Time-course study carried out at 2, 4 and 24 h with different aluminum compounds showed a persistent radioactivity 24 h after treatment only in the brain from animals treated with Al(acac)3. Morin stain localized AlIII only in neurons from animals treated with Al(acac)3. These findings indicate that AlIII alters the BBB function in the rat either permanently or transiently depending on the physiochemical properties of the metal coordination sphere. Implications of these results, in terms of AlIII as a potential toxic factor in humans, are considered and discussed.

Prognostic factors and survival in non-Hodgkin's lymphomas: the experience of the Istituto Oncologico Romagnolo (IOR).

In an attempt to evaluate natural history, prognostic factors and survival, the data of 340 patients with NHL were collected. 267 patients were evaluable for the analysis of prognostic factors and survival. The tumor samples were reviewed and reclassified according to the Kiel classification. At completion, 180 patients were affected by low-grade (LG)-NHL and 87 patients had high-grade (HG)-NHL. Numerous potential prognostic factors were analysed in univariate and multivariate analyses. Globally 154 patients (57.4%) obtained complete remission (CR) and 65 patients (24.3%) partial remission (PR). The response rate was similar in LG and HG-NHL groups. 5-years survival was 52% for all patients (53% in LG-NHL and 44% in HG-NHL). Median survival was 62 months in LG-NHL and 38 months in HG-NHL (p = n.s.). At the univariate analysis overall survival (OS) in LG-NHL was favourably influenced by age < 65 years (p = 0.004), performance status > 80 (p < 0.02), early clinical stage (p < 0.001), absence of systemic symptoms (p < 0.001), low serum LDH (p < 0.001) and achievement of CR (p < 0.001), while in the HG-NHL only by age (p = 0.005) and achievement of CR (p < 0.001). The multivariate analysis showed early clinical stage, low serum LDH, absence of systemic symptoms and achievement of CR as independent prognostic factors in LG-NHL and only achievement of CR in HG-NHL.(ABSTRACT TRUNCATED AT 250 WORDS)

Patterns of Pap smear use in the Rimini area: an analysis of women's attitudes to the test.

The use of the Pap test is a method of the prevention of cervical cancer in our local division of the Sanitary Unit and has been studied with the help of a questionnaire which was completed by women who had adopted this test. The socioeconomic characteristics, level of education, occupation and general attitudes regarding the Pap test as well as how the women had acquired knowledge of the test, have all been examined. From an analysis of the answers, we have been able to trace a precise social, economic and cultural profile of the type of women who take advantage of this test. Principally, we are dealing with women aged 40-49 years, often with children, with a medium to low level of education, who are mainly housewives and white-collar workers. Very few elderly women present themselves for the Pap test. We have noticed that there is a direct decrease in the use of preventive methods, proportional to the increase in age. These results demonstrate that an erratic use of this preventive method, in the absence of an organized screening programme, seems only to involve women who are among those at less risk from cervical cancer.

X-ray, NMR, and theoretical studies of the nootropic agent BMY-21502, a pyrrolidinone derivative.

The preferred crystalline, solution, and in vacuo arrangements of 1-[[1-[2-trifluoromethyl)-4-pyrimidinyl]-4-piperidinyl]methyl]-2-pyrroli dinone (BMY-21502) were investigated by means of single-crystal X-ray diffraction, 1H and 13C NMR spectroscopy, and semiempirical molecular orbital and molecular mechanics calculations. The X-ray powder diffraction pattern is also reported.

Neuroprotective effects of low-doses of aspirin.

Aspirin appears to have a neuroprotective role against glutamate excitotoxicity. In fact, recent animal studies have demonstrated the neuroprotective role of acetylsalicylic acid (ASA) against glutamatergic excitants. It has been pointed out that ASA is neuroprotective against hypoxic hypoxia, chemical hypoxia and also delays the decline of intracellular ATP. Prostaglandins may cause convulsions and high-doses of aspirin appear to protect neurons from excitotoxicity. A case is reported of a woman whose electroencephalogram (EEG) abnormalities reversed and whose psychological symptomatology regressed after treatment with low-doses of aspirin. This appears to be the first description of a disappearance of EEG abnormalities with low-doses of aspirin. The neuroprotective effect of ASA could be of extreme importance in metabolic neuronal disfunction, reversing both clinical symptoms and EEG genetic anomalies: it is probably due to transient neurotransmitter concentration disequilibrium caused by subclinical hypoxic cortical suffering. Copyright 2001 John Wiley & Sons, Ltd.

Madura's foot: report of a case caused by Madurella mycetomatis.

We present a case of mycetoma by Madurella mycetomatis on the foot of a Chinese young man, living in Italy for more than ten years. Clinically the lesion closely resembled and was initially misinterpreted as a vascular neoformation. We analyze the histological and morphological features of the Madurella mycetomatis infection through which we managed to type the etiological agent. Our case is worth reporting because of the rarity of this disease in Europe and the unusual clinical presentation. It also offers the opportunity to stress the need for the clinical suspicion of this dermatosis, considering the increase of immigration towards our regions.

Vinorelbine chemotherapy in non small cell lung cancer: experience in elderly patients.

This study involved 25 elderly (> 65 years old) patients (pts) with unresectable non small cell lung cancer (NSCLC) who were not eligible for polychemotherapy. The diagnosis of NSCLC was histologically or cytologically documented, and all of them had measurable or evaluable disease. The median age of the patients was 71 (range 65-77); 9 had been pretreated. The pts received 25 mg/m2 of vinorelbine weekly or bi-weekly depending on the results of blood tests. The treatment continued until disease progression or tolerance. No complete response was achieved: 3 pts (12%) had a partial response (RP) (8-12-14 months), 13 (52%) stable disease (SD) with an improvement in symptoms, such as cough and/or pain, and 9 pts (36%) progressed. Compliance with the therapy was acceptable. The main toxicity was hematological: neutropenia was observed in 16 pts, with only 1 case of grade 4 neutropenia without sepsis; grade 1-2 anemia occurred in 8 patients. The other toxicities included grade 1-2 neurotoxicity in 8 pts, chemical phlebitis in 2 pts and grade 3 cardiotoxicity reversible with medical treatment in 1 patient. The median survival time was 10 months (lower quartile 5 months, upper quartile 23 months) (Kaplan and Meyer method). Vinorelbine can be considered a rational choice in elderly pts with advanced NSCLC who are not suitable for aggressive polychemotherapy, with the aim of improving their quality of life in terms of symptoms and outpatient treatment.

Etoposide, doxorubicin and cisplatin (EAP regimen) in advanced gastric cancer.

The treatment of advanced gastric cancer is unsatisfactory. The response rates for single chemotherapy agents: 5-fluorouracil, mitomycin-c, methotrexate, cisplatin, adriamycin, nitrosoureas and etoposide are approximately 10-25% and response duration ranges from 3 to 6 months. Complete responses with single agents are rare. Combination chemotherapy produces higher response rates, but these responses are short. Recently the combination of etoposide, adriamycin and cisplatin (EAP regimen) has been reported to produce results superior to what have been previously reported with other regimens. Twenty-four consecutive patients with locally advanced or metastatic gastric cancer (stage III-IV) were treated between June 1990 and December 1992 with the EAP regimen at our Department. Twenty-two patients were evaluable for response and toxicity. Objective responses were observed in 8 of 22 patients (response rate 36%; 95% confidence interval 17% to 59%). No clinical complete response was found. The median duration of the response was 7 months (range 2 to 22). Myelosuppression represented the primary toxicity associated with the EAP regimen. Grade 4 leukopenia was observed in 4 patients (18%). Grade 3-4 thrombocytopenia was registered in two patients, and grade 3 anemia was detected in 4 patients (18%). The median survival for all patients was 8 months and 12 months for the 8 responding patients. The EAP regimen seems to be an effective chemotherapeutic regimen, but cannot be considered the standard therapy for patients with locally advanced or metastatic gastric cancer, because of the high incidence of moderate to severe myelotoxicity and a response rate and duration of survival similar, but not superior, to those obtained using a less toxic schedule.

Sex Differences in Hemisphere Preference As Assessed by a Paper-and-Pencil Test.

The present study examined sex differences in hemisphere preference (HP) assessed by the Preference Test (PT). This instrument is designed to measure the extent to which normal subjects rely on right-hemisphere or left-hemisphere cognition. Factor analysis on the total sample (N=1,057; 473 men and 584 women) revealed a clear two-factor structure (i.e., left-HP and right-HP), although separate analyses for men and women suggest that this structure is more straightforward in men than in women. The main differences between men and women have to do with PT items relevant to language abilities, where women tend to be more symmetrically distributed across the two factors. However, the frequency of right- and left-HP is similar in men and women and does not change for men when PT scores are recalculated after removal of unspecific items. Furthermore, once the items that assess verbal abilities were excluded, the corrected PT value for women showed higher right-HP. Our results provide some indications of a less pronounced lateralization of hemisphere-linked cognitive abilities in women.