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 (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.

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.

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 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.

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.

Online convective therapies: results from a hemofiltration trial.

With the introduction of the on-line preparation of dialysis fluids, the hemofiltration technique, which has never had a widespread diffusion in its old version with the infusion bags, has gained a new interest. We planned a prospective, randomized, 3-year-long study comparing survival and morbidity in ultrapure bicarbonate dialysis (BD) with on-line predilution hemofiltration (HF). Since comorbidity is one of the main factors limiting survival, the study was addressed to patients with a severe degree of comorbidity. The paper presents the preliminary results of the trial. Sixty-four patients were enrolled and randomized to either BD (N = 32) or HF (N = 32). Mean age and dialysis vintage were comparable. Twenty patients died during the study, 12 in BD and 8 in HF. The relative risk of death was 11% higher in patients treated with BD compared to those in the HF group (p < 0.005). The number of hospitalisation events per single patient was lower, even though not significantly, in HF compared to BD (1.94 + 1.26 in HF vs 2.48 + 1.98 in BD, p = NS). As concerns biochemistry, apart from beta-2-microglobulin, any other substantial difference was not found during the study, though the small solute concentration was generally a little more elevated in HF than in BD. Dialysis hypotension showed a trend to decrease in both the dialysis modalities up to near half of the trial, then, during the last year, it remained quite stable in HF, while, on the contrary, it increased in the BD group. By the end of the protocol, patients in HF showed a 2.5% incidence of acute dialysis hypotension, while patients in BD had 23%.

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.

Systemic lupus erythematosus induced by Epstein-Barr virus infection.

We report a 22-year-old woman who developed systemic lupus erythematosus (SLE) immediately after an Epstein-Barr virus (EBV)-induced mononucleosis infection. The link between these two conditions has long been suspected. The close temporal relationship, the course of the pathological events and the development of immunological changes in this case provide further evidence supporting the hypothesis that EBV infection could work as a trigger in some cases of SLE, particularly if the patient is genetically susceptible.

The Fixion nail in the lower limb. Preliminary results.

The Fixion nail is an intramedullary nail made of stainless steel, that may be used to treat fractures of the humerus and in the lower limb. This nail is made up of a cylinder that has 4 longitudinal bars which, once inserted in the bone segment, expands via a pressure hydraulic system using physiological solution. The nail may be introduced without reaming and after its expansion it adheres to the bone walls producing stabilization of the fracture. In order to guarantee good stability, the apex of the nail must exceed the fracture line by 5 cm. Indications were initially limited to type 32 and 42 A1-2-3 fractures of the mid third of the lower limb, to then be expanded to type B1 fractures in the AO system. A total of 20 nails were used in 19 patients, with an average time of 7 days for partial weight-bearing and 40 days for total weight-bearing, achieving consolidation on day 18 after an average of 5 months in the femur and 4 months in the tibia. Reaming of the intramedullary canal was carried out in all of the cases.

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.

Calciphylaxis in two patients with end-stage renal disease.

Fatal calciphylaxis (CPX) occurred in two 71-year-old females both requiring haemodialysis for end-stage renal disease. Case 2 also had an associated follicular lymphoplasmocytoid lymphoma. Although laboratory tests disclosed normal coagulation parameters, this woman had a striking cutaneous histological picture of vessel thrombosis and finally died of disseminated intravascular coagulation. CPX is a rare but potentially life-threatening complication of renal failure. The clinical picture is primarily characterized by livedoid purpura with subsequent cutaneous ischaemia and painful ulcerations. Cutaneous ischaemic phenomena are sustained by a progressive process of vascular calcification and thrombosis involving small to medium size arteries of the dermis and subcutis. Although not yet clearly explained, the pathogenetic role of a predisposing hypercoagulability state is currently the most frequently considered hypothesis.

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.

Breast involvement in immunolymphoproliferative disorders: report of two cases of multiple myeloma of the breast.

Breast involvement by immunolymphoproliferative disorders is rare. Primary and secondary malignant lymphomas of the breast are much more common than multiple myeloma, of which only 16 cases have been described. We report two cases of patients with an established diagnosis of multiple myeloma in whom breast involvement appeared during the course of the disease. We underline diagnostic difficulties caused by the lack of clinical and radiological features which allow us to differentiate between breast carcinoma and breast involvement by lymphoproliferative disease. Only fine needle aspiration and/or excisional biopsy can differentiate between immunolymphoproliferative disorders and epithelial or mesenchymal tumors of the breast.

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.