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.

Association of tumor-infiltrating lymphocytes with distant disease-free survival in the ShortHER randomized adjuvant trial for patients with early HER2+ breast cancer.

BACKGROUND: There is the need to identify new prognostic markers to refine risk stratification for HER2-positive early breast cancer patients. The aim of this study was to evaluate the association of tumor-infiltrating lymphocytes (TILs) with distant disease-free survival (DDFS) in patients with HER2-positive early breast cancer enrolled in the ShortHER adjuvant trial which compared 9 weeks versus 1-year trastuzumab in addition to chemotherapy, and to test the interaction between TILs and treatment arm. PATIENTS AND METHODS: Stromal TILs were assessed for 866 cases on centralized hematoxylin and eosin-stained tumor slides. The association of TILs as 10% increments with DDFS was assessed with Cox models. Kaplan-Meier curves were estimated for patients with TILs ≥20% and TILs <20%. Median follow-up was 6.1 years. RESULTS: Median TILs was 5% (Q1-Q3 1%-15%). Increased TILs were independently associated with better DDFS in multivariable model [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.59-0.89, P = 0.006, for each 10% TILs increment]. Five years DDFS rates were 91.1% for patients with TILs <20% and 95.7% for patients with TILs ≥20% (P = 0.025). The association between 10% TILs increments and DDFS was significant for patients randomized to 9 weeks of trastuzumab (HR 0.60, 95% CI 0.41-0.88) but not for patients treated with 1 year of trastuzumab (HR 0.89, 95% CI 0.71-1.12; test for interaction P = 0.088). For patients with TILs <20%, the HR for the comparison between the short versus the long arm was 1.75 (95% CI 1.09-2.80, P=0.021); whereas, for patients with TILs ≥20% the HR for the comparison of short versus long arm was 0.23 (95% CI 0.05-1.09, P = 0.064), resulting in a significant interaction (P = 0.015). CONCLUSIONS: TILs are an independent prognostic factor for HER2-positive early breast cancer patients treated with adjuvant chemotherapy and trastuzumab and may refine the ability to identify patients at low risk of relapse eligible for de-escalated adjuvant therapy.

Metformin plus chemotherapy versus chemotherapy alone in the first-line treatment of HER2-negative metastatic breast cancer. The MYME randomized, phase 2 clinical trial.

PURPOSE: To investigate the efficacy of metformin (M) plus chemotherapy versus chemotherapy alone in metastatic breast cancer (MBC). METHODS: Non-diabetic women with HER2-negative MBC were randomized to receive non-pegylated liposomal doxorubicin (NPLD) 60 mg/m2 + cyclophosphamide (C) 600 mg/m2 × 8 cycles Q21 days plus M 2000 mg/day (arm A) versus NPLD/C (arm B). The primary endpoint was progression-free survival (PFS). RESULTS: One-hundred-twenty-two patients were evaluable for PFS. At a median follow-up of 39.6 months (interquartile range [IQR] 24.6-50.7 months), 112 PFS events and 71 deaths have been registered. Median PFS was 9.4 months (95% CI 7.8-10.4) in arm A and 9.9 (95% CI 7.4-11.5) in arm B (P = 0.651). In patients with HOMA index < 2.5, median PFS was 10.4 months (95% CI 9.6-11.7) versus 8.5 (95% CI 5.8-9.7) in those with HOMA index ≥ 2.5 (P = 0.034). Grade 3/4 neutropenia was the most common toxicity, occurring in 54.4% of arm A patients and 72.3% of the arm B group (P = 0.019). M induced diarrhea (G2) was observed in 8.8% of patients in Arm A. The effect of M was similar in patients with HOMA index < 2.5 and ≥ 2.5, for PFS and OS. CONCLUSIONS: The MYME trial failed to provide evidence in support of an anticancer activity of M in combination with first line CT in MBC. A significantly shorter PFS was observed in insulin-resistant patients (HOMA ≥ 2.5). Noteworthy, M had a significant effect on CT induced severe neutropenia. Further development of M in combination with CT in the setting of MBC is not warranted.

Immunoglobulin G fragment C receptor polymorphisms and efficacy of preoperative chemotherapy plus trastuzumab and lapatinib in HER2-positive breast cancer.

Lapatinib enhances antibody-dependent cell-mediated cytotoxicity (ADCC) activity of trastuzumab. FcγR polymorphisms have been associated with both ADCC and clinical activity of trastuzumab in HER2+ breast cancer (BC) patients (pts). We analyzed FcγRIIa-H131R and FcγRIIIa-V158F polymorphisms in the CHER-LOB trial population of HER2+ BCs treated with preoperative chemotherapy plus trastuzumab (arm A), lapatinib (arm B) or both (arm C). Genotyping was successfully performed in 73/121 (60%) pts. A significant improvement in pathological complete response (pCR) rate was observed for the combination arm C, but only in FcγRIIIa V allele carriers (C vs A, 67 vs 27%, P=0.043; C vs B, 67 vs 22%, P=0.012). An independent interaction between arm C and FcγRIIIa V allele was found for pCR (odds ratio=9.4; 95% confidence interval, 2.3-39.6; P=0.003). No significant associations were observed between pCR and FcγRIIa polymorphism, and between pre-treatment tumor-infiltrating lymphocytes and FcγR polymorphisms. Our study provides evidence for a FcγRIIIa V allele-restricted pCR benefit from neoadjuvant trastuzumab plus lapatinib in HER2+ BC.

Molecular staging of the sentinel lymph node in melanoma patients: correlation with clinical outcome.

BACKGROUND: This study was designed to determine the debated prognostic significance of reverse transcriptase-polymerase chain reaction (RT-PCR) positivity in melanoma patients' sentinel lymph node (SLN) negative by conventional histopathology (PATH). PATIENTS AND METHODS: Patients with primary stage I-II cutaneous melanoma underwent radioguided sentinel lymphadenectomy. Their SLNs were assessed for tyrosinase (Tyr) and melanoma antigens recognized by T-cells (MART-1) mRNA expression using RT-PCR, in parallel with hematoxylin and eosin staining and immunohistochemistry. Tyr and MART-1 expression in the SLNs were correlated with PATH assay results, standard prognostic factors, time to progression and overall survival. RESULTS: Twenty-three of the 124 patients (18.5%) had positive SLNs by both PATH and RT-PCR (PATH+/PCR+). Sixteen patients (13%) were negative by PATH and positive by RT-PCR (PATH-/PCR+). Eighty-five patients (68.5%) had SLNs that were negative by both PATH and RT-PCR (PATH-/PCR-). At a median follow-up of 30 months, recurrence rates among the three cohorts were statistically different (PATH+/PCR+, 60%; PATH-/PCR+, 31%; PATH-/PCR-, 9.4%). Seven of 23 (30%) and two of 16 (12.5%) patients died in the PATH+/PCR+ and PATH-/PCR+ SLN groups, respectively, whereas no patient died in the PATH-/PCR- SLN group. CONCLUSIONS: RT-PCR is more sensitive than PATH to detect SLN metastases and it is a reliable predictor of disease relapse in stage I-II melanoma patients.

Anti-inflammatory activity of the crude extract from the fruits of Pterodon emarginatus Vog.

The vegetal species Pterodon emarginatus Vog. (Leguminosae/Papilonaceae), popularly known in Brazil as 'sucupira branca', is widely used by domestic medicine as an anti-inflammatory. From these observations, the hexanic crude extract (HCE) of the fruits was obtained and submitted for assessment of its anti-inflammatory activity. For this purpose, the following tests were used: (1) Determination of ED50 and LD50; (2) Paw edema induced by carrageenin, dextran, histamine and nystatin; (3) Peritonitis caused by carrageenin and (4) Granuloma test. The ED50 (oral) in the edema induced by carrageenin was 500 mg/kg, and LD50 (oral) was 4.02 g/kg. In the edema caused by nystatin, there was a significant inhibition by 45% (P < 0.05 student's t-test) at the 6th hour following the treatment. In the granuloma test performed in animals treated with HCE, there was an inhibition of the granulomatous tissue formation by 22%. The migration of neutrophils towards the peritoneal cavity was inhibited in HCE treated animals by 43% (P < 0.05). However, in the edema caused by dextran and histamine, there was no significant response in HCE treated animals.

Investigation of anti-inflammatory and antinociceptive activities of trans-dehydrocrotonin, a 19-nor-clerodane diterpene from Croton cajucara. Part 1.

The anti-inflammatory and antinociceptive effects of trans-dehydrocrotonin, isolated from the bark of Croton cajucara (Euphorbiaceae), were investigated using several animal models. The trans-dehydrocrotonin produced a significant inhibition of carrageenin-induced paw edema and cotton pellet granuloma in rats. It also inhibited the writhings in mice induced by acetic acid, but did not show a significant effect in the hot-plate test in mice. The LD50 of t-DCTN was 555.0 mg/kg (p.o.) for mice.

Quimioprofilaxia da doença de Chagas: bloqueio da transmissão transfusional por produtos naturais / Chemyprophylaxis of Chagas disease: blockage of blood transfusion transmission by natural products

Em busca da solução para o serio problema da transmissão transfusional da doença de Chagas em nosso meio, realizamos a avaliação de produtos naturais corn atividade tripanosomicida. Os testes "in vitro" foram realizados incubando-se a 4°C, sangue de camundongos contendo ± 10(6)/ ml formas tripomastigotas de Trypanosoma cruzi corn os extratos vegetais. Após diferentes períodos de incubação, frações sangüíneas foram examinadas em microscopia de fase. Os extratos que apresentaram atividade tripanosomicida ate 48 horas de incubação, foram examinados em microscopia eletrônica corn intuito de verificarmos sua toxicidade contra os elementos normais do sangue. Foram testados 242 extratos obtidos de 81 vegetais a 56 demonstraram atividade.

Considering the serius problem of blood transfusion transmission of Chagas disease in our environment, we realized the evalution of natural products against Chagas diseases. The tests were realized "in vitro" by in incubation at 4ºC mouse blood having ± 10(6)/ml of Trypanosoma cruzi, sample "y" and "Colombina" with the plant extracts. After different times of incubation, blood fractions were examined by phase microscopy. The drugs that showed activity until 48 hours of incubation, were examined by electron microscopy to virify the toxicity to blood elements. The tests were realized with 242 extracts from 81 plants and 56 extracts showed activity against T. cruzi.

Genotoxicity of the natural cercaricides "sucupira" oil and eremanthine in mammalian cells in vitro and in vivo.

"Sucupira" oil and the lactone eremanthine, extracted from Pterodon pubescens and Eremanthus elaeagnus, respectively, are known for their cercaricidal action in experimental animals. Because of their biological effect, they have the potential to be used for the prophylaxis of schistosomiasis caused by Schistosoma mansoni. To test the clastogenicity of these agents, "sucupira" oil, either pure or diluted in corn oil, was tested in vivo on Wistar rat bone marrow cells following dermal application. Metaphase analysis showed that the compound did not induce a significant increase in the frequencies of chromosomal aberrations. When eremanthine was tested on BALB/c mice following gavage at doses of 100, 200, and 300 mg/kg bw, it did not induce structural or numerical chromosomal aberrations. In the in vitro treatment of human lymphocyte cultures, eremanthine also did not cause any increase in chromosomal aberrations or sister chromatid exchanges at the following concentrations in culture medium: 1.25, 2.50, and 5.00 micrograms/ml. From these results, under our experimental conditions, neither "sucupira" oil nor eremanthine showed clastogenic effects on mammalian cells in vivo or in vitro.

[Chemoprophylactic activity on Schistosomiasis mansoni of soaps containing essential oil from the fruits of Pterodon pubescens]. / Atividade quimioprofilática na esquistossomose mansoni de sabonetes contendo óleo essencial de frutos de Pterodon pubescens.

The chemoprophylactic action of the essential oil of the fruit of Pterodon pubescens Benth (Leguminosae), incorporated in different soap formulations, was studied in experimental schistosomiasis. The formulations were used locally on the tails of mice which were exposed to Schistosoma mansoni cercariae immediately, 24, 72 or 168 hours later by the method of tail immersion. Protection was evaluated 45 days after exposure when the mice were sacrificed and the worms collected by perfusion. The results showed levels of protection varying from 0.0 to 100% depending on the formulation used. A methodology that allowed the evaluation of soap protection of mice exposed to natural infection in snail infested streams on the outskirts of Belo Horizonte, MG, was also developed. Promising results were obtained in that protection of between 57.5 and 31.1% was observed in field trials when soap was applied to the animals 24 and 48 hours earlier. Preliminary studies evaluating irritation and toxicity were favorable and showed that this new prophylactic weapon could contribute to the control of schistosomiasis.

[Chemoprophylactic activity of soaps containing essential oil from the fruit of Pterodon pubescens in schistosomiasis mansoni]. / Atividade quimioprofilática de sabonetes contendo óleo essencial de frutos de Pterodon pubescens na esquistossomose mansoni.

It has been studied the chemoprophylactic action on experimental schistosomiasis of the essential oil from Pterodon pubescens "sucupira branca" as an additive through different formulations, in toilet soap. Immediately or 24 hours later, groups of mice were exposed by tail method to Schistosoma mansoni cercariae. After 45 days of the exposition, the protective action of these soaps were evaluated. The results showed different levels of protection, ranging from 29.0 to 100.0%. Further studies are on going with the most promising formulations.

Atividade quimioprofilática de sabonetes contendo óleo essencial de frutos de Pterodon pubescens na esquistossomose mansoni / Chemoprophylactic activity of soaps containing essential oil of Pterodon pubescens fruits in Schistosomiasis mansoni

It has been studied the chemoprophylactic action on experimental schistosomiasis of the essential oil from Pterodon pubescens "sucupira branca" as an additive through different formulations, in toilet soap. Immediately or 24 hours later, groups of mice were exposed by tail method to Schistosoma mansoni cercariae. After 45 days of the exposition, the protective action of these soaps were evaluated. The results showed different levels of protection, ranging from 29.0 to 100.0%. Further studies are on going with the most promising formulations.

Quimioprofilaxia da esquistossomose: atividade moluscicida de produtos naturais - ensaios com caramulos adultos e desovas. / Chemoprophylaxis of schistosomiasis: molluscacidal activity of natural products - assays with adult snails and oviposition

Sao apresentados os dados relativos a atividade moluscicida de 159 extratos, de 84 plantas brasileiras, sobre Biomphalaria glabrata, o mais importante hospedeiro intermediario do Schistosoma mansoni no Brasil. Setenta e oito (49,0%) dos extratos mostraram atividade contra caramujos ou desovas, porem, somente vinte e nove (18,2%)foram ativos sobre ambos. Os extratos de duas especies de vegetais (Mikania hirsutissima e Qualea multiflora) foram letais aos caramujos adultos, na concentracao de 10 ppm