Observational cohort study to determine the degree and causes of variation in the rate of surgery or primary endocrine therapy in older women with operable breast cancer

Background In the UK there is variation in the treatment of older women with breast cancer, with up to 40% receiving primary endocrine therapy (PET), which is associated with inferior survival. Case mix and patient choice may explain some variation in practice but clinician preference may also be important. Methods A multicentre prospective cohort study of women aged >70 with operable breast cancer. Patient characteristics (health status, age, tumour characteristics, treatment allocation and decision-making preference) were analysed to identify whether treatment variation persisted following case-mix adjustment. Expected case-mix adjusted surgery rates were derived by logistic regression using the variables age, co-morbidity, tumour stage and grade. Concordance between patients’ preferred and actual decision-making style was assessed and associations between age, treatment and decision-making style calculated. Results Women (median age 77, range 70–102) were recruited from 56 UK breast units between 2013 and 2018. Of 2854/3369 eligible women with oestrogen receptor positive breast cancer, 2354 were treated with surgery and 500 with PET. Unadjusted surgery rates varied between hospitals, with 23/56 units falling outside the 95% confidence intervals on funnel plots. Adjusting for case mix reduced, but did not eliminate, this variation between hospitals (10/56 units had practice outside the 95% confidence intervals). Patients treated with PET had more patient-centred decisions compared to surgical patients (42.2% vs 28.4%, p < 0.001). Conclusions This study demonstrates variation in treatment selection thresholds for older women with breast cancer. Health stratified guidelines on thresholds for PET would help reduce variation, although patient preference should still be respected

Bridging the age gap: observational cohort study of effects of chemotherapy and trastuzumab on recurrence, survival and quality of life in older women with early breast cancer

Background: Chemotherapy improves outcomes for high risk early breast cancer (EBC) patients but is infrequently offered to older individuals. This study determined if there are fit older patients with high-risk disease who may benefit from chemotherapy. Methods: A multicentre, prospective, observational study was performed to determine chemotherapy (±trastuzumab) usage and survival and quality-of-life outcomes in EBC patients aged ≥70 years. Propensity score-matching adjusted for variation in baseline age, fitness and tumour stage. Results: Three thousands four hundred sixteen women were recruited from 56 UK centres between 2013 and 2018. Two thousands eight hundred eleven (82%) had surgery. 1520/2811 (54%) had high-risk EBC and 2059/2811 (73%) were fit. Chemotherapy was given to 306/1100 (27.8%) fit patients with high-risk EBC. Unmatched comparison of chemotherapy versus no chemotherapy demonstrated reduced metastatic recurrence risk in high-risk patients(hazard ratio [HR] 0.36 [95% CI 0.19–0.68]) and in 541 age, stage and fitness-matched patients(adjusted HR 0.43 [95% CI 0.20–0.92]) but no benefit to overall survival (OS) or breast cancer-specific survival (BCSS) in either group. Chemotherapy improved survival in women with oestrogen receptor (ER)-negative cancer (OS: HR 0.20 [95% CI 0.08–0.49];BCSS: HR 0.12 [95% CI 0.03–0.44]).Transient negative quality-of-life impacts were observed. Conclusions: Chemotherapy was associated with reduced risk of metastatic recurrence, but survival benefits were only seen in patients with ER-negative cancer. Quality-of-life impacts were significant but transient. Trial Registration: ISRCTN 46099296

Bridging The Age Gap: observational cohort study of effects of chemotherapy and trastuzumab on recurrence, survival and quality of life in older women with early breast cancer

Background: Chemotherapy improves outcomes for high risk early breast cancer (EBC) patients but is infrequently offered to older individuals. This study determined if there are fit older patients with high-risk disease who may benefit from chemotherapy. Methods: A multicentre, prospective, observational study was performed to determine chemotherapy (±trastuzumab) usage and survival and quality-of-life outcomes in EBC patients aged ≥70 years. Propensity score-matching adjusted for variation in baseline age, fitness and tumour stage. Results: Three thousands four hundred sixteen women were recruited from 56 UK centres between 2013 and 2018. Two thousands eight hundred eleven (82%) had surgery. 1520/2811 (54%) had high-risk EBC and 2059/2811 (73%) were fit. Chemotherapy was given to 306/1100 (27.8%) fit patients with high-risk EBC. Unmatched comparison of chemotherapy versus no chemotherapy demonstrated reduced metastatic recurrence risk in high-risk patients(hazard ratio [HR] 0.36 [95% CI 0.19–0.68]) and in 541 age, stage and fitness-matched patients(adjusted HR 0.43 [95% CI 0.20–0.92]) but no benefit to overall survival (OS) or breast cancer-specific survival (BCSS) in either group. Chemotherapy improved survival in women with oestrogen receptor (ER)-negative cancer (OS: HR 0.20 [95% CI 0.08–0.49];BCSS: HR 0.12 [95% CI 0.03–0.44]).Transient negative quality-of-life impacts were observed. Conclusions: Chemotherapy was associated with reduced risk of metastatic recurrence, but survival benefits were only seen in patients with ER-negative cancer. Quality-of-life impacts were significant but transient. Trial Registration: ISRCTN 46099296

Phoneutria nigriventer (armed spider) venom induces increased vascular permeability in rat and rabbit skin in vivo

FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOThe effect of intradermally injected Phoneutria nigriventer venom (PNV) on vascular permeability of both rat and rabbit skin has been investigated. Oedema formation was measured as the local extravascular accumulation at skin sites of intravenously injected 125I-human serum albumin. In both rat and rabbit PNV induced dose-dependent oedema which was greatly potentiated by the vasodilators calcitonin-gene-related peptide and prostaglandin E1. In rats, PNV-induced oedema was markedly reduced either by previous treatment of the animals with the histamine H1 antagonist mepyramine and the serotonin antagonist methysergide or when venom was dialysed, indicating a major role for histamine and serotonin. In rabbits, dialysis of the venom to remove histamine and serotonin did not reduce PNV-induced oedema, indicating presence of oedematogenic component(s) which are different from the amines histamine or serotonin.The effect of intradermally injected Phoneutria nigriventer venom (PNV) on vascular permeability of both rat and rabbit skin has been investigated. Oedema formation was measured as the local extravascular accumulation at skin sites of intravenously injected 125I-human serum albumin. In both rat and rabbit PNV induced dose-dependent oedema which was greatly potentiated by the vasodilators calcitonin-gene-related peptide and prostaglandin E1. In rats, PNV-induced oedema was markedly reduced either by previous treatment of the animals with the histamine H1 antagonist mepyramine and the serotonin antagonist methysergide or when venom was dialysed, indicating a major role for histamine and serotonin. In rabbits, dialysis of the venom to remove histamine and serotonin did not reduce PNV-induced oedema, indicating presence of oedematogenic component(s) which are different from the amines histamine or serotonin30910111016FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO90/12341; 90/4145-

Phoneutria Nigriventer (armed Spider) Venom Induces Increased Vascular Permeability In Rat And Rabbit Skin In Vivo

The effect of intradermally injected Phoneutria nigriventer venom (PNV) on vascular permeability of both rat and rabbit skin has been investigated. Oedema formation was measured as the local extravascular accumulation at skin sites of intravenously injected 125I-human serum albumin. In both rat and rabbit PNV induced dose-dependent oedema which was greatly potentiated by the vasodilators calcitonin-gene-related peptide and prostaglandin E1. In rats, PNV-induced oedema was markedly reduced either by previous treatment of the animals with the histamine H1 antagonist mepyramine and the serotonin antagonist methysergide or when venom was dialysed, indicating a major role for histamine and serotonin. In rabbits, dialysis of the venom to remove histamine and serotonin did not reduce PNV-induced oedema, indicating presence of oedematogenic component(s) which are different from the amines histamine or serotonin. © 1992.30910111016Antunes, Marangoni, Borges, Fontana, de Nucci, Pharmacological profile of Phoneutria nigriventer venom on rabbit vascular smooth muscle (1990) British Journal of Pharmacology, 101, p. 508PBrain, Williams, Inflammatory oedema induced by synergism between calcitonin gene-related peptide (CGRP) and mediators of increased vascular permeability (1985) Br. J. Pharmac., 86, pp. 855-860Diniz, Cordeiro, Junior, Kelly, Fischer, Reiman, Oliveira, Richardson, The purification and amino acid sequence of the lethal neurotoxin Tx1 from the venom of the Brazilian ‘armed’ spider Phoneutria nigriventer (1990) FEBS Lett., 263, pp. 251-253Entwistle, Johnstone, Medzihradszky, May, Isolation of a pure toxic polypeptide from the venom of the spider Phoneutria nigriventer and its neurophysiological activity on an insect femur preparation (1982) Toxicon, 20, pp. 1059-1067Fontana, Vital-Brazil, Mode of action of Phoneutria nigriventer spider venom at the isolated phrenic nerve-diaphragm of the rat (1985) Braz. J. Med. Biol. Res., 18, pp. 557-565Kaiser, The enzymatic activity of spider venom (1953) Mem. Inst. Butantan, 25, pp. 35-39Lucas, Spiders in Brazil (1988) Toxicon, 26, pp. 759-772Rezende, Jr, Cordeiro, Oliveira, Diniz, Isolation of neurotoxic peptides from the venom of the armed spider Phoneutria nigriventer (1991) Toxicon, 29, pp. 1225-1233Schenberg, Pereira-Lima, Phoneutria nigriventer venom (1971) Pharmacology and biochemistry of its components, 3, pp. 279-297. , W. Bucherl, E.E. Buckley, Venomous Animals and their Venoms, Academic Press, New YorkSpector, Willoughby, Endogenous mediators of increased vascular permeability in inflammation (1968) The Pharmacology of Inflammation, pp. 22-54. , English Universities Press LtdVital-Brazil, Leite, Fontana, Modo de ação da peçonha da aranha armadeira, Phoneutria nigriventer (Keyserling, 1891), nas aurículas isoladas de cobaia (1988) Ciênc. Cult., S Paulo, 40, pp. 181-185Williams, Prostaglandin E2, prostaglandin I2 and the vascular changes of inflammation (1979) Br. J. Pharmac., 65, pp. 517-52

Activation By Phoneutria Nigriventer (armed Spider) Venom Of Tissue Kallikrein-kininogen-kinin System In Rabbit Skin In Vivo

1. The purpose of the present study was to investigate the mechanisms by which venom from Phoneutria nigriventer spider induces increases in vascular permeability in rabbit skin. 2. Local oedema formation, in response to intradermally -injected agents, was measured in male New Zealand white rabbits as the local accumulation of i.v. injected 125I-labelled human serum albumin into skin sites. 3. Phoneutria nigriventer venom (10-30 μg/site) increased vascular permeability, which was inhibited by trasylol (10 μg/site) and the bradykinin B2 receptor antagonists D-Arg, [Hyp3,Thi5,8,D-Phe7]-BK (3 nmol/site) and Hoe 140 (0.3 nmol/site). In addition, the oedema induced by the venom was potentiated by the kinase II inhibitor, captopril (1 nmol/site). The lipoxygenased inhibitor, BWA4C (10 nmol/site) and the PAF antagonist, WEB 2086 (100 nmol/site) had no effect on the venom-induced increase in vascular permeability. 4. Incubation of rabbit plasma with Phoneutria nigriventer venom in vitro did not cause bradykinin formation. Further, the plasma kallikrein inhibitor, soybean trypsin inhibitor (10 μg/site), had no effect on the venom-induced increase in vascular permeability in rabbit skin. 5. These results indicate that the oedema produced by Phoneutria nigriventer venom is dependent on the activation of the tissue kallikrein-kinin system.109253954

Activation Of Tissue Kallikrein-kininogen-kinin System In Rabbit Skin By A Fraction Isolated From Phoneutria Nigriventer (armed Spider) Venom

Phoneutria nigriventer venom was fractionated by gel filtration followed by ion-exchange chromatography from which 16 fractions (I-XVI) were obtained and assayed in rabbit skin in order to identify those responsible for the increased vascular permeability observed with the whole venom. The fractions, and control mediators (tissue kallikrein, bradykinin and histamine) were intradermally injected in male New Zealand white rabbits. Local oedema formation was measured as the local accumulation of i.v. injected 125I-human serum albumin into skin sites. Fraction XIII was the only fraction assayed which significantly induced oedema formation. Fraction XIII-induced oedema was greatly reduced by either the protease inhibitor aprotinin or the bradykinin B2 receptor antagonist d-Arg,[Hyp3,Thi5,8,d-Phe7]-Bk, whereas the plasma kallikrein inhibitor soybean trypsin inhibitor failed to significantly affect this oedematogenic response. The kininase II inhibitor captopril markedly potentiated fraction XIII-induced oedema. Our results indicate that the increased vascular permeability induced by fraction XIII is due to local generation of kinins in response to tissue (but not plasma) kallikrein-kinin system activation. © 1993.311113851391Antunes, Marangoni, Brain, de Nucci, Phoneutria nigriventer (armed spider) venom induces increased vascular permeability in rat and rabbit skin in vivo (1992) Toxicon, 30, pp. 1011-1016Antunes, Marangoni, Borges, Hyslop, Fontana, de Nucci, Effect of Phoneutria nigriventer on rabbit vascular smooth muscle (1993) Braz. J. Med. Biol. Res., 26, pp. 81-91Brain, Williams, Inflammatory oedema induced by synergism between calcitonin gene-related peptide (CGRP) and mediators of increased vascular permeability (1985) Br. J. Pharmac., 86, pp. 855-860Brazil, Vellard, Contribuição ao estudo de venenos de aranhas (1925) Mem. Inst. Butantan, 2, pp. 1-70Brazil, Vellard, Contribuição ao estudo do veneno das aranhas II (1926) Mem. Inst. Butantan, 3, pp. 3-77Brazil, Vellard, Contribuição ao estudo do veneno das aranhas III (1926) Mem. Inst. Butantan, 3, pp. 243-294Chao, Tanaka, Margolius, Inhibitory effects of sodium and other monovalent cations on purified versus membrane-bound kallikrein (1983) J. biol. Chem., 258, pp. 6461-6465Cushman, Cheung, Sabo, Ondetti, Design of potent competitive inhibitors of angiotensin-converting enzyme. Carboxyalkanoyl and mercaptoalkanoyl amino acids (1977) Biochemistry, 16, pp. 5484-5491Diniz, Separação de proteínas e caracterização de substâncias ativas em venenos de aranhas do Brasil (1963) An. Acad. Bras. 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Protease enzyme activity (1979) Toxicon, 17, pp. 529-537Lazure, Leduc, Seidah, Chretien, Dube, Chapdelaine, Frenette, Tremblay, The major androgen-dependent protease in dog prostate belongs to the kallikrein family: confirmation by partial amino acid sequencing (1984) FEBS Lett., 175, pp. 1-7Lieberthal, Oza, Bernard, Levinsky, The effect of cations on the activity of human urinary kallikrein (1982) J. biol. Chem., 257, pp. 10,827-10,830Lucas, Spiders in Brazil (1988) Toxicon, 26, pp. 759-772Marangoni, Antunes, Brain, de Nucci, Phoneutria nigriventer (armed spider) venom activates tissue kallikrein-kininogen-kinin system in rabbit skin in vivo (1993) Br. J. Pharmac., 109, pp. 539-543Marangoni, Borges, Marangoni, Antunes, Vieira, Novello, Domont, de Nucci, Biochemical characterization of a vascular smooth muscle contracting polypeptide purified from Phoneutria nigriventer (armed spider) venom (1993) Toxicon, 31, pp. 377-384Margolius, Tissue kallikreins and kinins: regulation and roles in hypertensive and diabetic diseases (1989) A. Rev. Pharmac. Toxicol., 29, pp. 343-364Perret, Proteolytic activity of Tarantula venoms due to contamination with saliva (1977) Toxicon, 15, pp. 505-510Powers, Nasjletti, A novel kinin-generating protease (kininogenase) in the porcine anterior pituitary (1982) J. biol. Chem., 257, pp. 5594-5600Powers, Nasjletti, A kininogenase resembling glandular kallikrein in the rat pituitary pars intermedia (1983) Endocrinology, 112, pp. 1194-1200Proud, Kaplan, Kinin formation: mechanisms and role in inflammatory disorders (1988) A. Rev. Immunol., 6, pp. 49-83Proud, Bailey, Nustad, Gautvik, The immunological similarity of rat glandular kallikreins (1977) Biochem. J., 167, pp. 835-838Rezende, Jr, Cordeiro, Oliveira, Diniz, Isolation of neurotoxic peptides from the venom of the ‘armed spider’ Phoneutria nigriventer (1991) Toxicon, 29, pp. 1225-1233Schachter, Peret, Billing, Wheeler, Longridge, Immunolocalization of the protease kallikrein in the colon (1983) J. Histochem. Cytochem., 31, pp. 1255-1260Schenberg, Pereira-Lima, Pharmacology of the polypeptides from the venom of the spider Phoneutria fera (1966) Mem. Inst. Butantan, 33, pp. 627-638Schenberg, Pereira-Lima, Phoneutria nigriventer venom (1971) Pharmacology and biochemistry of its components, 3, pp. 279-297. , W. Bucherl, E.E. Buckley, Venomous Animals and Their Venoms, Academic Press, New YorkSpector, Willoughby, Endogenous mediators of increased vascular permeability in inflammation (1968) The Pharmacology of Inflammation, pp. 22-54. , English Universities PressVavrek, Stewart, Competitive antagonists of bradykinin (1985) Peptides, 6, pp. 161-164Vital Brazil, Leite, Fontana, Modo de ação da peçonha da aranha armadeira, Phoneutria nigriventer (Keyserling, 1891), nas aurículas isoladas de cobaia (1988) Cien̂c. Cul. S. Paulo, 40, pp. 181-185Vogel, Kallikrein inhibitors (1979) Bradykinin, Kallidin and Kallikrein. Handbook of Experimental Pharmacology, 25, pp. 163-225. , Springer, BerlinWilliams, Prostaglandin E2, prostaglandin I2 and the vascular changes of inflammation (1979) Br. J. Pharmac., 65, pp. 517-524Williams, Morley, Prostaglandins as potentiators of increased vascular permeability in inflammation (1973) Nature, 246, pp. 215-21