Rat is a likely test animal for determining the efficacy of proteinase inhibitor drugs directed toward human leukocyte elastase and cathepsin G. We therefore sought to assess and compare relevant properties of both human and rat leukocyte elastase and cathepsin G. Some differences between the pairs of proteinases from the two species were found, however both pairs of enzymes displayed comparable specificity toward various natural (plant and animal) proteinase inhibitors and also toward specific peptide substrates and a serine proteinase-specific reagent. Such overlapping specificity implies similarity of reactive center topography and sequence homology around the extended substrate/inhibitor binding regions of these proteinases. This apparent homology leads us to conclude that a pharmacologically effective inhibitor of leukocyte proteinases in the rat would probably also be effective in man.Human leukocyte elastase is arguably the most destructive enzyme present in the body. Its ability to degrade virtually all connective tissue components [l -31 has implicated its involvement in a wide variety of pathological conditions [I, 4 -141. Although the body normally possesses abundant levels of endogenous proteinase inhibitors, two of which (a-1 -proteinase inhibitor and a-2-macroglobulin) react very rapidly with human leukocyte elastase, elastase-mediated destruction of tissue nevertheless may occur when the enzyme/inhibitor balance is upset in favor of elastase. This suggests a potential therapeutic value for human leukocyte elastase-specific proteinase inhibitor drugs.Human cathepsin G has been implicated in a wide, and seemingly unrelated variety of disease processes by virtue of its ability to cleave many physiologically important proteins. It has been suggested that cathepsin G may play a role in the development of hypertension, based on its ability to convert both angiotensinogen [15] and angiotensin I [16] directly to angiotensin 11. Human cathepsin G has also been reported to cleave myosin and thus may be involved in muscle catabolism [17]. Fibronectin is cleaved into a reproducible set of fragments by the enzyme [IS] thus implicating cathepsin G in the regulation of fibronectin-mediated processes, such as cell adhesion [19], cell motility [20] and cell migration [21]. Although the involvement of cathepsin G in disease is less well documented than, e. g. human leukocyte elastase in emphysema [S -101, if the enzyme is inappropriately regulated Abhreviutions. %,PI, human alpha-I -proteinase inhibitor; Ac-AlaAla-(aza)Nle-ONp), acetyl-L-alanine-L-alanine-u-azanor-leucine-pnitrophenyl ester; Ac-Phe-ONp, N-acetyl-L-phenylalanine-p-nitrophenyl ester; Bz-Tyr-pNA, benzoyl-L-tyrosine-p-nitroanilide; BzTyr-OEt, N-benzoyl-L-tyrosine ethyl ester; HSA, human serum albumin; MeO-Suc-Ala-Ala-Pro-Phe-pNA, methoxy succinyl-L-ala-Enzymes. Leukocyte cathepsinG, both rat and human (EC 3.4.21.20); leukocyte elastase, both rat and human (EC 3.4.21.11). extracellularly the organism will likely suffer deleterious effects.Since anim...

Oncoplastic breast surgery encompasses a range of techniques used to provide equitable oncological outcomes compared with standard breast surgery while, simultaneously, prioritizing aesthetic outcomes. While the outcomes of oncoplastic breast surgery are promising, it can add an extra complexity to the treatment paradigm of breast cancer and impact on decision-making surrounding adjuvant therapies, like chemotherapy and radiotherapy. As such, early discussions at the multidisciplinary team meeting with surgeons, medical oncologists, and radiation oncologists present, should be encouraged to facilitate best patient care.

Background The impact of near-total resection of IDH-mutated anaplastic glioma (IDHmutAG) is well-established but there remains uncertainty of benefit in tumours of the insular cortex where the extent of safe resection may be limited. This study aimed to assess tumour volume reduction in patients following IMRT and impact of residual post-surgical volume. Methods and materials Patients with IDHmutAG involving insular cortex managed with IMRT from 2008 to 2019 had baseline patient, tumour and treatment factors recorded. Volumetric assessment of residual disease on MRI was performed at baseline, month+ 3 and month+ 12 post-IMRT. Potential prognostic factors were analysed for tumour reduction and relapse-free survival, and assessed by log-rank and Cox regression analyses. Results Thirty two patients with IDHmutAG of the insular cortex were managed with median follow-up post-IMRT of 67.2 months. Pathology was anaplastic astrocytoma (AAmut) in 20, and anaplastic oligodendroglioma (AOD) in 12 patients. Median pre-IMRT volume on T1 and T2Flair was 24.3cm3 and 52.2cm3. Twenty-seven patients were alive with 5-year relapse-free survival of 80%. There was a median 67 and 64% reduction from baseline occurring at 3 months post-IMRT for T1 and T2Flair respectively; and subsequent median 78 and 73% at 12 months. At 12 months AOD patients had median 83% T1 volume reduction compared to 63% in AAmut (p < 0.01). There was no difference on T2Flair volume (p = 0.64). No other pathological factors influenced volume reduction at 12 months. No factors were associated with relapse-free survival including baseline T1 (p = 0.52) and T2Flair (p = 0.93) volume. Conclusion IMRT provides large tumour volume reduction in IDHmutAG of the insular cortex. While maximal safe debulking remains standard of care when feasible, this patient cohort reported no significant negative impact of residual disease volume on relapse-free survival.

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Background: In IDH-mutated anaplastic glioma (IDHmutAG) of the insular cortex there remains uncertainty of benefit with near-total resection compared to limited surgery with radiation therapy (IMRT). This study aimed to assess tumour volume reduction in patients following IMRT and impact of residual post-surgical volume. Methods and Materials:Patients with IDHmutAG involving insular cortex managed with IMRT from 2008-2019 had baseline patient, tumour and treatment factors recorded. Volumetric assessment of residual disease on MRI was performed at baseline, month+3 and month+12 post-IMRT. Potential prognostic factors were analysed for tumour reduction and relapse-free survival, and assessed by log-rank and Cox regression analyses. Results: 32 patients with IDHmutAG of the insular cortex were managed with median follow-up post-IMRT of 67.2 months. Pathology was anaplastic astrocytoma (AAmut) in 20, and anaplastic oligodendroglioma (AOD) in 12 patients. Median pre-IMRT volume on T1 and T2Flair was 24.3cm3 and 52.2cm3. Twenty-seven patients were alive with 5-year relapse-free survival of 80%. There was a median 67% and 64% reduction from baseline occurring at 3 months post-IMRT for T1 and T2Flair respectively; and subsequent median 78% and 73% at 12 months. At 12 months AOD patients had median 83% T1 volume reduction compared to 63% in AAmut (p<0.01). There was no difference on T2Flair volume (p=0.64). No other pathological factors influenced volume reduction at 12 months. No factors were associated with relapse-free survival including baseline T1 (p=0.52) and T2Flair (p=0.93) volume.Conclusion:IMRT provides large tumour volume reduction in IDHmutAG of the insular cortex with no significant negative impact of residual disease volume on relapse-free survival.