Trastuzumab-Emtansine and Osimertinib Combination Therapy to Target HER2 Bypass Track Resistance in EGFR Mutation-Positive NSCLC.

Introduction: EGFR tyrosine kinase inhibitor improved the survival of patients with metastatic EGFR mutation-positive (EGFRm+) NSCLC. Despite high response rates, resistance develops inevitably in every patient. In up to 13%, HER2 protein overexpression is found on progression. We hypothesized that dual blockade of EGFR and HER2 by osimertinib combined with trastuzumab-emtansine (T-DM1) could reinduce tumor responses. Methods: In this multicenter, single-arm, phase 1-2 study (NCT03784599), patients with EGFRm+ NSCLC, progressing on osimertinib and HER2 overexpression were included. Patients were treated with T-DM1 3.6 mg/kg (intravenously) every 3 weeks and osimertinib 80 mg once a day. Primary end points were objective response rate (ORR) at 12 weeks and safety. Responses were assessed every 6 weeks (Response Evaluation Criteria in Solid Tumors 1.1). Sample size was calculated using Simon's two-stage minimax design (H0 = 41%, H1 > 55%, 80% power, one-sided type I error 10%: a ORR 16 of 36 was needed to proceed to 58 patients). Results: From January 2019 to April 2021, 27 patients were enrolled. ORR after 12 weeks of treatment was 4% (1 of 27). Median progression-free survival was 2.8 months (95% confidence interval: 1.4-4.6 mo). Most frequent treatment-related adverse events of any grade were fatigue, diarrhea, and nausea, among these, grade 3 in four patients. There were no grade 4 or 5 therapy-related adverse events. Conclusions: TRAEMOS (Trastuzumab-Emtansine and Osimertinib) is the first trial combining T-DM1 and osimertinib in patients with EGFRm+ NSCLC to target HER2 overexpression at osimertinib resistance. Safety profile was favorable compared with cytotoxic chemotherapy; but treatment revealed limited efficacy. Further clinical evaluation of this regimen is not warranted.

[Comparison of two coronary risk equivalents: diabetes mellitus and peripheral arterial disease]. / Risiken der Koronaräquivalente Diabetes mellitus und Periphere Arterielle Verschlusskrankheit im Vergleich.

BACKGROUND AND OBJECTIVE: Diabetes mellitus (DM) and peripheral arterial disease (PAD) are both coronary artery disease equivalents ("coronary equivalents"). It was the aim of this study to ascertain (1) to what extent each of these diseases differs from the other in respect of early death, (2) how frequently DM and PAD occur together in elderly patients seen in general practice and (3) what risk patients with DM and concomitant PAD carry. PATIENTS AND METHODS: In the prospective non-interventional study--"German Epidemiological Trial on Ankle Brachial Index"--6,880 unselected patients, aged 65 years or more, from 344 general medical practices were followed over five years and the incidence of deaths and of cardiovascular events recorded. DM was defined according to the medical diagnosis and/or if the HbA1c was > or = 6.5% and the ankle brachial index (ABI), determined by Doppler sonography. PAD was defined as an ABI of < 0.9 or the presence of intermittent claudication or state after peripheral revascularization/amputation. Survival rates were obtained using Kaplan-Meier estimate curves and Cox's proportional hazard model. 59 patients with an ABI > 1.5 were excluded from the study. Hazard ratios (HR with 95% confidence intervals [CI]) were adjusted according to known risk factors. RESULTS: The overall observation period for all the patients amounted to nearly 33000 patient-years (PY). The risk of death of patients with DM but no PAD (n = 1,220; 17.9%) was 1.5 times the risk of death (HR, 95% CI 1.2-1.8) of persons with neither disease (n = 4 172; 61.2%) and the risk of those with PAD but no DM (n = 918, 13;5%) was 1.7 times of those persons without either disease (HR, 95% CI 1.4-2.0). The risk for persons with DM and PAD (n = 511; 7.5%) was nearly 3 times that of persons without either disease, after adjustment for other cardiovascular risk factors (HR 2.8, 95% CI 2.3-3.4). The lower the ABI in persons with or without DM the greater the number of deaths per 1000 PY. CONCLUSIONS: These results confirm that diabetics and patients with PAD have a clearly increased risk of early death. These patients need intensive treatment of the risk factors. This is especially true for patients who have DM and PAD concomitantly.

Multi-level partnerships to promote health services among internally displaced in eastern Burma.

Ethnic populations in eastern Burma are the target of military policies that result in forced labour, destruction of food supplies, and massive forced displacement. Despite international assistance to Burmese refugees along the Thai-Burma border, traditional humanitarian models have failed to reach these internally displaced persons (IDPs) within Burma. Nevertheless, through the cultivation of a model (cross border local-global partnerships) 300,000 IDPs in eastern Burma now receive critical health services where, otherwise, there would be none. We describe key elements of the partnership model's genesis in eastern Burma. The role of the local partner, Backpack Health Worker Team (BPHWT), is highlighted for its indigenous access to the IDP populations and its maintenance of programmatic autonomy. These local elements are potentiated by international support for technical assistance, training, resources, and advocacy. International policy and investment should prioritize support of locally-driven health initiatives that utilize local-global partnerships to reach not only IDPs but also other war-torn or traditionally inaccessible populations worldwide.

[Metabolic syndrome and peripheral arterial occlusive disease as indicators for increased cardiovascular risk]. / Metabolisches Syndrom und periphere arterielle Verschlusskrankeit als Indikatoren für erhöhtes kardiovaskuläres Risiko.

BACKGROUND AND AIMS: The usefulness of the metabolic syndrome (MetS) or a low ankle brachial index (ABI), respectively, to identify patients with high risk for cardiovascular events has repeatedly been postulated. However, robust data on the prevalence and prognosis of such patients are missing in the primary care setting. PATIENTS AND METHODS: In the prospective, non-interventional "German epidemiological trial on Ankle Brachial Index (getABI) at total of 6880 unselected patients > or = 65 years were observed by their General Practitioners over 3 years. Death and cardiovascular events were recorded. The definition of MetS was similar to the one of NCEP ATP III (National Cholesterol Education Program--Adult Treatment Panel III). ABI (ratio of the systolic blood pressures measured at the distal part of the calf and at the upper arm) was measured with Doppler sonography. Peripheral arterial disease (PAD) was defined as ABI <0.9 or peripheral revascularization/amputation owing to PAD. Survival analyses were conducted with a Cox proportional hazard model. Hazard rate ratios (HRR, 95 % confidence intervals, CI) were multvariate adjusted. RESULTS: The observation time for the total cohort was more than 20,000 patient years (PY). Cardiovascular mortality in patients with MetS (n = 3040, 44 %) compared to patients without MetS (n = 3795; 55 %) was doubled (8.5 vs. 4.0 per 1,000 PY; HRR: 2.0; CI 1.3 - 2.9). Concomitant presence of MetS and PAD (n = 651; 9.5 %) increased the mortality risk compared to patients without both conditions (n = 3194; 46.4 %) drastically (21.1 vs. 3.0 per 1000 PY; HRR: 5.7; CI: 3.5 - 9.4). Similar significant risk increases also were noted for all-cause mortality or a combined endpoint of mortality and vascular morbidity. Further, in lower ABI categories cardiovascular event rates increased. CONCLUSIONS: Patients with MetS carry a substantially increased risk of premature death, especially cardiovascular death, and therefore require intensive treatment of their risk factors. This holds especially true if concomitant PAD is present.

Calcium antagonists ameliorate ischemia-induced endothelial cell permeability by inhibiting protein kinase C.

BACKGROUND: Dihydropyridines block calcium channels; however, they also influence endothelial cells, which do not express calcium channels. We tested the hypothesis that nifedipine can prevent ischemia-induced endothelial permeability increases by inhibiting protein kinase C (PKC) in cultured porcine endothelial cells. METHODS AND RESULTS: Ischemia was induced by potassium cyanide/deoxyglucose, and permeability was measured by albumin flux. Ion channels were characterized by patch clamp. [Ca2+]i was measured by fura 2. PKC activity was measured by substrate phosphorylation after cell fractionation. PKC isoforms were assessed by Western blot and confocal microscopy. Nifedipine prevented the ischemia-induced increase in permeability in a dose-dependent manner. Ischemia increased [Ca2+]i, which was not affected by nifedipine. Instead, ischemia-induced PKC translocation was prevented by nifedipine. Phorbol ester also increased endothelial cell permeability, which was dose dependently inhibited by nifedipine. The effects of non-calcium-channel-binding dihydropyridine derivatives were similar. Analysis of the PKC isoforms showed that nifedipine prevented ischemia-induced translocation of PKC-alpha and PKC-zeta. Specific inhibition of PKC isoforms with antisense oligodeoxynucleotides demonstrated a major role for PKC-alpha. CONCLUSIONS: Nifedipine exerts a direct effect on endothelial cell permeability that is independent of calcium channels. The inhibition of ischemia-induced permeability by nifedipine seems to be mediated primarily by PKC-alpha inhibition. Anti-ischemic effects of dihydropyridine calcium antagonists could be due in part to their effects on endothelial cell permeability.

Infiltracao do sistema nervoso central e das meninges nos linfomas com representacao leucemica. / Infiltration of central nervous system and meninges in lymphomas with leukemic presentation

Os autores fazem referencia a 4 pacientes com representacao leucemica no decurso de linfomas malignos que apresentaram infiltracao de celulas neoplasicas no sistema nervoso central e meninges. E feito o estudo anatomopatologico, encontrando-se em 2 deles a formacao de nodulos leucemicos no parenquima nervoso. Nos outros dois, houve regressao total de sintomatologia neurologica com o uso de metotrexate por via intratecal