Minimal residual disease in cancer therapy - Small things make all the difference

Minimal residual disease (MRD) is a major hurdle in the eradication of malignant tumors. Despite the high sensitivity of various cancers to treatment, some residual cancer cells persist and lead to tumor recurrence and treatment failure. Obvious reasons for residual disease include mechanisms of secondary therapy resistance, such as the presence of mutant cells that are insensitive to the drugs, or the presence of cells that become drug resistant due to activation of survival pathways. In addition to such unambiguous resistance modalities, several patients with relapsing tumors do not show refractory disease and respond again when the initial therapy is repeated. These cases cannot be explained by the selection of mutant tumor cells, and the precise mechanisms underlying this clinical drug resistance are ill-defined. In the current review, we put special emphasis on cell-intrinsic and -extrinsic mechanisms that may explain mechanisms of MRD that are independent of secondary therapy resistance. In particular, we show that studying genetically engineered mouse models (GEMMs), which highly resemble the disease in humans, provides a complementary approach to understand MRD. In these animal models, specific mechanisms of secondary resistance can be excluded by targeted genetic modifications. This allows a clear distinction between the selection of cells with stable secondary resistance and mechanisms that result in the survival of residual cells but do not provoke secondary drug resistance. Mechanisms that may explain the latter feature include special biochemical defense properties of cancer stem cells, metabolic peculiarities such as the dependence on autophagy, drug-tolerant persisting cells, intratumoral heterogeneity, secreted factors from the microenvironment, tumor vascularization patterns and immunosurveillance-related factors. We propose in the current review that a common feature of these various mechanisms is cancer cell dormancy. Therefore, dormant cancer cells appear to be an important target in the attempt to eradicate residual cancer cells, and eventually cure patients who repeatedly respond to anticancer therapy but lack complete tumor eradication.

Good reproducibility of heart rate variability after orthostatic challenge in patients with a history of acute coronary syndrome

BACKGROUND: Several parameters of heart rate variability (HRV) have been shown to predict the risk of sudden cardiac death (SCD) in cardiac patients. There is consensus that risk prediction is increased when measuring HRV during specific provocations such as orthostatic challenge. For the first time, we provide data on reproducibility of such a test in patients with a history of acute coronary syndrome. METHODS: Sixty male patients (65+/-8years) with a history of acute coronary syndrome on stable medication were included. HRV was measured in supine (5min) and standing (5min) position on 2 occasions separated by two weeks. For risk assessment relevant time-domain [standard deviation of all R-R intervals (SDNN) and root mean squared standard differences between adjacent R-R intervals (RMSSD)], frequency domain [low-frequency power (LF), high-frequency power (HF) and LF/HF power ratio] and short-term fractal scaling component (DF1) were computed. Absolute reproducibility was assessed with the standard errors of the mean (SEM) and 95% limits of random variation, and relative reproducibility by the intraclass correlation coefficient (ICC). RESULTS: We found comparable SEMs and ICCs in supine position and after an orthostatic challenge test. All ICCs were good to excellent (ICCs between 0.636 and 0.869). CONCLUSIONS: Reproducibility of HRV parameters during orthostatic challenge is good and comparable with supine position.

Electrocardiographic characteristics of patients with funnel chest before and after surgical correction using pectus bar: A new association with precordial J wave pattern.

OBJECTIVE Abnormal ECG findings suggestive of cardiac disease are frequent in patients with funnel chest, although structural heart disease is rare. Electrocardiographic characteristics and changes following new surgical treatments in young adults are not described so far. The aim of the study was to analyze electrocardiographic characteristics of patients with funnel chest before and after minimally invasive funnel chest correction by the Nuss procedure. METHODS Twenty-six patients with surgical correction of funnel chest using pectus bar were included. Twelve-lead ECGs before and later than one year after surgery were analyzed. RESULTS In postoperative ECGs, amplitude of P wave in lead II and negative terminal amplitude of P wave in lead V1 decreased from 0.13 to 0.10mV (p=0.03), and from 0.10 to 0.04mV (p<0.001), respectively. Mean QRS duration decreased from 108ms to 98ms (p=0.003) after correction. A pathological left and right Sokolow-Lyon index was observed in 35% and 23% of patients before, versus 8% (p=0.04) and 0% (p=0.01) after correction, respectively. In contrast, the rate of patients with J wave pattern in precordial leads V4-V6 increased from 8% before to 42% after surgery (p=0.004). CONCLUSIONS ECG abnormalities in patients with funnel chest are frequent, and can normalize after surgical correction by the Nuss procedure. De novo J wave pattern in precordial leads V4-V6 is a frequent finding after surgical funnel chest correction using pectus bar.