Mutational profiles associated with resistance in patients with BRAFV600E mutant colorectal cancer treated with cetuximab and encorafenib +/− binimetinib or alpelisib

Background Treatment strategies inhibiting BRAF in combination with EGFR have been developed in patients with BRAF^V600E mutant metastatic colorectal cancer, but intrinsic and secondary resistance remains a challenge. We aimed to investigate which genetic alterations cause intrinsic non-response and/or acquired resistance in these patients receiving therapies consisting of a backbone of BRAF and EGFR inhibition.Methods This was a cohort study on genetic alterations in patients with BRAF^V600E mutant advanced colorectal cancer treated with inhibitors of the MAPK pathway. We examined tumour tissue for genetic alterations at baseline, during treatment and at progression.Results In total, 37 patients were included in this cohort. Genetic alterations in EGFR and in PIK3CA are associated with non-response. A greater fraction of non-responders (75%) versus responders (46%) had at least one genetic alteration in other genes than TP53, APC or BRAF. Secondary resistance mutations (n = 16 patients) were observed most frequently in the PI3K pathway (n = 6) and in receptor tyrosine kinases (n = 4), leading to increased upstream signalling.Conclusions Genetic alterations in the PI3K and upstream receptor tyrosine kinases were mostly associated with intrinsic and acquired resistance. By understanding these alterations, simultaneous or alternating treatments with targeted inhibitors might improve response duration.Subject terms: Colon cancer, Tumour biomarkers     

Predictors of health-related quality of life in patients with moderate to severely active ulcerative colitis receiving biological therapy

Abstract

Background and aims: Patients with ulcerative colitis have reduced health-related quality of life compared to the general population. Current treatment strategy aims to reduce patients’ symptoms and increase health-related quality of life. We investigated which symptoms of ulcerative colitis correlate to decreased health-related quality of life.

Methods: Among 743 patients with moderate to severely active ulcerative colitis receiving biological therapy in a cross-sectional national study, we determined which disease-related symptoms, as measured by the Simple Clinical Colitis Activity Index, worsened health-related quality of life scores across the Short Health Scale dimensions, while adjusting for treatment, age, and clinical manifestation, and stratifying for sex, by means of multiple linear regression.

Results: Patients with active disease had decreased health-related quality of life compared to those with inactive disease (median 5.8 (range 4.5–7.5) vs. 2 (0.8–3.3)). Both sexes had decreased health-related quality of life in all dimensions for the symptoms: bowel frequency during daytime (0.37–0.86 and 0.46–0.84), urgency of defecation (0.54–0.79 and 0.49–0.65) and blood in stool (0.50–0.75 and 0.36–0.54) for men and women respectively. Women were more often negatively affected by bowel frequency during night-time (4 domains vs. 1) and arthritis (5 domains vs. 3). In non-stratified analysis female sex is an independent predictor of lower health-related quality of life for 3 domains (0.38–0.53).

Conclusions: Health-related quality of life was most prominently associated with bowel frequency during daytime, urgency of defecation, and blood in stool. Other symptoms associated for some health-related quality of life dimensions, and appear to vary between the sexes.     

Can heat therapy help patients with heart failure?

To review and analyze the clinical outcomes of thermal therapy (≤1.4°C increase in core body temperature) in patients with heart failure (HF). A systematic review and meta-analysis regarding the effects of thermal therapy on HF was done by searching PubMed, Ovid Medline, Ovid Embase, Scopus, and internal databases up to date (2019).

• Improvement in the New York Heart Association (NYHA) class : Ten studies with 310 patients showed significant improvement in NYHA class. Only 7 among 40 patients remained in Class IV and 99 patients in Class III from 155 patients. Increased patients in lower classes indicate that more patients showed improvement. Sixteen studies on 506 patients showed an overall improvement of 4.4% of left ventricular ejection fraction (LVEF). Four studies reported improved endothelial dysfunction by 1.7% increase in flow-mediated dilation (FMD) on 130 patients.
• Reduction in blood pressure: Thermal therapy reduced both systolic blood pressure (SBP) and diastolic blood pressure by 3.1% and 5.31%, respectively, in 431 patients of 15 studies.
• Decrease in cardiothoracic ratio (CTR): Eight studies reported an average of 5.55% reduction of CTR in a total of 347 patients.
• Improvement in oxidative stress markers: Plasma brain natriuretic peptide (BNP) levels significantly decreased (mean difference of 14.8 pg/dL) in 303 patients of 9 studies.
• Improvement of quality of life: Among 65 patients, thermal therapy reduced cardiac death and rehospitalization by 31.3%.

A slight increase in core body temperature is a promising, noninvasive, effective, and complementary therapy for patients with HF. Further clinical studies are recommended.     

Residualizing iodine markedly improved tumor targeting using bispecific antibody-based pretargeting.

Previous studies have shown that pretargeting allows rapid visualization of renal cell carcinomas (RCC) with an (111)In-labeled bivalent peptide. For radioimmunotherapy, a beta-emitting radionuclide labeled to a bivalent peptide is required. Therapeutic efficacy of these radionuclides depends on the E(max), physical half-life, and residence time of the radiolabel in the tumor. The (131)I radiolabel generally clears rapidly from the tumor after internalization and subsequent degradation of the bivalent l-amino acid peptide (l-a.a. peptide) in the tumor cells. To improve the residence time of the iodine label in the tumor, a new bivalent peptide was synthesized that is peptidase resistant and consists of 4 d-amino acids (d-a.a. peptide). Here we investigated the characteristics of the residualizing iodine label in SK-RC-52 RCC tumors. METHODS: The d-a.a. peptide was manually synthesized according to standard solid-phase Fmoc/HBTU (2-[1H-benzotriazole-1-yl]-1,1,3,3-tetramethyluronium hexafluorophosphate) chemistry. The uptake and retention in the tumor of (111)In-/(125)I-labeled bivalent peptides (l-a.a. peptide and d-a.a. peptide) were studied in female BALB/c athymic mice with subcutaneous SK-RC-52 RCC tumors. Tumors were pretargeted with the bispecific monoclonal antibody (bs-mAb) G250xDTIn-1 and, 72 h later, mice were injected intravenously with one of both radiolabeled peptides. The effect of bs-mAb-diDTPA-bs-mAb (DTPA is diethylenetriaminepentaacetic acid) bridging at the tumor cell surface on the internalization of the bs-mAb-diDTPA complex was investigated in SK-RC-52 tumor-bearing mice. RESULTS: The maximum uptake and retention of (125)I-labeled l-a.a. peptide in the tumor were significantly lower compared with that of the (111)In-labeled l-a.a. peptide. In contrast, the tumor uptake and retention of the (125)I-labeled d-a.a. peptide) were similar to that of the (111)In-labeled l-a.a. peptide but were superior at later time points. The biodistribution of the radioiodinated d-a.a. peptide was highly similar to that of the (111)In-labeled d-a.a. peptide, and both radiolabeled peptides were retained significantly better in the tumor than the (111)In-labeled l-a.a. peptide. bs-mAb-diDTPA-bs-mAb bridge formation did not affect internalization of the bs-mAb-diDTPA complex. CONCLUSION: Uptake and retention in the tumor of the iodinated peptide after pretargeting with a bs-mAb can be significantly improved using d-a.a. peptides. Accordingly, the radiation dose to the tumor, correlating with the therapeutic efficacy of pretargeted RCC, can be enhanced substantially.     

Dosimetry of radioiodine therapy in patients with nodular goiter after pretreatment with a single, low dose of recombinant human thyroid-stimulating hormone.

A single, low dose of recombinant human thyroid-stimulating hormone (rhTSH) doubles 24-h RAIU and causes a more homogeneous distribution of radioiodine on thyroid scintigrams of patients with nodular goiter. Pretreatment with rhTSH allows the therapeutic dose of (131)I to be reduced by 50%-60% without compromising the result of thyroid volume reduction. The present study focused on the dosimetric aspects of therapy with a reduced dose of (131)I after pretreatment with rhTSH in patients with nodular goiter. METHODS: Thirty-six patients were treated with (131)I to reduce thyroid volume. Nine patients were pretreated with a single dose of 0.01 mg of rhTSH, and 9 patients, with 0.03 mg of rhTSH. Two control groups of 9 patients, matched for thyroid weight and 24-h radioactive iodide uptake, were not pretreated with rhTSH. The therapeutic dose of (131)I was aimed at being sufficient to result in retention of 3.7 MBq of (131)I per gram of thyroid tissue at 24 h. Thyroid radioactivity after (131)I administration was measured every 24 h for 3 d and on days 7, 10, 14, 21, and 28. A model of iodine biokinetics was used to estimate absorbed doses in organs. Protein-bound (131)I activity was measured at 1, 2, 3, 7, and 10 d and at 2, 3, and 4 wk after (131)I therapy. RESULTS: The administered activities were 1.5 times lower in the 0.01-mg rhTSH group and 1.9 times lower in the 0.03-mg rhTSH group than in the control groups. The absorbed dose in the thyroid was similar in the rhTSH-pretreated groups and in the control groups. In the organs of excretion (bladder) and uptake (stomach) of inorganic iodide, the absorbed doses were 2- to 3-fold lower in the pretreated groups than in the control groups. The effective dose equivalent outside the thyroid was considerably lower in the rhTSH-pretreated groups than in their respective control groups (1.6-fold in the 0.01-mg rhTSH group and 2.3-fold in the 0.03-mg rhTSH group). The time course of protein-bound (131)I activity in serum and the cumulated protein-bound (131)I activity in serum did not differ significantly between rhTSH-pretreated and control groups. CONCLUSION: (131)I therapy after pretreatment with a single, low dose of rhTSH, with the dose reduced according to the rhTSH-induced increase in 24-h radioactive iodide uptake, caused lower radiation-absorbed doses in extrathyroidal organs and tissues, especially bladder and stomach, and no significant increase in the release of (131)I-labeled thyroid hormones into the circulation of patients with nodular goiter. Thus, this mode of therapy can be recommended, especially when the dose of radioiodine to be administered without rhTSH pretreatment is high.     

A model for compound action potentials and currents in a nerve bundle III: A comparison of the conduction velocity distributions calculated from compound action currents and potentials

In this paper, we present the experimentally measured Compound Action Current (CACs) and Compound Action Potentials (CAPs) from frog sciatic nerves and earthworm nerve cords. We used histologically prepared cross sections of these nerve bundles to determine the distribution of fiber diameters. A modified volume conduction model that includes frequency-dependent conductivities was used to compute the Single Fiber Action Signals (SFASs). The recorded CACs and CAPs are used to predict the Conduction Velocity Distributions (CVDs) from the nerve bundles. The predicted CVDs are then compared with the histological CVDs. Analysis of Compound Action Signals from the three giant axons in the earthworm nerve cord and microelectrode data for the transmembrane action potential demonstrate the validity of our mathematical model. We found that the CVDs predicted from the recorded CACs and CAPs differ from the histological CVD for a variety of reasons. The validity of the assumption of a linear relationship between axon diameter and conduction velocity of a propagating action signal was investigated using CVDs from both the CAC and CAP. Variations of the CVDs with the propagation distance of the CASs and the recording temperature were investigated.     

Radiographic loosening of cementless threaded acetabular cups No additional diagnostic value of arthrography in 30 patients

We compared arthrography with plain radiographs in 30 consecutive patients having a clinical diagnosis of loosening of a smooth-threaded acetabular prosthesis (Mecron, Berlin). Leakage of contrast at the interface between the ring and the bone on the medial side of the prosthesis was seen in 21 patients. Loosening of the cup was also visible on the plane radiographs and loosening was confirmed in all these patients at revision surgery. No false positive arthrographies were seen. In one patient, the arthrography was false negative because of a technical failure. We conclude that no additional information was obtained by arthrography.     

Partial and complete blockade of 5-hydroxytrytophan (5-HTP)-induced head twitches in the rat: A study of ritanserin (R 55 667), risperidone (R 64 766), and related compounds

A series of test compounds were studied for their ability to inhibit and block the head-twitch response to either intraperitoneal (i.p.) 5-hydroxytryptophan (5-HTP) or intravenous (i.v.) mescaline in rats. Both responses were found to be sensitive to serotonin S₂ antagonists, and there was very good agreement between the inhibitory doses in both tests, particularly for the selective serotonin S₂ antagonists ritanserin and seganserin. However, these two compounds did not block the 5-HTP response, although they completely abolished the mescaline response. In contrast, the mixed serotonin-dopamine-norepinephrine antagonist risperidone was a potent blocker of both responses. The use of various antagonists and the combination treatments of ritanserin with haloperidol or prazosin indicated that the 5-HTP response is abolished when potent serotonin S₂ antagonism is associated with antagonistic activity on either dopamine D₂ or α₁ receptors.