Monitoring the effect of first line treatment in RAS/RAF mutated metastatic colorectal cancer by serial analysis of tumor specific DNA in plasma.

BACKGROUND: Precision medicine calls for an early indicator of treatment efficiency. Circulating tumor DNA (ctDNA) is a promising marker in this setting. Our prospective study explored the association between disease development and change of ctDNA during first line chemotherapy in patients with RAS/RAF mutated metastatic colorectal cancer (mCRC). METHODS: The study included 138 patients with mCRC receiving standard first line treatment. In patients with RAS/RAF mutated tumor DNA the same mutation was quantified in the plasma using droplet digital PCR. The fractional abundance of ctDNA was assessed in plasma before treatment start and at every treatment cycle until radiologically defined progressive disease. RESULTS: RAS/RAF mutations were detected in the plasma from 77 patients. Twenty patients progressed on treatment and 57 stopped treatment without progression. The presence of mutated DNA in plasma was correlated with poor overall survival. A low level of ctDNA after the first cycle of chemotherapy was associated with a low risk of progression. On the other hand, a significant increase of ctDNA at any time during the treatment course was associated with a high risk of progression on continuous treatment. The first increase in ctDNA level occurred at a median of 51 days before radiologically confirmed progression. CONCLUSIONS: The results indicate that the ctDNA level holds potential as a clinically valuable marker in first line treatment of mCRC. A rapid decrease was associated with a prolonged progression free interval, whereas a significant increase gave notice of early progression with a relevant lead time.

MALT1 is an intrinsic regulator of regulatory T cells.

Regulatory T cells (Tregs) are crucial for the maintenance of immunological self-tolerance and their absence or dysfunction can lead to autoimmunity. However, the molecular pathways that govern Treg biology remain obscure. In this study, we show that the nuclear factor-κB signalling mediator mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is an important novel regulator of both Tregs originating in the thymus ('natural' or nTregs) and Tregs induced to differentiate from naive thymocyte helper (Th) cells in the periphery ('induced' or iTregs). Our examination of mice deficient for MALT1 revealed that these mutants have a reduced number of total Tregs. In young Malt1-/- mice, nTregs are totally absent and iTreg are diminished in the periphery. Interestingly, total Treg numbers increase in older Malt1-/- mice as well as in Malt1-/- mice subjected to experimentally induced inflammation. iTregs isolated from WT and Malt1-/- mice were indistinguishable with respect to their ability to suppress the activities of effector T cells, but Malt1-/- iTregs expressed higher levels of Toll-like receptor (TLR) 2. Treatment of WT and Malt1-/- Th cells in vitro with the TLR2 ligand Pam3Cys strongly enhanced the induction and proliferation of Malt1-/- iTregs. Our data suggest that MALT1 supports nTreg development in the thymus but suppresses iTreg induction in the periphery during inflammation. Our data position MALT1 as a key molecule that contributes to immune tolerance at steady-state while facilitating immune reactivity under stress conditions.

Chronophin is a glial tumor modifier involved in the regulation of glioblastoma growth and invasiveness.

Glioblastoma is the most aggressive primary brain tumor in adults. Although the rapid recurrence of glioblastomas after treatment is a major clinical challenge, the relationships between tumor growth and intracerebral spread remain poorly understood. We have identified the cofilin phosphatase chronophin (gene name: pyridoxal phosphatase, PDXP) as a glial tumor modifier. Monoallelic PDXP loss was frequent in four independent human astrocytic tumor cohorts and increased with tumor grade. We found that aberrant PDXP promoter methylation can be a mechanism leading to further chronophin downregulation in glioblastomas, which correlated with shorter glioblastoma patient survival. Moreover, we observed an inverse association between chronophin protein expression and cofilin phosphorylation levels in glioma tissue samples. Chronophin-deficient glioblastoma cells showed elevated cofilin phosphorylation, an increase in polymerized actin, a higher directionality of cell migration, and elevated in vitro invasiveness. Tumor growth of chronophin-depleted glioblastoma cells xenografted into the immunodeficient mouse brain was strongly impaired. Our study suggests a mechanism whereby the genetic and epigenetic alterations of PDXP resulting in altered chronophin expression may regulate the interplay between glioma cell proliferation and invasion.

[Arterial puncture or pulse oximetry?]. / Arteriepunktur eller pulsoksimetri?

Arterial puncture is the general accepted standard method for monitoring oxygen therapy in critically ill patients, but this technique is painful for the patient, has the potential of complications, and does not provide immediate continuous data. Pulse oximetry is a non-invasive method used to measure arterial oxygen saturation with a clinically acceptable accuracy of +/- 2%. Despite some limitations, pulse oximetry is considered to be reliable in most cases in detecting hypoxaemia and monitoring oxygen therapy in stationary units. The pulse oximeter can reduce the number of arterial punctures, personnel's time consumption, and limit oxygen abuse. Furthermore the new transportable and hand-held pulse oximeters offer new possibilities for continuous 24 hour monitoring of oxygen saturation also out of hospitals. The pulse oximeter can optimize monitoring patients' oxygen saturation in the stationary units, however, arterial puncture will remain the most reliable method in the assessment of hypoxaemia and hypercapnia, especially in acute situations.

[Malignant bone pain]. / Maligne knoglesmerter.

Bone pain is one of the most frequent causes of pain in patients with cancer, and the levels of metastases and bone pain are not directly correlated. Nociceptors in the periosteum are probably stimulated by halisteresis or by inflammatory oedema leading to an increase in the intraosseous pressure. Some authors believe that the nociceptors in bone are mediated via intraosseous mechanoreceptors in the bone-matrix. At a low pain level the initial treatment is acetylsalicylic acid, paracetamol or other nonsteroidal antiinflammatory drugs. At increasing pain level initial doses of oral opioids are added. In severe bone pain, where conventional therapy seems difficult, opioids are administered by invasive techniques. In localised bone pain palliative radiation is the first treatment of choice. Corticosteroids induce an analgetic effect indirectly by reducing the inflammatory oedema, inhibiting the synthesis of prostaglandins and may inhibit excitatory nerve fibres. Endocrine treatment, calcitonin and biophosphonates have shown a documented pain-relieving effect in patients with disseminated breast and prostate cancer. Chemotherapy has shown a pain-relieving effect in patients with disseminated breast cancer, surgical intervention is used in stabilizing osteolytic bones before or after a fracture ensuring a reasonable relief of pain.

[Paraquat poisoning. Treatment and prognosis]. / Paraquatforgiftning. Behandling og prognose.

Treatment of paraquat intoxication is most often in vain if initial treatment is delayed. We report a case where the patient was admitted 25 hours after oral intake of paraquat. The patient died due to respiratory insufficiency secondary to peroxidative pulmonary fibrosis in spite of combined continuous haemodialysis and haemofiltration. Principles of treatment are reviewed.

Subcutaneously versus subfascially administered lidocaine in pain treatment after inguinal herniotomy.

We conducted a randomized, prospective, double-blind trial to compare the efficacy of subfascial (SF) versus subcutaneous (SC) lidocaine (10 mL 1%) given in the wound postoperatively through a catheter placed in the respective layer intraoperatively. The initial pain scores were similar in the two groups before injection of lidocaine. In the SC group, there was a reduction in pain scores during rest from 4 to 3 (P > 0.05), during cough from 6 to 5 (P > 0.05), and during mobilization from 7 to 5.5 (P > 0.05) at 15 min. In the SF group, the reductions in pain scores were from 4 to 2 (P < 0.05), from 6 to 3 (P < 0.05), and from 7 to 3 (P < 0.05), respectively. Supplemental analgesics after the lidocaine administration were needed earlier in the SC group than in the SF group (P < 0.01). We conclude that postoperative pain treatment with local lidocaine application after herniotomy has a better effect when applied in the SF, rather than the SC, layer.