Chemotherapy-induced peripheral neurotoxicity (CIPN) is a severe dose-limiting adverse event of chemotherapy. Presently, the mechanism underlying the induction of CIPN remains unclear, and no effective treatment is available. In this study, through metabolomics analyses, we found that nab-paclitaxel therapy markedly increased serum serotonin [5-hydroxtryptamine (5-HT)] levels in both cancer patients and mice compared to the respective controls. Furthermore, nab-paclitaxel-treated enterochromaffin (EC) cells showed increased 5-HT synthesis, and serotonin-treated Schwann cells showed damage, as indicated by the activation of CREB3L3/MMP3/FAS signaling. Venlafaxine, an inhibitor of serotonin and norepinephrine reuptake, was found to protect against nerve injury by suppressing the activation of CREB3L3/MMP3/FAS signaling in Schwann cells. Remarkably, venlafaxine was found to significantly alleviate nab-paclitaxel-induced CIPN in patients without affecting the clinical efficacy of chemotherapy. In summary, our study reveals that EC cell-derived 5-HT plays a critical role in nab-paclitaxel-related neurotoxic lesions, and venlafaxine co-administration represents a novel approach to treating chronic cumulative neurotoxicity commonly reported in nab-paclitaxel-based chemotherapy.
Paclitaxel/toxicity* ; Animals ; Albumins/adverse effects* ; Serotonin/metabolism* ; Mice ; Humans ; Male ; Female ; Venlafaxine Hydrochloride/therapeutic use* ; Neurotoxicity Syndromes/metabolism* ; Middle Aged ; Schwann Cells/metabolism* ; Peripheral Nervous System Diseases/drug therapy* ; Antineoplastic Agents

OBJECTIVETo investigate the value of MRI with CUBE sequence in early evaluation of the efficacy of neoadjuvant therapy (NAT) for locally advanced rectal cancer.

METHODSInclusion criteria: (1) rectal cancer proven by biopsy; (2) locally advanced rectal cancer (T3-4 or positive lymph nodes) with distance from lower edge of tumor to anal verge within 12 cm diagnosed by MRI before NAT; (3) acceptance of NAT treatment regulations and completion of NAT; (4) completion of routine MRI scan and CUBE scan before and after 2-course NAT chemotherapy (including new neoadjuvant chemotherapy and chemoradiotherapy); (5) completion of surgery 6-8 weeks after NAT; (6) exclusion of any previous NAT due to rectal malignant tumor or other tumors; (7) exclusion of poor image quality of preoperative routine MRI insufficient for rectal cancer staging or of CUBE image insufficient for tumor volume measurement. Fifty patients with advanced local rectal cancer were recruited in our hospital from February 2014 to January 2016. All the patients underwent MRI before and after 2-course neoadjuvent therapy. Tumor volume on CUBE were measured and the volume changes were calculated: volume difference= pre-treatment volume-post-treatment volume, volume change rate= (pre-treatment volume-post-treatment volume)/ pre-treatment volume. All the patients were categorized into sensitive and non-sensitive group according to postsurgical pathology. Comparisons were made between both groups before and after therapy. ROC curve was used to evaluate the value of CUBE-associated parameters in predicting the efficacy of rectal cancer.

RESULTSAmong enrolled 50 patients with rectal cancer, 31 were male and 19 were female, with mean age of 49.1 years (range 21 to 70 years). T-staging by MRI before NAT was T2N1-2 in 1 case, T3 in 43 cases, T4 in 6 cases. The number of patients after NAT from tumor regression grading (TRG) 0 to TRG3 was 14, 13, 18, 5, respectively. The sensitive group and insensitive group were 45 cases and 5 cases. Mean tumor volume before and after preoperative 2-course NAT was 18.70 (4.14 to 91.77) cmand 9.26 (1.02 to 52.58) cm, respectively, whose difference was significant (U=-5.826, P<0.001). Both measure values of overall tumor volume before and after preoperative NAT between sensitive group and insensitive group did not show significant differences(all P>0.05). While sensitivity group had significantly higher volume difference and change rate compared to insensitive group [ (11.90±10.01) cmvs. (0.65±3.93) cm, P=0.005; 0.45±0.28 vs. 0.09±0.36, P=0.010]. ROC curve revealed that the optimal cutoff value of accurate identification of patients with NAT sensitive was 1.96 cmfor volume difference with sensitivity 86.7% and specificity 80%, and 0.06 for volume change rate with sensitivity 93.3% and specificity 60%.

CONCLUSIONMRI CUBE can predict the efficacy of NAT for early rectal cancer patients accurately and sensitively through the detection of tumor volume change before and after NAT.

Objective To determine whether or not 810 nm low power Ga-Al-As laser treatment can stimulate the regeneration of damaged optic nerves by measuring the expression of growth associated protein 43 ( GAP-43 )and flash-visual evoked potential (F-VEP). Methods Eighty-eight Wistar rats weighing (180-220) g were randomly divided into a laser therapy group with 40 rats,an injury group with 32 rats,and a normal control group with 16 rats.Each group was subdivided into 1st,3rd,6th and 9th week subgroups.A standardized crushing of the optic nerve was applied to make the model.After this,the laser therapy group was treated for 3 minutes daily at 60 mW applied transcutaneously to a 5 mm diameter spot on the injured optic nerve.The injury and normal control groups received the same treatment with no laser output.The expression of GAP-43 was detected by immunohistochemistry and RT-PCR after 1,3,6 and 9 weeks of treatment.F-VEP was measured pre-injury,immediately after injury and 1,3,6 and 9 weeks post injury. Results After the optic nerve was injured,obvious changes in F-VEP were detected,including significantly prolonged latencies of N1,P1 and N2 waves.The latency increased immediately after the optic nerve injured,and then recovered,but after 1 and 3 weeks the latency was still prolonged.There was significant recovery from the 3rd to the 9th week.In the laser therapy group,the peak latencies of the N1,P1 and N2 waves were also prolonged,but the changes were less than those in the injury group.Expression of GAP-43 was hardly detectable in normal retinas and optic nerves.GAP-43 had its highest expression level at 1 week post-injury,and then decreased.At the 1st,3rd and 6th week post-injury,the expression of GAP-43 in the laser therapy group was significantly higher than in the injury group.GAP-43 mRNA content in the retina showed the same tendency as GAP-43 protein. Conclusion A 810 nm low power Ga-Al-As laser can promote neural repair and axonal regeneration after optic nerve injury.