Apolipoprotein E-Containing Lipoproteins and LRP1 Protect From NMDA-Induced Excitotoxicity Associated With Reducing α2-Macroglobulin in Müller Glia.

Purpose: Optic nerve damage leads to impairment of visual functions. We previously demonstrated that apolipoprotein E-containing lipoproteins (E-LPs) protect retinal ganglion cells (RGCs) from degeneration in a glaucoma model of glutamate/aspartate transporter-deficient mice. This study aimed to determine whether E-LPs protect RGCs from N-methyl-D-aspartate (NMDA)-induced excitotoxicity, and to investigate the details of an indirect neuroprotective mechanism of E-LPs by reducing α2-macroglobulin, which interferes with the neuroprotective effect of E-LPs, in Müller glia. Methods: Excitotoxicity was caused by intravitreal injection of NMDA, and then retinae were subjected to immunoblotting or quantitative reverse transcription-PCR. Primary cultures of mouse mixed retinal cells and mouse Müller glia were used for evaluating the effects of E-LPs on the expression of α2-macroglobulin. Results: Intravitreal injection of E-LPs protected the optic nerve from degeneration and attenuated the increase in α2-macroglobulin in aqueous humor and retina of rats. E-LPs directly decreased the expression and secretion of α2-macroglobulin in primary cultures of Müller glia; this decrease in production of α2-macroglobulin was blocked by knockdown of the low-density lipoprotein receptor-related protein 1 (LRP1) with small interfering RNA. E-LPs promoted the phosphorylation of STAT3, whereas Stattic, an inhibitor of STAT3, restored the expression of α2-macroglobulin decreased by E-LPs. Conclusions: In addition to our previous findings of the protection of RGCs by E-LPs, the new observations in Müller glia indicate that a reduction of the intraocular α2-macroglobulin, regulated by the E-LP-LRP1-STAT3 pathway, might be an additional protective mechanism against excitotoxicity in the retina.

[Examination of Fever Risk Factors after Prophylaxis with G-CSF].

Febrile neutropenia is a serious adverse drugreaction to cancer chemotherapy. Prophylactic administration of granulocyte colony-stimulatingfactor (G-CSF)is recommended in patients who require cancer chemotherapy associated with a risk of febrile neutropenia or intense treatment. However, we had patients who developed fever after prophylactic administration of G-CSF. This study investigated the risk factors of fever after prophylactic administration of G-CSF. The subjects were patients who underwent preoperative chemotherapy with docetaxel, cisplatin, and 5-fluorouracil for esophageal cancer and prophylactic administration of G-CSF. Medical charts were retrospectively reviewed for age, sex, date of G-CSF administration, presence or absence of fever after G-CSF administration, Multinational Association for Supportive Care in Cancer(MASCC) risk index score at the time of G-CSF administration, and blood counts at the time of G-CSF administration. The MASCC risk index score(21[17-21]vs 20[19-21])and neutrophil count at the time of G-CSF administration were significantly higher in the non-fever group than in the fever group. Neither factor was an independent risk factor in the multivariate analysis. However, we considered that evaluation at the time of G-CSF administration is useful for early symptomatic treatment of febrile neutropenia.

Correction: A phase II trial of 1st-line modified-FOLFOXIRI plus bevacizumab treatment for metastatic colorectal cancer harboring RAS mutation: JACCRO CC-11.

[This corrects the article DOI: 10.18632/oncotarget.24702.].

A phase II trial of 1st-line modified-FOLFOXIRI plus bevacizumab treatment for metastatic colorectal cancer harboring RAS mutation: JACCRO CC-11.

FOLFOXIRI plus bevacizumab is considered a standard initial therapy for metastatic colorectal cancer (mCRC). However, few prospective trials have evaluated triplet therapy plus bevacizumab in patients with RAS mutant mCRC. Patients with an age of 20 to 75 years, and unresectable, measurable tumors harboring RAS mutation were given first-line treatment with bevacizumab (5 mg/kg on day 1) plus modified-FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, levofolinate 200 mg/m2, and fluorouracil 2400 mg/m2 as a 46-h continuous infusion on day 1, repeated every 2 weeks). The primary endpoint was the objective response rate (ORR) as evaluated by an external review board. Progression-free survival (PFS), overall survival, early tumor shrinkage (ETS), depth of response (DpR), and safety were secondary endpoints. Among 64 patients who were enrolled between October 2014 and August 2016, 62 were evaluable for efficacy (right-sided tumors in 27%). ORR and disease control rate were 75.8% (95% confidence interval [CI] 65.1-86.5) and 96.8%, respectively. ETS was 73.8%, and median DpR was 49.2%. Median PFS was 11.5 (95% CI 9.5-14.0) months as of the cut-off date of September 2017. Adverse events of grade 3 or 4 were neutropenia (54%), hypertension (32%), diarrhea (13%), anorexia (11%), peripheral neuropathy (2%), and febrile neutropenia (5%). In conclusion, this prospective trial demonstrated for the first time that FOLFOXIRI plus bevacizumab is an active first-line treatment for patients with RAS mutant mCRC. Modified-FOLFOXIRI plus bevacizumab might become an alternative regimen of triplet chemotherapy for mCRC in Japan.

[A Retrospective Investigation of Lacrimation in Patients Treated with S-1].

Lacrimation is among the typical adverse drug reactions associated with S-1 treatment. However, lacrimation frequencies differ between reports, and a clear consensus regarding reaction times, risk factors, and symptomatic treatment for lacrimation is lacking. We retrospectively investigated the reaction times, risk factors, and outcomes of symptomatic treatment for lacrimation in 202 patients treated with S-1. The median estimated creatinine clearance noted upon initiation of cancer treatment was 75.8mL/min. The median of the relative treatment intensity was 87.1%, while the incidence of lacrimation was 26.7%. The median cumulative dose of S-1 before the onset of lacrimation was 23,520 mg in all patients, and 5,050 mg in those who developed lacrimation. Of the patients who developed lacrimation, 40.7% developed this symptom within 2 months after starting S-1 treatment. There were no apparent risk factors. The most frequently employed symptomatic treatment was a physiological saline ophthalmic solution provided as a hospital preparation. After treatment with this ophthalmic solution, 29.4% of the affected patients showed improvement and 70.6% showed no change; none however, experienced worsening of symptoms. These results suggest that clinicians should assess the presence of lacrimation after starting treatment with S-1. Symptomatic treatment with an ophthalmic solution that does not have a tear retention capacity may be useful in patients who have developed lacrimation.

Five-weekly S-1 plus cisplatin therapy combined with trastuzumab therapy in HER2-positive gastric cancer: a phase II trial and biomarker study (WJOG7212G).

BACKGROUND: Five-weekly S-1 plus cisplatin (SP) therapy is the standard care for advanced gastric or esophagogastric junction cancer (GC/EGJC) in East Asia. However, its efficacy and safety when combined with trastuzumab therapy for human epidermal growth factor receptor 2 (HER2)-positive advanced GC/EGJC remains unclear. METHODS: Patients received 5-weekly SP therapy (S-1 at 40-60 mg twice daily for 21 days plus cisplatin at 60 mg/m2 on day 8, every 5 weeks) plus trastuzumab therapy (first dose of 8 mg/kg, then 6 mg/kg every 3 weeks). The primary end point was the response rate, and the secondary end points included progression-free survival, overall survival, safety, and serum biomarker levels. RESULTS: Forty-four patients were enrolled. The response rate, progression-free survival, and overall survival were 61% (95% confidence interval 46-76%), 5.9 months, and 16.5 months respectively. The commonest grade 3 or grade 4 adverse events were neutropenia (30%) and anorexia (25%). A significantly higher response rate (92% vs 43%; P = 0.008) and longer progression-free survival (median 14.5 months vs 4.2 months; P = 0.028) were observed in patients with high (n = 14) compared with low (n = 17) pretreatment serum neuregulin 1 levels. CONCLUSIONS: Five-weekly SP therapy combined with trastuzumab therapy showed a good antitumor response and acceptable toxicity in HER2-positive advanced GC/EGJC. Serum neuregulin 1 might be associated with the efficacy of this treatment regimen.

[A Patient with Cavitated Pulmonary Metastases Treated with Regorafenib].

A 61-year-old woman underwent surgical resection of rectal cancer(SI, N3, Stage IIIb)and received 12 courses of adjuvant mFOLFOX6 chemotherapy. Six months after completion of adjuvant chemotherapy, she was found to have pulmonary metastases, and was treated with FOLFIRI plus bevacizumab. After 6 courses of chemotherapy, the pulmonary nodules showed central cavitation without any change in size. After 6 additional courses of chemotherapy, pulmonary lesions increased in and had consolidated. She was treated with regorafenib as second-line chemotherapy for recurrent disease. After 6 courses of regorafenib, the pulmonary nodules became cavitated. According to the RECIST criteria, the tumor response was stable disease. However, the morphology was significantly changed and tumor growth had been controlled for a long time. Assessment of tumor response depends not onlyon size according to the RECIST criteria, but also on the morphologic response when we assess tumor response to molecular targeted drugs.