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1.
Folate Supplementation for Methotrexate Therapy in Patients With Rheumatoid Arthritis: A Systematic Review.
Liu, L, Liu, S, Wang, C, Guan, W, Zhang, Y, Hu, W, Zhang, L, He, Y, Lu, J, Li, T, et al
Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases. 2019;(5):197-202
Abstract
OBJECTIVE To review the evidence for benefits and harms of folate (folic acid or folinic acid) supplementation on methotrexate (MTX) treatment for rheumatoid arthritis (RA), to assess whether or not folate supplementation would reduce MTX toxicity or reduce MTX benefits, and to decide whether a higher MTX dosage is essential. METHODS We performed a sensitive search strategy and searched systematically the Medline, Embase, Web of Science and Cochrane Library databases from inception to 2 June 2016. Abstracts from major rheumatology meetings and major trial registers were also searched to retrieve all randomized controlled trials that interested us. RESULTS Seven studies with 709 patients were included. No significant heterogeneity was found between these trials. For RA patients treated with MTX, those supplied with folate were less likely to have elevated transaminase (odds ratio [OR] 0.15; 95% confidence interval [95% CI] 0.10, 0.23 [p < 0.00001]) and gastrointestinal side-effects such as nausea and vomiting (OR 0.71; 95% CI 0.51, 0.99 [p = 0.04]). Folate appeared to promote compliance to MTX as it reduced patient withdrawal compared to placebo (OR 0.29; 95% CI 0.21, 0.42 [p < 0.00001]). There was no statistical difference for mouth sores between folate and placebo (OR 0.83; 95% CI 0.57, 1.22 [p = 0.35]). As the markers of disease activity in those trials were not consistent, it was impossible to decide whether folate supplementation reduced MTX efficacy. Besides, we compared high-dose folate (≥25 mg per week) and low-dose folate (≤10 mg per week) on MTX efficacy, finding no statistical difference (OR 2.07; 95% CI 0.81, 5.30 [p = 0.13]), nor on MTX toxicity (OR 1.56; 95% CI 0.80,3.04 [p = 0.19]). CONCLUSION Folate supplementation can reduce the incidence of hepatotoxicity and gastrointestinal side-effects of MTX in patients with RA. It can also reduce patient withdrawal from MTX treatment. Although it tended to reduce mouth sores, it had no statistical significance. No significant difference was found between high-dose folate and low-dose folate on MTX efficacy or toxicity.
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2.
Resectable pancreatic adenocarcinoma neo-adjuvant FOLF(IRIN)OX-based chemotherapy - a multicenter, non-comparative, randomized, phase II trial (PANACHE01-PRODIGE48 study).
Schwarz, L, Vernerey, D, Bachet, JB, Tuech, JJ, Portales, F, Michel, P, Cunha, AS
BMC cancer. 2018;(1):762
Abstract
BACKGROUND At time of diagnosis, less than 10% of patients with pancreatic adenocarcinomas (PDAC) are considered to be immediately operable (i.e. resectable). Considering their poor overall survival (OS), only tumours without vascular invasion (NCCN 2017) should be considered for resection, i.e. those for which resection with disease-free margins (R0) is theoretically possible in absence of presurgery treatment. With regard to high R1 rates and undetectable locoregional and/or metastatic spreading prior to surgery explain (at least in part) the observed 1-year relapse and mortality rates of 50 and 25%, respectively. Today, upfront surgery followed by adjuvant chemotherapy is the reference treatment in Europe. The main limitation of the adjuvant approach is the low rate of completion of the full therapeutic sequence. Indeed, only 47 to 60% patients received any adjuvant therapy after resection compared to more than 75% for neoadjuvant therapy. No previous prospective study has compared this approach to a neoadjuvant FOLFIRINOX or FOLFOX chemotherapy for resectable PDAC. METHODS PANACHE01-PRODIGE48 is a prospective multicentre controlled randomized non comparative Phase II trial, evaluating the safety and efficacy of two regimens of neo-adjuvant chemotherapy (4 cycles of mFOLFIRINOX or FOLFOX) relative to the current reference treatment (surgery and then adjuvant chemotherapy) in patients with resectable PDAC. The main co-primary endpoints are OS rate at 12 months and the rate of patients undergoing the full therapeutic sequence. DISCUSSION The "ideal" cancer treatment for resectable PDAC would have the following characteristics: administration to the highest possible proportion of patients, ability to identify fast-progressing patients (i.e. poor candidates for surgery), a low rate of R1 resections (through optimisation of local disease control), and an acceptable toxicity profile. The neoadjuvant approach may meet all these criteria. With respect to published data on the efficacy of FOLFOX and mFOLFIRINOX, these two regimens are potential candidates for neoadjuvant use in the aim to optimising oncological outcomes in resectable PDAC. TRIAL REGISTRATION ClinicalTrials.gov , NCT02959879 . Trial registration date: November 9, 2016.
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3.
Phase III trial comparing UFT + PSK to UFT + LV in stage IIB, III colorectal cancer (MCSGO-CCTG).
Miyake, Y, Nishimura, J, Kato, T, Ikeda, M, Tsujie, M, Hata, T, Takemasa, I, Mizushima, T, Yamamoto, H, Sekimoto, M, et al
Surgery today. 2018;(1):66-72
Abstract
PURPOSE Oral adjuvant uracil and tegafur plus leucovorin (UFT/LV) is not inferior to standard weekly fluorouracil and folinate for stage II/III colon cancer. However, protein-bound polysaccharide K (PSK) has been evaluated as postoperative adjuvant therapy for colorectal cancer. This report is the first of MCSGO-CCTG, which compared UFT/LV to UFT/PSK as adjuvant chemotherapy for stage IIB or III colorectal cancer in patients who had undergone Japanese D2/D3 lymph node dissection. METHODS The primary endpoint was the 3-year disease-free survival (DFS). A randomized non-inferiority study compared UFT/LV to UFT/PSK. The overall survival, adverse events, compliance, and quality of life were also investigated as the secondary endpoints. RESULTS Between March 2006 and December 2010, 357 patients were randomized to UFT/PSK (n = 178) or UFT/LV (n = 179) (median age 65 years, colon/rectum 67.4/32.6%, stage IIB/IIIA/IIIB/IIIC 11.1/15.7/55.0/18.2%). The 3-year DFS rate was 82.3% in those receiving UFT/LV and 72.1% in those receiving UFT/PSK. The non-inferiority of UFT/PSK adjuvant therapy to UFT/LV therapy was not verified (-9.06%, 90% confidence interval -17.06 to -1.06%). The 3-year overall survival rate was 95.4% in those receiving UFT/LV and 90.7% in those receiving UFT/PSK. CONCLUSIONS As adjuvant chemotherapy for stage IIB and III colorectal cancer patients, UFT/PSK adjuvant therapy was not non-inferior to UFT/LV therapy with respect to the DFS.
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4.
Meta-analysis of Modified FOLFIRINOX Regimens for Patients With Metastatic Pancreatic Cancer.
Usón Junior, PLS, Rother, ET, Maluf, FC, Bugano, DDG
Clinical colorectal cancer. 2018;(3):187-197
Abstract
BACKGROUND We performed a meta-analysis of previous reports evaluating the effect of mFIO (modified FOLFIRINOX; leucovorin, 5-fluorouracil, irinotecan, oxaliplatin) regimens in advanced pancreatic cancer. MATERIALS AND METHODS We performed a meta-analysis of reported studies in PubMed, Scopus, and Web of Science (1950-2016) in December 2016. The inclusion criteria were randomized trials, prospective or retrospective cohorts, patients with metastatic pancreatic adenocarcinoma, the use of mFIO or FOLFIRINOX (FIO) chemotherapy, and available information for ≥ 1 efficacy endpoint (response rate, progression-free survival, and/or overall survival). The outcomes were compared according to the chemotherapy regimen using a random effects model. We also performed a meta-regression analysis to evaluate the effect of dose reductions on outcomes. RESULTS Of 2525 abstracts, 32 were considered eligible. Modifications in the FIO regimen included omission of the 5-fluorouracil bolus and/or dose reductions in infusional 5-fluorouracil, irinotecan, and/or oxaliplatin. mFIO was not associated with inferior response rates (32% vs. 33%; P = .879), lower rates of survival at 11 months (47% vs. 50%; P = .38), or lower 6-month progression-free survival rates (47% vs. 53%; P = .38). The meta-regression of the percentage of dose reduction failed to show any association. CONCLUSION The results of the present meta-analysis with a combined sample size of 1461 patients suggest that it is reasonable to consider mFIO regimens for patients with metastatic pancreatic adenocarcinoma.
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Tumour sidedness and intrinsic subtypes in patients with stage II/III colon cancer: analysis of NSABP C-07 (NRG Oncology).
Kim, SR, Song, N, Yothers, G, Gavin, PG, Allegra, CJ, Paik, S, Pogue-Geile, KL
British journal of cancer. 2018;(5):629-633
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Abstract
BACKGROUND We tested the association of colon tumour sidedness with prognosis and with molecular subtypes recently shown to be predictive of oxaliplatin benefit in stage III colon cancer. METHODS NSABP/NRG C-07 trial (N=1603) was used to determine association of tumour sidedness with molecular subtypes and recurrence-free survival (RFS) and overall survival (OS). RESULTS Sidedness was associated with molecular subtypes except stem-like/CMS4 subtype. Patients with stage III, left-sided tumours showed superior OS but not RFS. Sidedness was not associated with prediction of oxaliplatin benefit when combined with 5-Fu+LV. However, greater benefit from oxaliplatin was observed in a small subset of stage III patients with left-sided, enterocyte-subtype tumours (interaction HR=0.17, P=0.01). CONCLUSIONS Sidedness was associated with molecular subtypes and was predictive of OS in stage III colon cancer but was not predictive of RFS or oxaliplatin benefit in C-07. Molecular subtypes may provide more predictive value for oxaliplatin benefit than tumour sidedness.
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Protocol digest of randomized phase II study of modified FOLFIRINOX versus gemcitabine plus nab-paclitaxel combination therapy for locally advanced pancreatic cancer: Japan clinical oncology group study (JCOG1407).
Mizusawa, J, Fukutomi, A, Katayama, H, Ishii, H, Ioka, T, Okusaka, T, Ueno, H, Ueno, M, Ikeda, M, Mizuno, N, et al
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]. 2018;(7):841-845
Abstract
Gemcitabine is one of the standard treatments for locally advanced pancreatic cancer. Recent studies on metastatic pancreatic cancer have shown that combination chemotherapy with oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) and gemcitabine plus nab-paclitaxel (GnP) prolonged the overall survival compared with gemcitabine alone. To select the most promising chemotherapy, a randomized phase II selection design trial was started in July 2016 to compare between modified FOLFIRINOX and GnP for patients with locally advanced pancreatic cancer. A total of 124 patients will be enrolled from 36 Japanese institutions within 2.5 years. The primary endpoint is the proportion of 1-year overall survival, and secondary endpoints are progression-free survival, distant metastasis-free survival, response rate in patients with target lesions, CA19-9 response, adverse events, treatment-related death, early death, grade 4 non-hematological toxicity, and dose intensity. This trial has been registered with the UMIN Clinical Trials Registry [http://www.umin.ac.jp/ctr/index.htm], and the registration number is UMIN000023143.
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First-line Treatment of Advanced Biliary Ducts Carcinoma: A Randomized Phase II Study Evaluating 5-FU/LV Plus Oxaliplatin (Folfox 4) Versus 5-FU/LV (de Gramont Regimen).
Schinzari, G, Rossi, E, Mambella, G, Strippoli, A, Cangiano, R, Mutignani, M, Basso, M, Cassano, A, Barone, C
Anticancer research. 2017;(9):5193-5197
Abstract
BACKGROUND/AIM: Few clinical trials are available for advanced biliary tract carcinoma (BTC). We conducted this randomized phase II clinical trial to explore efficacy and safety of 5-fluorouracil/leucovorin (5-FU/LV - de Gramont) or the same regimen plus oxaliplatin (Folfox 4) as first-line treatment of advanced BTC. PATIENTS AND METHODS Primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), response and toxicity. RESULTS A total of 48 patients were enrolled, 23 in de Gramont arm and 25 in the Folfox arm. Disease control rate was 56.5% for de Gramont vs. 72% for Folfox. RR was 21.7% for de Gramont arm and 28% for Folfox arm (p=0.12). PFS was in favor of Folfox (5.2 vs. 2.8 months; p=0.031). OS was 7.5 and 13.0 months for de Gramont and Folfox arm respectively (p=0.0010). Toxicity was generally mild in both arms. CONCLUSION Folfox 4 could be considered a valid option as first-line treatment of BTC due to its efficacy and tolerability.
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[Two cases with generalized intracranial calcification due to hereditary folate malabsorption and literature review].
Zhang, Y, Wang, Q, Li, DX, Liu, YP, Song, JQ, Li, MQ, Qin, YP, Yang, YL
Zhonghua er ke za zhi = Chinese journal of pediatrics. 2016;(12):931-935
Abstract
Objective: This study aimed to investigate the clinical, biochemical and genetic features of two Chinese children with hereditary folate malabsorption. Method: Clinical features, laboratory examinations, treatment and SLC46A1 gene of two cases were studied. Reports on hereditary folate malabsorption utill September of 2016 were searched and the clinical and genetic characteristics of reported cases were summarized. Result: The two patients presented with megaloblastic anemia from their infant period and seizures, psychomotor retardation and regression. In case1, mean corpuscular volume (MCV) was 100 fl. Serum folate was 9.96 nmol/L. Folate and 5-methylenetetrahydrofolate in cerebrospinal fluid were 0 and 0.01 separately. In case 2, MCV was 93.9 fl. Serum folate was 4.49 nmol/L. The concentration of folate and 5-methylenetetrahydrofolate in cerebrospinal fluid were both zero. On their brain CT, progressive bilateral symmetrical calcification was observed. On their SLC46A1 gene, four mutations were identified. Case 1 had one novel mutation, c. 1238T>C (L413P) and c. 194-195insG (p.Cys66LeufsX99). From Case 2, two reported mutations, c. 1A>T (M1L) and c. 194-195insG (p.Cys66LeufsX99) were identified. The administration of folinic acid (60 to 120 mg per day) was initiated after diagnosis. Clinical improvement and normalized hematologic markers were observed after treatment. Totally 37 cases were reported in reviewed English literature, including 30 cases with mutations on SLC46A1 gene (only one Chinese patient). All the cases had the onset in infancy. The ratio of boys to girls was 1 to 1.5. Main manifestations were characterized by megaloblastic anemia (77%), failure to thrive (50%), diarrhea (27%), psychomotor retardation (63.6%), epilepsy (27%), and infection of respiratory system (45.5%). The concentration of folate in both serum and cerebrospinal fluid was decreased (72.7% and 63.6% respectively). Hypoimmunoglobulinemia accounted for 27.3%. Most of mutations in HFM were distributed between p. 65 and p. 68 (c.194-c.204), mainly due to insertion- or deletion-related frame shifts or generation of stop codons. Oral and parenteral folinic acid treatment was effective. Conclusion: Hereditary folate malabsorption often presented with megaloblastic anemia, abnormalities of digestive and nervous system, and hypoimmunoglobulinemia with recurrent infections. Low level of serum and CSF folate and screening SLC46A1 gene are keys to the etiologic study of the patients. Early supplement with folinic acid is beneficial to the prognosis.
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The basis for folinic acid treatment in neuro-psychiatric disorders.
Ramaekers, VT, Sequeira, JM, Quadros, EV
Biochimie. 2016;:79-90
Abstract
Multiple factors such as genetic and extraneous causes (drugs, toxins, adverse psychological events) contribute to neuro-psychiatric conditions. In a subgroup of these disorders, systemic folate deficiency has been associated with macrocytic anemia and neuropsychiatric phenotypes. In some of these, despite normal systemic levels, folate transport to the brain is impaired in the so-called cerebral folate deficiency (CFD) syndromes presenting as developmental and psychiatric disorders. These include infantile-onset CFD syndrome, infantile autism with or without neurologic deficits, a spastic-ataxic syndrome and intractable epilepsy in young children expanding to refractory schizophrenia in adolescents, and finally treatment-resistant major depression in adults. Folate receptor alpha (FRα) autoimmunity with low CSF N(5)-methyl-tetrahydrofolate (MTHF) underlies most CFD syndromes, whereas FRα gene abnormalities and mitochondrial gene defects are rarely found. The age at which FRα antibodies of the blocking type emerge, determines the clinical phenotype. Infantile CFD syndrome and autism with neurological deficits tend to be characterized by elevated FRα antibody titers and low CSF MTHF. In contrast, in infantile autism and intractable schizophrenia, abnormal behavioral signs and symptoms may wax and wane with fluctuating FRα antibody titers over time accompanied by cycling changes in CSF folate, tetrahydrobiopterin (BH4) and neurotransmitter metabolites ranging between low and normal levels. We propose a hypothetical model explaining the pathogenesis of schizophrenia. Based on findings from clinical, genetic, spinal fluid and MRI spectroscopic studies, we discuss the neurochemical changes associated with these disorders, metabolic and regulatory pathways, synthesis and catabolism of neurotransmitters, and the impact of oxidative stress on the pathogenesis of these conditions. A diagnostic algorithm and therapeutic regimens using high dose folinic acid, corticosteroids and milk-free diet is presented which has proven to be beneficial in providing adequate folate to the brain and decreasing the FRα autoantibody titer in those positive for the antibody.
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10.
Adjuvant Oral Uracil-Tegafur with Leucovorin for Colorectal Cancer Liver Metastases: A Randomized Controlled Trial.
Hasegawa, K, Saiura, A, Takayama, T, Miyagawa, S, Yamamoto, J, Ijichi, M, Teruya, M, Yoshimi, F, Kawasaki, S, Koyama, H, et al
PloS one. 2016;(9):e0162400
Abstract
BACKGROUND The high recurrence rate after surgery for colorectal cancer liver metastasis (CLM) remains a crucial problem. The aim of this trial was to evaluate the efficacy of adjuvant therapy with uracil-tegafur and leucovorin (UFT/LV). METHODS In the multicenter, open-label, phase III trial, patients undergoing curative resection of CLM were randomly assigned in a 1:1 ratio to either the UFT/LV group or surgery alone group. The UFT/LV group orally received 5 cycles of adjuvant UFT/LV (UFT 300mg/m2 and LV 75mg/day for 28 days followed by a 7-day rest per cycle). The primary endpoint was recurrence-free survival (RFS). Secondary endpoints included overall survival (OS). RESULTS Between February 2004 and December 2010, 180 patients (90 in each group) were enrolled into the study. Of these, 3 patients (2 in the UFT/LV group and 1 in the surgery alone group) were excluded from the efficacy analysis. Median follow-up was 4.76 (range, 0.15-9.84) years. The RFS rate at 3 years was higher in the UFT/LV group (38.6%, n = 88) than in the surgery alone group (32.3%, n = 89). The median RFS in the UFT/LV and surgery alone groups were 1.45 years and 0.70 years, respectively. UFT/LV significantly prolonged the RFS compared with surgery alone with the hazard ratio of 0.56 (95% confidence interval, 0.38-0.83; P = 0.003). The hazard ratio for death of the UFT/LV group against the surgery alone group was not significant (0.80; 95% confidence interval, 0.48-1.35; P = 0.409). CONCLUSION Adjuvant therapy with UFT/LV effectively prolongs RFS after hepatic resection for CLM and can be recommended as an alternative choice. TRIAL REGISTRATION UMIN Clinical Trials Registry C000000013.