Tumor Location Is Associated With the Prevalence of Braf And Pik3ca Mutations in Patients with Wild-Type Ras Colorectal Cancer: A Prospective Multi-Center Cohort Study in Japan.

BACKGROUND: Primary tumor location is a critical prognostic factor that also impacts the efficacy of anti-epidermal growth factor receptor (EGFR) therapy in wild-type RAS (KRAS/NRAS) metastatic colorectal cancer (CRC). However, the association between the incidence of BRAF and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations and primary tumor location remains unclear. METHODS: We prospectively collected tumor samples and clinical data of patients from 15 hospitals between August 2014 and April 2016 to investigate RAS, BRAF, and PIK3CA mutations using a polymerase chain reaction-based assay. According to the primary tumor location, patients were classified to right-sided (from cecum to splenic flexure) and left-sided (from descending colon to rectum) tumor groups. RESULTS: In total, 577 patients with CRC were investigated, 331 patients (57%) had CRC with wild-type RAS; of these 331 patients, 10.5%, 4.8%, and 5.9% patients harbored BRAFV600E, BRAFnon-V600E, and PIK3CA mutations, respectively. BRAF/PIK3CA mutations were more frequent in females, patients with right-sided tumors, and patients with peritoneal metastasis cases and less frequent in patients with liver metastases. The prevalence rates of BRAFV600E and PIK3CA mutations were higher in patients with right-sided tumors than in those with left-sided tumors (32.3% vs. 4.8% and 17.2% vs. 3.6%, respectively). CONCLUSIONS: More than half of the patients with right-sided CRC and wild-type RAS harbored BRAF/PIK3CA mutations, including BRAFnon-V600E, which may contribute to the difference in the anti-EGFR efficacy between the right- and left-sided CRC.

Bevacizumab Exacerbates Paclitaxel-Induced Neuropathy: A Retrospective Cohort Study.

BACKGROUND: Bevacizumab (BEV), a humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody, enhances the antitumor effectiveness of paclitaxel (PTX)-based chemotherapy in many metastatic cancers. A recent study in mice showed that VEGF receptor inhibitors can interfere with the neuroprotective effects of endogenous VEGF, potentially triggering the exacerbation of PTX-induced neuropathy. In clinical trials, exacerbation of neuropathy in patients who received PTX combined with BEV (PTX+BEV) has generally been explained by increased exposure to PTX owing to the extended duration of chemotherapy. We investigated whether the concurrent use of BEV is associated with the exacerbation of PTX-induced neuropathy. METHODS: Female patients with breast cancer who had received weekly PTX or PTX+BEV from September 2011 through May 2016 were studied retrospectively. PTX-induced neuropathy was evaluated at the same time points (at the 6th and 12th courses of chemotherapy) in both cohorts. A multivariate Cox proportional-hazards model was used to assess the independent effect of BEV on the time to the onset of neuropathy. RESULTS: A total of 107 patients (median age, 55 years; range, 32-83) were studied. Sixty-one patients received PTX as adjuvant chemotherapy, 23 received PTX for metastatic disease, and 23 received PTX+BEV for metastatic disease. Peripheral sensory neuropathy was worse in patients who received PTX+BEV than in those who received PTX alone: at the 6th course, Grade 0/1/2/3 = 4/13/4/0 vs. 25/42/6/0 (P = 0.095); at the 12th course, 2/3/11/3 vs. 7/30/23/2 (P = 0.016). At the 12th course, the incidence of Grade 2 or higher neuropathy was significantly higher in patients treated with PTX+BEV than in those treated with PTX alone (74% vs. 40%; P = 0.017). In multivariate analysis, BEV was significantly associated with an increased risk of neuropathy (HR 2.32, 95% CI 1.21-4.44, P = 0.012). CONCLUSIONS: The concurrent use of BEV could worsen PTX-induced neuropathy in patients with breast cancer.

Muscle wasting associated with the long-term use of mTOR inhibitors.

Some targeted therapies alter muscle mass due to interference with pathways of muscle metabolism. The effects of mammalian target of ra pamycin (mTOR) inhibitors on muscle mass have yet to be fully elucidated. In the present study, the computerized tomography (CT) scans of patients receiving mTOR inhibitors for at least 6 months taken at baseline and post-therapy were retrospectively retrieved, and body composition analyses were performed using the software, sliceOmatic version 5.0 (TomoVision, Inc., Magog, QC, Canada). The difference in body composition parameters was evaluated for significance. The time to treatment (TTF) failure was also compared between the sarcopenic and non-sarcopenic patients at the baseline. Of the 75 patients studied, 20 matched the inclusion criteria (including 16 males). The mean duration between the CT scans was 14.4±2.0 months. A total of 12 (60%) patients were sarcopenic at the baseline, whereas three more (75% in total) became sarcopenic following treatment. The use of mTOR inhibitors significantly decreased the skeletal muscle area (P=0.011) and lean body mass (P=0.007), although it had no effect on adipose tissue (P=0.163) or body weight (P=0.262). The rate of skeletal muscle wasting was 2.6 cm2/m2, or 2.3 kg in 6 months. The TTF did not differ between sarcopenic and non-sarcopenic patients, and was not significantly associated with any other parameter. To the best of our knowledge, this is the first study to demonstrate that the long-term use of mTOR inhibitors induces a marked loss of muscle mass. Due to the predictive and prognostic role of sarcopenia in cancer patients, these findings may have important clinical implications.

Trough plasma concentration of imatinib reflects BCR-ABL kinase inhibitory activity and clinical response in chronic-phase chronic myeloid leukemia: a report from the BINGO study.

Pharmacokinetic (PK) factors have been suggested to be involved in the unfavorable clinical responses of chronic myeloid leukemia (CML) patients treated with imatinib. The purpose of this study was to clarify prognostic implications of PK factors in CML patients treated with imatinib. The plasma trough (C(min)) level of imatinib and serum α(1)-acid glycoprotein (AGP) level were measured on two different days in 65 CML patients treated with imatinib for more than 12 months. We further examined whether the C(min) level of imatinib actually reflects inhibitory activity against BCR-ABL kinase using the plasma inhibitory activity (PIA) assay. Since the differences of five patients were statistically rejected by the Smirnov-Grubbs' test, we excluded them for further analysis. The C(min) level was strongly associated with the achievement of MMR at the 12th month, and ROC analysis demonstrated C(min) levels and their discrimination potential for major molecular response (MMR) with the best sensitivity (63.2%) and specificity (68.2%) at a C(min) threshold of 974 ng/mL. The α(1)-Acid glycoprotein (AGP) level was within the normal range in 57 of 60 patients, indicating little impact of AGP on our study. There was a weak correlation between PIA against phospho (P)-BCR-ABL and the C(min) level of imatinib (r(2) = 0.2501, P = 0.0007), and patient plasma containing >974 ng/mL imatinib sufficiently inhibited P-BCR-ABL. These results collectively indicated that maintaining ∼1000 ng/mL of C(min) was clinically and biologically important for the optimal response in CML patients treated with imatinib. A prospective intervention study is required to establish PK-based management in CML patients treated with imatinib.

[Significance of monitoring WT1 mRNA levels of peripheral blood and bone marrow in acute myeloid leukemia].

This study investigated the clinical value of monitoring peripheral blood (PB) WT1 mRNA levels in acute myeloid leukemia (AML) patients. We evaluated the correlation between PB and bone marrow (BM) WT1 mRNA levels in the follow-up period of the clinical course of 17 AML patients. The levels of fusion gene transcripts in PB were also monitored when detected before chemotherapy. Patients with sustained complete remission (CR) showed a trend toward a higher WT1 mRNA reduction rate by induction therapy than patients who relapsed after CR (p=0.09). Correlation between the WT1 levels of PB and BM samples obtained on the same day was relatively strong (R=0.87). Among the four fusion transcript-positive patients, the levels of fusion transcripts and WT1 showed a similar transition pattern. These findings suggest that WT1 mRNA is a useful marker to improve risk-stratification for post-induction therapy and to guide management of individual AML patients by monitoring minimal residual disease, especially for patients with no disease-specific marker. Since WT1 monitoring via PB sampling is simple and less invasive than BM sampling, the use of this marker also improves patient management.

[Pharmacokinetics of S-1].

S-1 is an attractive oral fluorouracil antitumor drug, which is being called "a self-rescuing drug". This novel oral fluoropyrimidine is combined with three pharmacological agents: tegafur (FT) which is a prodrug of 5-fluorouracil (5-FU), 5-chloro-2,4-dihydroxypyridine (CDHP) which inhibits dihydropyrimidine dehydrogenase (DPD) activity, and potassium oxonate (Oxo) which reduces gastrointestinal toxicity. Phase I and an early phase II clinical trials were performed about ten years ago, and these results had already been introduced to the Journal "Clinical Cancer Research Vol. 5, pages 2000-2005, 1999". The data of this article in this journal was referred from the results of the figures and tables based on the above trial. Most of the authors in this article have contributed on that pharmacokinetics study and published the above manuscripts. In that study, the pharmacokinetics of 5-FU, intact FT, CDHP and Oxo after administration of the standard dose of S-1 had been performed. These studies were carried out at two hospitals, Department of Surgery (Section 1) Sapporo Medical University and Chemotherapy Cancer Center, Cancer Institute Hospital and Japanese Foundation for Cancer Research (Ohtsuka). The number of patients accepted for this trial is twelve, 5 patients with gastric cancer, 4 with colorectal cancer and 3 with breast cancer. Single administration trial was referred to all patients, but consecutive administration trial was limited to ten patients. The results of plasma concentration, Cmax, Tmax, AUC0-14, and T1/2 of 5-FU, FT, CDHP, and Oxo were ascertained in details. It was a surprise that the indicated data was very similar to that of the intravenous 5-FU continuous infusion. Therefore, the low dose administration of 5-FU (FT) as S-1 may result in good antitumor effects with minimum adverse effects to the patients.

Therapeutic effects of beta-thujaplicin eardrops on canine Malassezia-related otitis externa.

An eardrop solution of beta-thujaplicin was examined for therapeutic effects on canine Malassezia-related otitis externa. Half to one ml of beta-thujaplicin solution of 100 microg/ml including DMSO 2% was injected everyday into both external ear canals of 31 cases for test-of-cure agreement. Fifteen score phases were established from the symptoms and cerumen smear biopsy findings, and score changes were recorded at least once a week. The means of the second and the third inspection day scores decreased significantly more than the previous value of each. In addition, the numbers of yeast-like organisms clearly decreased. These results suggest that beta-thujaplicin eardrops are effective for Malassezia-related otitis externa in dogs.

Effects of beta-thujaplicin on anti-Malassezia pachydermatis remedy for canine otitis externa.

The antifungal activity of beta-thujaplicin was evaluated against 51 Malassezia pachydermatis strains isolated from canine ear canals with or without otitis externa. For comparison, sensitivity tests were performed on M. pachydermatis isolates for nystatin, ketoconazole, and terbinafine HCl, all clinically available antifungal agents. The minimal inhibition concentrations over 50% of the tested isolates (MIC50) were 3.13 microg/ml for beta-thujaplicin and nystatin, 0.016 microg/ml for ketoconazole, and 1.56 microg/ml for terbinafine HCl. The antifungal effect for M. pachydermatis of beta-thujaplicin compared favorably with commercial antifungal agents. None of the 51 M. pachydermatis isolates showed resistance against any of the tested antibiotics investigated in this study. Ten representative isolates of M. pachydermatis were subcultured for 30 generations at concentrations close to the MIC levels of beta-thujaplicin, nystatin, ketoconazole, and terbinafine HCl, and examined to determine whether they had acquired resistance to each drug. As a result, M. pachydermatis was found to achieve resistance more easily for ketoconazole and terbinafine HCl than for beta-thujaplicin or nystatin. The MIC50 of beta-thujaplicin did not change during the course of subculture, and it is thought that the potential development of a resistant strain is low, even with continuous infusion for otitis externa therapy. beta-Thujaplicin is an inexpensive and safe treatment with anti-inflammatory and deodorant effects that can be recommended as an effective remedy for canine otitis externa.

Clinical evaluation of monotherapy with cefpirome for infections complicating hematological disorders.

The clinical effects of cefpirome (CPR) monotherapy were evaluated in 38 infected patients with hematological diseases. The underlying diseases of the patients were chiefly acute leukemia, myelodysplastic syndrome, malignant lymphoma, and aplastic anemia, and 18 patients were clinically neutropenic (<500 neutrophils/µL). Septicemia, pneumonia, or an unexplained fever, were the predominant complicating infections. The clinical efficacy of CPR was satisfactory or improved in 89.5% of patients. When compared to empirical combination therapy with 2 antibiotics, monotherapy with CPR reduced the drip infusion volume and the frequency of antibiotic administration, resulting in a better quality of life due to less frequent night urination, a low cost/benefit ratio, and reduction in nursing responsibilities. Due to this high efficacy rate, monotherapy with CPR should be considered as a front-line therapeutic approach in patients with infections accompanying hematological diseases, particularly those with neutropenia. J Infect Chemother 1996;2:75-78.

Emergence of Nonalbicans Candida Species in Immunocompromised Leukemia Patients during Fluconazole Treatment.

The incidence of the emergence of nonalbicans Candida species during fluconazole treatment was surveyed in leukemia patients who were severely immunocompromised due to either intensive chemotherapy or bone marrow transplantation during the 3-year period from April 1993 to March 1996. Thirty-three patients received either prophylactic or therapeutic fluconazole administration for at least 7 days. In 7 of these 33 patients (21.2%), nonalbicans Candida including C. krusei, C. glabrata, C. maris, and C. inconspicua emerged during, or immediately after, fluconazole administration, with C. inconspicua the most prevalent Candida spp. Since these yeast strains are resistant to fluconazole, it is possible that selection occurred favoring Candida spp. resistant to fluconazole. Therefore, surveillance for yeast strains resistant to fluconazole should be performed as a routine procedure during fluconazole administration. In cases of resistance, other effective antifungal agents should be administered.