A Randomized Controlled Phase 2 Study of Neoadjuvant Eribulin Versus Paclitaxel in Women with Operable Breast Cancer: The JONIE-3 Study.

OBJECTIVE: Neoadjuvant chemotherapy (NAC) is essential for surgical downstaging of early-stage breast cancer, but taxane administration is associated with neuropathy. We investigated whether eribulin induces less neuropathy than paclitaxel. METHODS: In this multicentre, randomised study (UMIN000012817), patients diagnosed with invasive breast cancer between December 2013 and April 2016 were randomly assigned to group E (eribulin followed by fluorouracil, epirubicin, and cyclophosphamide; FEC) or group P (paclitaxel followed by FEC). The primary endpoint was incidence of grade 1 or higher peripheral neuropathy according to the Common Terminology Criteria for Adverse Events (CTCAE). Secondary endpoints were pathological complete response (pCR), clinical response, breast-conserving surgery, adverse events, disease-free survival (DFS), and patient neurotoxicity questionnaire (PNQ) analysis. RESULTS: One hundred and eighteen cases were analyzed for safety and 115 were evaluated for efficacy. Peripheral sensory neuropathy was significantly lower in group E after week 6, while peripheral motor neuropathy in group E was significantly lower at weeks 9, 12, and 15. pCR in groups E and P was 20.7% and 29.8% (P = .289), respectively, and clinical response was 55.2% and 77.2% (P = .017), respectively. Three-year DFS was 89.7% in group E and 86.0% in group P (P = .561). Neutropenia was more frequent and more severe in group E. PNQ was evaluated for 4 years, and item 1 (sensory) was consistently lower in group E. CONCLUSION: Neuropathy was significantly less frequent and less severe in patients who received eribulin compared with paclitaxel. Thus, eribulin could be a good alternative to paclitaxel in patients suffering severe neuropathy.

[Necessity of Serum Calcium Concentration Measurement for Investigating Hypocalcemia Induced by Denosumab].

Denosumab is widely used for treating bone metastases in patients with advanced cancer. However, hypocalcemia has been reported as a serious adverse effect during this treatment. Therefore, monitoring serum calcium concentration is essential. During long-term continuous administration ofdenosumab, the burden ofeach blood sampling occasion and medical economics should be clarified; however, the appropriate blood sampling frequency has not yet been confirmed. In the present study, we performed a retrospective investigation of serum calcium concentration after denosumab administration. The results indicated that serum calcium concentration tended to increase with repeated administration. A significant increase was observed at the time ofthe third and sixth administration. This suggested that it was possible to reduce the frequency ofblood sampling during long-term administration ofdenosumab with appropriate calcium supplementation.

Efficacy of denosumab for restoring normal bone mineral density in women receiving adjuvant aromatase inhibitors for early breast cancer.

BACKGROUND: Osteoporosis is a major side effect of aromatase inhibitors (AIs), which are greatly effective in the treatment of breast cancer. However, there are no satisfactory measures against osteoporosis. In this multicenter, randomized, comparative study, we evaluate the efficacy of denosumab for preventing loss of bone mineral density (BMD) induced by adjuvant therapy with AI s in breast cancer patients with normal BMD. PATIENTS AND METHODS: The bone loss-suppressing effect of denosumab will be comparatively evaluated in postmenopausal patients scheduled to receive letrozole or anastrozole as a postoperative endocrine therapy for stage I-IIIA hormone-sensitive breast cancer and a control group. Patients will be administered letrozole 2.5 mg or anastrozole 1 mg once a day, and the treatment will be continued for 5 years unless recurrence, secondary cancer, or unacceptable toxicity develops. Patients in the denosumab group will receive a subcutaneous injection of 60 mg of denosumab every 6 months. The primary endpoint is the rate of change in the lumbar spine (L1-L4) BMD, as determined by dual-energy X-ray absorptiometry (DXA), 12 months after the start of the injection. The secondary endpoints were ETHICS AND DISSEMINATION:: The protocol was approved by the institutional review boards of Kyoto Prefectural University of Medicine and all the participating faculties. Written informed consent was obtained from all patients before registration, in accordance with the Declaration of Helsinki. Results of the study will be disseminated via publications in peer-reviewed journals. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT03324932, Japan Registry of Clinical Trial (jRCT): CRB5180001.

Effect of denosumab on low bone mineral density in postmenopausal Japanese women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer: 24-month results.

BACKGROUND: Aromatase inhibitors (AI) have been established as the gold-standard therapy for postmenopausal patients. Worldwide, adjuvant denosumab at a dose of 60 mg twice per year reduces the risk of clinical fractures in postmenopausal patients with breast cancer who received AI. However, the efficacy of denosumab in the treatment of AI-associated bone loss had not been prospectively evaluated in Japan. Previously, we reported the 12-month effect of denosumab in Japanese patients for the first time; the primary endpoint was the change in the percentage of bone mineral density (BMD) of the lumbar spine from baseline to 12 months. METHODS: This secondary follow-up study prospectively evaluated the change in the percentage of BMD of the lumbar spine from baseline to 24 months. Postmenopausal women with early-stage, histologically confirmed, hormone receptor-positive, invasive breast cancer who were receiving or scheduled to receive AI were included. Denosumab was administered subcutaneously on day 1 of the study and then 6, 12, 18, and 24 months. The lumbar spine and bilateral femoral neck BMD was measured at baseline and 6, 12, 18, and 24 months. RESULTS: At 18 and 24 months, the lumbar spine BMD increased by 5.9 and 7.0%, respectively. The femoral neck BMD also increased. Grade ≥ 2 hypocalcemia, osteonecrosis of the jaw, and atypical femoral fractures did not occur. CONCLUSIONS: Our prospective study showed that semiannual treatment with denosumab was associated with continuously increased BMD in Japanese women receiving adjuvant AI therapy for up to 24 months, regardless of prior AI treatment.

Augmentation of dietary glucosylceramide hydrolysis by the novel bacterium Glucerabacter canisensis NATH-2371T.

The purpose of this study was to evaluate the effects of intragastrical administration of Glucerabacter canisensis NATH-2371T on glucosylceramide (GluCer) digestion in mice. Although G. canisensis was unable to utilize starch and cellulose, coculture of G. canisensis with mouse fecal bacteria greatly increased GluCer hydrolysis in polysaccharide medium, indicating that G. canisensis grew in competition with other intestinal bacteria. Although most of the administered G. canisensis cells were detected in feces, some cells were present in the colorectum contents, which had GluCer-hydrolyzing activity. These results indicate that G. canisensis can viably transit through the mouse gut. Administration of G. canisensis to mice fed diets supplemented with GluCer or GluCer-containing foods significantly enhanced GluCer hydrolysis. Since G. canisensis did not show acute toxicity, it may be useful as a probiotic to augment GluCer hydrolysis in the large intestine. Abbreviations: GluCer: glucosylceramide; KPi: potassium phosphate buffer; C-M: chloroform-methanol.

Glucerabacter canisensis gen. nov., sp. nov., isolated from dog feces and its effect on the hydrolysis of plant glucosylceramide in the intestine of dogs.

A Gram-positive, obligately anaerobic, oval-rod shaped, non-spore-forming, and non-pigmented bacterium, designated strain NATH-2371T (= JCM31739T = DSM105698T), was isolated from dog feces. Comparative 16S rRNA gene sequence analysis revealed that strain NATH-2371T belongs to Clostridium cluster XIVa, and the closest strains were Coprococcus comes ATCC 27758T (94.8% 16S rRNA gene sequence similarity) and Clostridium nexile DSM 1787T (94.0%). Strain NATH-2371T produced acetate, formate, and ethanol from glucose. Predominant cellular fatty acids are C16:0 and C16:0 DMA. On the basis of the phenotypic and genotypic differences, strain NATH-2371T represents a novel species in a new genus of the family Lachnospiraceae, for which the name Glucerabacter canisensis gen. nov., sp. nov., is proposed. This strain was found to efficiently hydrolyze plant glucosylceramide (GluCer). The abundance of strain NATH-2371T in dog feces was higher in young dogs than in old dogs. Incubation of dog fecal bacteria showed that GluCer-hydrolyzing activity decreased with the age of dogs. The cell number of strain NATH-2371T in dog feces appeared to be correlated with GluCer hydrolysis. Thus, this bacterium is likely to play a major role in GluCer hydrolysis in the dog intestine.

Breakthrough fungemia due to Candida fermentati with fks1p mutation under micafungin treatment in a cord blood transplant recipient.

The prophylactic use of antifungal drugs in allogeneic hematopoietic cell transplant recipients has revealed that the rate of non-albicans candidemia has increased. We herein report the case of a patient with adult T-cell leukemia who developed candidemia due to Candida fermentati during micafungin treatment after cord blood transplantation. The isolate was identified on day 47 by sequencing of the internal transcribed spacer region of the ribosomal RNA gene. The sequencing of the hot spot region of fks1p of isolate revealed naturally occurring amino acid substitutions, which conferred reduced echinocandin susceptibility. This case highlights that breakthrough candidemia due to C. fermentati occurred in a patient receiving micafungin treatment.

[Exercise prescription and nutrition therapy].

In the report of World Health Organization, the leading global risks for mortality in the world are high blood pressure (12.8%), tobacco use (8.7%), high blood glucose (5.8%), physical inactivity (5.5%), and overweight and obesity (4.8%). Increased blood pressure levels cause the increased morbidity and mortality of chronic diseases, such as stroke, myocardial infarction, chronic kidney disease. Improving the high blood pressure is considered as common challenges around the world. Exercise prescription and nutrition therapy might be important non-pharmacologic therapies in the control of hypertension. Applying these therapies to the general population can help to prevent an increase in blood pressure and decrease elevated blood pressure levels for those with hypertension. Exercise prescription and nutrition therapy are discussed using the international guidelines.

Syntheses of aliphatic polycarbonates from 2'-deoxyribonucleosides.

Poly(2'-deoxyadenosine) and poly(thymidine) constructed of carbonate linkages were synthesized by polycondensation between silyl ether and carbonylimidazolide at the 3'- and 5'-positions of the 2'-deoxyribonucleoside monomers. The N-benzoyl-2'-deoxyadenosine monomer afforded the corresponding polycarbonate together with the cyclic oligomers. However, the deprotection of the N-benzoyl group resulted in the scission of the polymer main chain. Thus, the N-unprotected 2'-deoxyadenosine monomers were examined for polycondensation. However, there was involved the undesired reaction between the adenine amino group and the carbonylimidazolide to form the carbamate linkage. In order to exclude this unfavorable reaction, dynamic protection was employed. Strong hydrogen bonding was used in place of the usual covalent bonding for reducing the nucleophilicity of the adenine amino group. Herein, 3',5'-O-diacylthymidines that form the complementary hydrogen bonding with the adenine amino group were added to the polymerization system of the N-unprotected 2'-deoxyadenosine monomer. Consequently, although the oligomers (M(n) = 1000-1500) were produced, the contents of the carbamate group were greatly reduced. The dynamic protection reagents were easily and quantitatively recovered as the MeOH soluble parts from the polymerization mixtures. In the polycondensation of the thymidine monomer, there tended to be involved another unfavorable reaction of carbonate exchange, which consequently formed the irregular carbonate linkages at not only the 3'-5' but also the 3'-3' and 5'-5' positions. Employing the well-designed monomer suppressed the carbonate exchange reaction to produce poly(thymidine) with the almost regular 3'-5'carbonate linkages.

Benefit of FOLFOX to unresectable liver metastases secondary from colorectal carcinoma in an oncologic emergency.

Liver metastasis is an important prognostic factor in colorectal cancer. The efficacy of resection of metastatic lesions in liver metastasis of colorectal cancer is also widely recognized. However, studies on treatment methods of unresectable cases have not been sufficient and obtaining complete remission (CR) for liver metastasis is rare with chemotherapy. Selection of reliable chemotherapy for unresectable liver metastasis is an urgent necessity. The usefulness of oxaliplatin, 5-flurouracil and leucovorin combination therapy (FOLFOX) has recently been reported, but CR of liver metastasis is rare. The current status and new therapeutic significance of FOLFOX therapy are discussed based on the literature of colorectal cancer chemotherapy to date, and the clinical experience in which we obtained CR for liver metastasis is reported. The patient had stage IV rectal cancer, perforative peritonitis, pelvic abscess and simultaneous multiple liver metastasis. The patient underwent an emergency operation using the Hartmann's procedure. Liver metastasis is considered to be a prognostic factor and FOLFOX was selected as the postoperative chemotherapy, CR of the liver metastasis was obtained. FOLFOX was suggested to have new clinical significance in oncologic emergencies against unresectable liver metastasis in colorectal cancer and should serve as adjuvant chemotherapy that will contribute to improvement of treatment results.