Safety Profile of Ixazomib in Patients with Relapsed/Refractory Multiple Myeloma in Japan: An All-case Post-marketing Surveillance

Objective To evaluate the safety profile of ixazomib combined with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM) in clinical practice in Japan through an all-case post-marketing surveillance. Methods This was a nationwide non-interventional observational study conducted in Japan. The study included all patients who received ixazomib from May 24 to September 24, 2017. Ixazomib was administered to RRMM patients according to the Japanese package insert. All enrolled patients were observed until the completion of the sixth treatment cycle or until ixazomib discontinuation. The patient treatment course, including adverse events (AEs), was reported. Results The safety analysis set included 741 patients; the median age was 71 (range 35-92) years old, and the median number of prior treatment lines was 3 (range 1-30). Adverse drug reactions (ADRs) occurred in 572 (77.2%) patients, most commonly being thrombocytopenia (49.9%), diarrhea (29.2%), and nausea (12.4%). Serious ADRs occurred in 193 (26.0%) patients, most commonly being thrombocytopenia (9.9%) and diarrhea (5.9%). Thrombocytopenia, severe gastrointestinal disorders, infections, skin disorders, and peripheral neuropathy were prespecified as ADRs of clinical importance; the frequency of these ADRs (grade ≥3) were 28.5%, 9.4%, 7.4%, 2.2%, and 1.3%, respectively. Treatment discontinuation was most common with thrombocytopenia and severe gastrointestinal disorders (49 and 43 patients, respectively). Eleven patients died due to ADRs (16 events). Conclusion These results suggest that ixazomib has a tolerable safety profile in clinical practice in Japan. However, close AE management for thrombocytopenia and gastrointestinal disorders should be considered.     

PAX5 alterations in an infant case of KMT2A‐rearranged leukemia with lineage switch

Lineage switch is a rare event at leukemic relapse. While mostly known to occur in KMT2A‐rearranged infant leukemia, the underlying mechanism is yet to be depicted. This case report describes a female infant who achieved remission of KMT2A‐MLLT3‐rearranged acute monocytic leukemia, but 6 months thereafter, relapsed as KMT2A‐MLLT3‐rearranged acute lymphocytic leukemia. Whole exome sequencing of the bone marrow obtained pre‐post lineage switch revealed two somatic mutations of PAX5 in the relapse sample. These two PAX5 alterations were suggested to be loss of function, thus to have played the driver role in the lineage switch from acute monocytic leukemia to acute lymphocytic leukemia.     

Efficacy of hand-assisted laparoscopic surgery (HALS) in older adult patients (≥80 years) with primary colorectal cancer

BackgroundFrom 2004 to 2014, 821 colorectal cancer primary resections were conducted at our institution. Of these, 102 patients (12.4%) were older adults over 80 years old. underwent either the conventional laparotomy group (72 patients) or the hand-assisted laparoscopic surgery (HALS) group (30 patients).MethodsData were extracted for 102 patients over 80 years old who underwent primary resection for colorectal cancer and were divided into two groups: conventional laparotomy (CL) (n=72) and hand-assisted laparoscopy (n=30). Pre-operative characteristics and outcomes were compared.ResultsBaseline characteristics were similar between groups, except for age: CL group median 83.5 years old (range, 80–92 years old) and hand-assisted laparoscopy (HALS) group median 81.5 years old (range, 80–88 years old) (P=0.027). Pre-operative cardiac and lung function risk, performance status, and pathological classification stage (pStage) were almost similar between groups (P=0.668, P=0.176, P>0.999, P=0.217). No significant differences were found for operation time. The HALS group resulted in less blood loss (median 204 mL in the CL group and median 68 mL in the HALS group, P=0.003), shorter postoperative hospital stay (median was 18 days in the CL group and median was 12 days in the HALS group, P<0.001), and fewer postoperative wound infections (18 cases in the CL group and 2 cases in the HALS group, P=0.034). Five-year relapse-free survival (5Y-RFS) was 48.1% in the CL group and 73.3% in the HALS group (P=0.028). Five-year overall survival (5Y-OS) was 48.2% in the CL group and 73.3% in the HALS group (P=0.027).ConclusionsApproximately 70% of surgical treatment for patients over 80 years old with colorectal carcinoma were performed by CL. However, HALS had significant advantages including less blood loss, fewer wound infections, and shorter hospital stays. Therefore, HALS could proactively be considered to older adult patients with colorectal cancer.     

Anti-tumor effects of water-soluble propolis on a mouse sarcoma cell line in vivo and in vitro

The honeybee product propolis and its extracts are known to have biological effects such as antibiotic, anti-viral, anti-inflammatory and anti-tumor activities. This study was designed to investigate whether water-soluble propolis (WSP) inhibits tumor growth. The tumor cell line used was mouse sarcoma 180 (S-180), and its growth was determined in vitro and in vivo with exposure to different concentrations of WSP. The effects of WSP on tumor cells in vitro were evaluated by measuring the intracellular uptake of 3H-thymidine. 3H-thymidine uptake was inhibited in accordance with the concentration of WSP. The minimum concentration of WSP necessary for 3H-thymidine uptake inhibition was 1.0 microg/ml and uptake was suppressed to 88% of the level in non-treated cells at this concentration. In an experiment using tumor-bearing mice, oral administration of WSP was begun 24 hours after transplantation of S-180 cells. WSP was administered to the mice 5 times, every other day for 10 days. The doses were 320 mg/kg (10 mg/mouse) or 960 mg/kg (30 mg/mouse) of body weight. All mice were sacrificed 10 days after transplantation, and tumor growth was evaluated. The orally administered WSP significantly inhibited the growth of transplanted tumors (p < 0.05). Furthermore, histological findings revealed a significant reduction in mitotic cells and tumor invasion of the muscular tissue at both dose-levels of WSP.     

Vertebral derotation in adolescent idiopathic scoliosis causes hypokyphosis of the thoracic spine

The underlying purpose of this commentary and position paper is to achieve evidence-based recommendations on prevention of work-related musculoskeletal disorders (MSDs). Such prevention can take different forms (primary, secondary and tertiary), occur at different levels (i.e. in a clinical setting, at the workplace, at national level) and involve several types of activities. Members of the Scientific Committee (SC) on MSDs of the International Commission on Occupational Health (ICOH) and other interested scientists and members of the public recently discussed the scientific and clinical future of prevention of (work-related) MSDs during five round-table sessions at two ICOH conferences (in Cape Town, South Africa, in 2009, and in Angers, France, in 2010). Approximately 50 researchers participated in each of the sessions. More specifically, the sessions aimed to discuss new developments since 1996 in measures and classification systems used both in research and in practice, and agree on future needs in the field. The discussion focused on three questions: At what degree of severity does musculoskeletal ill health, and do health problems related to MSDs, in an individual worker or in a group of workers justify preventive action in occupational health? What reliable and valid instruments do we have in research to distinguish ??normal musculoskeletal symptoms?? from ??serious musculoskeletal symptoms?? in workers? What measures or classification system of musculoskeletal health will we need in the near future to address musculoskeletal health and related work ability? Four new, agreed-upon statements were extrapolated from the discussions: 1. Musculoskeletal discomfort that is at risk of worsening with work activities, and that affects work ability or quality of life, needs to be identified. 2. We need to know our options of actions before identifying workers at risk (providing evidence-based medicine and applying the principle of best practice). 3. Classification systems and measures must include aspects such as the severity, frequency, and intensity of pain, as well as measures of impairment of functioning, which can help in prevention, treatment and prognosis. 4. We need to be aware of economic and/or socio-cultural consequences of classification systems and measures.     

Metabolism of Cyanox in rat. II. Sex-related differences in oxidative dearylation and desulphuration

1. To examine the metabolites of Cyanox (O-4-cyanophenyl O, O-dimethyl phosphorothioate, cyanophos, CYAP) in brain, liver, blood cells and plasma during the early toxic period, the male and female rat was administered a single oral dose of [phenyl-¹⁴C]Cyanox at dose levels of 50?mg/kg and killed 5, 10 and 20 min thereafter. 2. Sex-related differences in the concentrations of metabolites were observed. Cyanoxon, produced by oxidative desulphuration, was observed in the brains of both sexes at all time points, but the concentrations were 2-6times higher in the male. The same metabolite was detected in the liver, blood cells and plasma of the male but not the female. The total concentrations of oxidative dearylation metabolites (4-cyanophenol +4-cyanophenylsulphate + glucuronide of 4-cyanophenol) in plasma, blood cell, brain and liver were larger in the male at all time points than those in the female, whereas the reverse was the case for demethylated metabolites (desmethylcyanox + desmethylcyanoxon) in all tissues except for the brain. 3. Studies of the in vitro metabolism of Cyanox revealed no sex-related difference for hepatic cytosolic fractions in terms of the major in vitro metabolic reaction, demethylation. On the other hand, the major reactions in microsomal fractions, oxidative desulphuration and oxidative dearylation, were significantly (2-3 times) greater in the male than in the female. 4. Oxidative desulphuration and oxidative dearylation, involving cytochrome P450 enzymes,were inhibited by male-specific ratCYP2C11 antiserum. The degreeof inhibition was more pronounced in the male case. Thus, the results strongly suggest that the 2C family of cytochrome P450 (male, CYP2C11 and CYP2C13; female, CYP2C12) contributes to oxidative desulphuration and dearylation of cyanox in the rat and that the activity of male-specific CYP2C11 (and CYP2C13) is greater than that of female-specific CYP2C12. The consequent greaterformation of cyanoxonin the male is consistent with the higher toxicity in this sex.