Predictors of olaparib discontinuation owing to adverse drug events in patients with ovarian, peritoneal, or fallopian tube cancer: a retrospective observational study.

We investigated predictors of olaparib discontinuation owing to adverse effects. Patients with ovarian, peritoneal, or fallopian tube cancers treated with olaparib at Osaka Medical and Pharmaceutical University Hospital between April 2018 and September 2022 were included in this study. The exclusion criteria were as follows: discontinuation of treatment due to disease progression, use of anaemia medications, and use of cytochrome P450 (CYP3A4) inhibitors. The follow-up period was 90 d. Of the 46 eligible patients, 21 patients discontinued olaparib, including 15 patients with grade 3 or higher anaemia, eight patients with grade 3 or higher neutropenia, and four patients with non-haematological toxicity (including multiple onset). Multivariate logistic regression analysis showed that grade 4 neutropenia and anaemia progression to grades 2-3 due to chemotherapy administered before olaparib administration were predictors of olaparib discontinuation. The severity of neutropenia and anaemia due to chemotherapy before olaparib administration may be a potential marker for its discontinuation.

Platelet count and dose, but not comorbidities, predict severe neutropenia in cabazitaxel-treated prostate cancer patients: A retrospective observational study.

OBJECTIVE: To determine the safety of cabazitaxel and predictors of severe neutropenia caused by cabazitaxel in a patient population that includes those with comorbidities. MATERIALS AND METHODS: Of 42 prostate cancer patients treated with cabazitaxel at Osaka Medical and Pharmaceutical University Hospital between September 2014 and June 2022, 33 were included in this study, whereas 6 patients who were outpatients and 3 who were discharged early within 7 days upon patient request were excluded. Logistic regression analysis was used to examine predictors of severe neutropenia. RESULTS: Of the 33 eligible patients, 24 had comorbidities, with hypertension being the most common (n = 19), followed by dyslipidemia (n = 14) and diabetes (n = 11). There was no statistically significant difference in the rate of severe neutropenia due to any of the comorbidities, depending on the presence or absence of the comorbidity. However, the rate of severe neutropenia was significantly higher in patients with baseline platelet levels < 22.4×104/µL and those receiving cabazitaxel doses > 34 mg/body. In the final model adjusted for age, body mass index, C-reactive protein, and monocyte count, lower baseline platelet levels and higher doses of cabazitaxel were also predictors of the development of severe neutropenia. CONCLUSION: Comorbidities such as hypertension, dyslipidemia, diabetes mellitus, cerebrovascular disease, chronic kidney disease, liver dysfunction, and cardiac disease did not affect the incidence of severe neutropenia in patients receiving cabazitaxel. The baseline platelet count and the dose of cabazitaxel were also suggested to be markers for the development of severe neutropenia.

Impact of prior bevacizumab therapy on the incidence of ramucirumab-induced proteinuria in colorectal cancer: a multi-institutional cohort study.

BACKGROUND: The association between prior bevacizumab (BEV) therapy and ramucirumab (RAM)-induced proteinuria is not known. We aimed to investigate this association in patients with metastatic colorectal cancer (mCRC). METHODS: mCRC patients who received folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus RAM were divided into with and without prior BEV treatment groups. The cumulative incidence of grade 2-3 proteinuria and rate of RAM discontinuation within 6 months (6M) after RAM initiation were compared between the two groups. RESULTS: We evaluated 245 patients. In the Fine-Gray subdistribution hazard model including prior BEV, age, sex, comorbidities, eGFR, proteinuria ≥ 2 + at baseline, and later line of RAM, prior BEV treatment contributed to proteinuria onset (P < 0.01). A shorter interval between final BEV and initial RAM increased the proteinuria risk; the adjusted odds ratios (95% confidence intervals) for the intervals of < 28 days, 28-55 days, and > 55 days (referring to prior BEV absence) were 2.60 (1.23-5.51), 1.51 (1.01-2.27), and 1.04 (0.76-1.44), respectively. The rate of RAM discontinuation for ≤ 6M due to anti-VEGF toxicities was significantly higher in the prior BEV treatment group compared with that in the no prior BEV treatment group (18% vs. 6%, P = 0.02). Second-line RAM discontinuation for ≤ 6M without progression resulted in shorter overall survival of 132 patients with prior BEV treatment (P < 0.01). CONCLUSION: Sequential FOLFIRI plus RAM after BEV failure, especially within 55 days, may exacerbate proteinuria. Its escalated anti-VEGF toxicity may negatively impact the overall survival.

Preventive effect of dexamethasone premedication on the development of infusion-related reaction in breast cancer patients receiving trastuzumab.

AIM: To clarify the incidence and risk factors of infusion-related reactions (IRRs) caused by trastuzumab in breast cancer patients and verify the preventive effects of dexamethasone. METHODS: All breast cancer patients newly treated with trastuzumab at the Osaka Medical and Pharmaceutical University Hospital from 1 January 2017 to 31 December 2020 were included. The electronic medical records were retrospectively reviewed. The outcome measure was the occurrence of IRRs of grade 1 or higher during trastuzumab infusion. Only dexamethasone and anticancer drugs administered concomitantly before trastuzumab were used as explanatory variables. RESULTS: The 176 patients included in the study received 2320 infusions. Fifty-eight patients (33.0%) experienced IRRs, and IRRs occurred in 80 (3.4%) of the total 2320 infusions. Owing to the hierarchical structure of the data, the independence of the observed values was evaluated using the intraclass correlation coefficient. Multivariate multilevel logistic regression analysis showed that premedication with dexamethasone lowered the risk of trastuzumab-induced IRRs (mg, per 1 unit, odds ratio [OR] = 0.61, 95% confidence interval [95% CI] 0.43-0.85, P = .003). In addition, preoperative status (OR = 38.9, 95% CI 5.4-278.7, P < .001) and high-dose trastuzumab (mg/kg, per 1 unit, OR = 60.6, 95% CI 20.1-182.9, P < .001) were independent risk factors for IRRs. CONCLUSION: The results of this study suggest that premedication with dexamethasone exhibits preventive effects on trastuzumab-induced IRRs in breast cancer patients. Future studies are needed to determine the optimal dose of dexamethasone to prevent IRRs and the impact of dexamethasone on the efficacy of trastuzumab in breast cancer.

Safety of Ramucirumab Regimen Without H1-antihistamine Premedication in Patients With Solid Cancers.

BACKGROUND/AIM: To prevent infusion-related reactions (IRRs), H1-antihistamines (H1AT) are recommended as a premedication for monoclonal antibodies, such as Ramucirumab (RAM), even though there are H1AT-related side effects, such as drowsiness and dizziness. Here, we investigated the safety of H1AT-free RAM regimens in patients with solid cancer. PATIENTS AND METHODS: We retrospectively reviewed the patients with solid cancer receiving RAM without H1AT at Osaka Medical College Hospital between 2015 and 2019. RESULTS: Among the 123 registered patients, 58 were identified as eligible. The total number of RAM infusions was 291, and the median number of RAM administration was 4 cycles (range=1-23 cycles). IRRs were not observed in any patient. CONCLUSION: Although our data are preliminary and limited, H1AT-free RAM regimens may be a treatment option for cancer patients having a significant risk of developing H1AT-related side effects. Further studies are needed to confirm the safety of H1AT-free RAM regimens.

[Cancer Patient Response Conference by Co-Medical Staff].

Often, co-medical staff are asked questions or consultations that are difficult to answer from cancer patients. However, as for the reply contents, each co-medical staff responded in various ways, there was no place to discuss an appropriate reply. At our hospital, we decided to hold a"Cancer Patient Response Conference"to enable us to respond appropriately regardless of years of service or occupation. This time, we investigated the effect of"Cancer Patient Response Conference"on the approach at Ishikiriseiki Hospital. As a result, it is possible for the co-medical staff to respond to empathy of the patient's feelings and to confirm the understanding of the patient, but it seemed that the response from the attending physician was good for the question about the life expectancy and the treatment effect etc. However, it was suggested that collaborative staff sharing patient problems and information at"Cancer Patient Response Conference"will be useful for future cancer patient response.

[Influence of the Site of Port Insertion on the Flow Velocity of 5-FU Continuous Intravenous Injection by Using a Compression-Type Portable Continuous Infuser for Colorectal Cancer Patients].

For the continuous intravenous injection off luorouracil (5-FU) over 46 hours in a chemotherapeutic regimen for colorectal cancer, a compression-type portable continuous infuser is used. However, there is an error in the flow velocity. Errors in the dose or time of administration completion may influence the efficacy and safety of 5-FU. Therefore, it is necessary to reduce the error in the flow velocity. The type of diluent, air temperature, and concentration of 5-FU are reportedly factors influencing the flow velocity. However, no study has examined the influence of the site of port insertion. In this study, we investigated factors associated with the flow velocity of 5-FU continuously and intravenously injected by using an infuser in patients with colorectal cancer, among whom the site of port insertion differed. The results showed that the site of port insertion influenced the flow velocity during the continuous intravenous injection of 5-FU using an infuser. It is important to reduce the error in the flow velocity by considering the site of port insertion in addition to the concentration of 5-FU and the air temperature.

[Effectiveness of intervention by the infection control team for cancer patients with a positive blood culture].

Cancer patients at a high risk of acquiring infectious diseases should be maintained in a facility where good infection control practices are followed. At our hospital, the infection control team(ICT)provides expertise, education, and support to the staff, helping them maintain proper standards, thereby minimizing the risks of infection. The ICT(established in 2004)has implemented infection control programs by employing an appropriate number of staff members after the revision of medical treatment fees in 2011. Our intervention program includes 2 general policies, namely, ordering and collection of blood cultures and intervention for the medical care of patients with positive blood cultures. In this study, we evaluated the effectiveness of our intervention for cancer patients with a positive blood culture. During the surveillance period(April 2011 to July 2012), 42 positive cases were determined to be infectious. ICT intervention was required in 37 cases. Our suggestions were accepted in 92%(34/37)of the cases, and improved outcome was estimated in 65%(22/34)of the cases. The results of our study contribute to the scientific bases on which routine clinical practices could be promoted in the future.

[Serotonin syndrome in a patient with small cell lung cancer].

The patient was a 67-year-old male who had been treated for several years with 150 mg fluvoxamine maleate due to depression. He visited our hospital with primary symptoms of swelling of the right upper extremity and dyspnea in August, XXXX. As a result of examinations, he was diagnosed with stage IIIB extended small cell lung cancer(T4N3M0). One course of carboplatin/etoposide(CBDCA/VP-16)therapy was started on October 1. Since the tumor size was reduced, thoracic effusion disappeared, and superior vena cava syndrome was alleviated, the therapy was changed to cisplatin/irinotecan (CDDP/CPT-11)on October 23, and the 3rd course was initiated on November 22. Anxiety and tremor appeared on the 4th day of the 3rd course and because they were exacerbated, and myoclonus appeared, a diagnosis of serotonin syndrome was made on the 38th day, and the administration of fluvoxamine maleate was discontinued. The symptoms were alleviated after the discontinuation, and the 4th course could be implemented. In this patient, serotonin syndrome was considered to have been induced by serotonin secretion promoted by the CDDP administration, and by serotonin in the brain increasing abnormally due to the SSRI.

Micafungin for empirical antifungal therapy in patients with febrile neutropenia: multicenter phase 2 study.

Empirical antifungal therapy is the current standard of care for patients with febrile neutropenia unresponsive to broad-spectrum antimicrobials. Although a number of antifungal agents are currently available, the need remains for effective but less toxic alternatives for this indication. We therefore conducted a phase 2 study of micafungin for 80 patients with hematologic diseases who were suffering from persistent or recurrent fever after at least 96 h of antibacterial therapy. The patients were treated with micafungin at a fixed dose of 150 mg/day. Of the 78 evaluable patients, 54 (69 %) achieved defervescence by the time of neutrophil recovery, and 56 (72 %) completed the treatment in accordance with the provision of the protocol. Four patients developed invasive fungal infection, nine changed antifungal therapy because of lack of efficacy, and three discontinued micafungin because of drug-related adverse events. Based on the composite end point taking account of these, the overall treatment success rate was 60 %, with the lower limit of a 90 % confidence interval (50.3 %) exceeding the predefined threshold success rate (50 %). These findings show the efficacy and safety of micafungin for empirical antifungal therapy in patients with persistent or recurrent febrile neutropenia, warranting further investigation of this drug in a phase 3 study.

[Comparison of chemotherapy side effects between elderly and young subjects].

UNLABELLED: With the aging of society, the number of elderly patients receiving chemotherapy has increased. Since organ function, particularly the liver and kidney function, is known to decrease with age, there is concern that severe side effects may develop in the elderly because of chemotherapy. It is a considerable challenge to establish safe, effective chemotherapy that enables elderly patients to maintain a favorable QOL. Therefore, we conducted a survey of the current status of chemotherapy side effects. METHODS: The subjects were patients enrolled in physician-led clinical trials between April 2006 and December 2010. A survey of the chemotherapy regimens used, PS, and, side effects(CTC-AE v3.0)was conducted to examine differences in the incidence and Grade of side effects between elderly and younger subjects(aged 65 years or older, and younger than 65 years, respectively). The subjects consisted of9 3 elderly and younger people, with mean ages of 70 and 59. 5 years, respectively. Myelosuppression of Grade 3, or more severe side effects in the elderly and younger subjects, was 22. 5% and 16. 3%, respectively. The incidence of side effects was slightly higher in the elderly than in the younger subjects. In general clinical practice, side effects are controlled by selecting regimens and adjusting doses for the elderly. However, in clinical trials in which the dosage is predetermined regardless of age, the elderly are more prone to develop side effects than young people. We compare and present the current status regarding the side effects, effectiveness, and contents of chemotherapy regimens.

Application of electrolysis for detoxification of an antineoplastic in urine.

Antineoplastics in excreta from patients have been considered to be one of the origins of cytotoxic, carcinogenic, teratogenic, and mutagenic contaminants in surface water. Recent studies have demonstrated that antineoplastics in clinical wastewater can be detoxified by electrolysis. In this study, to develop a method for the detoxification of antineoplastics in excreta, methotrexate solution in the presence of human urine was electrolyzed and evaluated. We found that urine inhibits detoxification by electrolysis; however, this inhibition decreased by diluting urine. In urine samples, the concentrations of active chlorine generated by anodic oxidation from 0.9% NaCl solution for inactivation of antineoplastics increased in dilution-dependent and time-dependent manner. These results indicate that electrolysis with platinum-based iridium oxide composite electrode is a possible method for the detoxification of a certain antineoplastic in urine.

Calpain-7 binds to CHMP1B at its second α-helical region and forms a ternary complex with IST1.

Some intracellular proteins involved in the endosomal sorting complex required for transport (ESCRT) system have microtubule interacting and transport (MIT) domains and bind to ESCRT-III protein family members named charged multivesicular body proteins (CHMPs) at their C-terminal regions containing MIT-interacting motifs (MIMs). While two types of MIMs (MIM1 and MIM2) have been reported, CHMP1B has MIM1 and IST1 has both MIM1 and MIM2. Previously, we demonstrated that CHMP1B and IST1 directly interacted with a tandem repeat of MIT domains of calpain-7 (CL7MIT) and that autolytic activity of calpain-7 was enhanced by IST1 in vitro but not by overexpression of IST1 in HEK293T cells. In this study, we detected enhancement of autolysis of mGFP-fused calpain-7 by coexpression with CHMP1B and observed further activation by additional coexpression of IST1 in HEK293T cells. We found that CL7MIT interacted with the second α-helical region of CHMP1B but not with the canonical C-terminal region containing MIM1 in vitro. Co-immunoprecipitation assays demonstrated that the interaction between CL7MIT and CHMP1B and between CL7MIT and IST1 became stronger when IST1 or CHMP1B was additionally coexpressed, suggesting formation of ternary complex of calpain-7, IST1 and CHMP1B. Moreover, subcellular fractionation analyses revealed increase of calpain-7 in membrane/organelle fractions by concomitant overexpression of these ESCRT-III family member proteins.

Missense mutations in PML-RARA are critical for the lack of responsiveness to arsenic trioxide treatment.

Arsenic trioxide (As2O3) is a highly effective treatment for patients with refractory/relapsed acute promyelocytic leukemia (APL), but resistance to As2O3 has recently been seen. In the present study, we report the findings that 2 of 15 patients with refractory/relapsed APL treated with As2O3 were clinically As2O3 resistant. Leukemia cells from these 2 patients harbored missense mutations in promyelocytic leukemia gene-retinoic acid receptor-α gene (PML-RARA) transcripts, resulting in amino acid substitutions of A216V and L218P in the PML B2 domain. When wild-type or mutated PML-RARA (PR-WT and PR-B/L-mut, respectively) were overexpressed in HeLa cells, immunoblotting showed SUMOylated and/or oligomerized protein bands in PR-WT but not in PR-B/L-mut after As2O3 treatment. Protein-localization analysis indicated that PR-WT in the soluble fraction was transferred to the insoluble fraction after treatment with As2O3, but PR-B/L-mut was stably detected in fractions both with and without As2O3. Immunofluorescent microscopy analysis showed PR-WT localization as a microgranular pattern in the cytoplasm without As2O3 and as a macrogranular pattern with As2O3. PR-B/L-mut was diffusely observed in the cytoplasm with and without As2O3. Nearly identical localization patterns were observed in patients' primary cells. Therefore, B2 domain mutations may play an important role in aberrant molecular responses toAs2O3 and may be critical for As2O3 resistance in APL.

Interaction between Shaoyao-Gancao-Tang and a laxative with respect to alteration of paeoniflorin metabolism by intestinal bacteria in rats.

Shaoyao-Gancao-Tang (SGT), a traditional Chinese herbal medicine (Kampo formulation) containing Shaoyao (Paeoniae Radix) and Gancao (Glycyrrhizae Radix), is co-administered with laxative sodium picosulfate as a premedication for relieving the pain accompanying colonoscopy. Paeoniflorin (PF), an active glycoside of SGT, is metabolized into the antispasmodic agent paeonimetabolin-I (PM-I) by intestinal bacteria after oral administration. The objective of the present study was to investigate whether the co-administered laxative (sodium picosulfate) influences the metabolism of PF to PM-I by intestinal bacteria. We found that the PF-metabolizing activity of intestinal bacteria in rat feces was significantly reduced to approximately 34% of initial levels by a single sodium picosulfate pretreatment and took approximately 6 days to recover. Repeated administration of SGT after the sodium picosulfate pretreatment significantly shortened the recovery period to around 2 days. Similar results were also observed for plasma PM-I concentration. Since PM-I has muscle relaxant activity, the present results suggest that repetitive administration of SGT after sodium picosulfate pretreatment might be useful to relieve the pain associated with colonoscopy.

Three novel single nucleotide polymorphisms of the human thiopurine S-methyltransferase gene in Japanese individuals.

In this study, the entire coding sequence and the exon-intron junctions of the thiopurine S-methyltransferase (TPMT) gene from 200 Japanese individuals were screened for mutation. Three novel single nucleotide polymorphisms (SNPs) were identified-106G>A in exon 3 (Gly36Ser, *20 allele), 967A>G in 3'-untranslated region, and -87C>T in intron 8. The allele frequencies were 0.003 for 106G>A, 0.003 for 967A>G, and 0.010 for IVS8 -87C>T. In addition, the three known SNPs, 474T>C (Ile158Ile), 719A>G (Tyr240Cys, *3C allele), and IVS4 +35C>T were detected at frequencies of 0.299, 0.010, and 0.421, respectively.

Bioavailability of glycyrrhizin from Shaoyao-Gancao-Tang in laxative-treated rats.

Shaoyao-Gancao-Tang (SGT), a traditional Chinese formulation composed of Shaoyao (Paeoniae Radix) and Gancao (Glycyrrhizae Radix), is frequently used in conjunction with laxatives such as sodium picosulfate in colonoscopy to relieve abdominal pains. We have investigated the alterations of the bioavailability of glycyrrhizin when SGT was co-administered with sodium picosulfate and we tried to identify a regimen that might minimize the alterations. Glycyrrhizin is one of the active glycosides in Gancao and SGT and is hydrolysed into the bioactive metabolite, 18 beta-glycyrrhetic acid (GA) by intestinal bacteria following oral administration. We found that the maximum plasma concentration (C(max)) and the area under the mean concentration vs time curve from zero to 24 h (AUC(0-24 h)) of GA from a single dose of SGT administered 5 h after a single pretreatment with sodium picosulfate were significantly reduced to 15% and 20% of the control level in rats, respectively. These reductions were still significant four days after sodium picosulfate pretreatment, but were restored by repetitive administration of SGT following sodium picosulfate pretreatment. Similar reductions and recovery were observed for the glycyrrhizin-metabolizing activity of intestinal bacteria in rat faeces. The results warrant clinical studies for co-administration of laxatives such as sodium picosulfate and SGT.

Existence of xenobiotic response element binding in Dictyostelium.

Xenobiotic response element (XRE) is a core nucleotide sequence at the upstream of inducible target genes for the transcription factor aryl hydrocarbon receptor (AhR) that is responsible for recognition of exogenous environmental pollutants in eukaryotic cells. Gel retardation electrophoresis revealed the presence of binding of a radiolabeled probe containing XRE in both cytosolic and nuclear preparations of the slime mold Dictyostelium. Unlabeled XRE probe was more potent in competing for XRE binding in both fractions than unlabeled XRE probe with a point mutation at the core element. Limited proteolysis by V8 protease did not markedly affect XRE binding in both fractions, while XRE binding decreased during in vitro incubation at 30 degrees C for up to 24 h at decline rates proportional to increasing pHs at a range of 6.5-8.5 in cytosolic fractions in a manner different from those in nuclear fractions. Deprivation of nutrients induced aggregation of cells within 4-8 h later, followed by formation of first finger tips around 12 h later and subsequent development to mobile slugs within 16 h and then to fruit bodies between 20 and 24 h later. The starvation led to a marked decrement of XRE binding in cytosolic fractions 4-36 h later, followed by a robust but transient increment of that in nuclear extracts 12-20 h afterward. However, XRE binding was not affected by antibodies against AhR-related proteins known to date in both fractions irrespective of nutritional conditions. These results suggest the abundance of as-yet unidentified proteins with high affinity for XRE in the slime mold Dictyostelium. The possibility that those proteins may be translocated from the cytoplasm to the nucleus in response to cellular development during starvation is feasible.