Prognostic Nutrition Index as an Indicator of Therapeutic Response to Lenvatinib Therapy in Hepatocellular Carcinoma.

BACKGROUND/AIM: Lenvatinib (LEN) has been approved as an oral tyrosine kinase inhibitor for advanced hepatocellular carcinoma (HCC). However, in some patients, LEN does not provide adequate therapeutic benefits. In this study, we examined the factors that affect the therapeutic response to LEN. PATIENTS AND METHODS: This retrospective cohort study involved patients with HCC who received LEN therapy at Osaka Metropolitan University Hospital. We used the delivered dose intensity to body surface area ratio for 60 days (2M-DBR) as an index of the therapeutic response. RESULTS: This study included 83 patients divided into two groups, the high 2M-DBR group (47 patients, 56.7%) and low 2M-DBR group (36 patients, 43.4%). Univariate analysis showed that Child-Pugh class, C-reactive protein, and prognostic nutrition index (PNI) were significant factors for high 2M-DBR. Furthermore, multivariate logistic regression analysis revealed that a PNI>39.15 was significantly associated with high 2M-DBR. CONCLUSION: A PNI cut-off value of less than 39.15 may indicate a poor response to LEN therapy. PNI, an easy, simple, and inexpensive tool, may be useful in identifying patients in need of early intervention.

Long-term use of foscarnet is associated with an increased incidence of acute kidney injury in hematopoietic stem cell transplant patients: A retrospective observational study.

BACKGROUND: Foscarnet is an important drug for the treatment of cytomegalovirus infection in patients undergoing hematopoietic stem cell transplantation (HSCT). Foscarnet is often discontinued because of the development of acute kidney injury (AKI). Thus, the identification of factors leading to the development of AKI is beneficial. This study aimed to investigate the incidence of AKI and the factors influencing AKI development in HSCT patients treated with foscarnet. METHODS: This was a retrospective observational study. Patients who underwent HSCT and received foscarnet at the Department of Hematology, Osaka City University Hospital, were identified from medical records. The patients were classified into AKI and non-AKI groups, and the risk factors associated with AKI were evaluated. For continuous variables, receiver-operating characteristic (ROC) curve analysis was used to calculate the optimal cutoff value. RESULTS: Thirty-five patients (47 cases) were assigned to the AKI (51.1%, 24/47) and non-AKI groups (48.9%, 23/47). The AKI group had a significantly longer foscarnet administration period than the non-AKI group (p = 0.049). The appropriate cutoff value for the foscarnet administration period using the ROC curve was 27 days. The incidence of AKI was significantly higher in cases who received foscarnet for more than 27 days (11/14, 78.6%) compared to those who received less than 27 days (13/33, 39.4%) (odds ratio: 5.64, 95% confidence interval 1.32-24.2, p = 0.024). CONCLUSION: The incidence of AKI was 51.1% in HSCT patients treated with foscarnet, and foscarnet administration for more than 27 days may be associated with the incidence of AKI.

Establishment of nedaplatin safety dose formula based on renal function for combination chemotherapy with nedaplatin and 5-fluorouracil in patients with esophageal cancer.

BACKGROUND: It is known that the area under the plasma concentration curve of nedaplatin (AUCNDP) is associated with the relative reduction ratio of platelets and that the AUCNDP is based on nedaplatin dose normalized by creatinine clearance (CrCL) (AUCdose/CrCL). Based on these relationships, in this retrospective study, we aimed to determine the unestablished doseNDP safe for patients with impaired renal function who received an initial combination chemotherapy with nedaplatin and 5-fluorouracil. METHODS: We performed a retrospective cohort analysis of consecutive patients with esophageal cancer who received an initial combination chemotherapy with ≤ 90 mg m-2 day-1 of nedaplatin on day 1 and 800 mg m-2 day-1 of 5-fluorouracil on days 1-5. AUCdose/CrCL was estimated using the formula, 3.2134 × doseNDP/CrCL + 4.4185. Data obtained during the first 28 days following nedaplatin administration were analyzed to compare AUCdose/CrCL between the patients with and without grade ≥ 3 thrombocytopenia. Receiver-operating characteristic (ROC) curve analysis was performed to determine the optimal AUCdose/CrCL cutoff value. RESULTS: Of the 136 patients included in this study, 8 (5.9%) presented with grade ≥ 3 thrombocytopenia. There were statistically significant differences in the AUCdose/CrCL between the patients with and those without grade ≥ 3 thrombocytopenia (11.79 vs. 10.09 µg h-1 mL-1; P = 0.00828). We found that the appropriate cutoff value for the AUCdose/CrCL using the ROC curve was 10.945 µg h-1 mL-1. CONCLUSIONS: Our results indicate that safe doseNDP should be estimated to satisfy the following formula: DoseNDP (mg) < CrCL × 2.031.

Pretreatment Platelet Count and Neutrophil/Lymphocyte Ratio Are Predictive Markers for Carboplatin Plus Pemetrexed Therapy-induced Thrombocytopenia.

BACKGROUND/AIM: This study aimed to identify the predictive markers for carboplatin-induced severe thrombocytopenia. PATIENTS AND METHODS: We conducted a retrospective cohort analysis of inpatients who received carboplatin and pemetrexed. RESULTS: Among the 106 eligible patients, the incidence rate of grade ≥3 thrombocytopenia was 29.2% (31/106). Multivariate analysis revealed that grade ≥3 thrombocytopenia was associated with platelet count ≤26.6×104/mm3 [odds ratio (OR)=24.70, 95% confidence interval (CI)=5.75-106.00; p<0.001], neutrophil/lymphocyte ratio (NLR) >2.856 (OR=15.10, 95%CI=2.89-78.60; p=0.0013) and prognostic nutritional index ≤42.511 (OR=6.25, 95%CI=1.53-25.60; p=0.011). In particular, patients with both platelet counts ≤26.6×104/mm3 and NLR >2.856 presented with significantly higher frequencies of thrombocytopenia compared to those without these two factors [23/34 patients (67.6%) vs. 8/72 patients (11.1%), OR=16.1, 95%CI=5.40-53.6; p<0.001]. CONCLUSION: Platelet counts ≤26.6×104/mm3 and NLR >2.856 are predictive markers for carboplatin-induced thrombocytopenia.

Low Eosinophil Percentages as a New Predictive Marker for Infusion Reactions Due to Trastuzumab.

BACKGROUND/AIM: Infusion reactions (IRs) often occur with trastuzumab. Although premedication by non-steroidal anti-inflammatory drugs can be effective to a certain extent, IRs are still common and infrequently severe. Therefore, a predictive marker that can select patients requiring further prophylaxis is useful for appropriate prevention, but remains unclear. PATIENTS AND METHODS: We conducted a retrospective analysis for 136 consecutive female inpatients aged 18 years and older who received 8 mg/kg of the initial trastuzumab administration for breast cancer with a 25-mg dose of rectal diclofenac before trastuzumab infusion between May 2007 and April 2019, in order to assess IRs. RESULTS: Overall, 57 patients were eligible for inclusion in the study. IRs were observed in 17.5% (10/57) of the patients. Univariate analysis showed that patients with a low eosinophil percentage (≤2%) were associated with IRs (p=0.016). CONCLUSION: A low eosinophil percentage can be a useful new predictive marker for trastuzumab-induced IRs in patients with breast cancer.

Time-lapse imaging of HeLa spheroids in soft agar culture provides virtual inner proliferative activity.

Cancer is a complex disease caused by multiple types of interactions. To simplify and normalize the assessment of drug effects, spheroid microenvironments have been utilized. Research models that involve agent measurement with the examination of clonogenic survival by monitoring culture process with image analysis have been developed for spheroid-based screening. Meanwhile, computer simulations using various models have enabled better predictions for phenomena in cancer. However, user-based parameters that are specific to a researcher's own experimental conditions must be inputted. In order to bridge the gap between experimental and simulated conditions, we have developed an in silico analysis method with virtual three-dimensional embodiment computed using the researcher's own samples. The present work focused on HeLa spheroid growth in soft agar culture, with spheroids being modeled in silico based on time-lapse images capturing spheroid growth. The spheroids in silico were optimized by adjusting the growth curves to those obtained from time-lapse images of spheroids and were then assigned virtual inner proliferative activity by using generations assigned to each cellular particle. The ratio and distribution of the virtual inner proliferative activities were confirmed to be similar to the proliferation zone ratio and histochemical profiles of HeLa spheroids, which were also consistent with those identified in an earlier study. We validated that time-lapse images of HeLa spheroids provided virtual inner proliferative activity for spheroids in vitro. The present work has achieved the first step toward an in silico analysis method using computational simulation based on a researcher's own samples, helping to bridge the gap between experiment and simulation.

Safety profile of the concomitant use of foscarnet and aerosolized pentamidine in allogeneic hematopoietic stem cell transplantation recipients.

BACKGROUND: Concomitant use of foscarnet and intravenous pentamidine can very frequently cause severe hypocalcemia. However, it is unknown whether aerosolized pentamidine has a similar adverse interaction with foscarnet. The present study was aimed at examining the safety profile of concomitantly used foscarnet and aerosolized pentamidine in patients receiving allogeneic hematopoietic stem cell transplantation. METHODS: Data from allogeneic hematopoietic stem cell recipients who had been administered foscarnet therapy for over 7 days were analyzed. We compared electrolyte abnormalities and serum creatinine level between patients who received aerosolized pentamidine concomitantly and those who did not. RESULTS: A total of 84 consecutive patients and 135 episodes of foscarnet therapy between May 2011 and April 2016 were evaluable. Of these 135 episodes, 25 episodes of therapy included concurrent therapy with 300 mg dose of aerosolized pentamidine once a month (pentamidine group) and 110 episodes did not (non-pentamidine group). The incident rates of grade 3/4 hypocalcemia did not significantly differ between the pentamidine and non-pentamidine groups (P = .207; 0/25 [0%] vs 10/110 [9.1%], respectively). In addition, we observed no significant difference in the incident rates of grade 3/4 serum creatinine increase between the two groups (P = 1.00; 0/25 [0%] vs 4/110 [3.6%], respectively). CONCLUSION: Our results suggest that the drug interactions between foscarnet and aerosolized pentamidine may not be clinically significant.

Calcium Channel Blockers Possibly Delay the Elimination of Plasma Methotrexate in Patients Receiving High-Dose Methotrexate Therapy.

Delayed elimination of plasma methotrexate (MTX), which leads to elevated toxicity, is often observed in patients receiving high-dose methotrexate (HD-MTX) therapy, despite of the preventive measures. In this study, we investigated the factors that delay elimination of plasma MTX in patients on HD-MTX therapy. Fifteen patients who received HD-MTX therapy (21 cycles) were classified into two groups: delayed elimination of plasma MTX (38.1%, 8/21) and normal elimination of plasma MTX (61.9%, 13/21). Patient characteristics, plasma MTX concentrations, laboratory values, and adverse reactions were compared between the two groups using Fisher's exact test. Univariate analysis showed that co-administration of calcium channel blockers was significantly associated with delayed elimination of plasma MTX (p = 0.042). This is the first report demonstrating that co-administration of calcium channel blockers may be a predictive factor of delayed elimination of plasma MTX in patients receiving HD-MTX therapy.

Effectiveness and safety of the pre-prescription of garenoxacin in comparison to moxifloxacin for low-risk febrile neutropenia in breast cancer patients undergoing adjuvant and neoadjuvant chemotherapy.

PURPOSE: The purpose of this study was to compare the efficacy of the pre-prescription of garenoxacin mesylate hydrate (GRNX) with that of moxifloxacin hydrochloride (MFLX) in the management of breast cancer patients with low-risk febrile neutropenia. METHODS: Data from female patients who had been instructed to take previously prescribed oral GRNX or MFLX for 3 days during adjuvant and neoadjuvant chemotherapy if their body temperature exceeded 38 °C were analyzed. This study compared the effectiveness between these fluoroquinolones using a propensity score matching analysis. RESULTS: The 330 patients received 1192 administrations of chemotherapy between May 2007 and April 2014 and 136 (41.2%) patients had a total of 212 (17.8%) febrile episodes. The frequencies of febrile episodes were 19.5% (113/579) and 16.2% (99/613) in the GRNX and MFLX groups, respectively. After propensity score matching, 384 episodes were matched in each group. Febrile events occurred in 80 and 56 cases in the GRNX and MFLX groups, respectively. Treatment success was identified in 80.0% (64/80) of cases in the GRNX group and 64.3% (36/56) of cases in the MFLX group (P = 0.0494). Additionally, the therapeutic use of granulocyte-colony stimulating factor was 6.3% (5/80) of cases in the GRNX group and 17.9% (10/56) of cases in the MFLX group (P = 0.0498). There were few differences in the frequency of adverse effects between the two groups. CONCLUSIONS: These results indicate that the pre-prescription of GRNX may be a more effective option for the management of low-risk febrile neutropenia during adjuvant and neoadjuvant chemotherapy for breast cancer.

Protection of stromal cell-derived factor 2 by heat shock protein 72 prevents oxaliplatin-induced cell death in oxaliplatin-resistant human gastric cancer cells.

Heat shock protein 72 (Hsp72) is a molecular chaperone that assists in the folding of nascent polypeptides and in the refolding of denatured proteins. In many cancers, Hsp72 is constitutively expressed at elevated levels, which can result in enhanced stress tolerance. Similarly, following treatment with anticancer drugs, Hsp72 binds to denatured proteins that may be essential for survival. We therefore hypothesized that Hsp72 client proteins may play a crucial role in drug resistance. Here, we aimed to identify proteins that are critical for oxaliplatin (OXA) resistance by analyzing human gastric cancer cell lines, as well as OXA-resistant cells via a mass spectrometry-based proteomic approach combined with affinity purification using anti-Hsp72 antibodies. Stromal cell-derived factor 2 (SDF-2) was identified as an Hsp72 client protein unique to OCUM-2M/OXA cells. SDF-2 was overexpressed in OXA-resistant cells and SDF-2 silencing promoted the apoptotic effects of OXA. Furthermore, Hsp72 prevented SDF-2 degradation in a chaperone activity-dependent manner. Together, our data demonstrate that Hsp72 protected SDF-2 to avoid OXA-induced cell death. We propose that inhibition of SDF-2 may comprise a novel therapeutic strategy to counteract OXA-resistant cancers.

[Analysis of Factors Influencing the Development of Hypomagnesemia in Patients Receiving Cetuximab Therapy for Head and Neck Cancer].

Cetuximab was approved in Japan as the only clinically available molecular targeted drug for the treatment of head and neck cancer. Hypomagnesemia associated with cetuximab is considered one of the most serious adverse events. However, the factors influencing the development of hypomagnesemia are not clear, although the drug was previously approved for the treatment of patients with colorectal cancer. Thus, we studied the factors involved in the development of hypomagnesemia in patients receiving cetuximab therapy for head and neck cancer. Patients' background data and laboratory values before starting cetuximab therapy did not affect the development of hypomagnesemia. Among patients who had never been treated with cisplatin (NT group), 36.4% developed hypomagnesemia. In contrast, all patients who had previously been treated with cisplatin (T group) developed hypomagnesemia (p=0.034). Magnesium is reabsorbed by transient receptor potential subfamily melastatin 6 (TRPM6) in the distal convoluted tubule. The expression level of TRPM6 is controlled by the epidermal growth factor (EGF) pathway. Cetuximab is an EGF receptor inhibitor and reduces the expression of TRPM6. Additionally, recent studies have shown that the expression of TRPM6 is reduced by cisplatin. Therefore, we considered that the serum magnesium level was cumulatively reduced by cetuximab and cisplatin. In conclusion, the T group was more likely to develop hypomagnesemia than the NT group, and therefore the serum magnesium level in the T group requires careful monitoring so that magnesium supplementation can be provided to patients when the level decreases.

Establishment of a 5-fluorouracil-resistant triple-negative breast cancer cell line.

Triple-negative breast cancers (TNBCs) are defined as tumors that lack expression of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2. Clinically, TNBC patients are treated with cytotoxic drugs including 5-fluorouracil (5-FU). However, TNBCs develop resistance to such drugs after a series of treatments. To elucidate the mechanisms of drug resistance, establishment of drug-resistant cancer cell lines should be one of the most useful model systems. However, 5-FU-resistant TNBC cell lines have not been previously reported. In this study, we established a 5-FU-resistant cell line, MDA-MB-231/5-FU, from the human TNBC cell line MDA-MB-231, by repeated exposure to stepwise increases in the concentration of 5-FU. The IC50 value of 5-FU for MDA-MB-231/5-FU was 5.5-fold that for the parental cells. The MDA-MB-231/5-FU cell line acquired resistance to not only 5-FU, but also vinorelbine, paclitaxel and gemcitabine. Additionally, we performed iTRAQ-based quantitative proteomics in MDA-MB-231/5-FU cells and the parental cells in order to characterize MDA-MB-231/5-FU. The proteins upregulated in the newly established cells were mainly classified into the categories of 'DNA recombination', 'cell cycle', 'complex assembly', 'cytoskeleton organization', 'transport' and 'negative regulation of cell death'. These proteins may be related to mechanisms of drug resistance in TNBCs. Our established MDA-MB-231/5-FU cell line should be a useful tool for identifying new mechanisms of drug resistance and new drug targets in TNBCs.