Clinical Utility of Inflammatory and Nutritious Index as Therapeutic Prediction of Nivolumab plus Ipilimumab in Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: Biomarkers for predicting the outcome of ipilimumab plus nivolumab (Nivo-Ipi) treatment in cancer patients have not been identified. Herein, we investigated the prognostic significance of inflammatory and nutritional markers in patients with advanced non-small cell lung cancer (NSCLC) receiving Nivo-Ipi. METHODS: Our study retrospectively analyzed 101 patients with advanced NSCLC who received Nivo-Ipi at a single institution. Inflammatory and nutritional indices were correlated with patient outcomes and included the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), systemic immune-inflammation index (SII), prognostic nutritional index (PNI), advanced lung cancer inflammation index (ALI), and Glasgow prognostic score (GPS). RESULTS: The NLR significantly correlated with the PLR, SII, PNI, ALI, and GPS. Regarding therapeutic efficacy, the NLR, SII, and PNI predicted a partial response, and all indices predicted progressive disease. In subgroup analyses, the SII, PNI, and ALI predicted the outcome of patients with adenocarcinoma, whereas only the PNI predicted the outcome of patients with non-adenocarcinoma. The PNI and SII were the most useful indices in patients with a programmed death ligand-1 expression level of <1% and ≥1%, respectively. CONCLUSION: The NLR, PLR, SII, PNI, ALI, and GPS were significantly associated with the outcome of Nivo-Ipi treatment in patients with NSCLC. The PNI was the most suitable marker regardless of histological type. The SII and PNI were the most promising markers for patients with and without PD-L1 expression, respectively.

A survey of hypercalciuria during chemotherapy in acute lymphoblastic leukemia.

BACKGROUND: Urolithiasis is an extremely rare complication in childhood acute lymphoblastic leukemia (ALL), and some reports have implicated corticosteroids during chemotherapy as a risk factor for it. However, only a few reports have analyzed urinary electrolytes in this context. METHODS: We retrospectively analyzed 55 patients with ALL who underwent chemotherapy between October 2007 and January 2019. Their median age was 9.3 years (range, 0.3-24.0 years) with 30 males and 25 females. Lineages were B-cell precursor ALL (BCP-ALL) in 42 patients, T-cell in nine and others in four patients. All patients received chemotherapy based on the Berlin-Frankfurt-Münster regimen. RESULTS: Forty-nine out of the 55 ALL patients exhibited hypercalciuria at least once during chemotherapy. Moreover, 36 patients with BCP-ALL, who were receiving identical Berlin-Frankfurt-Münster-based regimens, exhibited significantly high urinary calcium excretion immediately following high-dose glucocorticoid administration. Among the 55 ALL patients, urolithiasis was observed in one patient, a 6-year-old boy with BCP-ALL who developed urolithiasis at reinduction chemotherapy just after cessation of high-dose dexamethasone administration. CONCLUSIONS: Nearly 90% of the ALL patients studied developed hypercalciuria during chemotherapy in strong association with corticosteroid administration.

Associations between sex, age and spiritual well-being scores on the EORTC QLQ-SWB32 for patients receiving palliative care for cancer: A further analysis of data from an international validation study.

OBJECTIVE: The EORTC QOL Group has recently completed the cross-cultural development and validation of a standalone measure of spiritual well-being (SWB) for cancer patients receiving palliative care: the EORTC QLQ-SWB32. The measure includes four scales: Relationships with Others, Relationship with Self, Relationship with Someone or Something Greater, and Existential, plus a Global-SWB item. This paper reports on further research investigating relationships between sex, age and SWB for patients receiving palliative care for cancer-adjusting for other socio-demographic, clinical and function variables, including WHO performance status and EORTC QLQ-C15-PAL emotional and physical function scores. METHODS: Cross-sectional data from the validation study were used, and chi-square, independent t tests, Mann-Whitney U tests and multiple regression analyses applied. RESULTS: The study included 451 participants with advanced and incurable cancer, from 14 countries. Adjusted analyses found better scores for female participants than males on three of the four EORTC QLQ-SWB32 subscales; Relationship with others, Relationship with Someone or Something Greater and Existential plus Global-SWB. Older age was positively associated with better Relationship with Self. CONCLUSION: The findings from our participants suggest that it might be beneficial if healthcare providers seeking to address patients' spiritual needs pay particular attention to male patients, younger patients and those with poor emotional functioning.

Pharmacokinetic evaluation of intrapleural perfusion with hyperthermic chemotherapy using cisplatin in patients with malignant pleural effusion.

OBJECTIVES: Malignant pleural effusion (MPE) has a poor prognosis. Most patients are treated with tube thoracostomy and sclerotherapy, although its success rate is around 64%. We have investigated intrapleural perfusion with hyperthermic chemotherapy (IPHC) using cisplatin in a study with a pharmacokinetic evaluation. METHODS: Patients with MPE, performance status of 0-1, possibility of good lung expansion and Cr<1.2mg/dL were treated with IPHC. The circuit was filled with 2000mL of normal saline containing cisplatin at a dose of 80mg/m2. Under video-assisted thoracoscopic surgery, the thoracic cavity was filled and perfused at a speed of approximately 1L/min at a temperature of 43°C for 1h. Perfusion solution and plasma samples were periodically collected, and concentrations of protein-unbound (free) platinum, which was the active derivative of cisplatin, and total platinum were determined by flameless atomic absorption spectrometry. RESULTS: Twenty patients with MPE (8 lung cancers, 7 mesotheliomas, and 5 others) were enrolled in this study. Rate of free platinum concentration relative to total platinum concentration in perfusion solution after 1hr IPHC at 43°C was 61.1±12.9%. Area under curve (AUC) of free platinum in the pleural space was calculated to be 26.3µg/mLxh, resulting in complete control of pleural effusion for 3 months after IHPC in all cases (95% confidence interval: 83-100%). While, absorption rate of total platinum from the pleural space was 33.8±17.0% (27.4±13.6mg/m2), and the maximum concentration of total platinum in serum was low, 0.66±0.31µg/mL, resulting in controllable side effects; grade 1 renal toxicity: 6 patients, grade 1 emesis: 7 patients. CONCLUSIONS: IPHC with cisplatin showed favorable pharmacokinetic profiles for an optional treatment to control malignant pleural effusion.

[Hange-Shashin-to for preventing diarrhea during afatinib therapy].

Afatinib is an epidermal growth factor receptor-tyrosine kinase inhibitor(EGFR-TKI). In a randomized phase III study(Lux- Lung 3 study)employing patients harboring EGFR mutations, patients administered afatinib show a significantly longer progression free survival time(PFS)than those administeredcombination chemotherapy comprising cisplatin andpemetrexed . However, most of the patients(95.2%)treatedwith afatinib experiencedd iarrhea. In the present report, 16 patients with EGFR mutations were treatedby afatinib at our institution from May 2014 to December 2014. Twelve patients were administered a diarrhea prevention herbal medicine, Hange-shashin-to. Seven of 12 patients(58%)had no diarrhea during the 28 days of therapy. All 4 of the patients who did not receive Hange-shashin-to experienced diarrhea above Grade 1 within 6 days of starting therapy. The rate of diarrhea differed significantly between the patients receiving and not receiving Hangeshashin- to. In conclusion, preventive administration of Hange-shashin-to may reduce the occurrence of diarrhea during afatinib treatment.

Improvements of hypertriglyceridemia and hyperlacticemia in Japanese children with glycogen storage disease type Ia by medium-chain triglyceride milk.

BACKGROUND: Besides profound hypoglycemia with hyperlacticemia, glycogen storage disease type Ia (GSD Ia) presents hypertriglyceridemia that is often resistant to dietary treatment with cornstarch. The present study aimed to evaluate the effects of medium-chain triglycerides (MCT)--which are absorbed via the portal vein without being incorporated into chylomicrons--on hypertriglyceridemia and to explore otherwise metabolic changes in children with GSD Ia. PATIENTS AND METHODS: A 13-year-old boy with GSD Ia who received a dietary treatment with MCT milk after cornstarch administration and two infants also with GSD Ia, ages 6 and 7 months, who received MCT milk after carbohydrate-rich, lipid-poor milk were enrolled. In addition to serum glucose and lactate levels, serum levels of total cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol were serially determined. Simultaneously, serum levels of total carnitine, free carnitine, acylcarnitine, and ketone bodies were determined to evaluate fatty acid beta-oxidation. RESULTS: Mean glucose level (mmol/l) of patient 1 remained stable, the value being around 4.5, while those of patients 2 and 3 increased to this level from 4.00 and 3.72, respectively. Lactate levels were significantly decreased in all patients. Mean triglyceride levels (mM) of patient 1 decreased from 3.00 to 2.05. Also, triglyceride levels of patients 2 and 3 decreased from 2.74 and 3.15 to 2.13 and 2.70, respectively. HDL cholesterol, acylcarnitine, and ketone body levels increased in all patients after MCT administration, while total and free carnitine levels decreased. CONCLUSION: We describe here the beneficial effects on lipid and carbohydrate metabolisms in three Japanese children with GSD Ia. In light of the unfavorable influence of lipid restriction on growth and development in infancy, dietary treatment with MCT milk may be a better treatment for infants with GSD Ia. Further investigation should be required to confirm the efficacy of MCT milk in GSD Ia.

Effects of arginine treatment on nutrition, growth and urea cycle function in seven Japanese boys with late-onset ornithine transcarbamylase deficiency.

BACKGROUND: The aim of this study was to investigate the effects of arginine on nutrition, growth and urea cycle function in boys with late-onset ornithine transcarbamylase deficiency (OTCD). Seven Japanese boys with late-onset OTCD enrolled in this study resumed arginine treatment after the cessation of this therapy for a few years. Clinical presentations such as vomiting and unconsciousness, plasma amino acids and urinary orotate excretion were followed chronologically to evaluate urea cycle function and protein synthesis with and without this therapy. In addition to height and body weight, blood levels of proteins, lipids, growth hormone (GH), insulin-like growth factor-I (IGF-I) and IGF-binding protein -3 (IGFBP-3) were monitored. RESULTS: The frequency of hyperammonemic attacks and urinary orotate excretion decreased significantly following the resumption of arginine treatment. Despite showing no marked change in body weight, height increased gradually. Extremely low plasma arginine increased to normal levels, while plasma glutamine and alanine levels decreased considerably. Except for a slight increase in high-density lipoprotein cholesterol level, blood levels of markers for nutrition did not change. In contrast, low serum IGF-I and IGFBP-3 levels increased to age-matched control levels, and normal urinary GH secretion became greater than the level observed in the controls. CONCLUSION: Arginine treatment is able to reduces attacks of hyperammonemia in boys with late-onset OTCD and to increase their growth.

Weekly administration of irinotecan (CPT-11) plus cisplatin for refractory or relapsed small cell lung cancer.

PURPOSE: Weekly administrations of CPT-11 plus cisplatin together with an anti-diarrheal program, the Oral Alkalization and Control of Defecation [Int J Cancer 1999;83:491; Int J Cancer 2001;92:269; Cancer Res 2002;62:179], were evaluated in this phase II study for patients with refractory or relapsed small cell lung cancer. METHODS: Patients were treated by weekly administrations of 60 mg/m(2) CPT-11 plus 30 mg/m(2) cisplatin on Days 1, 8 and 15 over 4 weeks. Coinciding with the infusions and for 4 days thereafter, the anti-diarrheal program was practiced using orally administered sodium bicarbonate, magnesium oxide and basic water. RESULTS: Twenty-five patients who had prior treatments of etoposide and platinum containing regimens (16 refractory patients and nine relapsed patients) were entered. The mean dose-intensities of CPT-11 and cisplatin were 154.8 and 77.4 mg/m(2) per course, respectively. Therefore, 86% of the planned dose was delivered. There were 20 partial responses and an overall response rate of 80% (95% confidence interval, 62-96%) was obtained. The median time to progression and the median survival after starting this regimen were 3.6 and 7.9 months, respectively. The major toxicity was myelosuppression. Grades 3 and 4 neutropenia occurred in 24 and 12% of patients, respectively. One patient with febrile neutropenia was experienced, and Grade 3 diarrhea was observed in 8%. But there was no treatment death. CONCLUSION: Weekly administrations of CPT-11 plus cisplatin together with Oral Alkalization and Control of Defecation provide a practical and well tolerated regimen that was active for refractory or relapsed small cell lung cancer.

[Chemotherapy-induced diarrhea].

Chemotherapy-induced diarrhea is a well-documented side effect of many cancer treatments and is associated with increased morbidity and mortality. Chemotherapy-induced diarrhea negatively impacts patient quality of life and treatment outcome by requiring dose limitations or treatment interruption. The chemotherapeutic agent CPT-11 (irinotecan) has shown promising results as a single agent and in combination chemotherapy for the treatment of colorectal and small cell lung cancer. However, delayed onset diarrhea is considered to be its major dose-limiting toxicity. In some cases, it can be life threatening. To prevent CPT-11-induced delayed diarrhea, oral alkalization (OA) and control of defecation (CD) [Int J Cancer 92: 269-275, 2001] were developed based on fundamental studies [Int J Cancer 83: 491-496, 1999; Cancer Res 62: 179-187, 2002]. Oral administration of antibiotics [Cancer Res 56: 3752-3757, 1996; Clin Cancer Res 7: 1136-1141, 2001] or kampo medicine [Jpn J Cancer Res 86: 978-984, 1995; Jpn J Cancer Res 86: 985-989, 1995] to decrease beta-glucuronidase activity derived from bacteria in the large intestine was also reported to be successful in preventing delayed diarrhea. When CPT-11-induced delayed diarrhea occurs, the conventional treatment is loperamide [J Natl Cancer Inst 86: 446-449, 1994], and the early recognition and treatment of diarrhea with this opioid has reduced, although not entirely eliminated, patient morbidity. Other therapies are needed to treat patients with loperamide-refractory CPT-11 induced diarrhea, and the successful use of the somatostatin analogue octreotide has been reported [Support Care Cancer 9: 258-260, 2001; Ann Oncol 12: 227-229, 2001; Proc Am Soc Clin Oncol 21: 387a, 2002].

Phase I studies of nogitecan hydrochloride for Japanese.

BACKGROUND: SmithKline Beecham synthesized camptothecin analogs and identified nogitecan hydrochloride (topotecan) with a broad spectrum of antitumor activity and less toxicity than camptothecin. Because preclinical and overseas clinical data indicated the antitumor effect of nogitecan hydrochloride with a 5-day repeat-dose schedule, we carried out phase I studies in Japan to determine the maximum tolerated dose (MTD), pharmacokinetics, and antitumor effect of nogitecan hydrochloride. METHODS: Phase I studies of nogitecan hydrochloride given by single and 5-day repeat dosing were carried out in patients with various solid tumors at 15 medical institutions in Japan. Pharmacokinetic evaluations were performed for both single and 5-day repeated dosing. RESULTS: The dose-limiting factor (DLF) was reversible leucopenia, and the maximum tolerated dose (MTD) was higher than 22.5 mg/m2 in the single-dose study. In the 5-day repeat-dose study, the DLF was also reversible leucopenia, and the MTD was estimated to be 1.5 mg/m2 per day. The plasma concentration of nogitecan hydrochloride increased with increasing dose, and the half-life after single dosing ranged from 3 to 5h. There was no evidence of accumulation or delayed excretion during 5-day repeat dosing. CONCLUSION: Based on these results and the finding that there were responders among patients treated at 1.5 mg/m2 per day by 5-day repeat dosing in overseas studies, 5-day repeat dosing of 1.2mg/m2 per day, one dose level lower than the MTD, was selected for phase II studies in Japan.

[Ultrastructural changes of collagen fibrils in mouse dermal connective tissue after moxibustion treatment].

Morphological changes in mouse back skin, especially dermal connective tissue, were observed after moxibustion treatment. Various amounts of direct moxibustion and indirect moxibustion (column) were performed and the exact skin area was processed for light and electron microscopy. Just after treatment, epidermal cell layer was degenerated and increased amounts of mast cells were observed. Many unwinding collagen fibrils were prominent. Twenty-four hours after treatment, the number of unwinding fibrils decreased. Instead, tightly winding fibrils, sometimes thicker, were observed in a similar area. D-period of collagen fibrils did not change in any situation. Physical reaction to moxibustion varies depending on stimulation rate and/or approach, which includes the change of interstitial connective tissues as well as cellular profiles. It is also important to survey the time-dependent changes in moxibustion treatment.