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Cancer susceptibility is a critical factor in the understanding of carcinogenesis. Intraperitoneal (i.p.) injection of an iron chelate, ferric nitrilotriacetate (Fe‐NTA), produces hydroxyl radicals via Fenton reaction to induce ferroptosis in renal proximal tubules. Rats or mice subjected to repeated i.p. injections of Fe‐NTA develop renal cell carcinoma (RCC). To elucidate the molecular mechanisms that cause susceptibility to renal carcinogenesis, we first established an inter‐strain difference in the susceptibility to Fe‐NTA‐induced renal carcinogenesis in mice. Based on a previous observation of a low incidence of RCC with this model in C57BL/6J strain mice, we investigated A/J strain mice here, which demonstrated significantly higher susceptibility to Fe‐NTA‐induced renal carcinogenesis. Homozygous deletion of the Cdkn2a/2b tumor suppressor locus was detected for the first time in A/J strain mice. Focusing on ferroptosis and iron metabolism, we explored the mechanisms involved that lead to the difference in RCC development. We compared the protective responses in the kidney of A/J and C57BL/6J strains after Fe‐NTA treatment. After 3‐week Fe‐NTA treatment, A/J mice maintained higher levels of expression of glutathione peroxidase 4 and xCT (SLC7A11), leading to a lower level of lipid peroxidation. Simultaneously, A/J mice had decreased expression of transferrin receptor and increased expression of ferritin to greater degrees than C57BL/6 mice. After a single Fe‐NTA injection, higher levels of oxidative cell damage and cytosolic catalytic Fe(II) were observed in C57BL/6J mice, accompanied by a greater increase in lipocalin‐2. Lipocalin‐2 deficiency significantly decreased oxidative renal damage. Our results suggest that a genetic trait favoring ferroptosis resistance contributes to high susceptibility to Fe‐NTA‐induced RCC in A/J strain. Cancer susceptibility is an important issue when considering cancer prevention. In this paper, we used an iron‐mediated oxidative stress‐induced renal carcinogenesis model in mice and found that ferroptosis resistance is an important factor determining cancer susceptibility.

Some hemodialysis patients are not suitable for creation of an arteriovenous fistula (AVF) or arteriovenous graft (AVG). However, they can receive a tunneled cuffed central venous catheter (tcCVC), but this carries risks of infection and mortality. We aimed to evaluate the safety and effectiveness of brachial artery transposition (BAT) versus those of tcCVC. This retrospective study evaluated hemodialysis patients who underwent BAT or tcCVC placement because of severe heart failure, hand ischemia, central venous stenosis or occlusion, inadequate vessels for creating standard arteriovenous access, or limited life expectancy. The primary outcome was whole access circuit patency. Thirty-eight patients who underwent BAT and 25 who underwent tcCVC placement were included. One-year patency rates for the whole access circuit were 84.6% and 44.9% in the BAT and tcCVC groups, respectively. The BAT group was more likely to maintain patency (unadjusted hazard ratio: 0.17, 95% confidence interval: 0.05–0.60, p  = 0.006). The two groups did not have significantly different overall survival (log-rank p  = 0.146), although severe complications were less common in the BAT group (3% vs. 28%, p  = 0.005). Relative to tcCVC placement, BAT is safe and effective with acceptable patency in hemodialysis patients not suitable for AVF or AVG creation.

The prevalence of CKD may be higher in patients with cancer than in those without due to the addition of cancer-specific risk factors to those already present for CKD. In this review, we describe the evaluation of kidney function in patients undergoing anticancer drug therapy. When anticancer drug therapy is administered, kidney function is evaluated to (1) set the dose of renally excretable drugs, (2) detect kidney disease associated with the cancer and its treatment, and (3) obtain baseline values for long-term monitoring. Owing to some requirements for use in clinical practice, a GFR estimation method such as the Cockcroft–Gault, MDRD, CKD-EPI, and the Japanese Society of Nephrology’s GFR estimation formula has been developed that is simple, inexpensive, and provides rapid results. However, an important clinical question is whether they can be used as a method of GFR evaluation in patients with cancer. When designing a drug dosing regimen in consideration of kidney function, it is important to make a comprehensive judgment, recognizing that there are limitations regardless of which estimation formula is used or if GFR is directly measured. Although CTCAEs are commonly used as criteria for evaluating kidney disease-related adverse events that occur during anticancer drug therapy, a specialized approach using KDIGO criteria or other criteria is required when nephrologists intervene in treatment. Each drug is associated with the different disorders related to the kidney. And various risk factors for kidney disease associated with each anticancer drug therapy.

Concurrent chemoradiotherapy is the standard treatment for unresectable stage III non‐small cell lung cancer (NSCLC). The long‐term feasibility and efficacy of vinorelbine and cisplatin with concurrent thoracic radiotherapy were investigated. Eighteen patients received cisplatin (80 mg/m2) on day 1 and vinorelbine (20 mg/m2 in level 1, and 25 mg/m2 in level 2) on days 1 and 8 every 4 weeks for four cycles in a phase I trial. Ninety‐three patients received the same chemotherapy regimen except for the fixed vinorelbine (20 mg/m2) dosage and consolidation therapy with docetaxel (60 mg/m2, every 3 weeks). The thoracic radiotherapy consisted of a single dose of 2 Gy once daily to a total dose of 60 Gy. A total of 111 patients were analyzed in the present study: male/female, 91/20; median age, 60 years; stage IIIA/IIIB, 50/61; and squamous/non‐squamous histology, 26/85. The 3‐, 5‐, and 7‐year overall survival rates (95% CI) were 43.2% (33.9–52.2), 25.2% (17.6–33.5), and 23.2% (15.8–31.4), respectively. The median progression‐free survival and median survival time (95% CI) were 13.5 (10.1–16.7) months and 30.0 (24.3–38.8) months, respectively. Four patients (4%) experienced Grade 5 pulmonary toxicities from 4.4 to 9.4 months after the start of treatment. In conclusion, approximately 15% of patients with unresectable stage III NSCLC could be cured with chemoradiotherapy without severe late toxicities after 10 months of follow‐up. Although based on the data from highly selected population participated in phase I and phase II trial, this analysis would strengthen and confirm the previous reports concerning concurrent chemoradiotherapy with third generation cytotoxic agents. (Cancer Sci 2013; 104: 93–97)

PurposeCombination carboplatin and S-1 is active in the treatment of non-small cell lung cancer (NSCLC). However, data on this combination for elderly patients with NSCLC are insufficient.MethodsEligibility criteria were no prior chemotherapy, Stage IIIB or IV NSCLC, performance status 0–1, age ≥ 75 years, and adequate hematological, hepatic, and renal functions. Carboplatin was administered on day 1 and S-1 was administered orally, twice a day, between days 1 and 14, repeated every 3 weeks. In phase I, the primary purpose was determination of the recommended dose. Starting doses of carboplatin and S-1 were area under the curve (AUC) of 4 and 80 mg/m2/day, respectively. In the extension study, the effects and tolerability of this combination therapy of recommended dose were confirmed.ResultsA total of 10 patients were entered into phase I and 14 patients were entered into the extension study. The recommended doses for this drug combination are AUC 5 for carboplatin and 80 mg/m2/day every 3 weeks for S-1. With carboplatin and S-1 combination therapy at the recommended dose, the response rate was 30.0% [95% confidence interval (CI) 12–54%] and the disease control rate was 90.0% (95% CI 68–99%). Thrombocytopenia and neutropenia were major adverse events.ConclusionsThe recommended doses for this combination therapy are carboplatin AUC 5 and S-1 80 mg/m2/day every 3 weeks, and this combination is effective with tolerable toxicities for advanced NSCLC patients ≥ 75 years old.

Protein arginine methyltransferase 5 (PRMT5) is a well-known epigenetic regulatory enzyme. However, the role of PRMT5-mediated arginine methylation in gene transcription related to cardiac fibrosis is unknown. Here we show that fibroblast-specific deletion of PRMT5 significantly reduces pressure overload-induced cardiac fibrosis and improves cardiac dysfunction in male mice. Both the PRMT5-selective inhibitor EPZ015666 and knockdown of PRMT5 suppress α-smooth muscle actin (α-SMA) expression induced by transforming growth factor-β (TGF-β) in cultured cardiac fibroblasts. TGF-β stimulation promotes the recruitment of the PRMT5/Smad3 complex to the promoter site of α-SMA. It also increases PRMT5-mediated H3R2 symmetric dimethylation, and this increase is inhibited by Smad3 knockdown. TGF-β stimulation increases H3K4 tri-methylation mediated by the WDR5/MLL1 methyltransferase complex, which recognizes H3R2 dimethylation. Finally, treatment with EPZ015666 significantly improves pressure overload-induced cardiac fibrosis and dysfunction. These findings suggest that PRMT5 regulates TGF-β/Smad3-dependent fibrotic gene transcription, possibly through histone methylation crosstalk, and plays a critical role in cardiac fibrosis and dysfunction. Epigenetic mechanisms play a key role in cardiac fibrosis associated with heart failure. Here, the authors show that protein arginine methyltransferase 5 (PRMT5), an epigenetic writer, regulates fibrotic gene transcription through histone methylation in mice.

BackgroundAcute kidney injury (AKI) is a globally critical issue. Most studies about AKI have been conducted in limited settings on perioperative or critically ill patients. As a result, there is little information about the epidemiology and risk factors of AKI in the general population.MethodsWe conducted a population-based cohort study using the Shizuoka Kokuho Database. We included subjects with records of health checkup results. The observation period for each participant was defined as from the date of insurance enrollment or April 2012, whichever occurred later, until the date of insurance withdrawal or September 2020, whichever was later. Primary outcome was AKI associated with admission based on the ICD-10 code. We described the incidence of AKI and performed a multivariate analysis using potential risk factors selected from comorbidities, medications, and health checkup results.ResultsOf 627,814 subjects, 8044 were diagnosed with AKI (incidence 251 per 100,000 person-years). The AKI group was older, with more males. Most comorbidities and prescribed medications were more common in the AKI group. As novel factors, statins (hazard ratio (HR) 0.84, 95% confidence interval (CI) 0.80–0.89) and physical activity habits (HR 0.79, 95% CI 0.75–0.83) were associated with reduced incidence of AKI. Other variables associated with AKI were approximately consistent with those from previous studies.ConclusionsThe factors associated with AKI and the incidence of AKI in the general Japanese population are indicated. This study generates the hypothesis that statins and physical activity habits are novel protective factors for AKI.

Background Neoadjuvant chemotherapy (NAC) combined with human epidermal growth factor receptor 2 (HER2)-targeted agents is the mainstay of treatment of HER2-positive (HER2 +) breast cancer (BC). We investigated intrinsic subtypes and clinicopathological features as predictors of outcomes of NAC in HER2 + early-stage BC patients. Methods Of 186 consecutive patients with early-stage HER2 + BC, as determined by immunohistochemistry (IHC) and fluorescence in situ hybridization, who received NAC plus HER2-targeted agents, 167 with an available biopsy specimen were eligible for inclusion. Intrinsic subtypes were determined by MammaPrint and Blueprint (MP/BP). Whole-slide images of HER2 IHC staining were used to evaluate intensity of HER2 staining. Results MP/BP subtype was determined for 124 patients: Luminal-A, 17 patients; Luminal-B, 23 patients; HER2, 76 patients; and Basal, 8 patients. Pathological complete response (pCR) rate was significantly higher in HER2 than in non-HER2 cases ( p  < 0.001). High-intensity ( p  = 0.001) and BP-determined HER2 intrinsic subtype ( p  = 0.024) were identified as independent factors for pCR prediction. Neither Luminal subtype was found in IHC estrogen receptor (ER)-negative patients; however, 54.3% of IHC ER-positive patients had HER2 subtype. Five-year distant disease–free survival by MP/BP subtype was Luminal-A, 92.3%; Luminal-B, 81.6%; HER2, 84.0%; and Basal, 80.0%. Of the 23 patients whose subtypes were compared before and after surgery, 10 had a change in subtype. Conclusions High HER2 intensity and HER2 intrinsic subtype could be a means for predicting achievement of pCR. The findings indicate the essential role of MP/BP subtyping in the treatment of HER2 + BC. Trial registration UMIN000049957.

Etoposide and irinotecan are key drugs in the treatment of small-cell lung cancer. We did this study to investigate whether combined chemotherapy with cisplatin, etoposide, and irinotecan was superior to topotecan monotherapy as second-line chemotherapy in patients with sensitive relapsed small-cell lung cancer. We did this open-label, multicentre, randomised phase 3 trial at 29 institutions in Japan. Patients with small-cell lung cancer that responded to first-line treatment but showed evidence of disease relapse or progression at least 90 days after completion of the first-line treatment were eligible to participate. Enrolled patients were randomly assigned (1:1) to receive combination chemotherapy with cisplatin plus etoposide plus irinotecan or topotecan alone. Randomisation was done via the minimisation method with biased-coin balancing for Eastern Cooperative Oncology Group performance status, disease stage at enrolment, and institution. Combination chemotherapy consisted of five 2-week courses of intravenous cisplatin 25 mg/m2 on days 1 and 8, intravenous etoposide 60 mg/m2 on days 1–3, and intravenous irinotecan 90 mg/m2 on day 8, with granulocyte colony-stimulating factor given by hypodermic injection every day starting from day 9 of the first course (except on the days anticancer drugs were given). Topotecan therapy consisted of four courses of intravenous topotecan 1·0 mg/m2 on days 1–5, every 3 weeks. The primary endpoint was overall survival in the intention-to-treat population, which was analysed with a one-sided α of 5%, and safety was assessed in all patients who received at least one dose of study drug. The trial is registered with University Hospital Medical Information Network Clinical Trials Registry, number UMIN000000828. Between Sept 20, 2007, and Nov 30, 2012, 180 patients were enrolled, with 90 assigned to each treatment group. The median follow-up for censored patients was 22·7 months (IQR 20·0–35·3). Overall survival was significantly longer in the combination chemotherapy group (median 18·2 months, 95% CI 15·7–20·6) than in the topotecan group (12·5 months, 10·8–14·9; hazard ratio 0·67, 90% CI 0·51–0·88; p=0·0079). The most common grade 3 or 4 adverse events were neutropenia (75 [83%] patients in the combination chemotherapy group vs 77 [86%] patients in the topotecan group), anaemia (76 [84%] vs 25 [28%]), and leucopenia (72 [80%] vs 46 [51%]). Grade 3 or 4 febrile neutropenia was more common in the combination chemotherapy group than in the topotecan group (28 [31%] vs six [7%]), as was grade 3 or 4 thrombocytopenia (37 [41%] vs 25 [28%]). Serious adverse events were reported in four (4%) patients in the topotecan group and nine (10%) in the combination chemotherapy group. Two treatment-related deaths (one each of pneumonitis and pulmonary infection) occurred in the topotecan group and one (febrile neutropenia with sepsis) occurred in the combination chemotherapy group. Combination chemotherapy with cisplatin plus etoposide plus irinotecan could be considered the standard second-line chemotherapy for selected patients with sensitive relapsed small-cell lung cancer. National Cancer Center and the Ministry of Health, Labour and Welfare of Japan.

Mechanisms of progression of chronic kidney disease (CKD), a major health care burden, are poorly understood. EGFR stimulates CKD progression, but the molecular networks that mediate its biological effects remain unknown. We recently showed that the severity of renal lesions after nephron reduction varied substantially among mouse strains and required activation of EGFR. Here, we utilized two mouse strains that react differently to nephron reduction--FVB/N mice, which develop severe renal lesions, and B6D2F1 mice, which are resistant to early deterioration--coupled with genome-wide expression to elucidate the molecular nature of CKD progression. Our results showed that lipocalin 2 (Lcn2, also known as neutrophil gelatinase-associated lipocalin [NGAL]), the most highly upregulated gene in the FVB/N strain, was not simply a marker of renal lesions, but an active player in disease progression. In fact, the severity of renal lesions was dramatically reduced in Lcn2-/- mice. We discovered that Lcn2 expression increased upon EGFR activation and that Lcn2 mediated its mitogenic effect during renal deterioration. EGFR inhibition prevented Lcn2 upregulation and lesion development in mice expressing a dominant negative EGFR isoform, and hypoxia-inducible factor 1α (Hif-1α) was crucially required for EGFR-induced Lcn2 overexpression. Consistent with this, cell proliferation was dramatically reduced in Lcn2-/- mice. These data are relevant to human CKD, as we found that LCN2 was increased particularly in patients who rapidly progressed to end-stage renal failure. Together our results uncover what we believe to be a novel function for Lcn2 and a critical pathway leading to progressive renal failure and cystogenesis.