A retrospective study of sentinel lymph node biopsy for skin cancer in Japan: Comparison with breast cancer and evaluation of factors related to its use.

BACKGROUND: Sentinel lymph node biopsy (SLNB) underuse has been reported for skin cancers; however, actual performance rates have not been compared. The objective of this study was to investigate the SLNB performance rate in skin cancers covered by health insurance in Japan and compare it with that in breast cancer. METHODS: This was a retrospective study of the SLNB performance rate in SLNB-eligible patients with breast or skin cancer from 2018 to 2019, utilizing a database linked to the Hospital-Based Cancer Registry and Diagnosis Procedure Combination survey. Demographic and tumor characteristics were analyzed using logistic regression. RESULTS: A total of 71,652 patients were included in this study. SLNB was performed in 86.4% (57,904/67,036) of the patients with breast cancer, 44.7% (694/1552) with melanomas, 3.1% (89/2849) with squamous cell carcinomas (SCCs), and 13.5% (29/215) with Merkel cell carcinomas (MCCs). The performance rate of SLNB was significantly lower for skin cancers than for breast cancers (odds ratio [OR], 0.03; p < 0.001). In addition, the performance rates of SLNB were significantly lower for SCCs and MCCs than for melanomas (SCC: OR, 0.04; p < 0.001; MCC: OR, 0.19; p < 0.001). Factors associated with SLNB performance included age, sex, year of incidence, primary tumor site, T stage, and number of hospital beds. CONCLUSIONS: SLNB is underutilized for skin cancer. Further investigation is required to explore the reasons for its underutilization so that it may be implemented more universally.

Chapter 1: Evaluation of kidney function in patients undergoing anticancer drug therapy, from clinical practice guidelines for the management of kidney injury during anticancer drug therapy 2022.

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.

Baseline cardiac function checkup in patients with gastric or breast cancer receiving trastuzumab or anthracyclines.

BACKGROUND: Although trastuzumab and anthracyclines are frequently used to treat breast cancer (BC) and gastric cancer (GC), cardiotoxicity is a serious concern. The cardiac function assessment is recommended at baseline before initiating treatment. However, the prevalence rates of baseline cardiac checkups are unknown. METHODS: The national database of hospital-based cancer registries linked to the health services-utilization data was used to study patients with newly diagnosed stage IV BC and GC (n = 6271) who received trastuzumab (n = 4324, 69.0%) or anthracyclines between January 2012 and December 2015. The baseline ultrasound echocardiogram (UCG) performance rate and factors related to adequate UCG performance for all patients and those receiving trastuzumab were analyzed. RESULTS: The adequate baseline UCG checkup rate was higher in patients treated with trastuzumab than in those treated with anthracyclines (71.8% vs 44.1%, respectively). Additionally, patients with GC were less likely to receive an adequate baseline UCG performance than those with BC (70.4% vs 75.0%, respectively). After adjusting for potential confounders, patients with anthracycline-treated BC and GC were less likely to receive adequate baseline UCG performance than those with trastuzumab-treated BC (odds ratio [OR]: 0.24, 95% confidence interval [CI]: 0.20-0.28, and OR: 0.07, 95% CI: 0.03-0.16, respectively). Furthermore, patients with trastuzumab-treated GC were less likely to receive adequate baseline UCG performance than those with BC (OR: 0.65, 95% CI: 0.50-0.84). CONCLUSIONS: The baseline UCG was less likely to be performed in patients receiving anthracyclines than in those receiving trastuzumab, as well as in patients with GC than in those with BC.

Differences in the performance of adjuvant chemotherapy between hemodialysis and nonhemodialysis patients.

BACKGROUND: The survival of hemodialysis (HD) patients with cancer is poor, which may be caused by undertreatment due to renal dysfunction. Particularly, adjuvant chemotherapy after surgery may be considered optional because of its preventive nature. This study investigated the current frequency of administration of adjuvant chemotherapy to HD patients compared with non-HD patients in Japan. METHODS: We used data from the Hospital-Based Cancer Registries national database linked to health services utilization data to analyze cases of newly diagnosed colon cancer, gastric cancer, breast cancer, and non-small cell lung cancer (NSCLC) at the stages where adjuvant chemotherapy is generally required. We compared the performance rate of adjuvant chemotherapy and the adjuvant chemotherapy regimens between HD and non-HD patients from October 2011 to December 2017. RESULTS: Of the 99,761 patients who underwent curative surgery, 1207 (1%) were HD patients. HD patients received adjuvant chemotherapy less frequently than non-HD patients (24% vs. 63%, p < 0.001). After adjusting for potential confounders, HD remained negatively related to adjuvant chemotherapy administration for all four cancer types. Among all patients who received adjuvant chemotherapy 0(N = 61,873), HD patients were less likely to receive standard regimens and chemotherapy requiring dose adjustment than non-HD patients (88% vs. 95%, p < 0.001 and 92% vs. 98%, p < 0.001, respectively). This trend was particularly pronounced among patients with gastric cancer. CONCLUSIONS: HD patients were less likely to receive adjuvant chemotherapy with standard regimens than non-HD patients.

Effect of M2-like macrophages of the injured-kidney cortex on kidney cancer progression.

Chronic kidney disease (CKD) affects kidney cancer patients' mortality. However, the underlying mechanism remains unknown. M2-like macrophages have pro-tumor functions, also exist in injured kidney, and promote kidney fibrosis. Thus, it is suspected that M2-like macrophages in injured kidney induce the pro-tumor microenvironment leading to kidney cancer progression. We found that M2-like macrophages present in the injured kidney promoted kidney cancer progression and induced resistance to anti-PD1 antibody through its pro-tumor function and inhibition of CD8+ T cell infiltration. RNA-seq revealed Slc7a11 was upregulated in M2-like macrophages. Inhibition of Slc7a11 with sulfasalazine inhibited the pro-tumor function of M2-like macrophages and synergized with anti-PD1 antibody. Moreover, SLC7A11-positive macrophages were associated with poor prognosis among kidney cancer patients. Collectively, this study dissects the characteristic microenvironment in the injured kidney that contributed to kidney cancer progression and anti-PD1 antibody resistance. This insight offers promising combination therapy with anti-PD1 antibody and macrophage targeted therapy.

Cardiac Function Checkup During Trastuzumab Therapy Among Patients With Breast Cancer.

BACKGROUND: Appropriate cardiac function evaluation before trastuzumab therapy is recommended. However, there are no data that show the current practice of appropriate cardiac evaluation for patients receiving postsurgical adjuvant trastuzumab (adjuvant group) and patients with metastatic disease (metastatic group). MATERIALS AND METHODS: We assessed patients with newly diagnosed breast cancer who received trastuzumab between October 2011 and December 2016 using the national database of the Hospital-Based Cancer Registry. We defined appropriate cardiac function checkup as having ultrasound echocardiogram (UCG) before the start of trastuzumab as well as within 6 months after trastuzumab initiation for the adjuvant group, and having UCG before trastuzumab for the metastatic group. RESULTS: In the adjuvant group (14,501 patients), 34.7% of patients received appropriate UCG checkup. Factors related to appropriate UCG were 65 years or older (OR 1.54, 95% CI 1.41-1.69), advanced stage (stage II OR 1.18, 95% CI 1.07-1.30, stage III OR 1.08, 95% CI 0.96-1.23 compared to stage I), and surgical department (OR 0.57, 95% CI 0.47-0.70). In the metastatic group (1734 patients), appropriate UCG checkup was performed in 72.1% of the patients. Factors associated with appropriate UCG included 65 years or older (OR 1.45, 95% CI 1.10-1.91) and anthracycline use before trastuzumab (OR 0.59, 95% CI 0.44-0.80). UCG checkup rate improved from 2012 to 2015 in both the adjuvant and metastatic groups. CONCLUSION: Although many patients still received suboptimal UCG checkup, it has been improving over time. The level of appropriate UCG checkup was different between physicians with different specialties.

Profile of Daprodustat in the Treatment of Renal Anemia Due to Chronic Kidney Disease.

Anemia is a major complication of chronic kidney disease (CKD), which mainly results from appropriate erythropoietin production impairment. Prolyl hydroxylase domain (PHD) inhibitors are currently being developed and approved in some countries as a new treatment for CKD patients with anemia due to the stabilization of intracellular hypoxia-inducible factor (HIF) 1α and HIF2α by PHD inhibition. Daprodustat is one of the orally administrated small-molecule HIF-PH inhibitors, leading to an increase in erythropoietin production, which is regulated by HIF. Also, daprodustat is expected to improve iron metabolism. Recently, several clinical trials showed its efficacy and safety in both hemodialysis- and non-hemodialysis- dependent CKD patients. In addition, some international Phase 3 studies are underway to confirm these effects and reveal the safety profile. This article summarizes the development process and results of each clinical trial.

Epidemiology and practice patterns for male breast cancer compared with female breast cancer in Japan.

BACKGROUND: The incidence of male breast cancer (MBC), although rare, has shown an increase. However, the current epidemiology of and practice patterns for MBC remain unclear. This study evaluated the characteristics and care patterns for MBC compared with female breast cancer (FBC) in Japan. METHODS: Using the National Database of Hospital-Based Cancer Registries (HBCR) linked to the Diagnosis Procedure Combination data, we analyzed newly diagnosed breast cancer cases between January 2012 and December 2015 at participating hospitals in a large quality-of-care monitoring project. We employed logistic regression models to assess cancer treatment differences between MBC and FBC in patients who were indicated for adjuvant radiation therapy and neo-adjuvant/adjuvant chemotherapy. RESULTS: Of 142,636 breast cancer patients, 870 (0.61%) were MBC patients. At diagnosis, the mean age of MBC patients was 10 years older than FBC patients (70 vs 60 years; P < .001). Advanced-stage cancer was more frequently observed in MBC than in FBC (stage III/IV 18.9%/6.1% vs 10.6%/5.2%). Despite this, MBC patients were less likely to receive adjuvant radiation therapy and neo-adjuvant/adjuvant chemotherapy. Gender was an independent treatment determinant factor for chemotherapy decisions. CONCLUSION: MBC patients were older and had higher stages of cancer than FBC patients at diagnosis, but received suboptimal treatment.

Association between chronic kidney disease and mortality in stage IV cancer.

BACKGROUND: Chronic kidney disease (CKD) is known to be associated with cancer mortality. However, no study has considered the well-known cancer prognostic factors, ECOG Performance Status (PS) and cancer treatment, as confounding factors. We assessed the independent relationship between CKD and cancer death in stage IV cancer patients. METHODS: In this retrospective observational study, we included stage IV cancer patients diagnosed from 2009 to 2014 in a single center. We collected baseline clinical and laboratory variables, and cancer-specific variables, and assessed the presence of CKD. Our primary outcome was all-cause mortality. The secondary outcome was cancer-specific mortality and site-specific cancer mortality. RESULTS: Among 961 eligible stage IV cancer patients (median age 69 years, 51.8% male), 150 patients had CKD. During follow-up (median 9.8 months), 638 patients died, of whom 526 patients died from cancer. After adjusting for prognostic variables, including ECOG PS and cancer treatment, all-cause mortality and cancer-specific mortality were significantly higher in CKD patients than in non-CKD patients (HR 1.41, 95% CI 1.13-1.77 and HR 1.43, 95% CI 1.12-1.83, respectively). In patients with breast and kidney and urinary tract cancers, CKD was associated with a significantly increased risk of death (HR 7.01, 95% CI 1.47-33.4 and HR 3.33, 95% CI 1.42-7.78, respectively). CONCLUSIONS: CKD at the time of stage IV cancer diagnosis was associated with all-cause mortality and cancer-specific mortality. Moreover, the association between CKD and cancer-specific death was site specific for breast cancer and kidney and urinary tract cancer.

Prolyl hydroxylase inhibition protects the kidneys from ischemia via upregulation of glycogen storage.

Hypoxia-inducible factor (HIF) mediates protection via hypoxic preconditioning in both, in vitro and in vivo ischemia models. However, the underlying mechanism remains largely unknown. Prolyl hydroxylase domain proteins serve as the main HIF regulator via hydroxylation of HIFα leading to its degradation. At present, prolyl hydroxylase inhibitors including enarodustat are under clinical trials for the treatment of renal anemia. In an in vitro model of ischemia produced by oxygen-glucose deprivation of renal proximal tubule cells in culture, enarodustat treatment and siRNA knockdown of prolyl hydroxylase 2, but not of prolyl hydroxylase 1 or prolyl hydroxylase 3, significantly increased the cell viability and reduced the levels of reactive oxygen species. These effects were offset by the simultaneous knockdown of HIF1α. In another in vitro ischemia model induced by the blockade of oxidative phosphorylation with rotenone/antimycin A, enarodustat-enhanced glycogen storage prolonged glycolysis and delayed ATP depletion. Although autophagy is another possible mechanism of prolyl hydroxylase inhibition-induced cytoprotection, gene knockout of a key autophagy associated protein, Atg5, did not affect the protection. Enarodustat increased the expression of several enzymes involved in glycogen synthesis, including phosphoglucomutase 1, glycogen synthase 1, and 1,4-α glucan branching enzyme. Increased glycogen served as substrate for ATP and NADP production and augmented reduction of glutathione. Inhibition of glycogen synthase 1 and glutathione reductase nullified enarodustat's protective effect. Enarodustat also protected the kidneys in a rat ischemia reperfusion injury model and the protection was partially abrogated by inhibiting glycogenolysis. Thus, prolyl hydroxylase inhibition protects the kidney from ischemia via upregulation of glycogen synthesis.

Early postoperative inflammatory response by procedure types: stapler-based segmentectomy versus lobectomy.

OBJECTIVE: Perioperative C-reactive protein (CRP) levels have become a contentious topic on the surgical outcome of lung cancer, but the influence of the procedure types has not been precisely investigated. From this viewpoint, we compared two types of thoracoscopic anatomical lung resection: segmentectomy and lobectomy. METHODS: This was a retrospective study involving patients who underwent standardized anatomical lung resection at a single institute from 2014 to 2017; CRP levels were routinely measured on postoperative days 1, 3, and 5. Changes in the CRP levels from the preoperative period were calculated (ΔCRP), and factors associated with a higher ΔCRP value were analyzed. RESULTS: Among 186 patients included, 91 (48.9%) patients underwent stapler-based segmentectomy and 95 (51.1%) patients underwent lobectomy. The segmentectomy group showed significantly higher ΔCRP values on every measurement day than the lobectomy group, in spite of shorter operation time, smaller blood loss, shorter drainage periods, shorter dissection time, and limited lymph node dissection. The number of stapler cartridges for the lung parenchyma was significantly larger in the segmentectomy group. Regression analyses indicated that procedure type and smoking history were associated with a higher ΔCRP value, whereas no significant difference was indicated in the smoking history between the groups. CONCLUSION: In our cohort, stapler-based thoracoscopic segmentectomy was associated with an increase in acute inflammatory response despite favorable perioperative outcome compared to lobectomy. Local surgical stress and damage in the remaining segments might play a key role and warrants further investigation.

Renal thrombotic microangiopathy during nintedanib treatment for idiopathic pulmonary fibrosis
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Agents that block vascular endothelial growth factor (VEGF) and its downstream pathway have been reported to be associated with nephrotoxicity including hypertension, proteinuria, and renal dysfunction. Bevacizumab, a monoclonal antibody against VEGF, is known to cause thrombotic microangiopathy (TMA), while tyrosine kinase inhibitors (TKIs) that block VEGF downstream are mainly associated with minimal change disease or focal segmental glomerulosclerosis. The question regarding the source of the diverse phenotypes of nephrotoxicity associated with these agents remains enigmatic. Nintedanib, a multitargeted TKI, blocks fibroblast growth factor and platelet-derived growth factor receptor as well as VEGF receptor, and is indicated for the treatment of idiopathic pulmonary fibrosis. We describe a case of a 45-year-old male who presented with isolated proteinuria of 1.3 g/g Cr 3 years after beginning nintedanib treatment. The kidney biopsy revealed histological features consistent with renal TMA. He underwent single lung transplantation 6 months later, which enabled cessation of nintedanib, and, 1 month later, his proteinuria results were negative. Unlike other types of TKIs, the pathological findings of nintedanib-induced nephrotoxicities have been limitedly reported. This is the first case of isolated proteinuria likely caused by nintedanib-induced TMA.