Autologous concentrated bone marrow injection for precollapse osteonecrosis of the femoral head concurrent with contralateral total hip arthroplasty: protocol for a clinical trial.

INTRODUCTION: The femoral head contralateral to the collapsed femoral head requiring total hip arthroplasty (THA) often manifests in the precollapse stage of osteonecrosis of the femoral head (ONFH). It is not yet demonstrated how autologous concentrated bone marrow injection may prevent collapse of the femoral head concurrent with contralateral THA. The primary objective is to evaluate the efficacy of autologous concentrated bone marrow injection for the contralateral, non-collapsed, femoral head in patients with bilateral ONFH, with the ipsilateral collapsed femoral head undergoing THA. METHODS AND ANALYSIS: This is a multicentre, prospective, non-randomised, historical-data controlled study. We will recruit patients with ONFH who are scheduled for THA and possess a non-collapsed contralateral femoral head. Autologous bone marrow will be collected using a point-of-care device. After concentration, the bone marrow will be injected into the non-collapsed femoral head following the completion of THA in the contralateral hip. The primary outcome is the percentage of femoral head collapse evaluated by an independent data monitoring committee using plain X-rays in two directions 2 years after autologous concentrated bone marrow injection. Postinjection safety, adverse events, pain and hip function will also be assessed. The patients will be evaluated preoperatively, and at 6 months, 1 year and 2 years postoperatively. ETHICS AND DISSEMINATION: This protocol has been approved by the Certified Committee for Regenerative Medicine of Tokyo Medical and Dental University and Japan's Ministry of Healthy, Labour and Welfare and will be performed as a class III regenerative medicine protocol, in accordance with Japan's Act on the Safety of Regenerative Medicine. The results of this study will be submitted to a peer-review journal for publication. The results of this study are expected to provide evidence to support the inclusion of autologous concentrated bone marrow injections in the non-collapsed femoral head in Japan's national insurance coverage. TRIAL REGISTRATION NUMBER: jRCTc032200229.

Changepoint Detection in Heart Rate Variability Indices in Older Patients Without Cancer at End of Life Using Ballistocardiography Signals: Preliminary Retrospective Study.

BACKGROUND: In an aging society such as Japan, where the number of older people continues to increase, providing in-hospital end-of-life care for all deaths, and end-of-life care outside of hospitals, such as at home or in nursing homes, will be difficult. In end-of-life care, monitoring patients is important to understand their condition and predict survival time; this information gives family members and caregivers time to prepare for the end of life. However, with no clear indicators, health care providers must subjectively decide if an older patient is in the end-of-life stage, considering factors such as condition changes and decreased food intake. This complicates decisions for family members, especially during home-based care. OBJECTIVE: The purpose of this preliminary retrospective study was to determine whether and how changes in heart rate variability (HRV) indices estimated from ballistocardiography (BCG) occur before the date of death in terminally ill older patients, and ultimately to predict the date of death from the changepoint. METHODS: This retrospective pilot study assessed the medical records of 15 older patients admitted to a special nursing home between August 2019 and December 2021. Patient characteristics and time-domain HRV indices such as the average normal-to-normal (ANN) interval, SD of the normal-to-normal (SDNN) interval, and root mean square of successive differences (RMSSD) from at least 2 months before the date of death were collected. Overall trends of indices were examined by drawing a restricted cubic spline curve. A repeated measures ANOVA was performed to evaluate changes in the indices over the observation period. To explore more detailed changes in HRV, a piecewise regression analysis was conducted to estimate the changepoint of HRV indices. RESULTS: The 15 patients included 8 men and 7 women with a median age of 93 (IQR 91-96) years. The cubic spline curve showed a gradual decline of indices from approximately 30 days before the patients' deaths. The repeated measures ANOVA showed that when compared with 8 weeks before death, the ratio of the geometric mean of ANN (0.90, 95% CI 0.84-0.98; P=.005) and RMSSD (0.83, 95% CI 0.70-0.99; P=.03) began to decrease 3 weeks before death. The piecewise regression analysis estimated the changepoints for ANN, SDNN, and RMSSD at -34.5 (95% CI -42.5 to -26.5; P<.001), -33.0 (95% CI -40.9 to -25.1; P<.001), and -35.0 (95% CI -42.3 to -27.7; P<.001) days, respectively, before death. CONCLUSIONS: This preliminary study identified the changepoint of HRV indices before death in older patients at end of life. Although few data were examined, our findings indicated that HRV indices from BCG can be useful for monitoring and predicting survival time in older patients at end of life. The study and results suggest the potential for more objective and accurate prognostic tools in predicting end-of-life outcomes.

Impact of Istradefylline on Levodopa Dose Escalation in Parkinson's Disease: ISTRA ADJUST PD Study, a Multicenter, Open-Label, Randomized, Parallel-Group Controlled Study.

INTRODUCTION: A higher levodopa dose is a risk factor for motor complications in Parkinson's disease (PD). Istradefylline (IST) is used as adjunctive treatment to levodopa in PD patients with off episodes, but its impact on levodopa dose titration remains unclear. The objective of this study was to investigate the effect of IST on levodopa dose escalation in PD patients with wearing-off. METHODS: This was a multicenter, open-label, randomized, parallel-group controlled study (ISTRA ADJUST PD) in which PD patients experiencing wearing-off (n = 114) who were receiving levodopa 300-400 mg/day were randomized to receive IST or no IST (control). Levodopa dose was escalated according to clinical severity. The primary endpoint was cumulative additional levodopa dose, and secondary endpoints were changes in symptom rating scales, motor activity determined by a wearable device, and safety outcomes. RESULTS: The cumulative additional levodopa dose throughout 37 weeks and dose increase over 36 weeks were significantly lower in the IST group than in the control group (both p < 0.0001). The Movement Disorder Society Unified Parkinson's Disease Rating Scale Part I and device-evaluated motor activities improved significantly from baseline to 36 weeks in the IST group only (all p < 0.05). Other secondary endpoints were comparable between the groups. Adverse drug reactions (ADRs) occurred in 28.8% and 13.2% of patients in the IST and control groups, respectively, with no serious ADRs in either group. CONCLUSION: IST treatment reduced levodopa dose escalation in PD patients, resulting in less cumulative levodopa use. Adjunctive IST may improve motor function more objectively than increased levodopa dose in patients with PD. TRIAL REGISTRATION: Japan Registry of Clinical Trials: jRCTs031180248.

Conventional versus lateral fasciotomy for prevention of lateral femoral cutaneous nerve injury in the non-fan-type nerve in total hip arthroplasty with direct anterior approach.

Aims: Lateral femoral cutaneous nerve (LFCN) injury is a potential complication after the direct anterior approach for total hip arthroplasty (DAA-THA). The aim of this study was to determine how the location of the fasciotomy in DAA-THA affects LFCN injury. Methods: In this trial, 134 patients were randomized into a lateral fasciotomy (n = 67) or a conventional fasciotomy (n = 67) group. This study was a dual-centre, double-blind, prospective randomized controlled two-arm trial with parallel group design and a 1:1 allocation ratio. The primary endpoint was the presence of LFCN injury, which was determined by the presence of numbness, decreased sensation, tingling, jolt-like sensation, or pain over the lateral aspect of the thigh, excluding the surgical scar, using a patient-based questionnaire. The secondary endpoints were patient-reported outcome measures (PROMs) using the Western Ontario and McMaster Universities osteoarthritis index (WOMAC), Japanese Orthopaedic Association Hip Disease Evaluation Questionnaire (JHEQ), and the Forgotten Joint Score-12 (FJS-12). Assessments were obtained three months after surgery. Results: The incidence of LFCN injury tended to be lower in the lateral fasciotomy group (p = 0.089). In the lateral fasciotomy group, there were no significant differences in the mean PROM scores between patients with and without LFCN injury (FJS-12: 54.42 (SD 15.77) vs 65.06 (SD 26.14); p = 0.074; JHEQ: 55.21 (SD 12.10) vs 59.72 (SD 16.50); p = 0.288; WOMAC: 82.45 (SD 6.84) vs 84.40 (SD 17.91); p = 0.728). In the conventional fasciotomy group, there were significant differences in FJS-12 and JHEQ between patients with and without LFCN injury (FJS-12: 43.21 (SD 23.08) vs 67.28 (SD 20.47); p < 0.001; JHEQ: 49.52 (SD 13.97) vs 59.59 (SD 15.18); p = 0.012); however, there was no significant difference in WOMAC (76.63 (SD 16.81) vs 84.16 (SD 15.94); p = 0.107). Conclusion: The incidence of LFCN injury at three months after THA was comparable between the lateral and conventional fasciotomy groups. Further studies are needed to assess the long-term effects of these approaches.

Assessment of Elastic Laminal Invasion Contributes to an Objective pT3 Subclassification in Colon Cancer.

The extent of tumor spread influences on the clinical outcome, and which determine T stage of colorectal cancer. However, pathologic discrimination between pT3 and pT4a in the eighth edition of the American Joint Committee on Cancer (AJCC)-TNM stage is subjective, and more objective discrimination method for deeply invasive advanced colon cancer is mandatory for standardized patient management. Peritoneal elastic laminal invasion (ELI) detected using elastic staining may increase the objective discrimination of deeply invasive advanced colon cancer. In this study, we constructed ELI study group to investigate feasibility, objectivity, and prognostic utility of ELI. Furthermore, pT classification using ELI was investigated based on these data. At first, concordance study investigated objectivity using 60 pT3 and pT4a colon cancers. Simultaneously, a multi-institutional retrospective study was performed to assess ELI's prognostic utility in 1202 colon cancer cases from 6 institutions. In the concordance study, objectivity, represented by κ, was higher in the ELI assessment than in pT classification. In the multi-institutional retrospective study, elastic staining revealed that ELI was a strong prognostic factor. The clinical outcome of pT3 cases with ELI was significantly and consistently worse than that of those without ELI. pT classification into pT3 without ELI, pT3 with ELI, and pT4a was an independent prognostic factor. In this study, we revealed that ELI is an objective method for discriminating deeply invasive advanced colon cancer. Based on its feasibility, objectivity, and prognostic utility, ELI can subdivide pT3 lesions into pT3a (without ELI) and pT3b (with ELI).

High platelet-to-lymphocyte ratios in triple-negative breast cancer associates with immunosuppressive status of TILs.

BACKGROUND: Rating lymphocytes (TILs) are a prognostic marker in breast cancer and high TIL infiltration correlates with better patient outcomes. Meanwhile, parameters involving immune cells in peripheral blood have also been established as prognostic markers. High platelet-to-lymphocyte ratios (PLRs) and neutrophil-to-lymphocyte ratios (NLRs) are related to poor outcomes in breast cancer, but their mechanisms remain unknown. To date, TILs and these parameters have been examined separately. METHODS: We investigated the relationship between TILs and the peripheral blood markers, PLR and NLR, in the same patients, using surgical specimens from 502 patients with invasive breast carcinoma without preoperative chemotherapy. For analysis of triple-negative breast cancer (TNBC) patient outcomes, 59 patients who received preoperative chemotherapy were also examined. For immune cell profiling, multiplexed fluorescent immunohistochemistry (mfIHC) of CD3, CD4, CD8, FOXP3 and T-bet, was conducted. RESULTS: A positive correlation between PLR and TIL was observed in TNBC (P = 0.013). On mfIHC, tumors in patients with high PLR and NLR contained more CD3+CD4+FOXP3+ T-cells (P = 0.049 and 0.019, respectively), while no trend was observed in CD8+ T-cells. TNBC patients had different patterns of outcomes according to TIL and PLR, with the TIL-high/PLR-low group having the lowest rate of disease relapse and death, and the longest distant metastasis-free and overall survivals, while the TIL-low/PLR-high group had the shortest survivals. CONCLUSIONS: Our data suggest that the combination of PLR with TIL assessment may enable more accurate prediction of patient outcomes with TNBC.

von Willebrand factor activity levels are influenced by driver mutation status in polycythemia vera and essential thrombocythemia patients with well-controlled platelet counts.

von Willebrand factor ristocetin cofactor (vWF activity) and platelet count (PLT) are negatively correlated in patients with polycythemia vera (PV) and essential thrombocythemia (ET). However, vWF activity does not always normalize upon controlling PLT in those patients. To address this issue, we investigated the correlation between vWF activity and PLT in PV and ET patients. The negative correlation between vWF activity and PLT was stronger in calreticulin mutation-positive (CALR+) ET than in Janus kinase 2 mutation-positive (JAK2+) PV or ET groups. When PLT were maintained at a certain level (<600 × 109 /L), low vWF activity (<50%) was more frequently observed in JAK2+ PV patients than in JAK2+ ET (p = .013) or CALR+ ET (p = .013) groups, and in PV and ET patients with ≥50% JAK2+ allele burden than in those with allele burden <50% (p = .015). High vWF activity (>150%) was more frequent in the JAK2+ ET group than in the CALR+ ET group (p = .005), and often associated with vasomotor symptoms (p = .002). This study suggests that some patients with JAK2+ PV or ET have vWF activity outside the standard range even with well-controlled PLT, and that the measurement of vWF activity is useful for assessing the risk of thrombosis and hemorrhage.

Daprodustat for anaemia in patients with heart failure and chronic kidney disease: A randomized controlled study.

AIMS: Hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors have been developed for the treatment of renal anaemia; however, no study has evaluated the safety and efficacy of HIF-PH inhibitors in patients with heart failure (HF). This study was designed to evaluate the safety and efficacy of daprodustat, a HIF-PH inhibitor, in patients with HF and renal anaemia. METHODS AND RESULTS: We designed a pilot, multi-centre, open-label, randomized controlled study, in which 50 patients with HF complicated with chronic kidney disease and anaemia will be randomized 1:1 to either the daprodustat or control group at seven sites in Japan. Study entry requires New York Heart Association Class II HF symptoms or a history of hospitalization due to HF, an estimated glomerular filtration rate of <60 mL/min/1.73 m2 , and a haemoglobin level of 7.5 to <11.0 g/dl. Patients randomized to the daprodustat group will be treated with oral daprodustat, and the dose will be uptitrated according to the changes in the haemoglobin level from previous visits. In this study, we will evaluate the impact of HIF-PH inhibitors on cardiac function using advanced cardiovascular imaging modalities, including cardiac magnetic resonance imaging. The primary outcome is the haemoglobin level at 16 weeks of randomization, and all adverse events will be recorded and evaluated for any association with daprodustat treatment. CONCLUSION: Considering the hypothetical upside and downside of using HIF-PH inhibitors in anaemic patients with HF and chronic kidney disease, and because there are virtually no safe and effective treatments for patients with anaemia not caused by iron deficiency, our study results will contribute significantly to this field.

Lateral versus conventional fasciotomy for prevention of lateral femoral cutaneous nerve injury in total hip arthroplasty with direct anterior approach: a study protocol for a dual-center, double-blind, randomized controlled trial.

BACKGROUND: An incision for total hip arthroplasty (THA) via the direct anterior approach (DAA) is generally made outside of the space between the sartorius and tensor fasciae latae muscles to prevent lateral femoral cutaneous nerve (LFCN) injury. Anatomical studies have revealed that the LFCN courses between the sartorius and tensor fasciae latae muscles. When the LFCN branches radially while distributing in the transverse direction from the sartorius muscle to the tensor fasciae latae muscle, it is called the fan type. Studies suggest that damage to the fan type LFCN is unavoidable during conventional fasciotomy. We previously demonstrated that injury to non-fan variation LFCN occurred in 28.6% of patients who underwent THA by fasciotomy performed 2 cm away from the intermuscular space. This suggests that the conventional approach also poses a risk of LFCN injury to non-fan variation LFCN. LFCN injury is rarely reported in the anterolateral approach, which involves incision of fascia further away than the DAA. The purpose of this study is to investigate how the position of fasciotomy in DAA affects the risk of LFCN injury. METHODS: We will conduct a prospective, randomized, controlled study. All patients will be divided into a fan variation and a non-fan variation group using ultrasonography before surgery. Patients with non-fan variation LFCN will receive conventional fasciotomy and lateral fasciotomy in the order specified in the allocation table created in advance by our clinical trial center. The primary endpoint will be the presence of LFCN injury during an outpatient visit using a patient-based questionnaire. The secondary endpoints will be assessed based on patient-reported outcomes at 3 months after surgery in an outpatient setting using the Western Ontario and McMaster Universities Osteoarthritis Index, the Japanese Orthopaedic Association Hip-disease Evaluation Questionnaire, and the Forgotten-Joint Score-12. DISCUSSION: We hypothesize that the incidence of LFCN injury due to DAA-THA is reduced by making the incision further away from where it is typically made in conventional fasciotomy. If our hypothesis is confirmed, it will reduce the disadvantages of DAA and improve patient satisfaction. TRIAL REGISTRATION: UMIN Clinical Trials Registry, UMIN000035945 . Registered on 20 February, 2019.

A pilot study examining the efficacy of hochuekkito for improving quality of life in patients with myeloproliferative neoplasms.

BACKGROUND: The prognosis of Philadelphia chromosome-negative myeloproliferative neoplasms is relatively favorable, but the quality of life can be severely affected by myeloproliferative neoplasm-related symptoms such as fatigue, pruritus, night sweats, bone pain, fever and weight loss. In this study, we administered hochuekkito, a traditional herbal medicine, to patients with myeloproliferative neoplasms and investigated whether there was a reduction in myeloproliferative neoplasm-related symptoms. METHODS: We conducted a randomized parallel-group pilot study. Patients were assigned to a hochuekkito administration or non-hochuekkito administration group. Myeloproliferative neoplasm-related symptoms based on Myeloproliferative Neoplasm Symptom Assessment Form total symptom score and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 were examined before hochuekkito administration and 4 and 8 weeks after administration. RESULTS: Among the 42 patients included in the analysis, 21 were assigned to the hochuekkito group and 21 were assigned to the control group. After administering hochuekkito, the median values of Myeloproliferative Neoplasms Symptom Assessment Form total symptom score at 4 and 8 weeks in the hochuekkito group demonstrated a decreasing trend; however, the difference between the two groups was not significant. CONCLUSIONS: In this study, we were unable to demonstrate significant differences between the hochuekkito and control groups in terms of the efficacy of hochuekkito in treating myeloproliferative neoplasm-related symptoms. However, there were cases that presented prominent improvement in symptoms in the hochuekkito group. The only reported adverse event was grade 1 impaired hepatic function. Therefore, hochuekkito might be a therapeutic option for patients with severely affected quality of life due to myeloproliferative neoplasm-related symptoms.

Evaluating the impact of adjunctive istradefylline on the cumulative dose of levodopa-containing medications in Parkinson's disease: study protocol for the ISTRA ADJUST PD randomized, controlled study.

BACKGROUND: Levodopa remains the most effective symptomatic treatment for Parkinson's disease (PD) more than 50 years after its clinical introduction. However, the onset of motor complications can limit pharmacological intervention with levodopa, which can be a challenge when treating PD patients. Clinical data suggest using the lowest possible levodopa dose to balance the risk/benefit. Istradefylline, an adenosine A2A receptor antagonist indicated as an adjunctive treatment to levodopa-containing preparations in PD patients experiencing wearing off, is currently available in Japan and the US. Preclinical and preliminary clinical data suggested that adjunctive istradefylline may provide sustained antiparkinsonian benefits without a levodopa dose increase; however, available data on the impact of istradefylline on levodopa dose titration are limited. The ISTRA ADJUST PD study will evaluate the effect of adjunctive istradefylline on levodopa dosage titration in PD patients. METHODS: This 37-week, multicenter, randomized, open-label, parallel-group controlled study in PD patients aged 30-84 years who are experiencing the wearing-off phenomenon despite receiving levodopa-containing medications ≥ 3 times daily (daily dose 300-400 mg) began in February 2019 and will continue until February 2022. Enrollment is planned to attain 100 evaluable patients for the efficacy analyses. Patients will receive adjunctive istradefylline (20 mg/day, increasing to 40 mg/day) or the control in a 1:1 ratio, stratified by age, levodopa equivalent dose, and presence/absence of dyskinesia. During the study, the levodopa dose will be increased according to symptom severity. The primary study endpoint is the comparison of the cumulative additional dose of levodopa-containing medications during the treatment period between the adjunctive istradefylline and control groups. Secondary endpoints include changes in efficacy rating scales and safety outcomes. DISCUSSION: This study aims to clarify whether adjunctive istradefylline can reduce the cumulative additional dose of levodopa-containing medications in PD patients experiencing the wearing-off phenomenon, and lower the risk of levodopa-associated complications. It is anticipated that data from ISTRA ADJUST PD will help inform future clinical decision-making for patients with PD in the real-world setting. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCTs031180248 ; registered 12 March 2019.

Anatomic Resection for Hepatocellular Carcinoma: Prognostic Impact Assessed from Recurrence Treatment.

BACKGROUND: The oncologic advantage of anatomic resection (AR) for primary hepatocellular carcinoma (HCC) remains controversial. This study aimed to evaluate the clinical advantages of AR for primary HCC by using propensity score-matching and by assessing treatment strategies for recurrence after surgery. METHODS: The study reviewed data of patients who underwent AR or non-anatomic resection (NAR) for solitary HCC (≤ 5 cm) in two institutions between 2004 and 2017. Surgical outcomes were compared between the two groups in a propensity score-adjusted cohort. The time-to-interventional failure (TIF), defined as the elapsed time from resection to unresectable/unablatable recurrence, also was evaluated. RESULTS: The inclusion criteria were met by 250 patients: 77 patients (31%) with AR and 173 patients (69%) with NAR. In the propensity score-matched populations (AR, 67; NAR, 67), the 5-year recurrence-free survival (RFS) for AR was better than for NAR (62% vs 35%; P = 0.005). No differences, however, were found in the 5-year overall survival between the two groups (72% vs 78%; P = 0.666). The 5-year TIF rates for the NAR group (60%) also were similar to those for the AR group (66%) (P = 0.413). In the cohort of 67 patients, curative repeat resection or ablation therapy was performed more frequently for the NAR patients (42%) than for the AR patients (10%) (P < 0.001). CONCLUSION: For solitary HCC, AR decreases recurrence after the initial hepatectomy. However, aggressive curative-intent interventions for recurrence compensate for the impaired RFS, even for patients undergoing NAR.

Relationship between labral length and symptoms in patients with acetabular dysplasia before rotational acetabular osteotomy.

The aim of this study was to investigate the relationship between acetabular labral length and symptoms in patients with acetabular dysplasia. In a retrospective medical record review, 218 patients with acetabular dysplasia who had undergone rotational acetabular osteotomy were identified. After implementing the inclusion and exclusion criteria, 53 patients were analyzed for preoperative symptoms measured by the Japanese Orthopaedic Association Hip Disease Evaluation Questionnaire (JHEQ), acetabular bone morphology parameters by anteroposterior pelvic radiographs and labral parameters by radial magnetic resonance imaging. Spearman's correlation coefficients were calculated among JHEQ scores, bone morphologic parameters and labral parameters. Multiple linear regression models to determine the predictive variables of JHEQ score and labral length were obtained. There was no correlation between bone morphologic parameters and JHEQ scores. Labral length measured anteriorly correlated with JHEQ pain {r [95% confidence interval (CI)] = -0.335 (-0.555, -0.071), P = 0.014}, movement subscale [r (95% CI) = -0.398 (-0.603, -0.143), P = 0.003], mental subscale [r (95% CI) = -0.436 (-0.632, -0.188), P = 0.001] and total JHEQ score [r (95% CI) = -0.451 (-0.642, -0.204), P = 0.001]. The multiple linear regression results showed that anterior labral length was independently associated with JHEQ subscales in some models. Meanwhile, age, acetabular head index and total JHEQ score were independently associated with anterior labral length in all models. Labral length, notably in anterosuperior area, in patients with symptomatic acetabular dysplasia was related to patient's symptom. Labral length may be an important objective image finding that can be used to assess the severity of cumulative hip instability.

Clinicopathological Examination of Metaplastic Spindle Cell Carcinoma of the Breast: Case Series.

BACKGROUND: Spindle cell carcinoma (SpCC) of the breast is a rare histological type, a subtype of metaplastic carcinoma characterized by atypical spindle cell and epithelial carcinoma. The proportions of the spindle cell and epithelial components vary among tumours. Due to its rarity, biological characteristics of this disease have been poorly studied. METHODS: In total, 10 patients with SpCC were surgically treated at our institution from January 2007 to December 2018. We retrospectively investigated these SpCC cases, focusing on the differences between spindle cell and epithelial components. Microsatellite status was also examined. RESULTS: Nine cases were triple-negative breast cancer (TNBC). The rates of high tumour grade were 70% in spindle cell components and 56% in epithelial components (P = .65), while the mean Ki67 labelling index were 63% and 58%, respectively (P = .71). Mean programmed death ligand 1 (PD-L1) expression in these components was 11% and 1%, respectively (P = .20). All 10 tumours were microsatellite stable. Patient outcomes of triple-negative SpCC did not differ from those of propensity-matched patients with conventional TNBC. CONCLUSIONS: Spindle cell components showed higher values in factors examined, although there was no statistically significant difference. Our data reveal that these 2 components of SpCC may be of different biological nature.

Association Between Kidney Function Decline and Baseline TNFR Levels or Change Ratio in TNFR by Febuxostat Chiefly in Non-diabetic CKD Patients With Asymptomatic Hyperuricemia.

Background: The levels of circulating tumor necrosis factor receptor (TNFR) 1 and 2 help predict the future decline of estimated glomerular filtration rate (eGFR) chiefly in patients with diabetes. It has been recently reported that the change ratio in TNFR1 by SGLT2 inhibitor treatment is also related with future GFR decline in patients with diabetes. The aims of this study are to investigate the association between baseline TNFR levels and early change in TNFR levels by the non-purine selective xanthine oxidase inhibitor, febuxostat, and future eGFR decline chiefly in chronic kidney disease (CKD) patients without diabetes. Methods: We conducted a post-hoc analysis of the FEATHER study on patients with asymptomatic hyperuricemia and CKD stage 3, who were randomly assigned febuxostat 40 mg/day or matched placebo. This analysis included 426 patients in whom baseline stored samples were available. Serum TNFR levels at baseline were measured using enzyme-linked immunosorbent assay. Those levels were also measured using 12-week stored samples from 197 randomly selected patients. Results: Compared with placebo, short-term febuxostat treatment significantly decreased the median percent change from baseline in serum uric acid (-45.05, 95% CI -48.90 to -41.24 mg/dL), TNFR1 (1.10, 95% CI-2.25 to 4.40), and TNFR2 (1.66, 95% CI -1.72 to 4.93), but not TNFR levels. Over a median follow-up of 105 weeks, 30 patients (7.0%) experienced 30% eGFR decline from baseline. In the Cox multivariate model, high levels of baseline TNFR predicted a 30% eGFR decline, even after adjusting for age, sex, systolic blood pressure, high sensitivity C-reactive protein, uric acid, and presence or absence of febuxostat treatment and diabetes, in addition to baseline albumin to creatinine ratio and eGFR. Conclusion: Early change in circulating TNFR levels failed to predict future eGFR decline; however, regardless of febuxostat treatment, the elevated baseline level of TNFR was a strong predictor of 30% eGFR decline even in chiefly non-diabetic CKD patients with asymptomatic hyperuricemia.

Ipsilateral breast tumor control following hypofractionated and conventional fractionated whole-breast irradiation for early breast cancer: a long-term follow-up.

PURPOSE: Long-term follow-up of Japanese women with breast cancer who underwent hypofractionated whole-breast irradiation (HF-WBI) has not been well documented. Therefore, we compared the treatment results of HF-WBI and conventional fractionated (CF)-WBI. METHODS: Patients with stage 0-II breast cancer receiving partial mastectomy were eligible for this prospective observational study. The HF-WBI consisted of 43.2 Gy in 16 fractions to the whole breast, with an additional tumor-bed boost of 8.1 Gy in three fractions for patients with positive or less than 5 mm surgical margins. A total of 615 patients (400: HF-WBI and 215: CF-WBI) who were treated between 2006 and 2008 were investigated. Propensity score matching was conducted based on age, tumor grade, and margin status, and 372 matched cases were investigated for examining factors relating to intrabreast tumor recurrence (IBTR). RESULTS: With a median follow-up period of 9.4 years, age and margin status were independent factors associated with IBTR occurrence (P = 0.006 and 0.016, respectively). The 10-year ipsilateral breast tumor control (IBTC) rates after HF-WBI and CF-WBI were 96.5% and 95.3%, respectively (P = 0.606). The 10-year IBTC rates according to margin status were 88.0% with positive margins, 94.9% with 5 mm margins, and 98.0% with negative margins (P = 0.014). CONCLUSIONS: There was no difference in IBTC between CF-WBI and HF-WBI in our patients. Positive surgical margin was a risk factor independently associated with IBTC rates after CF-WBI and HF-WBI. Further investigation is required to establish adequate treatment strategies for patients with positive surgical margins.

Clinicopathological features of breast cancer without mammographic findings suggesting malignancy.

BACKGROUND: Mammography (MG) is widely used for screening examinations. Dense breast reduces MG screening sensitivity, possibly delaying diagnosis. However, little is known about the characteristics of breast cancers without MG findings indicative of malignancy. Hence, we investigated breast cancer patients with tumors not detected by MG. PATIENTS AND METHODS: In total, 1758 Japanese patients with breast cancer, undergoing curative surgery between 2012 and 2018 without neo-adjuvant chemotherapy, were retrospectively investigated. Clinicopathological features were compared between patients without (MG-negative) and with (MG-positive) cancer-specific findings on MG. The current study included cases who came to our hospital after experiencing subjective symptoms, or whose tumors were detected by MG and/or US-screening. We reviewed results of both MG and US conducted at our institution. RESULTS: There were 201 MG-negative cases (11.4%). In patients with invasive disease, multivariate analysis revealed MG-negative patients to have higher breast density on MG (p < 0.001). Tumors of MG-negative patients were smaller (p < 0.001), showed less lymph node involvement (p = 0.011), and were of lower grade (p = 0.027). The majority of MG-negative tumors were found by ultrasound screening, being smaller than tumors in patients with subjective symptoms. In the MG-negative group, tumor characteristics such as tumor grade did not differ between those detected by screening versus subjective symptoms. CONCLUSION: Most tumors in MG-negative group patients were identified by US screening and the diseases were found at early stages with low malignancy. The usefulness of additional ultrasound with MG-screening might merit further investigations.

Indications for Nonoperative Management of Uncomplicated Appendicitis in Children: A Prospective Analysis at a Single Institution.

Aim: To assess nonoperative management (NOM) of uncomplicated appendicitis (UC-appy) in children to determine factors influencing prognosis and review the literature. Materials and Methods: All UC-appy cases presenting younger than 16 years between 2015 and 2018 who had NOM (one dose of intravenous analgesia and intravenous piperacillin/tazobactam 112.5 mg/kg 8 hourly) and were followed up for at least 3 months were reviewed prospectively (n = 146). Perceived pain and fever were assessed 12 hourly, biochemistry daily. If predetermined cutoff results were not achieved at each assessment, NOM was abandoned and urgent laparoscopic appendectomy (ULA) performed. Results: NOM succeeded in 48.6% (S-NOM; n = 71) and failed in 51.4% (F-NOM; n = 75). Mean age at presentation (10.7 ± 2.5 versus 8.6 ± 3.7 years old; P < .0001) and duration of preadmission fever (1.0 ± 0.9 versus 2.1 ± 1.2 days; P < .0001) were the only significantly different criteria between S-NOM and F-NOM. Optimal cutoff values using receiver operating characteristic curve analysis were 7.0 years old (32% sensitivity and 93% specificity) and 1.0 day (95% sensitivity and 25% specificity), respectively. NOM was abandoned for persistent pain, prolonged fever, or raised white blood count at 12 hours in 20/75 (26.7%), 24 hours in 31/75 (41.3%), 36 hours in 14/75 (18.7%), and 48-72 hours in 10/75 (13.3%). At ULA, perforation was identified in 14/75 (18.7%). Complications arising within 3 months of ULA were residual abscess (n = 7/75; 9.3%) and transient ileus (n = 1/75; 1.3%). Conclusion: It would appear that surgery may be more appropriate for children with UC-appy when they are younger and febrile before admission for longer.

Surgical Results of Carotid Endarterectomy for Twisted Carotid Bifurcation.

BACKGROUND: The internal carotid artery is normally positioned posterolateral to the external carotid artery at the carotid bifurcation. An anatomic variation with the internal carotid artery positioned medial to the external carotid artery, the so-called twisted carotid bifurcation (TCB), is sometimes encountered in patients undergoing carotid endarterectomy (CEA). Little is known about the TCB or the implications for CEA. OBJECTIVE: The present study investigated the demographics and surgical results of our patients with TCB who underwent CEA, and demonstrates the surgery in a video clip. METHODS: Eleven of our series of 73 consecutive CEA patients (15.1%) had a TCB (TCB group). The basic surgical method was the same for both the TCB and non-TCB groups. RESULTS: The patient demographics were almost identical between the 2 groups. No significant difference was observed in the degree of stenosis, the duration of operation, or the surgery-related complications between the 2 groups. However, 9 of 11 cases were right-sided in the TCB group; the only significant difference between the groups. CONCLUSIONS: CEA for TCB can be safely performed by extension of the normal procedure, but with more meticulous preoperative assessment and gentle maneuvers. The reason for the right-side dominance is still unknown. Further investigation is needed of this anatomic entity.

Association between circulating tumor necrosis factor-related biomarkers and estimated glomerular filtration rate in type 2 diabetes.

Chronic inflammation plays a crucial role in the development/progression of diabetic kidney disease. The involvement of tumor necrosis factor (TNF)-related biomarkers [TNFα, progranulin (PGRN), TNF receptors (TNFR1 and TNFR2)] and uric acid (UA) in renal function decline was investigated in patients with type 2 diabetes (T2D). Serum TNF-related biomarkers and UA levels were measured in 594 Japanese patients with T2D and an eGFR ≥30 mL/min/1.73 m2. Four TNF-related biomarkers and UA were negatively associated with estimated glomerular filtration rate (eGFR). In a logistic multivariate model, each TNF-related biomarker and UA was associated with lower eGFR (eGFR <60mL /min/1.73 m2) after adjustment for relevant covariates (basic model). Furthermore, UA and TNF-related biomarkers other than PGRN added a significant benefit for the risk factors of lower eGFR when measured together with a basic model (UA, ΔAUC, 0.049, p < 0.001; TNFα, ΔAUC, 0.022, p = 0.007; TNFR1, ΔAUC, 0.064, p < 0.001; TNFR2, ΔAUC, 0.052, p < 0.001) in receiver operating characteristic curve analysis. TNFR ligands were associated with lower eGFR, but the associations were not as strong as those with TNFRs or UA in patients with T2D and an eGFR ≥30 mL/min/1.73 m2.