Kumamoto City Hospital

BACKGROUND: Breast cancer is associated with a relatively good prognosis. Prognostic factors examined to date are related to early recurrence while those related to late recurrence and their countermeasures remain unclear. Therefore, we examined the factors related to late recurrence. PATIENTS AND METHODS: From January 1980 to August 2012, 4,774 patients who underwent primary treatment and estrogen (ER) and progesterone receptor (PgR) assessment were enrolled in this study. The patients were divided into two groups, those with a follow-up period <10 years and those without any recurrence at 10 years but who continued follow-up examinations. Recurrence occurred in 711 patients followed up for <10 years and in 51 patients for ≥10 years. RESULTS: The overall 10-year cumulative disease-free survival rate was 79.5%, and the recurrence rate at ≥10 years was 5.8%. A multivariate analysis revealed that the factors related to late recurrence were PgR positivity and positive nodes. This result differed from that for early recurrence in terms of ER/PgR, Ki-67 index and p53 overexpression. CONCLUSION: PgR positivity and lymph node metastases significantly correlated with late recurrence. Therefore, it is important to evaluate appropriate measures such as treatment period and treatment regimen for hormone-sensitive patients.

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

This report was written by the Japanese Society of Dysphagia Rehabilitation, the Japanese Association of Rehabilitation Nutrition, the Japanese Association on Sarcopenia and Frailty, and the Society of Swallowing and Dysphagia of Japan to consolidate the currently available evidence on the topics of sarcopenia and dysphagia. Histologically, the swallowing muscles are of different embryological origin from somatic muscles, and receive constant input stimulation from the respiratory center. Although the swallowing muscles are striated, their characteristics are different from those of skeletal muscles. The swallowing muscles are inevitably affected by malnutrition and disuse; accumulating evidence is available regarding the influence of malnutrition on the swallowing muscles. Sarcopenic dysphagia is defined as dysphagia caused by sarcopenia of the whole body and swallowing-related muscles. When sarcopenia does not exist in the entire body, the term "sarcopenic dysphagia" should not be used. Additionally, sarcopenia due to neuromuscular diseases should be excluded; however, aging and secondary sarcopenia after inactivity, malnutrition and disease (wasting disorder and cachexia) are included in sarcopenic dysphagia. The treatment of dysphagia due to sarcopenia requires both dysphagia rehabilitation, such as resistance training of the swallowing muscles and nutritional intervention. However, the fundamental issue of how dysphagia caused by sarcopenia of the swallowing muscles should be diagnosed remains unresolved. Furthermore, whether dysphagia can be caused by primary sarcopenia should be clarified. Additionally, more discussion is required on issues such as the relationship between dysphagia and secondary sarcopenia, as well as the diagnostic criteria and means for diagnosing dysphagia caused by sarcopenia. Geriatr Gerontol Int 2019; 19: 91-97.

BACKGROUND: Coronary spasm can be induced by acetylcholine, serotonin, ergonovine, or histamine, all of which cause vasodilation when the endothelium is intact by releasing nitric oxide (NO). Coronary spasm is promptly relieved by nitroglycerin, which vasodilates through its conversion to NO. It is thus possible that NO release may be deficient in the spasm arteries in patients with coronary spastic angina (CSA). The aim of this study was to determine whether NO release is deficient in coronary arteries of patients with CSA. METHODS AND RESULTS: NG-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthase, was infused into coronary arteries in 21 patients with coronary spastic angina (CSA) and in 28 control patients. Coronary spasm was induced by intracoronary injection of acetylcholine and was documented angiographically in all patients with CSA. L-NMMA dose-dependently decreased basal luminal diameter of coronary arteries in control patients, whereas it had no effect on basal diameter of the spasm arteries in patients with CSA. L-NMMA abolished the dilator response to acetylcholine and enhanced the constrictor response to acetylcholine in control arteries, whereas it had no effect on the constrictor response to acetylcholine in spasm arteries. Intracoronary infusion of L-arginine did not affect the diameter of spasm or control arteries. The dilator response to nitroglycerin was increased markedly in spasm arteries compared with control arteries, whereas response to diltiazem did not differ between them. CONCLUSIONS: There is a deficiency in endothelial NO activity in spasm arteries, which leads to the supersensitivity of the artery to the vasodilator effect of nitroglycerin and to the vasoconstrictor effect of acetylcholine in patients with CSA. This deficient endothelial NO activity plays an important role in the pathogenesis of coronary spasm.

This multicentre, randomized, phase II study was conducted to examine whether the addition of mogamulizumab, a humanized anti-CC chemokine receptor 4 antibody, to mLSG15, a dose-intensified chemotherapy, further increases efficacy without compromising safety of patients with newly diagnosed aggressive adult T-cell leukaemia-lymphoma (ATL). Patients were assigned 1:1 to receive mLSG15 plus mogamulizumab or mLSG15 alone. The primary endpoint was the complete response rate (%CR); secondary endpoints included the overall response rate (ORR) and safety. The %CR and ORR in the mLSG15-plus-mogamulizumab arm (n = 29) were 52% [95% confidence interval (CI), 33-71%] and 86%, respectively; the corresponding values in the mLSG15 arm (n = 24) were 33% (95% CI, 16-55%) and 75%, respectively. Grade ≥ 3 treatment-emergent adverse events, including anaemia, thrombocytopenia, lymphopenia, leucopenia and decreased appetite, were observed more frequently (≥10% difference) in the mLSG15-plus-mogamulizumab arm. Several adverse events, including skin disorders, cytomegalovirus infection, pyrexia, hyperglycaemia and interstitial lung disease, were observed only in the mLSG15-plus-mogamulizumab arm. Although the combination strategy showed a potentially less favourable safety profile, a higher %CR was achieved, providing the basis for further investigation of this novel treatment for newly diagnosed aggressive ATL. This study was registered at ClinicalTrials.gov, identifier: NCT01173887.

BACKGROUND: The clinical presentation of patients with organic acidurias (OAD) and urea cycle disorders (UCD) is variable; symptoms are often non-specific. AIMS/METHODS: To improve the knowledge about OAD and UCD the E-IMD consortium established a web-based patient registry. RESULTS: We registered 795 patients with OAD (n = 452) and UCD (n = 343), with ornithine transcarbamylase (OTC) deficiency (n = 196), glutaric aciduria type 1 (GA1; n = 150) and methylmalonic aciduria (MMA; n = 149) being the most frequent diseases. Overall, 548 patients (69 %) were symptomatic. The majority of them (n = 463) presented with acute metabolic crisis during (n = 220) or after the newborn period (n = 243) frequently demonstrating impaired consciousness, vomiting and/or muscular hypotonia. Neonatal onset of symptoms was most frequent in argininosuccinic synthetase and lyase deficiency and carbamylphosphate 1 synthetase deficiency, unexpectedly low in male OTC deficiency, and least frequently in GA1 and female OTC deficiency. For patients with MMA, propionic aciduria (PA) and OTC deficiency (male and female), hyperammonemia was more severe in metabolic crises during than after the newborn period, whereas metabolic acidosis tended to be more severe in MMA and PA patients with late onset of symptoms. Symptomatic patients without metabolic crises (n = 94) often presented with a movement disorder, mental retardation, epilepsy and psychiatric disorders (the latter in UCD only). CONCLUSIONS: The initial presentation varies widely in OAD and UCD patients. This is a challenge for rapid diagnosis and early start of treatment. Patients with a sepsis-like neonatal crisis and those with late-onset of symptoms are both at risk of delayed or missed diagnosis.

BACKGROUND: The disease course and long-term outcome of patients with organic acidurias (OAD) and urea cycle disorders (UCD) are incompletely understood. AIMS: To evaluate the complex clinical phenotype of OAD and UCD patients at different ages. RESULTS: Acquired microcephaly and movement disorders were common in OAD and UCD highlighting that the brain is the major organ involved in these diseases. Cardiomyopathy [methylmalonic (MMA) and propionic aciduria (PA)], prolonged QTc interval (PA), optic nerve atrophy [MMA, isovaleric aciduria (IVA)], pancytopenia (PA), and macrocephaly [glutaric aciduria type 1 (GA1)] were exclusively found in OAD patients, whereas hepatic involvement was more frequent in UCD patients, in particular in argininosuccinate lyase (ASL) deficiency. Chronic renal failure was often found in MMA, with highest frequency in mut(0) patients. Unexpectedly, chronic renal failure was also observed in adolescent and adult patients with GA1 and ASL deficiency. It had a similar frequency in patients with or without a movement disorder suggesting different pathophysiology. Thirteen patients (classic OAD: 3, UCD: 10) died during the study interval, ten of them during the initial metabolic crisis in the newborn period. Male patients with late-onset ornithine transcarbamylase deficiency were presumably overrepresented in the study population. CONCLUSIONS: Neurologic impairment is common in OAD and UCD, whereas the involvement of other organs (heart, liver, kidneys, eyes) follows a disease-specific pattern. The identification of unexpected chronic renal failure in GA1 and ASL deficiency emphasizes the importance of a systematic follow-up in patients with rare diseases.

OBJECTIVES: The aim of this study was to investigate the effects of a leucine-enriched amino acid supplement on muscle mass, muscle strength, and physical function in post-stroke patients with sarcopenia. METHODS: We conducted an eight-wk, two-parallel group intervention, randomized controlled, blinded outcome assessment among 44 post-stroke older patients with sarcopenia. Sarcopenia was defined as a loss of skeletal muscle mass and decreased muscle strength according to the Asian Working Group for Sarcopenia criteria. The intervention group (n = 21) received a leucine-enriched amino acid supplement; the control group (n = 23) did not. Both groups performed low-intensity resistance training in addition to a post-stroke rehabilitation program. A primary outcome of physical function by using the motor domain of Functional Independence Measure (FIM), and secondary outcomes of appendicular muscle mass (skeletal muscle mass index [SMI]) measured via bioelectrical impedance analysis and muscle strength as handgrip strength were measured at baseline and at the end of the intervention. RESULTS: ; 95% confidence interval, 0.01-2.11). CONCLUSIONS: We demonstrated that an eight-wk intervention consisting of a leucine-enriched amino acid supplementation and low-intensity resistance training increased muscle mass, strength, and physical function in post-stroke patients with sarcopenia.

The choice of adjuvant systemic therapy is based on targeted therapy in line with the St. Gallen Consensus meeting. In addition to the traditional parameters, the panel recommended the use of proliferation markers and multigene assays. The purpose of the present study was to evaluate the clinical significance of proliferative activity using the Ki-67 index as a prognostic marker and as a predictor of recurrence time in breast cancer patients. The Ki-67 index was measured in 3,652 cases with primary breast cancer from 1987 to 2009. Out of these patients, 2,638 cases were evaluated simultaneously for estrogen receptor, progesterone receptor and HER2 from 1997, and these were analyzed as a prognostic factor according to their subtypes. The Ki-67 index exhibited a wide range of 1-99%, with a median of 20%, and cases were divided into 2 or 3 index groups; <20% and ≥20% (and ≥50%). The median Ki-67 index of tumors with luminal A was 17%, and that of luminal B type tumors was 29%. The Ki-67 index of HER2 tumors was 40% and that of triple negative tumors was 50%. A higher Ki-67 index significantly correlated with a higher grade of malignancy. Patients with a higher Ki-67 index had significantly lower disease-free survival (DFS) and overall survival rates. Moreover, there was a significant difference in the recurrence time. Multivariate analysis revealed that the Ki-67 index was a significant factor for DFS, irrespective of nodal status, and that Ki-67 was a significant marker only in luminal A type tumors. Furthermore, luminal A type cases with high Ki-67 had a similar DFS as the luminal B type cases. A higher Ki-67 index (≥20%) significantly correlated with other biological markers, poorer prognosis and early recurrence, particularly in luminal A type tumors. It is important to take the Ki-67 index into consideration in the treatment and follow-up of breast cancer patients.

BACKGROUND: The clinical features of ipsilateral breast tumor recurrence (IBTR) after breast conserving therapy (BCT) for early stage breast cancer were analyzed from long-term follow-up of BCT in Japan. The purpose of this study was to clarify risk factors of IBTR and the impact of IBTR on development of distant metastases in this ethnic group. METHODS: Patients (N = 1901)with unilateral breast cancer < or = 3 cm in diameter who underwent BCT at 18 Japanese major breast cancer treatment institutes from 1986 to 1993 were registered in this study. Survival rates, the incidences of IBTR and distant metastases, and annual rates of IBTR and distant metastases after primary operation were calculated by the Kaplan-Meier method. A Cox proportional hazards model was used to estimate the risks of IBTR and distant metastases. A Cox model was also used to estimate the risks of distant metastases after IBTR in the group of IBTR. RESULTS: At a median follow-up time of 107 months, the 10-year overall and disease-free survival rates were 83.9% and 77.8%, respectively. The 10-year cumulative rates of IBTR were 8.5% in the patients with postoperative irradiation and 17.2% in the patients without irradiation. The 10-year cumulative distant metastasis rate was 10.9%. On multivariate analysis, young age, positive surgical margin, and omission of radiation therapy were significant predictors of IBTR. In addition, IBTR significantly correlated with subsequent distant metastases (hazard ratio, 3.93; 95% confidence interval, 2.676-5.771; P < 0.0001). Among patients who developed IBTR, initial lymph node metastases and short interval to IBTR were significant risk factors for subsequent distant metastasis. CONCLUSIONS: Young age, positive surgical margin, and omission of radiation therapy seemed to be important factors in relation to local control. The authors' results also indicated that IBTR is significantly associated with subsequent distant metastasis. Patients with positive nodal status at primary operation or with short interval from primary operation to IBTR are at especially high risk of distant metastasis. It remains unclear, however, whether IBTR is an indicator or a cause of subsequent distant metastases.

BACKGROUND AND PURPOSE: Although digital subtraction angiography (DSA) is considered the criterion standard for depiction of intracranial aneurysms, it is often difficult to determine the relationship of overlapping vessels to aneurysms when using 2D DSA. We compared 2D and 3D DSA in evaluation of intracranial aneurysms. METHODS: Thirty-six consecutive patients with cerebral aneurysms underwent 2D and 3D DSA. After standard 2D DSA, rotational DSA was performed. Maximum intensity projection (MIP) and shaded surface display (SSD) images were created from the rotational DSA data sets. All images were assessed randomly for overall image quality, presence of aneurysm, presence of aneurysmal lobulation, visualization of aneurysmal neck, and relationship to adjacent vessels. Data analysis was conducted for 40 aneurysms treated by clip placement. RESULTS: One aneurysm that was not detected at 2D DSA was classified as uncertain on the basis of rotational DSA. All aneurysms were classified as probably or definitively present on the basis of MIP and SSD findings. Overall image quality of rotational DSA, MIP, and SSD was statistically inferior to that of the standard 2D DSA for visualization of distal arteries. However, MIP and SSD images were significantly superior to those of standard 2D DSA for all other evaluations. For detection of lobulation, SSD images were significantly superior to other images, and for visualization of aneurysmal neck and relationship to neighboring arteries, SSD images were significantly superior to those of rotational DSA. For evaluation of the relationship to neighboring arteries, MIP images were significantly superior to those of rotational DSA. CONCLUSION: Three-dimensional DSA, especially SSD, provided more detailed information for evaluating cerebral aneurysms than did standard 2D and rotational DSA.

In Japan, urea cycle disorders (UCDs) are one of the most frequent inborn errors of metabolism, estimated to have a prevalence of 1 per 50,000 live births. In an attempt to develop more effective treatment and enhance the quality of life, we investigated the clinical manifestations and prognosis of 216 patients with UCDs diagnosed and treated between 1978 and 1995. These included 92 cases of neonatal-onset UCD and 116 of late-onset UCD. Two cases of ornithine transcarbamylase (OTC) deficiency in males and 2 cases of argininosuccinase (AL) deficiency were diagnosed prospectively. By far the most common disorder was OTC deficiency, accounting for 2/3 of all cases. At the end of 1995, the 5-year survival rate was 22% for the neonatal-onset type and 41% for the late-onset type. Among the 20 long-term survivors with neonatal-onset UCD, 18 (90%) had moderate to severe neurodevelopmental deficits; this contrasts with 13 of 47 (28%) survivors with the late-onset type. In analysing 108 UCD cases, peak blood ammonia level during the first hyperammonaemic attack was correlated with neurodevelopmental outcome. When the concentration of blood ammonia was less than 180 mumol/L (5 times normal), there was no severe neurological damage. When the concentration of blood ammonia exceeded 350 mumol/L (10 times normal) at the first hyperammonaemic attack, the patients died or had severe neurological deficits. Our data point to the importance of early diagnosis and aggressive treatment.

The evolutionary loss of hepatic urate oxidase (uricase) has resulted in humans with elevated serum uric acid (urate). Uricase loss may have been beneficial to early primate survival. However, an elevated serum urate has predisposed man to hyperuricemia, a metabolic disturbance leading to gout, hypertension, and various cardiovascular diseases. Human serum urate levels are largely determined by urate reabsorption and secretion in the kidney. Renal urate reabsorption is controlled via two proximal tubular urate transporters: apical URAT1 (SLC22A12) and basolateral URATv1/GLUT9 (SLC2A9). In contrast, the molecular mechanism(s) for renal urate secretion remain unknown. In this report, we demonstrate that an orphan transporter hNPT4 (human sodium phosphate transporter 4; SLC17A3) was a multispecific organic anion efflux transporter expressed in the kidneys and liver. hNPT4 was localized at the apical side of renal tubules and functioned as a voltage-driven urate transporter. Furthermore, loop diuretics, such as furosemide and bumetanide, substantially interacted with hNPT4. Thus, this protein is likely to act as a common secretion route for both drugs and may play an important role in diuretics-induced hyperuricemia. The in vivo role of hNPT4 was suggested by two hyperuricemia patients with missense mutations in SLC17A3. These mutated versions of hNPT4 exhibited reduced urate efflux when they were expressed in Xenopus oocytes. Our findings will complete a model of urate secretion in the renal tubular cell, where intracellular urate taken up via OAT1 and/or OAT3 from the blood exits from the cell into the lumen via hNPT4.

Given the growing awareness of and concern for potential carcinogenic effects of exposure of children to ionizing radiation at CT, optimizing acquisition parameters is crucial to achieve diagnostically acceptable image quality at the lowest possible radiation dose. Among currently available dose reduction techniques, recent technical innovations have allowed the implementation of low tube voltage scans and iterative reconstruction (IR) techniques into daily clinical practice for pediatric CT. The benefits of lowering tube voltage include a considerable reduction in radiation dose and improved contrast on images, especially when an iodinated contrast medium is used. The increase in noise, which is attributed to decreased photon penetration, is a major drawback but is not as severe as that at adult CT because of the small body size of children. In addition, use of IR algorithms can suppress increased noise, yielding wider applicability for low tube voltage scans. However, a careful implementation strategy and methodologic approach are necessary to maximize the potential for dose reduction while preserving diagnostic image quality under each clinical condition. The potential pitfalls of and topics related to these techniques include (a) the effect of tube voltage on the surface radiation dose, (b) the effect of window settings, (c) accentuation of metallic artifacts, (d) deterioration of low contrast detectability at low-dose settings, (e) interscanner variation of x-ray spectra, and (f) a comparison with the use of a spectral shaping technique. Appropriate use of low tube voltage and IR techniques is helpful for radiation dose reduction in most applications of pediatric CT. Online DICOM image stacks are available for this article. ©RSNA, 2018 An earlier incorrect version of this article appeared online. This article was corrected on March 28, 2019.

OBJECTIVES: To examine whether the extent of fibroproliferative changes on high-resolution CT (HRCT) scan influences prognosis, ventilator dependency and the associated outcomes in patients with early acute respiratory distress syndrome (ARDS). DESIGN: A prospective observational cohort study. SETTING: Intensive care unit in a teaching hospital. PARTICIPANTS: 85 patients with ARDS who met American-European Consensus Conference Criteria and eligible criteria. INTERVENTIONS: HRCT scans were performed and prospectively evaluated by two independent observers on the day of diagnosis and graded into six findings according to the extent of fibroproliferation. An overall HRCT score was obtained by previously published method. PRIMARY AND SECONDARY OUTCOMES: The primary outcome was 60-day mortality. Secondary outcomes included the number of ventilator-free days, organ failure-free days, the incidence of barotraumas and the occurrence of ventilator-associated pneumonia. RESULTS: Higher HRCT scores were associated with statistically significant decreases in organ failure-free days as well as ventilator-free days. Multivariate Cox proportional hazards model showed that the HRCT score remained an independent risk factor for mortality (HR 1.20; 95% CI 1.06 to 1.36; p=0.005). Multivariate analysis also revealed that the CT score had predictive value for ventilator weaning within 28 days (OR 0.63; 95% CI 0.48 to 0.82; p=0.0006) as well as for an incidence of barotraumas (OR 1.61; 95% CI 1.08 to 2.38; p=0.018) and for an occurrence of ventilator-associated pneumonia (OR 1.46; 95% CI 1.13 to 1.89; p=0.004). A HRCT score <210 enabled prediction of 60-day survival with 71% sensitivity and 72% specificity and of ventilator-weaning within 28 days with 75% sensitivity and 76% specificity. CONCLUSIONS: Pulmonary fibroproliferation assessed by HRCT in patients with early ARDS predicts increased mortality with an increased susceptibility to multiple organ failure, including ventilator dependency and its associated outcomes.

OBJECTIVES: We investigated the incidence, clinical characteristics, outcome and factors associated with aphasia and early improvement in acute ischemic stroke. METHODS: We consecutively studied 855 patients with acute ischemic stroke who were admitted to our hospital within 48 h after onset and who were not comatose on admission. Assessment of aphasia was performed on admission (day 0) and day 10. We examined the incidence, severity, and subtypes of aphasia, and compared the clinical background of patients with and without aphasia on admission, and also those with and without early improvement by day 10. In addition, we investigated the independent factors associated with the presence of aphasia on admission and with early improvement. RESULTS: Of the 855 patients, 130 (15.2%) had aphasia on admission. The National Institutes of Health Stroke Scale (NIHSS) on admission (OR 1.21; 95% CI 1.17-1.26) was a significant and independent factor associated with the presence of aphasia on admission. Early improvement was seen in 56 of 121 aphasic patients (46.3%) who were still alive on day 10. A history of hypercholesterolemia (OR 3.27; 95% CI 1.14-9.39) was a significant and independent factor associated with early improvement in aphasia during the acute phase and NIHSS on admission (OR 0.95; 95% CI 0.90-0.99) was marginally significant. CONCLUSION: It is difficult to predict the outcome of aphasia within the first few days after the onset of ischemic stroke.

// Hitomi Mori 1, * , Makoto Kubo 1, * , Rin Yamaguchi 2 , Reiki Nishimura 3 , Tomofumi Osako 3 , Nobuyuki Arima 4 , Yasuhiro Okumura 5 , Masayuki Okido 6 , Mai Yamada 1 , Masaya Kai 1 , Junji Kishimoto 7 , Yoshinao Oda 8 , Masafumi Nakamura 1 1 Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan 2 Department of Pathology, Kurume University Medical Center, Kurume, Japan 3 Breast Center, Kumamoto Shinto General Hospital, Kumamoto, Japan 4 Department of Pathology, Kumamoto Shinto General Hospital, Kumamoto, Japan 5 Department of Breast and Endocrine Surgery, Kumamoto City Hospital, Kumamoto, Japan 6 Department of Surgery, Hamanomachi Hospital, Fukuoka, Japan 7 Department of Research and Development of Next Generation Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan 8 Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan * These authors have contributed equally to this work Correspondence to: Makoto Kubo, email: mkubo@tumor.med.kyushu-u.ac.jp Keywords: programmed cell death ligand-1, tumor-infiltrating lymphocytes, triple-negative breast cancer, biomarker, prognosis Received: August 02, 2016&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: December 27, 2016&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: January 17, 2017 ABSTRACT This study included patients with primary triple-negative breast cancer (TNBC) who underwent resection without neoadjuvant chemotherapy between January 2004 and December 2014. Among the 248 TNBCs studied, programmed cell death ligand-1 (PD-L1) expression was detected in 103 (41.5%) tumors, and high levels of tumor-infiltrating lymphocytes (TILs) were present in 118 (47.6%) tumors. PD-L1 expression correlated with high levels of TILs, but was not a prognostic factor. Patients with TILs-high tumors had better overall survival than those with TILs-low tumors ( P = 0.016). There was a strong interaction between PD-L1 expression and TILs that was associated with both recurrence-free survival ( P = 0.0018) and overall survival ( P = 0.015). Multivariate Cox proportional hazards model analysis showed that PD-L1-positive/TILs-low was an independent negative prognostic factor for both recurrence-free survival and overall survival. Our findings suggest that PD-L1-positive/TILs-low tumors are associated with a poor prognosis in patients with TNBC, and that it is important to focus on the combination of PD-L1 expression on tumor cells and TILs present in the tumor microenvironment. These biomarkers may be useful for stratification of TNBCs and for predicting prognosis and developing novel cancer immunotherapies.

CD138 expression is a hallmark of plasma cells and multiple myeloma cells. However, decreased expression of CD138 is frequently observed in plasma cells of myeloma patients, although the clinical significance of this is unclear. To evaluate the significance of low expression of CD138 in MM, we examined the phenotypes of MM cells expressing low levels of CD138. Flow cytometric analysis of primary MM cells revealed a significant decrease in CD138 expression in patients with relapsed/progressive disease compared with untreated MM patients. Patients with low levels of CD138 had a worse overall survival compared with patients with high levels of CD138, in newly diagnosed patients and patients receiving high-dose chemotherapy followed by autologous stem-cell transplantation. Two MM cell lines, KYMM-1 (CD138- low) and KYMM-2 (CD138- high), were established from a single MM patient with decreased CD138 expression. High expression of BCL6 and PAX5, and downregulation of IRF4, PRDM1 and XBP1 was observed in KYMM-1 compared with KYMM-2 cells, indicative of the immature phenotype of KYMM-1. KYMM-1 was less sensitive to lenalidomide than KYMM-2, while no difference in sensitivity to bortezomib was observed. KYMM-2 cells were further divided in CD138+ and CD138- fractions using anti-CD138-coated magnetic beads. CD138- cells sorted from the KYMM-2 cell line also showed high BCL6, low IRF4 expression and decreased sensitivity to lenalidomide compared with CD138+ cells. Our observations suggest that low CD138 expression relates to i) poor prognosis, ii) immature phenotype and iii) low sensitivity to lenalidomide. The observed distinct characteristics of CD138 low MM cells, suggest this should be recognized as a new clinical entity. Establishment of a treatment strategy for MM cells expressing low levels of CD138 is needed to improve their poor outcome.

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.

BACKGROUND: In breast cancer, ER/PgR, HER2, and Ki-67 are important biological markers for predicting prognosis and making effective treatment decisions. In addition, changes in markers due to relapse are also clinically experienced; however, the frequency and clinical significance are still not fully understood. Thus, changes in markers and their correlations with prognosis were investigated. PATIENTS AND METHODS: Out of the patients with relapse from 1997 to March 2011, there were 97 consecutive patients from whom the lesion was resected and evaluated by immunostaining. The biopsy sites were chest wall, lymph node, ipsilateral breast tumor recurrence, lungs, bones, ovaries and brain. The markers sought were ER, PgR, HER2, p53 and Ki-67. RESULTS: The hormone receptor positive rate from the primary tumor to recurrence decreased from 63.9% to 57.7% and from 56.7% to 43.3% for ER and PgR, respectively. Changes in the positive/negative evaluation were seen at the rate of 10.3% and 25.8% for ER and PgR, respectively. The Ki-67 index increased significantly from a mean of 29.1% at primary tumor to 36.3% at relapse. When divided into 2 groups (< 50% and ≥50%), changes were seen in 24.7%. On the other hand, the rates of changes in HER2 and p53 positivity were 14.4% and 12.4%. The changes in subtypes were seen in 25%, however, the lowest rate of change was seen in the triple negative cases. Although there was no notable difference in the rate of change between disease-free interval (DFI) and PgR, Ki-67, p53 and HER2, there was a significant difference in the change rates in the ER. A multivariate analysis revealed that the status of distant metastasis and PgR level at relapse, and Ki-67 levels at primary tumor were all significant factors. CONCLUSION: Estrogen receptor and PgR decreased while Ki-67 increased due to relapse; however, the rate of change was high for PgR and Ki-67. Change in the subtypes was seen in 25%. In addition, PgR at relapse and Ki-67 at primary tumor were significant factors for post-relapse prognosis while PgR becoming negative was a poor prognostic factor. These findings are important for making effective treatment decisions.