Simultaneously Detected Liver and Lung Metastases from Colorectal Carcinoma: A Potential Treatment Strategy.

BACKGROUND/AIM: No clear treatment strategy for simultaneously detected liver and lung metastases (SLLM) of colorectal carcinoma has been established, to date. We aimed to identify the prognostic factors for SLLM and propose an appropriate treatment option. PATIENTS AND METHODS: This retrospective study included 64 patients with SLLM: 32 underwent pulmonary resection after hepatectomy in 32, while the other 32 underwent hepatectomy alone in 32. Poor prognostic factors and a suitable strategy for SLLM were assessed. RESULTS: Multivariate analysis showed that preoperative carcinoembryonic antigen (CEA) level ≥20 ng/ml (p=0.001) and unresected lung metastases (p=0.001) were independent prognostic factors for poor overall survival. Compared with the non-pulmonary resection group, the rate of R1 resection of liver tumors (46.8% vs. 15.6%; p=0.007), incidence of complications after hepatectomy (Clavien-Dindo grade ≥III: 21.8% vs. 0%; p=0.005) and having four or more metastatic lung nodules (40.6% vs. 3.2%; p=0.001) were significantly higher in the group that underwent hepatectomy only. CONCLUSION: Preoperative CEA ≥20 ng/ml and unresectable pulmonary nodules were prognostic factors for poor survival of patients with SLLM. Furthermore, the presence of more than four pulmonary nodules was a preoperative predictive factor for unresectable pulmonary nodules. R1 resection and the occurrence of complications after hepatectomy should be avoided; a smooth transition from hepatectomy to pulmonary resection is important.

Glasgow Prognostic Score Predicts Survival and Recurrence Pattern in Patients With Hepatocellular Carcinoma After Hepatectomy.

BACKGROUND/AIM: The prognostic significance of the Glasgow Prognostic Score (GPS) on outcomes of liver resection for hepatocellular carcinoma (HCC) remains unclear; the aim of the study was to assess its significance. PATIENTS AND METHODS: A total of 480 patients with HCC who underwent liver resection with curative intent at the Yokohama City University Hospital and Medical Center were enrolled in the study. Patients were classified into three groups: GPS-0, C-reactive protein (CRP) ≤1.0 mg/dl serum albumin ≥3.5 g/dl; GPS-1, CRP >1.0 mg/dl or serum albumin <3.5 g/dl; and GPS-2, CRP >1.0 mg/dl, serum albumin <3.5 g/dl. Prognostic factors for overall survival (OS) and disease-free survival (DFS) were analyzed retrospectively. The recurrence pattern was also investigated using GPS. RESULTS: Of the 480 patients, 382 (79.6%), 81 (16.9%), and 17 (3.5%) were assigned to GPS-0, GPS-1, and GPS-2, respectively. Elevated GPS, indocyanine green retention rate at 15 min, and protein induced by vitamin K antagonist-II (PIVKA-II) were significantly associated with a poor OS. Elevated GPS, alpha-fetoprotein, and PIVKA-II were significantly associated with a poor DFS by multivariate analysis. The number of patients with liver-only recurrence in GPS-0, GPS-1, and GPS-2 was 179 (86.1%), 40 (78.4%), and 9 (69.2%), respectively. The number of patients with four or more intrahepatic metastases in the GPS-0, GPS-1, and GPS-2 groups, was 33 (17.9%), 11 (27.5%), and 8 (88.9%), respectively. The number of patients with four or more intrahepatic metastases in the GPS-2 group was significantly higher (p<0.001). CONCLUSION: Preoperative GPS is a useful predictor of OS and recurrence pattern after liver resection with a curative intent for HCC.

Nonreciprocal Directional Dichroism in Magnetoelectric Spin Glass.

Optical absorption spectra in the visible and near-infrared light were measured for magnetoelectric spin glass Ni_{0.4}Mn_{0.6}TiO_{3} under various field-cooled conditions. Despite the absence of long-range magnetic-dipole order, this spin-glass system exhibits nonreciprocal directional dichroism (NDD) at zero external field after a magnetoelectric field-cooled procedure. This result is distinct from previous studies on NDD in systems with magnetic toroidal moments induced either by long-range magnetic-dipole order or by applying crossed electric and magnetic fields. The present Letter conclusively demonstrates that the observed NDD originates from magnetoelectrically induced ferroic order of magnetic toroidal moments without conventional magnetic-dipole order.

Efficacy of Adjuvant Chemotherapy Following Curative Resection of Colorectal Cancer Liver Metastases.

BACKGROUND/AIM: Routine use of adjuvant chemotherapy (AC) following hepatectomy for colorectal liver metastases (CRLM) is not universally practiced because of the lack of supporting evidence. Therefore, we investigated the efficacy of AC following curative CRLM resection. PATIENTS AND METHODS: Among the 742 patients who underwent their first hepatectomy for CRLM at our institution, 335 were stratified into surgery alone (SA; n=162) and AC (n=173) groups. Poor prognostic factors for SA were identified using multivariate logistic regression analysis. Propensity score matching was used to compare the clinical outcomes between SA and AC groups according to the number of prognostic factors. RESULTS: Multivariate analysis showed that preoperative carcinoembryonic antigen (CEA) levels (≥10 ng/ml; p=0.01), primary lymph node metastases (≥1; p=0.0001), and the number (n≥4; p=0.01) and maximum diameter (≥5 cm; p=0.00001) of CRLM tumours were independent poor prognostic factors for overall survival (OS) in the SA group. Patients with ≥3 risk factors were categorized as being high risk. After propensity score matching, the 5-year OS rate was significantly higher in the AC group (n=13) than that in the SA group (n=15; 47.9% vs. 7.3%; p=0.03) among high-risk patients. CONCLUSION: Adjuvant chemotherapy after curative CRLM resection may improve the prognosis of patients with three or more risk factors including preoperative CEA levels ≥10 g/ml, primary lymph node metastases ≥1, number (≥4) and maximum diameter (≥5 cm) of CRLM tumours.

Surgical Indications for Huge Hepatocellular Carcinoma.

BACKGROUND/AIM: This study aimed to retrospectively analyse adverse predictors to identify patients with huge hepatocellular carcinoma who were not appropriate candidates for hepatic resection. PATIENTS AND METHODS: From 551 patients with hepatocellular carcinoma who underwent hepatectomy between 1992 and 2019, 92 were diagnosed with huge hepatocellular carcinoma (diameter >10 cm) and 115 were diagnosed with large hepatocellular carcinoma (diameter=5-10 cm). Clinical features and overall and disease-free survival rates were compared between the two groups. RESULTS: Cumulative overall survival was significantly worse in the huge group than in the large group (p=0.035). In the huge group, multivariate analyses revealed that liver cirrhosis, multiple intrahepatic metastases (≥4), poor histological grade, and macroscopic portal vein invasion were significantly associated with poor prognosis. CONCLUSION: We identified four adverse predictors of survival and determined that patients with two or more predictors are not appropriate candidates for straightforward hepatic resection.

Mechanical regulation of bone homeostasis through p130Cas-mediated alleviation of NF-κB activity.

Mechanical loading plays an important role in bone homeostasis. However, molecular mechanisms behind the mechanical regulation of bone homeostasis are poorly understood. We previously reported p130Cas (Cas) as a key molecule in cellular mechanosensing at focal adhesions. Here, we demonstrate that Cas is distributed in the nucleus and supports mechanical loading-mediated bone homeostasis by alleviating NF-κB activity, which would otherwise prompt inflammatory processes. Mechanical unloading modulates Cas distribution and NF-κB activity in osteocytes, the mechanosensory cells in bones. Cas deficiency in osteocytes increases osteoclastic bone resorption associated with NF-κB-mediated RANKL expression, leading to osteopenia. Upon shear stress application on cultured osteocytes, Cas translocates into the nucleus and down-regulates NF-κB activity. Collectively, fluid shear stress-dependent Cas-mediated alleviation of NF-κB activity supports bone homeostasis. Given the ubiquitous expression of Cas and NF-κB together with systemic distribution of interstitial fluid, the Cas-NF-κB interplay may also underpin regulatory mechanisms in other tissues and organs.

Risk Factors Associated With Early Recurrence of Borderline Resectable Pancreatic Ductal Adenocarcinoma After Neoadjuvant Chemoradiation Therapy and Curative Resection.

BACKGROUND/AIM: To identify risk factors of early recurrence after neoadjuvant chemoradiation therapy (NACRT) and curative pancreatectomy in patients with borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: Sixty-one patients with BR-PDAC who underwent curative resection after NACRT during July 2009-June 2014 were included. Patients were divided into early recurrence (i.e., developed recurrence within 1 year after pancreatectomy; n=30) and late/non-recurrence groups (n=31). The patient characteristics, clinicopathological factors of early recurrence, and survival time were retrospectively compared between groups. RESULTS: In the univariate analysis, the maximum standardized uptake value (SUVmax), microvascular invasion, and lymph node metastasis were associated with early recurrence. In the multivariate analysis, the pre-NACRT SUVmax and microvascular invasion in the early recurrence group were significantly different from that in the late/non-recurrence group. A pre-NACRT SUVmax >4.1 was an independent predictor of poor recurrence-free and overall survival. CONCLUSION: SUVmax and microvascular invasion are independent predictors of poor recurrence-free and overall survival after NACRT for BR-PDAC. Although complete pancreatectomy after NACRT was performed, approximately half of the patients had recurrence within 1 year.

Ferroelectricity by Bose-Einstein condensation in a quantum magnet.

The Bose-Einstein condensation is a fascinating phenomenon, which results from quantum statistics for identical particles with an integer spin. Surprising properties, such as superfluidity, vortex quantization or Josephson effect, appear owing to the macroscopic quantum coherence, which spontaneously develops in Bose-Einstein condensates. Realization of Bose-Einstein condensation is not restricted in fluids like liquid helium, a superconducting phase of paired electrons in a metal and laser-cooled dilute alkali atoms. Bosonic quasi-particles like exciton-polariton and magnon in solids-state systems can also undergo Bose-Einstein condensation in certain conditions. Here, we report that the quantum coherence in Bose-Einstein condensate of the magnon quasi particles yields spontaneous electric polarization in the quantum magnet TlCuCl3, leading to remarkable magnetoelectric effect. Very soft ferroelectricity is realized as a consequence of the O(2) symmetry breaking by magnon Bose-Einstein condensation. The finding of this ferroelectricity will open a new window to explore multi-functionality of quantum magnets.

Severe Sepsis After Living Donor Liver Transplantation: Risk Factors and Outcomes.

BACKGROUND: The post-operative mortality and morbidity rates associated with living-donor liver transplantation (LDLT) are still relatively high. Several papers have reported the risk factors associated with post-operative infectious complications, but few have analyzed the risk factors with respect to the severity of sepsis. The aim of this study was to clarify the risk factors that affect severe sepsis after LDLT. METHODS: For 63 LDLT patients at our institute, we compared peri-operative characteristics in 29 patients who developed sepsis after surgery and 34 patients who did not. The sepsis group was further divided into severe sepsis (n = 16) and sepsis (n = 13) subgroups to identify significant peri-operative risk factors. RESULTS: Multivariate analysis identified 3 significant risk factors for post-operative sepsis after LDLT: ABO incompatibility (P = .015), low estimated glomerular filtration rates (<90 mL/min/1.73 m(2); P = .074), and low peripheral lymphocyte counts (<850/µL; P = .008). Multivariate analysis showed that the only significant risk factor for severe sepsis was a low pre-operative lymphocyte count (<850/µL; P = .01). In the 2 sepsis subgroups, the 5- and 10-year survival rates for the severe sepsis subgroup (37.5% and 37.5%) were significantly lower than for the sepsis subgroup (83.3% and 62.5%; P = .05). The lung was the most common site of severe sepsis (n = 8; 50.0%). CONCLUSIONS: Patients who developed severe sepsis after LDLT had poor long-term survival, with pre-operative lymphocyte counts <850/µL being the significant risk factor. Pre-operative nutritional intervention and rehabilitation should be considered to improve LDLT outcomes.

Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1.

Caloric restriction (CR) is known to retard aging and delay functional decline as well as the onset of diseases in most organisms. Ghrelin is secreted from the stomach in response to CR and regulates energy metabolism. We hypothesized that in CR ghrelin has a role in protecting aging-related diseases. We examined the physiological mechanisms underlying the ghrelin system during the aging process in three mouse strains with different genetic and biochemical backgrounds as animal models of accelerated or normal human aging. The elevated plasma ghrelin concentration was observed in both klotho-deficient and senescence-accelerated mouse prone/8 (SAMP8) mice. Ghrelin treatment failed to stimulate appetite and prolong survival in klotho-deficient mice, suggesting the existence of ghrelin resistance in the process of aging. However, ghrelin antagonist hastened death and ghrelin signaling potentiators rikkunshito and atractylodin ameliorated several age-related diseases with decreased microglial activation in the brain and prolonged survival in klotho-deficient, SAMP8 and aged ICR mice. In vitro experiments, the elevated sirtuin1 (SIRT1) activity and protein expression through the cAMP-CREB pathway was observed after ghrelin and ghrelin potentiator treatment in ghrelin receptor 1a-expressing cells and human umbilical vein endothelial cells. Furthermore, rikkunshito increased hypothalamic SIRT1 activity and SIRT1 protein expression of the heart in the all three mouse models of aging. Pericarditis, myocardial calcification and atrophy of myocardial and muscle fiber were improved by treatment with rikkunshito. Ghrelin signaling may represent one of the mechanisms activated by CR, and potentiating ghrelin signaling may be useful to extend health and lifespan.

Expression dynamics of CXCL12 and CXCR4 during the progression of mycosis fungoides.

BACKGROUND: Mycosis fungoides (MF) classically presents from patch stage to plaque stage over a number of years and finally progresses to tumour stage with nodal or visceral involvement. The mechanism of progression remains incompletely elucidated. Chemokines and their receptors are known to be involved in disease mechanisms, with CXCL12 and CXCR4 playing a critical role in carcinogenesis, invasion and cancer cell migration in various carcinomas. OBJECTIVES: To investigate the expression of CXCL12 and CXCR4 in different cutaneous stages of MF. METHODS: Formalin-fixed, paraffin-embedded skin samples from 40 patients with MF (21 patch stage, 10 plaque stage, nine tumour stage) and 30 non-neoplastic control skin samples were analysed. CXCL12 and CXCR4 were assessed by quantitative reverse-transcription polymerase chain reaction and immunohistochemical staining. RESULTS: The expression level of mRNA for CXCL12 in plaque-stage MF was significantly higher than in control skin (P = 0.0035), or patch-stage (P = 0.0108) or tumour-stage disease (P = 0.0089). The CXCR4 mRNA expression level in plaque-stage disease was significantly higher than in control skin (P = 0.0090) or patch-stage disease (P = 0.0387). CXCL12- and CXCR4-positive cell rates in patch-stage and plaque-stage MF were significantly higher than those in control skin (P < 0.0001). CXCL12- and CXCR4-positive cell rates in tumour-stage MF were significantly lower than those in patch- and plaque-stage disease (P = 0.0274 and P = 0.0492, respectively). CONCLUSIONS: Our data suggest that neoplastic T cells in MF are exposed to the microenvironment, given the abundance of CXCL12 during its progression, and also that neoplastic T cells express CXCR4, especially in the pretumour stage. We reveal that the CXCL12-CXCR4 axis plays a critical role in MF progression.

Erythroderma as a paraneoplastic cutaneous disorder in systemic anaplastic large cell lymphoma.

BACKGROUND: Paraneoplastic cutaneous disorders (PCDs) or dermadromes are skin conditions that have an association with internal malignancies but are not themselves malignant. We report the first two cases of systemic anaplastic large cell lymphoma (s-ALCL) accompanied by erythroderma and multiple leg ulcers as PCDs. CASE 1: A 52-year-old Japanese man presented with disseminated itchy papular erythemas which he had over his entire body for the preceding 5 years that later exacerbated to erythroderma. Multiple punched-out ulcers also developed on his lower legs. Superficial lymph nodes (LNs) were swollen, and a left axillary LN biopsy demonstrated dense CD30(+) atypical large cell (ALC) infiltration. By contrast, lymphocytes infiltrating into the erythroderma and leg ulcers were CD30(-) , and T-cell receptor ß (TCRß) chain gene rearrangement was negative in skin biopsy specimens. Thus, he was diagnosed with s-ALCL. Not only his s-ALCL but also his erythroderma and leg ulcers responded well to chemotherapy. CASE 2: A 71-year-old Japanese woman presented with erythroderma that persisted for approximately 20 years after mastectomy. At her initial hospital visit, she was diagnosed with s-ALCL by biopsy of swollen left inguinal LNs. Similar to Case 1, CD30(+) ALCs were negative in skin samples with normal TCRß chain gene rearrangement. As the erythrodermic skin lesion responded well to chemotherapy for s-ALCL, it was considered a PCD. CONCLUSION: s-ALCL development may be predicted by the precedence and concurrence of intractable paraneoplastic erythrodermic and ulcerative skin lesions, as reported in our two cases.

Prediction of time-dependent interaction of aspirin with ibuprofen using a pharmacokinetic/pharmacodynamic model.

WHAT IS KNOWN AND OBJECTIVE: Low-dose aspirin is widely used for prevention of thrombosis, but combined use of aspirin with non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, reduces the antiplatelet effect of aspirin. However, there has been no report describing the effects of the timing of the ibuprofen dose on the degree of interaction between low-dose aspirin and ibuprofen. The purpose of this study was to predict the time-course of the antiplatelet effect of low-dose aspirin when ibuprofen is administered as a single dose or repeatedly in combination with aspirin at various time intervals. METHODS: We simulated ex vivo platelet aggregation using a previously developed pharmacokinetic (PK)/pharmacodynamic (PD) model. RESULTS AND DISCUSSION: The antiplatelet effect of low-dose aspirin (81 mg) was predicted to be markedly reduced when ibuprofen (200 mg; the usual prescribed dose in Japan) was administered 1 h or less after aspirin, but not when it was administered more than 2 h after the administration of aspirin. Moreover, the administration of ibuprofen up to 12 h before aspirin completely abrogated the antiplatelet effect of aspirin. When ibuprofen (200 mg) was administered three times daily for 3 days (day 1 to day 3) on a background of continuous low-dose aspirin (81 mg) once daily, 2 h after aspirin, no reduction in the antiplatelet effect of aspirin was predicted on day 1, but a reduction is predicted from day 2, with no return to the initial level until more than 3 days after discontinuation of ibuprofen. A marked reduction in the antiplatelet effect of aspirin was also seen on the same schedule when the dosage of ibuprofen was 150 mg, which is the dose used in over-the-counter (OTC) preparations. WHAT IS NEW AND CONCLUSION: This study indicates that the antiplatelet effect of low-dose aspirin can be markedly reduced with combined use of ibuprofen, depending on the timing of co-administration. As even the lower OTC dose of ibuprofen (150 mg) was enough to affect the antiplatelet effect of aspirin, health professionals should take into account patients' use of OTC ibuprofen when prescribing low-dose aspirin.

Individual differences in prothrombin time-international normalized ratio variation following coadministration of the anticancer agents S-1 and warfarin: 3 case reports.

OBJECTIVE: We report three cases of elevated prothrombin time-international normalized ratios (PT-INR) following the initiation of coadministration of warfarin and S-1, a preparation containing tegafur (FT), gimeracil (CDHP), and oteracil potassium (Oxo). CASE SUMMARIES: The three cases included 2 men and 1 woman aged 79, 71, and 54 y, respectively. PT-INRs were in the range of 2.0 - 3.0 before therapy but were elevated to values in the range of 3.79 - 4.92 within 8 - 17 days after initiating the coadministration of warfarin (1.5 - 3.5 mg/d) and S-1 (80 - 120 mg/d). When the drug interactions in Cases 1 - 3 were evaluated using the Drug Interaction Probability Scale, each of these cases was assessed as "probable". DISCUSSION: The drug interaction between warfarin and S-1 presumably leads to elevated PT-INR because the 5-fluorouracil (5-FU), which is metabolite of FT in S-1, inhibits the metabolic processing of S-warfarin by cytochrome P450 (CYP) 2C9. However, individual differences in the metabolic production of 5-FU from FT because of genetic polymorphisms in CYP2A6 and individual variation in the levels of renal function may lead to complications when 5-FU is coadministered with warfarin as compared to when 5-FU is administered alone. CONCLUSION: It is essential that the dosage level of warfarin is appropriately adjusted by frequent PT-INR measurements when warfarin and S-1 are coadministered.