Bilateral atypical ulnar fractures occurring after long-term treatment with bisphosphonate for 7 years and with teriparatide for 2 years: a case report.

Most atypical fractures associated with the long-term treatment with bisphosphonates (BP) commonly develop in the femoral shaft or subtrochanteric region. We report a rare case of bilateral atypical ulnar fractures in an 86-year-old woman with osteoporosis who finished the treatment with teriparatide for 2 years after long-term treatment with BP. She slid down from an approximately 30-cm-tall seat and slightly contused her left elbow. Plain radiography revealed that both ulnae had a noncomminuted short oblique fracture with cortical thickening and sclerosis at the fracture site. Based on the clinical and radiological findings, she was diagnosed with bilateral atypical ulnar fractures. The fracture of the left ulna was completely displaced and treated surgically. On the other hand, since the right ulna was an incomplete fracture, it was treated conservatively. During surgery, drilling with Kirschner wire and curettage were performed in the osteosclerotic lesion, and an autologous cancellous bone graft was inserted from the ipsilateral olecranon. Bone union was achieved in both fractures at 1 year after surgery. There have been no reports regarding the development of atypical ulnar fractures occurring after the long-term treatment with BP and 2-year use of teriparatide, and the treatment strategies of such fractures have not been established. If teriparatide cannot be used after occurring atypical fractures, the use of low-intensity pulsed ultrasound (LIPUS) and subsequent treatment for osteoporosis are recommended for the bone union. In addition, the treatment of the osteosclerotic lesion and rigid internal fixation are required in surgery.

Correction to: Bilateral atypical ulnar fractures occurring after long-term treatment with bisphosphonate for 7 years and with teriparatide for 2 years: a case report.

The original version of this article, published on 10 September 2020 contained a mistake.

Atezolizumab plus bevacizumab versus lenvatinib or sorafenib in non-viral unresectable hepatocellular carcinoma: an international propensity score matching analysis.

BACKGROUND: A growing body of evidence suggests that non-viral hepatocellular carcinoma (HCC) might benefit less from immunotherapy. MATERIALS AND METHODS: We carried out a retrospective analysis of prospectively collected data from consecutive patients with non-viral advanced HCC, treated with atezolizumab plus bevacizumab, lenvatinib, or sorafenib, in 36 centers in 4 countries (Italy, Japan, Republic of Korea, and UK). The primary endpoint was overall survival (OS) with atezolizumab plus bevacizumab versus lenvatinib. Secondary endpoints were progression-free survival (PFS) with atezolizumab plus bevacizumab versus lenvatinib, and OS and PFS with atezolizumab plus bevacizumab versus sorafenib. For the primary and secondary endpoints, we carried out the analysis on the whole population first, and then we divided the cohort into two groups: non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) population and non-NAFLD/NASH population. RESULTS: One hundred and ninety patients received atezolizumab plus bevacizumab, 569 patients received lenvatinib, and 210 patients received sorafenib. In the whole population, multivariate analysis showed that treatment with lenvatinib was associated with a longer OS [hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.44-0.95; P = 0.0268] and PFS (HR 0.67; 95% CI 0.51-0.86; P = 0.002) compared to atezolizumab plus bevacizumab. In the NAFLD/NASH population, multivariate analysis confirmed that lenvatinib treatment was associated with a longer OS (HR 0.46; 95% CI 0.26-0.84; P = 0.0110) and PFS (HR 0.55; 95% CI 0.38-0.82; P = 0.031) compared to atezolizumab plus bevacizumab. In the subgroup of non-NAFLD/NASH patients, no difference in OS or PFS was observed between patients treated with lenvatinib and those treated with atezolizumab plus bevacizumab. All these results were confirmed following propensity score matching analysis. By comparing patients receiving atezolizumab plus bevacizumab versus sorafenib, no statistically significant difference in survival was observed. CONCLUSIONS: The present analysis conducted on a large number of advanced non-viral HCC patients showed for the first time that treatment with lenvatinib is associated with a significant survival benefit compared to atezolizumab plus bevacizumab, in particular in patients with NAFLD/NASH-related HCC.

Structural evolution in the neutron-rich nuclei ¹°6Zr and ¹°8Zr.

The low-lying states in ¹°6Zr and ¹°8Zr have been investigated by means of ß-γ and isomer spectroscopy at the radioactive isotope beam factory (RIBF), respectively. A new isomer with a half-life of 620 ± 150 ns has been identified in ¹°8Zr. For the sequence of even-even Zr isotopes, the excitation energies of the first 2⁺ states reach a minimum at N = 64 and gradually increase as the neutron number increases up to N = 68, suggesting a deformed subshell closure at N = 64. The deformed ground state of ¹°8Zr indicates that a spherical subshell gap predicted at N = 70 is not large enough to change the ground state of ¹°8Zr to the spherical shape. The possibility of a tetrahedral shape isomer in ¹°8Zr is also discussed.

ß-decay half-lives of very neutron-rich Kr to Tc isotopes on the boundary of the r-process path: an indication of fast r-matter flow.

The ß-decay half-lives of 38 neutron-rich isotopes from (36)Kr to (43)Tc have been measured; the half-lives of (100)Kr, (103-105)Sr, (106-108)Y, (108-110)Zr, (111,112)Nb, (112-115)Mo, and (116,117)Tc are reported here. The results when compared with previous standard models indicate an overestimation in the predicted half-lives by a factor of 2 or more in the A≈110 region. A revised model based on the second generation gross theory of ß decay better predicts the measured half-lives and suggests a more rapid flow of the rapid neutron-capture process (r-matter flow) through this region than previously predicted.

Identification of lenvatinib prognostic index via recursive partitioning analysis in advanced hepatocellular carcinoma.

BACKGROUND: After the advent of new treatment options for advanced hepatocellular carcinoma (HCC), the identification of prognostic factors is crucial for the selection of the most appropriate therapy for each patient. PATIENTS AND METHODS: With the aim to fill this gap, we applied recursive partitioning analysis (RPA) to a cohort of 404 patients treated with lenvatinib. RESULTS: The application of RPA resulted in a classification based on five variables that originated a new prognostic score, the lenvatinib prognostic index (LEP) index, identifying three groups: low risk [patients with prognostic nutritional index (PNI) >43.3 and previous trans-arterial chemoembolization (TACE)]; medium risk [patients with PNI >43.3 but without previous TACE and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage B (BCLC-B)]; high risk [patients with PNI <43.3 and ALBI grade 2 and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage C (BCLC-C)]. Median overall survival was 29.8 months [95% confidence interval (CI) 22.8-29.8 months] in low risk patients (n = 128), 17.0 months (95% CI 15.0-24.0 months) in medium risk (n = 162) and 8.9 months (95% CI 8.0-10.7 months) in high risk (n = 114); low risk hazard ratio (HR) 1 (reference group), medium risk HR 1.95 (95% CI 1.38-2.74), high risk HR 4.84 (95% CI 3.16-7.43); P < 0.0001. The LEP index was validated in a cohort of 127 Italian patients treated with lenvatinib. While the same classification did not show a prognostic value in a cohort of 311 patients treated with sorafenib, we also show a possible predictive role in favor of lenvatinib in the low risk group. CONCLUSIONS: LEP index is a promising, easy-to-use tool that may be used to stratify patients undergoing systemic treatment of advanced HCC.

Nonalcoholic steatohepatitis in hepatocarcinoma: new insights about its prognostic role in patients treated with lenvatinib.

BACKGROUND: Hepatocellular carcinoma (HCC) treatment remains a big challenge in the field of oncology. The liver disease (viral or not viral) underlying HCC turned out to be crucial in determining the biologic behavior of the tumor, including its response to treatment. The aim of this analysis was to investigate the role of the etiology of the underlying liver disease in survival outcomes. PATIENTS AND METHODS: We conducted a multicenter retrospective study on a large cohort of patients treated with lenvatinib as first-line therapy for advanced HCC from both Eastern and Western institutions. Univariate and multivariate analyses were performed. RESULTS: Among the 1232 lenvatinib-treated HCC patients, 453 (36.8%) were hepatitis C virus positive, 268 hepatitis B virus positive (21.8%), 236 nonalcoholic steatohepatitis (NASH) correlate (19.2%) and 275 had other etiologies (22.3%). The median progression-free survival (mPFS) was 6.2 months [95% confidence interval (CI) 5.9-6.7 months] and the median overall survival (mOS) was 15.8 months (95% CI 14.9-17.2 months). In the univariate analysis for OS NASH-HCC was associated with longer mOS [22.2 versus 15.1 months; hazard ratio (HR) 0.69; 95% CI 0.56-0.85; P = 0.0006]. In the univariate analysis for PFS NASH-HCC was associated with longer mPFS (7.5 versus 6.5 months; HR 0.84; 95% CI 0.71-0.99; P = 0.0436). The multivariate analysis confirmed NASH-HCC (HR 0.64; 95% CI 0.48-0.86; P = 0.0028) as an independent prognostic factor for OS, along with albumin-bilirubin (ALBI) grade, extrahepatic spread, neutrophil-to-lymphocyte ratio, portal vein thrombosis, Eastern Cooperative Oncology Group (ECOG) performance status and alpha-fetoprotein. An interaction test was performed between sorafenib and lenvatinib cohorts and the results highlighted the positive predictive role of NASH in favor of the lenvatinib arm (P = 0.0047). CONCLUSION: NASH has been identified as an independent prognostic factor in a large cohort of patients with advanced HCC treated with lenvatinib, thereby suggesting the role of the etiology in the selection of patients for tyrosine kinase treatment. If validated, this result could provide new insights useful to improve the management of these patients.

MAC-CCD system: a novel lymphocyte microwell-array chip system equipped with CCD scanner to generate human monoclonal antibodies against influenza virus.

We previously developed a lymphocyte microwell-array system, which effectively detects antigen-specific B-cells by monitoring intracellular Ca(2+) mobilization at the single-cell level with a fluorescent Ca(2+) indicator, fluo-4. However, it is difficult for the system to perform time-lapse monitoring. Here, we developed a novel method, a lymphocyte microwell-array chip system equipped with a charge-coupled device (CCD) time-lapse scanner (MAC-CCD system), for monitoring intracellular Ca(2+) mobilization. The MAC-CCD system is able to monitor intracellular Ca(2+) mobilization of more than 15,000-20,000 individual live B-cells every 10 s. In addition, we adopted a correlation method in a MAC-CCD system, which enabled us to detect B-cells with a frequency of as few as 0.046%. Furthermore, we succeeded in obtaining six influenza nucleoprotein-specific human monoclonal antibodies from the peripheral blood of influenza-vaccinated volunteers. These results demonstrate that the MAC-CCD system with a correlation method could detect very rare antigen-specific B-cells.

The glucagon-like peptide-1 receptor agonist liraglutide improves hypoxia-induced pulmonary hypertension in mice partly via normalization of reduced ET(B) receptor expression.

The glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide is an incretin hormone mimetic used in the treatment of diabetes. However, the effects of liraglutide on pulmonary hypertension (PH) and pulmonary endothelin (ET) system are unknown. Eight-week-old C57BL6/J mice were injected liraglutide or vehicle for 5 weeks. One week after injection, the mice were exposed to either room air (normoxia) or chronic hypoxia (10 % O(2)) for 4 weeks. The right ventricular systolic pressure (RVSP) was significantly higher in hypoxia + vehicle group than in normoxia + vehicle group. ET-1 mRNA expression in the lungs was comparable among all the groups. ET(B) mRNA and protein expression in the lungs was significantly lower in hypoxia + vehicle group than in normoxia + vehicle group. The above changes were normalized by liraglutide treatment. The expression of phospho-eNOS and phospho-AMPK proteins in the lungs was significantly higher in hypoxia + liraglutide group than in normoxia + vehicle group. We demonstrated for the first time that liraglutide effectively improved RVSP and RV hypertrophy in hypoxia-induced PH mice by activating eNOS through normalization of impaired ET(B) pathway and augmentation of AMPK pathway. Therefore, GLP-1R agonists can be promising therapeutic agents for PH.

Effects of nonsteroidal antiinflammatory drugs on collagen biosynthesis of cultured chondrocytes.

In conclusion, the data obtained from the present study show that TA has less effect than indomethacin or ASA on cultured chondrocytes in gene expression and synthesis of collagen. These findings cannot be directly interpolated to clinical application, but attention to pharmacologic activities of NSAIDs on chondrocytes may have future applications. Two major NSAIDs, TA, indomethacin, and ASA, were examined for their effects on the biosynthesis and gene expression of articular cartilage collagen. The biosynthesis of type II collagen was suppressed to 70% to 80% of the control by indomethacin and ASA. TA did not suppress collagen synthesis. To know the gene expression of type II collagen, dot blot hybridization was performed using type II collagen cDNA. The effects of NSAIDs on the amount of type II collagen mRNA were consistent with those on collagen biosynthesis. Thus, TA had the least effect on cultured chondrocytes.

Choledochocele with obstructive jaundice: a case report and a review of the Japanese literature.

A case of a 57-year-old farmer with a rare type of choledochal cyst (choledochocele; Alonso-Lej's type III) is described. The patient was admitted because of obstructive jaundice and acute biliary infection. Abdominal computed tomography scan showed a cystic lesion in the head of the pancreas, and endoscopic retrograde cholangiopancreatography disclosed cystic dilatation of the terminal portion of the common bile duct. It was suspected that the choledochocele could swell and compress the common bile duct, causing obstructive jaundice and acute cholangitis; therefore, it was surgically resected. We also reviewed 61 cases of choledochocele reported in Japan; the findings were similar to those reported in the English literature.

Effects of tamoxifen, medroxyprogesterone acetate and estradiol on tumor growth and oncogene expression in MCF-7 breast cancer cell line transplanted into nude mice.

The effects of three hormonal agents with a different mechanism of action (tamoxifen [TAM], medroxyprogesterone acetate [MPA] and estradiol [E2]) on tumor growth, differentiation and oncogene expression were evaluated using the estrogen-receptor positive human breast carcinoma cell line MCF-7 transplanted into nude mice. In MCF-7 tumors treated with E2, tumor incidence, mean weight of tumors, 3H-thymidine labelling index, differentiation antigen HMFGM (human milk-fat globule membrane) and ras p21, c-myc, neu oncogene products, the level was significantly increased. On the other hand MPA suppressed all of them. TAM increased the level of c-myc expression and HMFGM antigen, but suppressed the others. This evidence indicates that E2 induces both proliferation and differentiation of MCF-7 tumor cells. MPA suppresses both proliferation and differentiation, and TAM induces differentiation and suppresses proliferation.

Role of lipid peroxidation in acetaminophen-induced hepatotoxicity: comparison with carbon tetrachloride.

The effect of acetaminophen on lipid peroxidation in vivo and in vitro was studied in rat liver and the data were compared with those with carbon tetrachloride. Carbon tetrachloride increased diene conjugates in vivo and thiobarbituric acid reactive substance production in vitro in the liver microsomal incubation. These changes were further enhanced by ethanol that has previously been shown to increase carbon tetrachloride-induced hepatotoxicity. On the other hand, acetaminophen did not increase diene conjugates in vivo and inhibited thiobarbituric acid reactive substance production in vitro. These effects were minimally affected by ethanol which has previously been shown to inhibit acetaminophen-induced hepatotoxicity. Thus, lipid peroxidation may play a minimal role in acetaminophen-induced hepatotoxicity in contrast with carbon tetrachloride-induced hepatotoxicity.

Inhibition of acetaminophen hepatotoxicity by acetaldehyde in the rat.

Since we have observed that acetaldehyde, an oxidative metabolite of ethanol, inhibits acetaminophen activation in rat liver microsomes, the in vivo effect of acetaldehyde on acetaminophen hepatotoxicity was tested. In vivo experiments in 3-methylcholanthrene-pretreated male Sprague-Dawley rats showed that administration of cyanamide (20 mg/kg, i.p.) and acetaldehyde (600 mg/kg, s.c.) given 3 and 1 h, respectively, prior to acetaminophen (500 mg/kg, i.p.) but not cyanamide alone prevented acetaminophen hepatotoxicity as assessed by serum transaminases and histology. Acetaldehyde may partly be responsible for the inhibitory effect of ethanol on acetaminophen hepatotoxicity.

Role of medullasin in nifedipine-induced gingival overgrowth in rats.

To clarify the possible pathophysiological role of medullasin, a neutrophil elastase-like proteinase, in nifedipine (NF)-induced gingival overgrowth, a rat model of gingival overgrowth was first established using a diet containing NF. The relation between histopathological changes and the distribution of the proteinase was then investigated. Thirty-two, specific pathogen-free 20 day-old, male, Fisher 344 rats were fed a diet containing NF and killed at 2, 8, 16 and 32 weeks. Control rats (n = 32) were fed the same diet but without the drug. The mandible of each rat was resected and sectioned at 4-microm thickness buccolingually between the first and second molars. Computer image analysis was used to evaluate the extent of overgrowth in the approximal gingiva of each sample. To examine medullasin activity, the mean percentage of medullasin-positive cells per total cells counted in the pocket epithelium and the connective tissue adjacent to the epithelium of approximal gingiva was determined immunohistochemically. The height of the mid-portion and the area in NF-treated group increased significantly with time (with the exception of area at 2 weeks) compared with the corresponding regions in the control group. A marked inflammatory-cell infiltration and elongated rete pegs, especially in the mid-portion of approximal gingiva, were seen in the NF-treated group. The mean percentages of medullasin-positive cells in the NF-treated group at 8, 16 and 32 weeks were significantly higher than those of the control. Although medullasin-positive cells were mainly neutrophils, in several samples of the NF-treated group they were recognized as macrophage-like. These findings suggest that medullasin may be involved in host defence and immunoregulation in a NF-induced rat model of gingival overgrowth.

Enhanced renal susceptibility to ischemia-reperfusion injury in the rat with obstructive jaundice.

BACKGROUND/AIMS: To investigate the susceptibility of kidneys to ischemia-reperfusion injury under obstructive jaundice. MATERIALS AND METHODS: Bile ducts of male rats were ligated for five days, right kidneys were removed, and vascular clamps were placed across left renal arteries for 30 minutes. RESULTS: Twenty-four hours later, ischemia-reperfusion produced renal injury in jaundiced rats as shown by increased serum creatinine and urea nitrogen levels. Histological observation showed tubular damages. These changes were minimal after ischemia-reperfusion in control rats. Renal thiobarbituric acid reactive substance contents were increased after bile duct ligation, which did not change after ischemia-reperfusion. On the other hand, ischemia-reperfusion produced a significant increase in renal thiobarbituric acid reactive substance contents in control rats. Renal glutathione contents were increased two fold after bile duct ligation and they were significantly decreased by ischemia-reperfusion. CONCLUSIONS: Kidneys in obstructive jaundice appear to be susceptible to ischemia-reperfusion injury. Although protective roles of GSH is suggested, the role of oxygen radicals in this type of renal injury remains to be further elucidated.

The modified extended mastectomy using the trap-door method as a staging operation.

The choice of operation for breast cancer must be directed towards giving the best chance of local control of the disease. Extended radical mastectomy may be beneficial for patients with internal mammary lymph node metastases, although it has remained controversial. The anterior chest defect created by extended radical mastectomy should be avoided in patients with no metastasis in the internal mammary lymph nodes. This paper, proposes a new technique of modified extended mastectomy using the trap-door method as a staging operation and an intermediate operation between modified radical mastectomy and extended radical mastectomy. In this operation, the axillary dissection could be performed by reflecting the pectoralis major muscle and the internal mammary lymph nodes could be dissected by reflecting the parasternal chest wall in trap-door fashion. In cases in which the metastasis is histologically found in the internal mammary content, extended radical mastectomy by sternal splitting is preferred.

Regional lymph node metastases in well-differentiated thyroid carcinoma.

The status of regional lymph node metastases was assessed in 171 patients with thyroid cancer who underwent a variety of thyroidectomy procedures with regional lymph node dissection at Kanazawa University, from January 1979 to March 1986. The rates of regional lymph node metastasis in minimal and ordinary thyroid cancer were 57% and 84% respectively. Since the rates of lymph node metastasis were high not only in the central cervical compartment but also in the lateral jugular compartment, modified radical neck dissection in the ipsilateral neck is at least recommended in patients with these thyroid cancers. Furthermore, high frequencies of bilateral regional lymph node metastases were found in patients with obviously widespread involvement of the bilateral lobes, with cancer located in the isthmus, with clinically detectable bilateral or contralateral jugular lymph node metastases and with histological involvement in the contralateral paratracheal lymph nodes. Bilateral modified radical neck dissection is recommended in these patients.

[A case of advanced gastric cancer with multiple liver metastases showing marked response to new combination chemotherapy using 5-FU, THP and MMC (FTM)].

A 67-year-old man with advanced gastric cancer with multiple liver metastases was treated by a new combination chemotherapy using 5-FU, THP and MMC (FTM). After the first course of FTM, both abnormal liver function and the elevated level of serum CA 19-9 were restored. After the second course of FTM, the primary lesion became a small ulcer around cardia. A partial response was recognized both in the primary lesion and in the liver metastases. No serious side effect was observed except for leukocytopenia, which was controlled by G-CSFS. This new combination chemotherapy (FTM) was suggested to be useful even for far advanced gastric cancer.

[Influence of endocrine therapy on the proliferation of estrogen (ER) positive cells and ER negative cells of human breast cancer (MCF-7)].

The influence of endocrine therapy on the proliferation of estrogen receptor (ER) positive cells and ER negative cells of human breast cancer (MCF-7) serially transplanted into nude mice was analyzed by tumor growth, dextran-coated charcoal (DCC) method, ER-immunocytochemical assay (ER-ICA) and ER-immunocytochemically stained 3H-thymidine autoradiography. In the tamoxifen (TAM) group and the medroxyprogesterone acetate (MPA) group, tumor growth was inhibited, but it was promoted in the 17 beta-estradiol dipropionate (E2) group. The ER level by the DCC method significantly decreased in the TMA, the MPA and the E2 groups. The ER-ICA showed that the ER positive cells rate in the TAM and the MPA group decreased, but it increased in E2 group. However, the ER-immunocytochemically stained 3H-thymidine autoradiography showed that not only the labelling index of ER-positive cells but also that of ER negative cells significantly decreased in the TAM and the MPA groups, but significantly increased in the E2 groups. Therefore it was concluded that endocrine therapy affected the proliferation of both ER positive cells and ER negative cells of ER positive breast cancer.